De novo Design of Organic Photocatalysts: Bithiophene Derivatives for the Visible-light Induced C?H Functionalization of Heteroarenes

Article abstract of DOI:10.1002/adsc.201801571

Herein, we report the de novo synthesis and characterization of a series of substituted bithiophene derivatives as novel and inexpensive organic photocatalysts. DFT calculations were used to predict a priori their absorption spectra and redox potentials, which were then confirmed with empirical data. The photocatalytic activity of this novel class of organic photoredox catalyst was demonstrated in two visible-light mediated strategies for the C?H functionalization of heteroarenes. The implementation of these strategies in a continuous-flow photo-microreactor afforded moderate to excellent yields within few minutes of reaction time. Due to their straightforward synthesis, low cost and good photocatalytic properties we believe that the proposed bithiophene derivatives could be employed as a new class of organic photoredox catalysts. (Figure presented.).

Full text of DOI:10.1002/adsc.201801571

Title: De novo design of organic photocatalysts: bithiophene
derivatives for the visible-light induced C-H functionalization of
heteroarenes
Authors: Cecilia Bottecchia, Raul Martin, Irini Abdiaj, Ettore Crovini,
Jesus Alcazar, Jesus Jorduna, Maria Blesa, Jose Carrillo,
Pilar Prieto, and Timothy Noel
This manuscript has been accepted after peer review and appears as an
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 Digital 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 when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801571
Link to VoR: http://dx.doi.org/10.1002/adsc.201801571

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
De novo design of organic photocatalysts: bithiophene
derivatives for the visible-light induced C-H functionalization of
heteroarenes
Cecilia Bottecchiaa†, Raúl Martínb†, Irini Abdiajc, Ettore Crovinia, Jesús Alcazarc, Jesús
Ordunad, María Jesús Blesad, José R. Carrillob*, Pilar Prietob and Timothy Noёla*
a
Department of Chemical Engineering and Chemistry, Micro Flow Chemistry and Synthetic Methodology, Eindhoven
University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands. E-Mail: t.noel@tue.nl
Departamento de Química Orgánica, Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La
b
Mancha-IRICA, 13071 Ciudad Real, Spain. Email: joseramon.carrillo@uclm.es
Janssen Research & Development, Calle Jarama 75A, 45007 Toledo, Spain.
Departamento de Química Orgánica, Facultad de Ciencias–Instituto de Ciencias de Materiales de Aragón, Universidad
c
d
de Zaragoza-CSIC, 50009-Zaragoza, Spain.
† These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Herein, we report the de novo synthesis and
characterization of a series of substituted bithiophene
derivatives as novel and inexpensive organic
photocatalysts.
More recently, a number of studies demonstrated that
organic photocatalysts often provide valuable and
inexpensive alternatives to transition metals.[4-5]
Nevertheless, the choice of a suitable organic
photocatalyst might be limited for reactions
proceeding in acidic medium (e.g. Eosin Y is pH
sensitive) or in reducing environments promoting
photobleaching.[6]
In this light, the development of novel classes of
organic photoredox catalysts with good redox
properties, and largely available or easily prepared in
high yields would contribute to further advance
research in photoredox catalysis.[7]
Due to their functional properties and versatility,
deriving from the ease of functionalization of the ring
as well as the lengthening of the chain, thiophene
based materials are of broad interest across multiple
disciplines. For example, in organic electronics their
semiconductor properties are exploited in organic
field-effect transistors (OFETs) and in photovoltaic
devices.[8] However, examples showing their use in
the field of photoredox catalysis remain scarce.[9]
Thus, we became interested in probing the
photocatalytic properties of a series of 2,2'-
bithiophene-based derivatives decorated with
different electron donating and electron withdrawing
groups (see Scheme S1 in SI).
In order to rapidly evaluate the suitability of said
structures as photoredox catalysts, we reasoned that
computational studies might represent a useful tool to
predict their properties a priori. Specifically, through
TD-DFT[10] calculations (M06-2X[11], using CPCM[12]
see SI for further details), the absorption maximum
and emission maximum of this class of compounds
were calculated, together with their redox potentials.
Based on this theoretical information and taking into
DFT calculations were used to predict a priori their
absorption spectra and redox potentials, which were then
confirmed with empirical data. The photocatalytic activity
of this novel class of organic photoredox catalyst was
demonstrated in two visible-light mediated strategies for
the C-H functionalization of heteroarenes. The
implementation of these strategies in a continuous-flow
photo-microreactor afforded moderate to excellent yields
within few minutes of reaction time. Due to their
straightforward synthesis, low cost and good photocatalytic
properties we believe that the proposed bithiophene
derivatives could be employed as a new class of organic
photoredox catalysts.
Keywords: Organic photocatalysts, Photoredox catalysis,
DFT calculations, C-H functionalization, Continuous flow
Visible-light photoredox catalysis received
increasing attention in the last decade as a powerful
strategy enabling novel transformations under mild
reaction conditions (i.e. room temperature,
atmospheric pressure and visible-light irradiation).[1]
In photoredox catalysis, the ability of a photocatalyst
to absorb light in the visible light range, reach an
excited state and then undergo either energy or
electron transfers with the substrates of interest is
paramount.[2] Generally speaking, Ir and Ru
polypyridyl complexes are among the most employed
photocatalyst, offering excellent redox potentials in
their excited states and long-lived exciton lifetimes.[3]
However, the main drawbacks associated with their
use are their prohibitive costs and scarce
availability.[4]
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
account the commercial availability of the required withdrawing groups. Moreover, a good correlation
starting materials, we selected a cluster of six between the experimental oxidation potentials and the
molecules to be synthesized (Figure 1). Hammett constant values for the substituents on the
Photocatalysts A to F were all obtained in good to arene ring was found (see SI section 5). Notably, such
excellent yields through
a
one-step double correlation hints at the possibility to carefully design
starting from other members of this photocatalytic series with
Sonogashira cross-coupling,
inexpensive and readily available alkynyl precursors increasing redox potential by further modulating the
(see experimental section and general procedure 1 in nature and position of the substituents on the aryl ring.
SI).[13] The optimized procedure was performed with For all members of the series, the theoretical
minimal amount of solvent, under microwave reduction potentials were calculated to be higher than
irradiation and employing recycled Pd catalyst.
-2V, and thus could not be confirmed experimentally
Gratifyingly, the calculated theoretical values for the due to the limited potential window of CHCl3.[14] By
maximum absorption were found to be in good combining the calculated oxidation/reduction
agreement with the experimental measurements potentials with the E0,0 values, the excited state
(Figure 1). The UV-Visible spectra of all of the potentials for compounds A to F were also derived
studied compounds showed a unique absorption band (Figure 2, and SI section 2). Notably, all compounds
in the 400 nm region with significant tailing towards of the series showed excited state potentials
the blue light region, thus supporting our initial comparable to commonly used photocatalysts.[3-4]
hypothesis that these compounds might be useful in To test the activity of the bithiophene derivatives as
visible-light driven catalytic reactions.
photoredox
catalysts,
we
commenced
our
investigations by employing them in the C-H
functionalization of heteroarenes with malonate
derivatives.[15]
Table 1: Optimization of reaction conditions for the C-H
functionalization of 3-Me indole with Br-malonate
GC-FID
Yield (%)b
87
Changes from initial reaction
conditionsa
Entry
1
2
none
1 mol% Th-BT-Th as photocatalystc
79
1 mol% Ru(bpy)3Cl2•6H2O as
3
4
5
41
75
82
photocatalyst
400 nm LEDs, 30 min reaction time
2 mol% D, 400 nm LEDs, 30 min
reaction time
5 mol% D, 400 nm LEDs, 30 min
6
7
8
70
0
reaction time
No light, no photocatalyst
Figure 1: Overview of the six 2,2'-bisthiophene-based
photocatalyst synthesized and comparison of their
calculated vs experimental properties. All potential values
are reported vs SCE (Saturated Calomel Electrode). For
details on the calculations and on the experimental data we
refer to SI. Calc = calculated values. Exp = experimental
values.
Light (either 465 or 400 nm), no
photocatalyst
0
Continuous flow, 400 nm LEDs, 7
min reaction timee
9
81 (70d)
aReaction conditions: 0.4 mmol 3-Me indole (1a, 1 eq), Br-
malonate (2 equiv), Ph3N (1.5 equiv), 1.0 mol%
photocatalyst D in 2.5 ml DMF (0.16 M), irradiation with
The redox properties of the reported bithiophenes
were followed by Cyclic Voltammetry (CV) and
Differential Pulse Voltammetry (DPV) in CHCl3 (for
the voltammograms see SI section 3) and matched
closely the calculated theoretical values (Figure 1).
As expected, compounds A, B and C, bearing
electron-donating groups, showed lower oxidation
potential than compounds D and E, bearing electron-
b
465 nm LEDs, 5 hours reaction time. Yield determined by
GC-FID with decafluorobiphenyl as internal standard.
cbenzothiadiazole-based photocatalyst, see ref.[9] and SI for
d
e
structure. Isolated yield. For detailed flow conditions, see
SI.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
The same transformation was previously reported to studies, novel methodologies for the introduction of
2+
proceed with either Ru(bpy)3 or with an organic fluorine atoms in drug candidates are in high demand
photocatalyst, and was therefore selected as in the pharmaceutical industry.[18]
benchmark reaction.[9, 15] As depicted in Table 1, we
initially tested the ability of our photocatalysts to
catalyse the reaction between 3-Me indole (1a) and
Br-malonate in presence of triphenylamine as
sacrificial electron donor. Subjected to blue LED
irradiation, 87% of the desired alkylated indole (2a)
was obtained within 5 hours with 1 mol% of
photocatalyst D (Table 1, entry 1). All other members
of the series were tested under identical conditions
and resulted in similar or inferior yields (see SI
section 6). Gratifyingly, our photocatalyst
2+
outperformed Ru(bpy)3 (Table 1 entry 3), and
compared positively with the benzothiadiazole-based
organic photocatalyst Th-BT-Th (Table 1, entry 2,
reference [9], see SI section 6 for structure). In order to
better match the irradiation wavelength with the
photocatalyst maximum absorption, we then
conducted the reaction under irradiation with 400 nm
LEDs, obtaining 75% of product within only 30
minutes. (Table 1, entry 4). Higher concentrations of
photocatalyst did not result in increased amounts of
product (Table 1 entry 5 and 6). Control experiments
revealed that both the presence of light and of the
photocatalyst were essential to achieve product
formation (Table 1 entry 7, and 8). Finally, in order
to overcome the limitations associated with
photochemical reactions performed in batch reactors
(i.e. limited light penetration, sub-optimal mixing),
we implemented the use of a continuous flow
capillary microreactor (I.D. 760 μm, 2.5 mL reactor
volume).[16] Owing to the efficient irradiation of the
reaction mixture achievable in microflow reactors, a
good isolated yield of 2a (70%) was obtained within
Scheme 1: Scope of the C-H functionalization of
heteroarenes with malonate derivatives. Reaction
conditions: 0.4 mmol of substrate, 1 mol% D, 1.5 equiv. of
Ph3N, 2 equiv. Br-malonate in 2.5 ml DMF (0.16 M).
only 7 minutes of residence time (Table 1, entry 9).
With optimized conditions in hand, we then
explored the scope of this transformation (Scheme 1).
A series of heteroaromatic compounds were tested:
Reactions performed in a capillary microflow reactor,
both N-protected and unprotected indoles underwent
irradiation with 400 nm LEDs, with different residence
the reaction in good to excellent yields (2a-b). The
a
times depending on the substrate, isolated yields Amount
functional group tolerance towards halides (2c) and
of di-substituted product obtained.
esters (2d) was demonstrated.
In this context, mild methodologies for the late-stage
trifluoromethylation of potential drug candidates
occupy a prominent role. Several photoredox-based
trifluoromethylation methodologies have been
reported in the last years, relying mostly on the use of
The reaction proceeded with good yield also on a
protected tryptophan moiety (2f), thus suggesting a
possible application of this methodology in the
context of bioconjugation chemistries.[17] 3-Me
benzofuran was also successfully alkylated (2e). To
further demonstrate the utility of this transformation,
a series of 5-membered heterocycles were tested:
pyrroles (3a, 3b), thiophene (3c) and furans (3d, 3e)
were all found to be competent substrates, yielding
the corresponding alkylated products in moderate to
excellent yields.
Encouraged by the positive results obtained for the C-
H functionalization of heteroarenes with malonate
derivatives, we turned our attention to the possibility
of employing our organic photocatalysts for the C-H
trifluoromethylation and difluoroalkylation of
heteroarenes. Due to the importance of fluorinated
moieties in structure-activity relationship (SAR)
expensive
transition
metal-based
photoredox
catalyst.[19] We commenced our attempts toward the
trifluoromethylation of heteroarenes in continuous
flow by employing photocatalyst D, gaseous and
inexpensive
trifluoromethyl
agent
iodide
N,N,N′,N′-
(TMEDA) as
as
trifluoromethylating
and
Tetramethylethane-1,2-diamine
sacrificial electron donor.[20]
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
complex 5- and 6-membered heterocycles) was
demonstrated in this case.
Both trifluoromethylated indole (4a) and imidazo[1,2-
a]pyridine (4b) derivatives were obtained in
synthetically
useful
yields,
while
the
trifluoromethylated pyrrole derivative 4c was
obtained with a 56% yield. Pyridine derivatives 4d
and 4e were isolated in modest yields. Unfortunately,
for compounds obtained in modest yields prolonging
reaction time in the photoreactor did not contribute to
increase the conversion of starting materials.
Next, the applicability of our methodology to other
nitrogen containing heterocycles was demonstrated
with compounds 4g and 4i. Notably, the
perfluoroalkylated derivative 4h, obtained via the use
of IC4F9 as fluorinating agent, was also isolated in a
22% yield.
Finally, the aniline derivative 4f was obtained in 54%
yields as a separable mixture of ortho- and para-
regioisomers. In order to further demonstrate the
reactivity of the develop photocatalysts, we then
focused on the introduction of a difluoroester moiety
(Fehler! Verweisquelle konnte nicht gefunden
werden.), which is a precursor of high interest in the
preparation of radio-labeled 18F compounds for
positron-emission tomography (PET) scan.[22],[23] By
employing Br-CF2COOEt as fluorinating agent, the
corresponding indoles (5a, 5b) and imidazo[1,2-
a]pyridine (5c) derivatives were obtained in good
yields. Similarly, the Br-pyridone derivative 5d was
obtained in 50% yield. Interestingly, when aniline
derivatives were employed for this transformation a
one-pot tandem difluoroalkylation/amidation was
observed,
resulting
in
the
formation
of
difluorooxindoles derivatives 5e-g.[24]
Fluorescence quenching studies on the reactions
studied demonstrated that both reductive and
oxidative single electron transfers (SET) are viable
pathways for the excited state of photocatalyst D (see
SI section 7). Such versatility in terms of redox
properties further highlights the potential of this novel
photocatalyst series in a broad range of photocatalytic
reactions.
Scheme 2: Scope of the trifluoromethylation and
difluoroalkylation of heteroarenes. Reaction conditions: 0.5
mmol of substrate, 1 mol% D, 3 equiv. TMEDA, 4 equiv.
CF3I/ 2 equiv. BrCF2COOEt in 5 ml DMF (0.1M).
Reactions performed in a Vapourtec UV-150 photoreactor,
irradiation with 450 nm blue LEDs and 20 min residence
time, isolated yields. aLC-MS yield. For a detailed
procedure for compounds 5e, 5f and 5g, we refer to SI,
section 8.
In conclusion, we reported the rational de novo
synthesis of a novel class of 2,2'-bithiophene-based
organic photocatalysts. DFT calculations were used to
predict a priori the spectroscopic properties and the
redox potentials of an array of molecules, of which
six were then synthesized and characterized. The
experimental data were found to be in good
agreement with the theoretical values. The activity of
this class of molecules as photocatalyst was then
showcased in the C-H functionalization of
heteroarenes with malonate derivatives. The activity
of the tested compounds was comparable with that of
other commonly used organic or transition-metal
Notably, the formation of a gas-liquid slug flow
regime in our continuous system resulted in improved
mixing, while granting an efficient and homogeneous
irradiation of the reaction mixture and affording a safe
handling of the gas reactant.[16] The results obtained
for the trifluoromethylation of a diverse set of
heteroarenes are summarized in Scheme 2. It is worth
noting that, under analogous reaction conditions, a
similar gas-liquid trifluoromethylation had been
2+
photocatalysts (i.e. Th-BT-Th and Ru(bpy)3 ), and a
series of derivatives was obtained in good to excellent
yields. Process intensification in a microflow
photoreactor afforded increased yields and reduced
reaction times. Moreover, the implementation of our
photocatalyst for the trifluoromethylation and
2+
reported by our research group with either Ru(bpy)3
or with Eosin Y.[21] Gratifyingly, the results obtained
with photocatalyst D were comparable with those
obtained with the other two photocatalyst. Moreover,
a broader reaction scope (i.e. functionalization of
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
Acknowledgements
difluoroalkylation of heteroarenes and benzofused
heteroarenes was also demonstrated. Mechanistic
insight via fluorescence quenching studies and Stern-
Volmer analysis indicated that these photocatalyst can
undergo both reductive and oxidative quenching
pathways. Due to their inexpensive nature, good
absorption in the 400 nm range and their favourable
redox potentials, we believe that this novel class of
2,2'-bithiophene-based organic photocatalyst could
find interesting applications in photoredox catalysis.
C.B., I.A., J.A. and T.N. acknowledge the European Union for a
Marie Curie ITN Grant (Photo4Future, Grant No. 641861).
Financial support from Junta de Comunidades de Castilla La
Mancha (JCCM-FEDER) (project SBPLY/17/180501/000189)
and Gobierno de Aragón, grupo de referencia E14_17R is
acknowledged. R. Martín is grateful to MEC for an FPU
studentship. Moreover, technical support from the High
Performance Computing Service of the University of Castilla La
Mancha is gratefully acknowledged. The authors would like to
acknowledge Mr. Alberto Fontana for his help with LC-MS
analysis.
Experimental Section
References
General procedure for the synthesis of photocatalysts
A-F
[1] a) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
Chem. Rev. 2013, 113, 5322-5363; b) J. W. Tucker, Y.
Zhang, T. F. Jamison, C. R. J. Stephenson, Angew.
Chem., Int. Ed. 2012, 51, 4144-4147.
A mixture of 5,5'-dibromo-2,2'-bithiophene (0.100 g, 0.31
mmol), the corresponding acetylene derivative (0.77 mmol),
DBU (0.094 g, 0.62 mmol), CuI (0.0017 g, 0.015 mmol)
and Pd-EncatTM TPP30 (Palladium acetate and
triphenylphosphine, microencapsulated in
a polyurea
[2] a) K. L. Skubi, T. R. Blum, T. P. Yoon, Chem. Rev.
2016, 116, 10035-10074; b) J. M. R. Narayanam, C. R.
J. Stephenson, Chem. Soc. Rev. 2011, 40, 102-113.
matrix, 0.026 g, 0.035 mmol) was charged under argon to a
dried microwave vessel. MeCN (1 mL) was added. The
vessel was closed and irradiated at 140 °C for 25 min. The
crude reaction product was purified by chromatography,
eluting with hexane/ethyl acetate to give analytically pure
photocatalysts A to F.
[3] D. M. Arias-Rotondo, J. K. McCusker, Chem. Soc. Rev.
2016, 45, 5803-5820.
[4] N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116,
General procedure for the C-H functionalization of
heteroarenes with malonate derivatives in continuous
flow
10075-10166.
[5] a) D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4,
355-360; b) A. Joshi-Pangu, F. Lévesque, H. G. Roth, S.
F. Oliver, L.-C. Campeau, D. Nicewicz, D. A. DiRocco,
J. Org. Chem. 2016, 81, 7244-7249; c) E. Speckmeier,
T. Fischer, K. Zeitler, J. Am. Chem. Soc. 2018, DOI:
10.1021/jacs.8b08933.
In an oven-dried vial equipped with a magnetic stirrer and a
PTFE septum, 2.0 mg (1 mol %) of RA48 was added to a
mixture of the hetero-arene substrate (0.4 mmol, 1 equiv.),
Br-malonate (0.8 mmol, 2 equiv.) in 1.25 ml of DMF. In
another vial, Ph3N (0.6 mmol, 1.5 equiv) was dissolved in
1.25 ml of DMF. The two solution were merged with a T-
mixer prior entering the microcapillary flow reactor (PFA
tubing, 0.76 mm ID, 2.5 mL reactor volume). The reactor
was irradiated with 400 nm purple LEDs. For the residence
time of every substrate we refer to the compound
characterization in SI. The reaction mixture collected from
the outlet was diluted with H2O and extracted with Et2O
(2x) and EtOAc (1x). The combined organic layers were
washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude was then pre-adsorbed onto silica, dried
in vacuo and purified by flash chromatography to yield the
desired alkylated product.
[6] a) M. Majek, F. Filace, A. J. v. Wangelin, Beilstein J.
Org. Chem. 2014, 10, 981-989; b) G. Oster, N.
Wotherspoon, J. Chem. Phys. 1954, 22, 157-158.
[7] a) J. Luo, J. Zhang, ACS Catal. 2016, 6, 873-877; b) H.
Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi,
Nature 2012, 492, 234-238.
[8] a) W.-I. Hung, Y.-Y. Liao, C.-Y. Hsu, H.-H. Chou, T.-
H. Lee, W.-S. Kao, J. T. Lin, Chem. - Asian J. 2014, 9,
357-366; b) Y. Lin, Y. Li, X. Zhan, Chem. Soc. Rev.
2012, 41, 4245-4272; c) K. Takimiya, M. Nakano, Bull.
Chem. Soc. Jpn. 2018, 91, 121-140.
General procedure for the trifluoromethylation and
difluoroalkylation of heteroarenes in continuous flow
In an oven-dried vial equipped with a magnetic stirrer and a
PTFE septum, 2.5 mg (1 mol %) of RA48 was added to a
mixture of the hetero-arene substrate (0.5 mmol, 1 equiv.),
BrCF2COOEt (1.0 mmol, 2 equiv.) in 2.5 ml of DMF. In
another vial, TMEDA (1.5 mmol, 3 equiv) was dissolved in
2.5 ml of DMF. The two solution were merged with a T-
mixer prior entering the Vapourtec Photoreactor
(fluoropolymer tube, 1.3 mm ID, 5 mL) and the total liquid
flowrate was set to 0.25 mL/min (20 minutes residence
time). For trifluoromethylation reaction, gaseous CF3I was
added via a mass flow controller (2.45 ml/min, 4eq) and the
gaseous stream was merged with the liquid one with a T-
mixer prior to entering the photoreactor. The reactor was
irradiated with 54 blue LEDs (450 nm, total power 24W).
The reaction mixture collected from the outlet was diluted
with H2O and extracted with Et2O (2x) and EtOAc (1x).
The combined organic layers were washed with brine,
dried over MgSO4 and concentrated in vacuo. The crude
was then pre-adsorbed onto silica, dried in vacuo and
purified by flash chromatography to yield the desired
alkylated product.
[9] L. Wang, W. Huang, R. Li, D. Gehrig, P. W. M. Blom,
K. Landfester, K. A. I. Zhang, Angew. Chem., Int. Ed.
2016, 55, 9783-9787.
[10] a) R. G. Parr, W. Yang, in Density-Functional Theory
of Atoms and Molecules, Oxford University Press, USA,
1994; b) C. Adamo, D. Jacquemin, Chem. Soc. Rev.
2013, 42, 845-856.
[11] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2007, 120,
215-241.
[12] a) J. Andzelm, C. Kölmel, A. Klamt, J. Chem. Phys.
1995, 103, 9312-9320; b) M. Cossi, N. Rega, G.
Scalmani, V. Barone, J. Comput. Chem. 2003, 24, 669-
681.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
[13] a) R. Martín, P. Prieto, J. R. Carrillo, I. Torres, C. A.
Strassert, K. Soloviova, A. M. Rodríguez, L. Sánchez,
Á. Díaz-Ortiz, Dyes Pigm. 2018, 151, 327-334; b) M. J.
Pastor, I. Torres, C. Cebrián, J. R. Carrillo, Á. Díaz-
Ortiz, E. Matesanz, J. Buendía, F. García, J. Barberá, P.
Prieto, L. Sánchez, Chem. - Eur. J. 2015, 21, 1795-1802.
[14] N. Elgrishi, K. J. Rountree, B. D. McCarthy, E. S.
Rountree, T. T. Eisenhart, J. L. Dempsey, J. Chem.
Educ. 2018, 95, 197-206.
[15] L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W.
Tucker, C. R. J. Stephenson, Org. Lett. 2010, 12, 3104-
3107.
[16] a) D. Cambié, C. Bottecchia, N. J. W. Straathof, V.
Hessel, T. Noël, Chem. Rev. 2016, 116, 10276-10341;
b) M. B. Plutschack, B. Pieber, K. Gilmore, P. H.
Seeberger, Chem. Rev. 2017, 117, 11796-11893.
[17] C. Bottecchia, T. Noel, Chem. - Eur. J. 2018, DOI:
10.1002/chem.201803074.
[18] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320-330; b) Y. Zhou, J.
Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A.
Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116,
422-518.
[19] a) I. Abdiaj, C. Bottecchia, J. Alcazar, T. Noёl,
Synthesis 2017, 49, 4978-4985; b) T. Chatterjee, N.
Iqbal, Y. You, E. J. Cho, Acc. Chem. Res. 2016, 49,
2284-2294; c) J. W. Beatty, J. J. Douglas, K. P. Cole, C.
R. J. Stephenson, Nat. Commun. 2015, 6, 7919; d) N.
Iqbal, J. Jung, S. Park, E. J. Cho, Angew. Chem., Int. Ed.
2014, 53, 539-542; e) D. A. Nagib, D. W. C.
MacMillan, Nature 2011, 480, 224-228; f) N. Iqbal, S.
Choi, E. Kim, E. J. Cho, J. Org. Chem. 2012, 77,
11383-11387.
[20] N. Iqbal, S. Choi, E. Ko, E. J. Cho, Tetrahedron Lett.
2012, 53, 2005-2008.
[21] a) N. J. W. Straathof, H. P. L. Gemoets, X. Wang, J.
C. Schouten, V. Hessel, T. Noël, ChemSusChem 2014,
7, 1612-1617; b) N. Straathof, D. Osch, A. Schouten, X.
Wang, J. Schouten, V. Hessel, T. Noël, J. Flow Chem.
2015, 4, 12-17.
[22] a) T. Khotavivattana, S. Verhoog, M. Tredwell, L.
Pfeifer, S. Calderwood, K. Wheelhouse, T. Lee Collier,
V. Gouverneur, Angew. Chem., Int. Ed. 2015, 54, 9991-
9995; b) S. Preshlock, M. Tredwell, V. Gouverneur,
Chem. Rev. 2016, 116, 719-766; c) P. W. Miller, N. J.
Long, R. Vilar, A. D. Gee, Angew. Chem., Int. Ed. 2008,
47, 8998-9033.
[23] a) J. Jung, E. Kim, Y. You, E. J. Cho, Adv. Synth.
Catal. 2014, 356, 2741-2748; b) X. Pan, H. Xia, J. Wu,
Org. Chem. Front. 2016, 3, 1163-1185.
[24] L.-C. Yu, J.-W. Gu, S. Zhang, X. Zhang, J. Org.
Chem. 2017, 82, 3943-3949.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801571
Advanced Synthesis & Catalysis
COMMUNICATION
De novo design of organic photocatalysts:
bithiophene derivatives for the visible-light induced
C-H functionalization of heteroarenes
Adv. Synth. Catal. Year, Volume, Page – Page
Cecilia Bottecchiaa†, Raúl Martínb†, Irini Abdiajc,
Ettore Crovinia, Jesús Alcazarc, Jesús Ordunad,
María Jesús Blesad, José R. Carrillob*, Pilar Prietob
and Timothy Noёla*
7
This article is protected by copyright. All rights reserved.