Implementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid and Selective Reductive Photoredox Transformations in Continuous Flow

Article abstract of DOI:10.1002/ejoc.201900952

The reductive transformation of aryl halides and carbonyl compounds is a key step in many photoredox transformations. By combining a highly reducing organic photocatalyst with a thiol hydrogen atom transfer (HAT) catalyst, we showcase rapid and highly selective reactions of these synthetically important starting materials in continuous flow. The fast reduction of aryl iodides, bromides and chlorides has been demonstrated with residence times in some cases below one minute. Selectivity between mono- and di-dehalogenation could also be achieved in some cases. Aryl ketones, aldehydes and imines were shown to undergo facile pinacol couplings, and the coupling of an aryl chloride with a styrene was also successful.

Full text of DOI:10.1002/ejoc.201900952

A Journal of
Accepted Article
Title: Implementing Hydrogen Atom Transfer (HAT) Catalysis for
Rapid and Selective Reductive Photoredox Transformations in
Continuous Flow
Authors: Alexander Steiner, Jason D Williams, Juan A. Rincon, Oscar
De Frutos, Carlos Mateos, and C. Oliver Kappe
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900952
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900952
Supported by

10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
Implementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid
and Selective Reductive Photoredox Transformations in
Continuous Flow
Alexander Steiner,[a,b] Jason D. Williams,[a,b] Juan A Rincón,[c] Oscar de Frutos,[c] Carlos Mateos,[c] and
C. Oliver Kappe*[a,b]
Abstract: The reductive transformation of aryl halides and carbonyl
compounds is a key step in many photoredox transformations. By
combining a highly reducing organic photocatalyst with a thiol
hydrogen atom transfer (HAT) catalyst, we showcase rapid and highly
selective reactions of these synthetically important starting materials
in continuous flow. The fast reduction of aryl iodides, bromides and
chlorides has been demonstrated with residence times in some cases
below one minute. Selectivity between mono- and di-dehalogenation
could also be achieved in some cases. Aryl ketones, aldehydes and
imines were shown to undergo facile pinacol couplings, and the
coupling of an aryl chloride with a styrene was also successful.
Recently, these reductions have also been achieved using
organocatalysts with strongly reducing excited states.[10] Amongst
the most reducing of these are phenothiazine-based catalysts,
such as N-phenylphenothiazine (PTH), whose excited state
reduction potential reaches –2.1 V vs SCE (Figure 1b).[10b,11]
Accordingly, this type of readily available catalyst has enabled
photochemical
transformations
which
were
previously
unachievable by the most reducing catalysts available,[12] for
example couplings of aryl chlorides with electron rich olefins.[13]
However, these transformations can be extremely slow, often
requiring reaction times of several days. Taking into account the
limitations of scaling up photochemical reactions, these methods
are impractical on a preparatively significant scale.
Introduction
In the field of photoredox catalysis, transformations involving the
reduction of (hetero)aryl species have received significant
attention as complementary synthetic methods to standard
transition metal-catalyzed functionalization.[1] The generation of
(hetero)aryl radicals by a photoredox system has been explored
in some detail from various precursor species, but most
commonly aryl diazonium salts.[2] Facile reduction can be
achieved by a variety of readily available metal and organic
photocatalysts,[3] but their highly reactive nature can also be
problematic. The starting materials themselves can be unstable,
and radical chain mechanisms are often believed to be at play,
potentially harming reaction selectivity (Figure 1a).
a) Aryl diazonium salts
N2X
- Unstable starting material
Photocatalyst
R
R
- Radical chain reactivity can
reduce selectivity
b) Aryl halides using organic or precious metal photocatalyst
X
Photocatalyst
- Slow reaction rate
R
R
organic photocatalyst and HAT catalyst in flow
This work:
c)
365 nm
Due, in part, to their abundant applications in cross coupling
reactions, aryl halides represent a stable and readily available
class of reaction precursor. However, when compared to aryl
diazonium salts, far higher potentials are required to facilitate their
reduction and generate the corresponding aryl radical.[4] Despite
this, there are many examples of photoredox catalytic systems
capable of performing these reactions. In most cases, this
requires either a precious metal catalyst,[5] or a more complex
system: catalyst activation by two consecutive photoinduced
electron transfer (PET) events;[6] additional hydrocarbon “energy
acceptor”;[7] or catalyst complexation by lanthanide salts.[8]
Separately, a recent report also describes the electrochemical
reduction of aryl halides.[9]
X
H
R
R
Photocatalyst
HAT catalyst
- Metal free and low loading of cheap thiol catalyst
- Application to aryl halide and carbonyl reductions
- Rapid reactions: residence times <1 min
productivity increase
×
- Scalable in continuous flow: >20
Figure 1. Previous work showing reductive transformations of aryl diazonium
salts and aryl halides, versus this flow process.
Flow chemistry has been demonstrated as a valuable tool
for photochemical transformations, in part due to improved light
penetration across a short path-length.[14] This bestows an
inherent scalability, which is unachievable in batch, and often a
substantially increased rate of reaction.[15] To achieve a usable
level of productivity, though, relatively short residence times are
required, highlighting the importance of fast reaction kinetics.[16]
Herein, we describe the development and continuous flow
application of an organic photoredox catalyst system, which
enables reductive transformations of aryl halides and carbonyls
with unprecedented selectivity and reaction rate (Figure 1c).
[a]
A. Steiner, Dr. J. D. Williams, Prof. Dr. C. O. Kappe,
Center for Continuous Flow Synthesis and Processing (CC FLOW),
Research Center Pharmaceutical Engineering GmbH (RCPE),
Inffeldgasse 13, 8010 Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
Homepage: http://goflow.at
A. Steiner, Dr. J. D. Williams, Prof. Dr. C. O. Kappe,
Institute of Chemistry, University of Graz, NAWI Graz,
Heinrichstrasse 28, 8010 Graz (Austria)
Dr. C. Mateos, Dr. J. A. Rincón, Dr. O. de Frutos
Centro de Investigación Lilly S. A. Avda. de la Industria 30,28108
Alcobendas-Madrid (Spain)
[b]
[c]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
Results and Discussion
reaction rate when compared to the previously reported batch
procedure, which required a 72 h reaction time to reach an
equivalent result.[11a] Again, the thiol was found to be
indispensable, since its removal resulted in a comparatively
sluggish reaction which provided only 74% yield in 28 min
residence time (entry 6).
For comparison, the reaction was examined with a lower
catalyst loading. The lower loading of 2.5 mol% was found to have
an insignificant effect on the reaction (entry 7 vs entry 8), yet
conversion dropped upon further lowering the loading to 1 mol%
(entry 7 vs entry 9). The nature of irradiation was also found to be
of importance. Whilst using a slightly longer UVA wavelength
(385 nm, entry 10) had no significant impact on the reaction,
moving into the visible region (405 nm, entry 11) saw a
During our studies of photochemical reductive
transformations of aryl halides, using conditions based on those
reported previously,[11b] we observed a significant increase in
reaction rate of 4-bromobenzonitrile (1a), by the addition of a
small quantity (5 mol%) of cyclohexanethiol (CySH) as HAT
catalyst. A more detailed reaction time course (Figure 2) revealed
an almost 5-fold increase in initial rate, resulting in complete
reaction in 30 min, versus >4 h. With our interests in the scalability
of photochemical transformations in flow, and the corresponding
effect of reaction rate upon their productivity, we opted to further
explore this phenomenon and its application to a continuous flow
protocol.
PTH (5 mol%), CySH (5 mol%),
HCOOH (5 equiv), DIPEA (5 equiv)
X
H
MeCN (0.1 M), 365 nm LEDs,
20 °C, 3.5 bar, flow
NC
X = Br,
NC
3a
1a
2a
Cl,
Reaction
time [min]
Deviation from standard
conditions
Yield
Entry
Compound
3a[a] [%]
1
2
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
30
240
1
batch[b]
batch, no CySH[b]
none
98
96
97
87
96
74
78
75
57
75
51
64
3
4
15
3
no CySH
5
none
6
28
1
no CySH
7
none
8
1
2.5 mol% PTH
1 mol% PTH
385 nm LEDs
405 nm LEDs
50% LED power
9
1
Figure 2. Time course demonstrating the increase in rate observed upon
incorporating CySH (5 mol%) into the reaction mixture.
10
11
12
1
1
1
Optimization studies began with dehalogenation of 4-
bromobenzonitrile (1a) (Table 1).[17] In every case, the reaction
showed excellent selectivity for the hydrodehalogenated product
3a, with no significant by-products observed. The batch
comparison with and without thiol, described above, achieved
98% yield of benzonitrile (3a) in 30 min rather than 96% in 4 h
(entry 1 vs entry 2).
Upon translating this procedure to continuous flow, using a
commercial plate-based photoreactor (Corning Advanced-Flow
Lab Photo Reactor, 2.8 mL volume),[17] gas formation was
observed (assumed to be CO2), so a backpressure regulator
(Zaiput) was used to apply a low pressure of 3.5 bar, which
successfully maintained a homogeneous flow regime. In flow, the
reaction showed a further significant increase in rate, whereby
87% yield was achieved in a residence time of 15 min without
CySH (entry 4), compared to 97% in 1 min when CySH was
added (entry 3). The significance of this result is immediately
apparent when comparing reaction productivity between these
two cases. The addition of CySH in flow increased the productivity
of this reaction by a factor of >20, from 0.1 g h–1 to 2.2 g h–1.
Following these promising results, dehalogenation of the
corresponding aryl chloride substrate 2a was also examined in
flow. Complete conversion was observed, achieving a 96% yield
in 3 min (entry 5). This also represents an outstanding increase in
Table 1. Optimization of reductive dehalogenation using 4-bromobenzonitrile
(1a) and 4-chlorobenzonitrile (2a). [a]Reported yields were determined by
HPLC, calibrated against an internal standard. [b]Reaction carried out with 2.5
mol% PTH photocatalyst.
substantial decrease in yield. Decreasing the LED power to 50%
of the maximum (calculated photon flux of 0.61 E m–2 s–1 vs
1.22 E m–2 s–1) showed only a moderate decrease in yield (entry
7 vs entry 12). This is perhaps unsurprising, since estimation of
light absorbance by the Beer-Lambert law predicts that only 20%
of incident light is being absorbed in this reaction system.[17]
Accordingly, it is likely that under these conditions the reaction
does not operate under a light-limited kinetic regime.
The specific reaction conditions and reagent loadings were
further explored using a Design of Experiments (DoE) study.[17]
This provided an excellent linear model, suggesting that low
reaction concentration and high formic acid and DIPEA (N,N-
diisopropylethylamine) loading would provide the fastest reaction.
In order to work under practically favorable reaction conditions,
we opted to maintain the current conditions of 0.1 M concentration,
with 5 equivalents of acid and amine.
Using the identified optimal conditions, an investigation of
the reaction scope was undertaken (Scheme 1). Aryl iodides 4b
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10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
and 4c were dehalogenated quantitatively with a residence time
of just 1 min. Following on from these promising results, more
challenging (hetero)aryl bromide substrates were then examined.
A p-substituted ester (1d) could be dehalogenated quantitatively
in 5 min. The heterocyclic substrate, 3-bromoquinoline 1f also
To probe the procedure’s selectivity between single- and
double dehalogenation, dihalogenated substrates were also
examined. 3,5-Dibromopyridine (5) underwent facile double
dehalogenation in 5 min, but by shortening the residence time to
0.5 min, and reducing light intensity, good selectivity for single
provided an excellent yield of its corresponding product, quinoline, debromination was achieved, leading to 91% yield of 3-
despite the possibility of further reduction of this product itself
(E1/2 = –2.08 V vs SCE).[18]
bromopyridine. Selectivity between bromide and chloride in the
ester 6 could be achieved by the same principle, producing the
chlorinated product in 91% yield, or enabling double
dehalogenation in 95% yield at a longer residence time.
One significant incompatibility which was observed in these
results was that of aldehydes and ketones. Indeed, when
attempting to dechlorinate m-chlorobenzaldehyde (7a), different
reactivity was observed, whereby the pinacol coupling product
was formed. This could be expected, since the redox potentials of
aryl aldehydes (benzaldehyde E1/2 = –1.93 V vs SCE)[4] and aryl
ketones (acetophenone E1/2 = –2.11 V vs SCE)[4] suggest that
they may be directly reduced by the excited state photocatalyst.
Stern-Volmer quenching studies showed significant fluorescence
quenching by acetophenone, further supporting this mechanistic
proposal.[17]
p-Bromobenzoic acid (1c) was dehalogenated with some
success, but did not undergo complete conversion in 28 min. The
use of an even more strongly reducing photocatalyst, N-(1-Np)-
phenothiazine (Np-PTH, E1/2* = –2.23 V vs SCE),[19] enabled a
96% yield in a shorter residence time (10 min). Similarly, 2-
bromothiophene (1g) showed incomplete reduction with the
standard PTH catalyst, but was pushed to completion in 20 min
using the N-naphthyl variant. Improved reactivity was also
observed with p-trifluoromethylbromobenzene (1e), which gave
96% yield of its dehalogenated product in 20 min whilst keeping
the trifluoromethyl group intact.[17]
PTH (2.5 mol%), CySH (5 mol%),
HCOOH (5 equiv), DIPEA (5 equiv)
Ar
X
Ar
H
N
MeCN (0.1 M), 365 nm LEDs,
20 °C, 3.5 bar, flow
Cl
PTH (2.5 mol%), CySH (5 mol%),
HCOOH (5 equiv), DIPEA (5 equiv)
O
HO
Cl
aryl bromides
R
aryl iodides
I
MeCN (0.1 M), 365 nm LEDs,
OH
R
20 °C, 3.5 bar, flow
Cl
7a
8a
, 93%, 5 min
Br
1f
Br
4b
2H
R = H
, 99%, 1 min
4c
CO
[a]
, 99%, 5 min
S
1a
R = CN
, 97%, 1 min
1c
, 98%, 1 min
CO
[b]
H
, 96%, 10 min
CO2
HO
HO
BnHN
aryl chlorides
Cl
1d
Et
, 99%, 5 min
CF 2
R
[b]
1e
, 96%, 20 min
3
OH
NHBn
OH
Br
[b]
1g
, 90%, 20 min
[a]
2a
R = CN
CO
, 96%, 3 min
8b
8c
, 98%, 3 min
8d
, 80%, 5 min
, 96%, 3 min
2c
H
, 83%, 28 min
dihalogenated
Br
CO2
Me
CO2
2h
2Me
, 98%, 1 min
Br
Scheme 2. Pinacol couplings of aldehydes, ketones and imines. Isolated
yields are shown.
R
Br
6
Cl
N
[c]
[c]
5
, 91%, 0.5 min
, 91%, 0.5 min
Cl
(ArBr product)
87%, 5 min
(ArCl product)
95%, 4 min
2i
R = CO Me
CO2
, 94%, 1 min
This pinacol product 8a was formed with complete
selectively in a short residence time of 5 min, leading to a 93%
yield (Scheme 2). This reaction was also found to be completely
selective in the case of ketones (product 8c) and performed well
with imines (product 8d). These results show a significant
improvement in reaction rate and selectivity, when compared to
all previously reported photoredox pinacol coupling procedures,
which rely on an amine redox mediator rather than direct carbonyl
reduction.[20]
2j
2Et
, 99%, 3 min
(bis dehalogenation) (bis dehalogenation)
Scheme 1. Substrate scope of dehalogenation reaction. Yields were
determined by HPLC, using an internal standard calibrated against the
reaction product(s). [a]Reaction was carried out using 5 mol% of PTH
photocatalyst. [b]Reaction was carried out using more reducing photocatalyst,
Np-PTH. [c]Reaction was carried out using 25% light intensity.
Turning
towards
mechanistic
investigation,[21]
Various
aryl
chlorides
were
also
successfully
dehalogenation experiments using DCOOD displayed only a
minor extent of deuterium incorporation, similar to previous
observations.[10b] Furthermore, no change in quenching constant
was observed by the addition of CySH in fluorescence quenching
studies.[17] Therefore, the mechanism by which this thiol additive
accelerates the reaction is proposed to be in mediating the
regeneration of ground state photocatalyst.[21] This requires a
potential of –0.68 V (vs SCE),[10b] so its oxidation of DIPEA
dehalogenated by this method, tolerating esters in the o- and p-
positions (2h, 2i and 2j). Interestingly, it was found that the
presence of an ethyl ester in place of a methyl ester called for
slightly elongated reaction time (2i versus 2j). Furthermore, the p-
chlorobenzoic (2c) acid reacted substantially faster than its
bromo- analogue, when using the standard PTH photocatalyst
(83% vs 59% yield after 28 min).
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10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
(E1/2 = +0.94 V vs SCE)[23] is an unfavorable process. Conversely,
formate oxidation, coupled with HAT to cyclohexanethiyl radical is
likely far more facile.[12a] Another possible mechanism for
regeneration of ground state photocatalyst is proton-coupled
electron transfer (PCET) from the thiol.[24] Further evidence and
discussion of the reaction mechanism can be found in the
Supporting Information.
Seeking to apply this methodology to other synthetically
useful transformations, the coupling of 4-chlorobenzonitrile (2a)
with the styrene derivative 1,1-diphenylethylene (9) was
examined (Scheme 3). The desired reductive coupling product 10
was obtained in a good 61% yield. Similar transformations using
aryl bromide starting materials have required long reaction times
(>24 h) to reach a similar yield,[6b][7] compared to the 10 minute
residence time used in this case.
Keywords: photoredox • continuous flow • hydrogen atom
transfer • flow photochemistry • aryl halides
[1]
[2]
C. S. Wang, P. H. Dixneuf, J. F. Soulé, Chem. Rev. 2018, 118, 7532–
7585.
a) I. Ghosh, L. Marzo, A. Das, R. Shaikh, B. König, Acc. Chem. Res.
2016, 49, 1566–1577; b) F. Mo, G. Dong, Y. Zhang, J. Wang, Org. Biomol.
Chem. 2013, 11, 1582–1593.
[3]
a) N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075–10166;
b) M. Anselmo, A. Basso, S. Protti, D. Ravelli, ACS Catal. 2019, 9, 2493–
2500.
[4]
[5]
H. G. Roth, N. A. Romero, D. A. Nicewicz, Synlett 2016, 27, 714–723.
For examples of iridium catalysis for the photochemical reduction of
(hetero)aryl iodides and bromides, see: a) J. J. Devery, J. D. Nguyen, C.
Dai, C. R. J. Stephenson, ACS Catalysis 2016, 6, 5962–5967; b) J. D.
Nguyen, E. M. D’Amato, J. M. R. Narayanam, C. R. J. Stephenson, Nat.
Chem. 2012, 4, 854–859; c) R. A. Aycock, H. Wang, N. T. Jui, Chem. Sci.
2017, 8, 3121–3125; d) A. Arora, J. D. Weaver Acc. Chem. Res. 2016,
49, 2273–2283 e) C. P. Seath, D. B. Vogt, Z. Xu, A. J. Boyington, N. T.
Jui, J. Am. Chem. Soc. 2018, 140, 15525-15534.
PTH, CySH,
HCOOH, DIPEA
Cl
Ph
Ph
Ph
Ph
MeCN, 365 nm LEDs,
= 10 min
[6]
a) I. Ghosh, T. Ghosh, J. I. Bardagi, B. König, Science 2014, 346, 725–
728; b) I. Ghosh, B. König, Angew. Chem. Int. Ed. 2016, 55, 7676–7679;
c) R. S. Shaikh, S. J. S. Düsel, B. König, ACS Catal. 2016, 6, 8410–8414;
d) L. Marzo, I. Ghosh, F. Esteban, B. König, ACS Catal. 2016, 6, 6780–
6784; e) J. I. Bardagi, I. Ghosh, M. Schmalzbauer, T. Ghosh, B. König,
Eur. J. Org. Chem. 2018, 34–40; f) A. Seegerer, P. Nitschke, R. M.
Gschwind, Angew. Chem. Int. Ed. 2018, 57, 7493–7497.
I. Ghosh, R. S. Shaikh, B. König, Angew. Chem. Int. Ed. 2017, 56, 8544–
8549.
NC
NC
flow, tRes
2a
9
10,
61%
Scheme 3. Reductive coupling of aryl chloride with a styrene derivative.
Conditions: aryl chloride (0.85 mmol), 1,1-diphenylethylene (4.25 mmol), PTH
(10 mol%), CySH (5 mol%), HCOOH (4.25 mmol), DIPEA (4.25 mmol), MeCN
(0.1 M), 365 nm LEDs, 50 °C, conducted in flow with a 10 minute residence
time, 3.5 bar back pressure, 0.85 mmol scale. Isolated yield is shown.
[7]
[8]
[9]
A. U. Meyer, T. Slanina, A. Heckel, B. König, Chem. Eur. J. 2017, 23,
7900–7904.
Conclusion
J. Ke, H. Wang, L. Zhou, C. Mou, J. Zhang, L. Pan, Y. R. Chi, Chem. Eur.
J. 2019, 25, 6911–6914.
In summary, we have demonstrated the effectiveness of
HAT catalysis in combination with a strongly reducing organic
photoredox catalyst in flow, improving reaction rate and selectivity
of aryl halide and carbonyl reductions. The application of
continuous flow has acted to further accelerate these
transformations, in one case increasing productivity by a factor of
>20. Furthermore, the tuning of residence time and light intensity
allows control over reaction selectivity in some cases, where
single dehalogenation of dihalogenated aryl halides can be
achieved. The catalytic system is also effective in pinacol
couplings, achieving significantly higher yields in short reaction
times, when compared to previous reports. Mechanistic
experiments suggest that the thiol additive is involved in
regeneration of the ground state photocatalyst, rather than any
excited state interaction. Finally, the reduction of an aryl chloride
was performed in the presence of a styrene radical trap, to
achieve a reductive coupling.
[10] a) R. Matsubara, T. Yabuta, U. Md Idros, M. Hayashi, F. Ema, Y. Kobori,
K. Sakata, J. Org. Chem. 2018, 83, 9381–9390; b) E. H. Discekici, N. J.
Treat, S. O. Poelma, K. M. Mattson, Z. M. Hudson, Y. Luo, C. J. Hawker,
J. R. de Alaniz, Chem. Commun. 2015, 51, 11705–11708.
[11] a) S. O. Poelma, G. L. Burnett, E. H. Discekici, K. M. Mattson, N. J. Treat,
Y. Luo, Z. M. Hudson, S. L. Shankel, P. G. Clark, J. W. Kramer, C. J.
Hawker, J. R. de Alaniz, J. Org. Chem. 2016, 81, 7155–7160; b) N. J.
Treat, H. Sprafke, J. W. Kramer, P. G. Clark, B. E. Barton, J. R. de Alaniz,
B. P. Fors, C. J. Hawker, J. Am. Chem. Soc. 2014, 136, 16096–16101.
[12] a) H. Wang, N. T. Jui, J. Am. Chem. Soc. 2018, 140, 163–166; b) F.-D.
Lu, D. Liu, L. Zhu, L.-Q. Lu, Q. Yang, Q.-Q. Zhou, Y. Wei, Y. Lan, W.-J.
Xiao, J. Am. Chem. Soc. 2019, 141, 6167–6172.
[13] A. J. Boyington, C. P. Seath, A. M. Zearfoss, Z. Xu, N. T. Jui, J. Am.
Chem. Soc. 2019, 141, 4147–4153/
[14] a) D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel, T. Noël, Chem.
Rev. 2016, 116, 10276–10341; b) Y. Su, N. J. W. Straathof, V. Hessel,
T. Noël, Chem. Eur. J. 2014, 20, 10562–10589; c) K. Loubière, M.
Oelgemöller, T. Aillet, O. Dechy-Cabaret, L. Prat, Chem. Eng. Process.
- Process Intensif. 2016, 104, 120–132.
[15] T. Noël, J. Flow Chem. 2017, 7, 87–93.
[16] For selected examples of throughput optimization for flow photochemical
transformations, see: a) K. C. Harper, E. G. Moschetta, S. V Bordawekar,
S. J. Wittenberger, ACS Cent. Sci. 2019, 5, 109–115; b) Y. Su, K.
Kuijpers, V. Hessel, T. Noël, React. Chem. Eng. 2016, 1, 73–81; c) J. D.
Williams, M. Nakano, R. Gérardy, J. A. Rincon, O. de Frutos, C. Mateos,
J.-C. M. Monbaliu, C. O. Kappe, Org. Process Res. Dev. 2019, 23, 78–
87; d) J. D. Williams, Y. Otake, G. Coussanes, I. Saridakis, N. Maulide,
C. O. Kappe, ChemPhotoChem 2019, 3, 229–232.
Acknowledgements
The CCFLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport, Innovation
and Technology (BMVIT), the Austrian Federal Ministry of
Science, Research and Economy (BMWFW), and by State of
Styria (Styrian Funding Agency (SFG)). The authors gratefully
acknowledge Corning SAS for the generous loan of the Corning
Advanced-Flow Lab Photoreactor used in this study.
[17] See the Supporting Information for further details.
[18] K. Daasbjerg, Acta Chem. Scand. 1993, 47, 398–402.
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10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
[19] X. Pan, C. Fang, M. Fantin, N. Malhotra, W. Y. So, L. A. Peteanu, A. A.
Isse, A. Gennaro, P. Liu, K. Matyjaszewski, J. Am. Chem. Soc. 2016,
138, 2411–2425.
[20] a) M. Nakajima, E. Fava, S. Loescher, Z. Jiang, M. Rueping, Angew.
Chem. Int. Ed. 2015, 54, 8828–8832; b) S. Okamoto, K. Kojiyama, H.
Tsujioka, A. Sudo, Chem. Commun. 2016, 52, 11339–11342; c) E. Della
Rocca, T. P. Jansen, R. Perciaccante, P. Ceroni, P. G. Cozzi, G.
Rodeghiero, F. Bertoni, M. Marchini, A. Gualandi, Chem. Commun. 2018,
54, 10044–10047.
[21] For a review of methods to determine photoredox mechanisms, see: L.
Buzzetti, G. E. M. Crisenza, P. Melchiorre, Angew. Chem. Int. Ed. 2019,
58, 3730–3747.
[22] L. Capaldo, D. Ravelli, Eur. J. Org. Chem. 2017, 2017, 2056–2071.
[23] A. F. Garrido-Castro, H. Choubane, M. Daaou, M. C. Maestro, J. Alemán,
Chem. Commun. 2017, 53, 7764–7767.
[24] a) K. Qvortrup, D. A. Rankic, D. W. C. MacMillan, J. Am. Chem. Soc.
2014, 136, 626–629; b) N. Hoffmann, Eur. J. Org. Chem. 2017, 1982–
1992.
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10.1002/ejoc.201900952
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Flow Photochemistry
Alexander Steiner, Jason D. Williams,
Juan A. Rincón, Oscar de Frutos, Carlos
Mateos and C. Oliver Kappe*
Page No. – Page No.
To reach useful productivity in a flow photochemical transformation, relatively fast
reaction rates are preferable. We report a procedure, combining photo- and hydrogen
atom transfer catalysis, which is capable of reducing aryl halides and carbonyl
compounds in very short reaction times, in continuous flow.
Implementing Hydrogen Atom
Transfer (HAT) Catalysis for Rapid
and Selective Reductive Photoredox
Transformations in Continuous Flow
This article is protected by copyright. All rights reserved.