Continuous UV-Flow Microsystem for Efficient Radical Generation from Organotrifluoroborates by Photoredox Catalysis

Article abstract of DOI:10.1002/ejoc.201600728

An efficient continuous-flow protocol for C–O and C–C bond formation from organoborates by photoredox catalysis under UV irradiation was explored. The combination of a cyclometalated iridium photocatalyst, high-power UV light-emitting diode irradiation, and microreactor technology resulted in very efficient radical generation. The flow device enabled determination of highly accurate kinetic data that allowed the observation of good correlations with the standard Hammett σ (–0.26 to 0.227) values for a wide variety of substituents on the benzyl moiety (? = –4.70, R²= 0.98). Good to excellent yields were obtained for a variety of substrates by applying significantly short residence times.

Full text of DOI:10.1002/ejoc.201600728

A Journal of
Accepted Article
Title: Continuous UV-Flow Microsystem for Efficient Radical Generation from Or-
ganotrifluoroborates by Photoredox Catalysis
Authors: Nassim El Achi; Mael Penhoat; Youssef Bakkour; Christian Rolando; Lae-
titia Chausset-Boissarie
This manuscript has been accepted after peer review and the authors have elected to
post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Di-
gital Object Identifier (DOI) given below. The VoR will be published online in Early
View as soon as possible and may be different to this Accepted Article as a result
of editing. Readers should obtain the VoR from the journal website shown below
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for the content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600728
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600728
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201600728
COMMUNICATION
Continuous UV-Flow Microsystem for Efficient Radical
Generation from Organotrifluoroborates by Photoredox Catalysis
Nassim El Achi,[a] Maël Penhoat,[a] Youssef Bakkour,[b] Christian Rolando[a] and Laëtitia Chausset-
Boissarie*[a]
Abstract: An efficient continuous-flow protocol for C-O and C-C
bond formation from orgonoborates by photoredox catalysis under
UV irradiation is presented. The combination of cyclometalated
Iridium photocatalyst, High Power UV LEDs irradiation and the
microreactor technology results in very efficient radical generation.
Flow device enabled the determination of highly accurate kinetic
data that allowed the observation of good correlations with the
standard Hammett σ [-0.26-0.227] values for a wide variety of
substituents on the benzyl (ρ = -4.70, R2 = 0.98). Good to excellent
yields were obtained for a variety of substrates by applying
significantly short residence times.
combination with UV irradiation would result in a significant
improvement of the radical generation from
organotrifluoroborates as the Iridium catalyst has a wide
absorption band in the near UV. Flow chemistry based on
microfluidic technology has currently gained a lot of interest due
to its significant advancement over the classical batch processes
with respect to reduced consumption of chemicals, solvents,
time and thus energy along with enhanced yields, selectivity and
control over reaction conditions.[10] Moreover, microfluidic
systems can usually be designed using simple and cost effective
material. In batch reactors, light penetration through the reaction
media is limited which restrains the efficiency of photochemical
processes. These drawbacks can be overcome with continuous
microflow reactors since their small optical lengths improve
sample irradiation and also enhance heat and mass transfer.[11]
Herein, we describe the development of a continuous-flow
protocol for C-O and C-C bond formation from
organotrifluoroborates by photoredox catalysis under UV
irradiation. This process has been successfully applied to
several substrates and to the best of our knowledge constitutes
an original example of UV generated radicals from
organoborates by photoredox catalysis under continuous-flow
conditions.
Introduction
Organoboron derivatives are readily available, stable, non-toxic
and selective radical precursors in comparison to other
organometallics.[1] They are currently used in a variety of metal
catalyzed radical reactions; however, an excess of the oxidant is
generally needed.[2] Alternatively, the pioneering work by the
group of Akita and Koike demonstrated that organoboronates,
and notably benzyltrifluoroborates, can be effective precursors
for C-centered radicals that are generated by a single electron
transfer (SET) oxidative processes under photocatalytic
conditions to be later used for C-O and C-C bond formation.[3]
A
Results and Discussion
metal-free alternative, using 9-mesityl-10-methylacridinium
perchlorate as an organic photoredox catalyst, has also been
reported.[4] Recently, this methodology was applied to potassium
alkoxyalkyl-,[5] thioalkyl-,[6] and aminoalkyltrifluoroborates.[7]
Following up, the group of Chen reported the alkenylation and
alkynylation of alkyltrifluoroborates by photoredox catalysis.[8]
More importantly, Molander and coworkers further extended the
methodology to nickel catalyzed arylation of alkyl radicals
generated from alkyltrifluoroborates by photoredox catalysis.[9]
Despite significant advances in this chemistry, these
transformations require several hours to even a few days to
reach completion for some substrates.
At the outset of the study, potassium p-methoxy-
benzyltrifluoroborate 1a was chosen as the model substrate with
TEMPO as a radical scavenger and the commercially available
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6)] as
a photoredox catalyst to
establish the most efficient conditions for the photocatalytic
radical generation. When realized in a batch reactor with the
conditions reported by Akita,[3] the reaction needed 18 h to give
91% yield (entry 1). We then decided to perform the reaction in
flow. The continuous flow microfluidic system was composed of
a high pressure syringe pump delivering the homogeneous
reaction mixture at specific flow rates to a commercially
In this context, we envisaged that continuous-flow systems in
available
microreactor
(Dwell
Device-Mikroglas).
This
microreactor is made up of FOTURAN® glass that is transparent
up to 300 nm allowing to work at a wide range of wavelengths
(UV-A & visible). We found that using the microfluidic system
has remarkably accelerated the rate of the reaction (80 % of
yield after 20 min) (entry 2). This can be explained using Beer-
Lambert Law (A = ε × c × l); for a given ε and c, the quantity of
light that goes through the system decreases with the increase
in the optical length. Consequently, the small optical length
provided by the microfluidic system has a great impact on the
rate of the reaction. Indeed, for a classical batch system whose
optical length is around 4 cm, a significant portion of the reaction
mixture is left unilluminated. In contrast, the small optical length
[a]
[b]
Minuaturisation pour la Synthèse, l’Analyse et la Protéomique
(MSAP), USR CNRS 3290, Université de Lille 1
59655 Villeneuve d’Ascq, France
E-mail: laetitia.chausset-boissarie@univ-lille1.fr
Laboratory of Applied Chemistry, Faculty of Science III
Lebanese University
PO Box 826, Tripoli, Lebanon
Supporting information for this article is given via a link at the end of
the document.

European Journal of Organic Chemistry
10.1002/ejoc.201600728
COMMUNICATION
(0.5 mm) provided by our microfluidic reactor ensures that the
injected reaction mixture is fully and homogeneously irradiated.
3
2.5
2
1.5
1
Table 1. Optimization of the C-O bond formation under continuous flow
conditions[a]
0.5
0
330
380
430
480
Wavelength (nm)
Figure 1. Absorption spectrum of [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) in acetone.
Entry
Catalyst
[mol %]
Reactor
type[b]
Irradiation[c]
Time[d]
Yield
[%][e]
With the optimized conditions in hand, we investigated the
substrate scope of the C-O bond formation under flow conditions
and the results are summarized in table 2.
1
2
3
4
5
6
7
8
2
2
2
2
2
2
1
-
Batch
Flow
Blue
Blue
Blue
White
UV
18 h
91
80
20 min
20 min
20 min
20 min
2.5 min
2.5 min
2.5 min
Batch
Batch
Batch
Flow
17
Table 2. C-O bond formation of various organoborates 1 under continuous
35
flow conditions[a]
>98
98
Entry
Product
Time [min]
Yield [%][b]
UV
Flow
UV
98
1
2
3
4
5
6
7
8
R = p-OMe (2a)
Ph (2b)
2.5
45
20
80
80
40
90
40
93
86
95
33
85
95
62
28
Flow
UV
Trace
[a]. Reaction conditions: 1a (0.05 mmol, 1 equiv), TEMPO (0.125 mmol,
2.5 equiv), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6)] (ppy: 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine, dtbbpy: 4,4-di-tert-butyl-2,2’-bipyridine) (x mol%)
in acetone (1.5 mL) under an atmosphere of Ar. [b] Dwell device
manufactured by Mikroglass Chemtech Mainz, Germany with a rectangular
shape of dimensions 115 mm × 2 mm × 0.5 mm was used as photo-
microreactor. [c] Blue HP spots LEDs (λ = 452 ± 15 nm, 50 W electrical
power, 4500 lumen, 100 mW.cm-2); Cool White Lexman LEDs (13.5 W
electrical power, 6500 K, 875 lumen); UV LEDs (λ = 365 ± 15 nm, 250
mW.cm-2). [d] Reaction time = residence time. [e] Yield was determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard.
R = p-Me (2c)
R = p-Cl (2d)
R = p-F (2e)
R = m-Me (2f)
R = m-OMe (2g)
(2h)
(2i)
9
60
35
Thus, radical C-O bond formation could be achieved under flow
conditions within shorter times than in batch while maintaining
very high yields. We therefore speculated that using cool White
LEDs or UV LEDs (365 nm) would have a beneficial effect since
Ir(III) exhibits unresolved wide absorption band located around
380 nm assigned to MLCT transitions (Figure 1). Unfortunately,
no improvement was observed when using White LEDs.
However, excellent yields were obtained with an impressive
enhancement in the reaction rate under UV irradiation (entries 3-
5). Thanks to the flow device, the reaction time was further
reduced even when the catalyst loading was diminished to 1
mol% (entries 6-7). This clearly demonstrates the superiority of
the flow conditions in combination with UV irradiation as
compared to the known procedure. Interestingly, only a trace of
the product was obtained in the absence of the photocatalyst
confirming that the generation of the radical is not due to the
photoinduced electron transfer (PET) in response to UV light[2a,
12] (entry 8).
10
11
40
70
40
(2j)
360
(2k)
12
13
360
360
25
(2l)
Traces[c]
(2m)
[a]. Reaction conditions: 1a (0.05 mmol, 1 equiv), TEMPO (0.125 mmol,
2.5 equiv), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6)] (1 mol%) in acetone (1.25 mL)
under an atmosphere of Ar. Dwell device manufactured by Mikroglass
Chemtech Mainz, Germany with a rectangular shape of dimensions 115
mm × 2 mm × 0.5 mm was used as photo-microreactor. UV LEDs (λ = 365
± 15 nm, 250 mW.cm-2). [b] Isolated Yield. [c] Only starting material was
recovered.

European Journal of Organic Chemistry
10.1002/ejoc.201600728
COMMUNICATION
revealed a negative ρ value of -4.70 (R2 = 0.98). A negative
sigma value is consistent with a preference for electron rich
substrate and thus a decrement of electron density in the
transition state.
We found that a variety of benzyltrifluoroborates with different
substituents could be successfully oxidized to the desired
compound with moderate to good yields (33%-95%) in short
reaction times (2.5 min-90 min) (entries 1-7). Presumably due to
electronic effects, the presence of electron-donating substituents
appeared to significantly shorten the residence time (entries 1,
3). The scope proved to be quite large ranging from
heterobenzylic trifluoroborates to tertiary- and more importantly
to the previously unreacted secondary alkyltrifluoroborates but
with a modest yield due to the presence of unreacted starting
materials (entries 8-12). Finally, only traces of product were
detected from the reaction with more challenging substrates like
primary alkyltrifluoroborates (entry 13).
Table 3. Relative rates and
σ
values for different substituents on
benzyltrifluoroborates
.
]
Substituent
k(x) [min-1]
log(k(x)/k(H)
)
σ
σ
H
0.047
1.343
0.263
0.006
0.028
0.096
0.013
0
0
0
p-OMe
p-Me
p-Cl
1.445
0.741
-0.908
-0.225
0.305
-0.582
-0.268
-0.170
0.227
0.062
-0.069
0.115
0.24
0.11
0.12
-0.08
0.03
-0.02
p-F
m-Me
m-OMe
Figure 3. Hammett correlations of log(k) with various σ values
These results combined with the first order rate law established
previously confirm that the radical formation is the rate limiting
step (see Scheme1) where a heterolytic cleavage of C-B bond of
organotrifluoroborate occurs along with the photooxidation by
the catalyst.
Figure 2. Kinetic plot of the flow reaction of substituted trifluoroborate salt with
TEMPO.
The C-O bond formation was used as a probe for the radical
generation. To obtain an insight into the features of the reaction,
kinetics were easily carried out using the flow device by varying
the residence times (Figure 2). For every substrate studied, the
reaction follows a clean apparent first order rate law (R2 = 0.97
to 0.99). The latter strongly suggests an observed degenerative
order for the photoredox catalyst concentration so that the rate
limiting step involves the excited catalyst. This limiting step could
correspond to radical formation (Scheme 1). The relative rate
constants k(x) were combined with the appropriate σ values[13]
(Table 3) to construct the Hammett plot (Figure 3). A linear
correlation could only be obtained with the standard σ which

European Journal of Organic Chemistry
10.1002/ejoc.201600728
COMMUNICATION
Scheme 1. Reaction mechanism for the C-O bond formation.[3]
reaction with cyclopentanone was slow leading to only a trace of
the product (entry 7).
Finally, the corresponding alcohol could be produced through
reductive N-O bond cleavage. However in order to directly
obtain the alcohol derivatives a very convenient methodology for
the oxidation of organotrifluoroborates which proceeds through
an alkyl migration mechanism has been developed.[14]
Conclusions
In conclusion we have demonstrated that a continuous-flow
microreactor in combination with UV irradiation could be used for
the generation of radical from boronates to form C-O and C-C
bonds with the same yields as those obtained using the batch
procedure but with drastically shorter reaction times. Further
investigations are ongoing in our laboratory to extend the work
using the current continuous-flow system to form various new C-
C bonds.
Table 4. Photocatalytic C-C bond formation under continuous flow
conditions[a]
Experimental Section
Entry
Alkene 3
Time [min]
Yield 4 [%][b]
Typical procedure for the continuous C-O bond formation from
organoboron 1. A solution of (4-methoxybenzyl)-trifluoroborate potassium
salt 1a (29.5 mg, 50 μmol), TEMPO (19.5 mg, 125 μmol) and
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (0.5 mg, 1 mol%) in 1.5 mL of dry acetone
was degassed by three freeze-pump-thaw cycles. The resulting reaction
1
2
15
30
94
90
(3a)
(3b)
3
4
30
30
57
43
mixture was pumped through the Mikroglas Dwell Device reactor (Vint
=
1.15 mL) at a flow rate of 460 μL.min-1 (2.5 min of residence time). The
reaction mixture was irradiated by UV LEDs (irradiance at surface of
reactor: 230 mW.cm-2). The collected reaction mixture was concentrated
under vacuum and the residue was purified by flash chromatography on
silica gel to afford a colourless oil (12.9 mg, 93 % yield).
(3c)
(3d)
5
180
48
Typical procedure for the continuous C-C bond formation from
organoboron 1. A solution of (4-methoxybenzyl)-trifluoroborate potassium
salt 1a (28.5 mg, 125 μmol), acrylonitrile (53 mg, 1 mmol) and
(3e)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.5 mg,
3 mol%) in 2 mL of dry
6
7
180
180
40
acetone/MeOH (3/1) was degassed by three freeze-pump-thaw cycles.
The resulting reaction mixture was pumped through a homemade reactor
(FEP tubing, ID 0.8 mm, tubing length = 2.98 m, Vint = 1.5 mL) at a flow
rate of 100 μL.min-1 (15 min of residence time). The reaction mixture was
irradiated by UV LEDs (irradiance at surface of reactor: 230 mW.cm-2).
The collected reaction mixture was concentrated under vacuum and the
residue was purified by flash chromatography on silica gel to afford a
colourless oil (20 mg, 94 % yield).
(3f)
Traces
(3g)
[a]. Reaction conditions: 1a (0.125 mmol, 1 equiv), Alkene (1 mmol, 8
equiv), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6)] (3 mol%) in acetone/MeOH (1.5/0.5
mL) under an atmosphere of Ar. Transparent fluorinated ethylene
propylene (FEP) tubing (ID 0.8 mm, tubing length = 2.98 m, V = 1.5 mL).
UV LEDs (λ = 365 nm ± 15 nm, irradiance up to 3 W.cm-2) was used as
photo-microreactor. [b] Isolated Yield.
Acknowledgements
The authors gratefully acknowledge the CNRS and the Lebanon
Association for Scientific Research (LASeR) for the financial
support.
To demonstrate further the synthetic utility of the methodology,
we also examined the possibility to operate Giese-type reactions
with activated olefins for C-C bond formation (Table 4). The yield
of the reaction was only 15% when using our previous
conditions. By increasing the reaction time, the catalyst loading
to 3 mol% and the power of the LEDs, a 94% yield was obtained.
Typical electron deficient alkenes (3a-d) gave the corresponding
adduct in moderate to good yields (entries 1-4). The reaction
with less activated or cyclic alkenes provided modest yields due
to unreacted starting material, dimerization of the benzyl radical
and formation of oxidized by-products (entry 5-6). Finally, the
Keywords: Continuous flow photochemistry • Photoredox
catalysis • Trifluoroborates Reagents • Kinetics
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COMMUNICATION
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European Journal of Organic Chemistry
10.1002/ejoc.201600728
COMMUNICATION
COMMUNICATION
Flow Technology*
Nassim El Achi, Maël Penhoat, Youssef
Bakkour, Christian Rolando, Laëtitia
Chausset-Boissarie*
Page No. – Page No.
An efficient continuous-flow protocol for C-O and C-C bond formation from
orgonoborates by photoredox catalysis under UV irradiation is presented. The
combination of cyclometalated Iridium photocatalyst and High Power UV LEDs irradiation
with simple microreactor results in very efficient radical generation, with the same level of
yields as those of the known batch procedure but with remarkably shorter reaction times.
Continuous UV-Flow Microsystem for
Efficient Radical Generation from
Organotrifluoroborates
Photoredox Catalysis
by