Accelerated Discovery in Photocatalysis using a Mechanism-Based Screening Method

Article abstract of DOI:10.1002/anie.201600995

Herein, we report a conceptually novel mechanism-based screening approach to accelerate discovery in photocatalysis. In contrast to most screening methods, which consider reactions as discrete entities, this approach instead focuses on a single constituent mechanistic step of a catalytic reaction. Using luminescence spectroscopy to investigate the key quenching step in photocatalytic reactions, an initial screen of 100 compounds led to the discovery of two promising substrate classes. Moreover, a second, more focused screen provided mechanistic insights useful in developing proof-of-concept reactions. Overall, this fast and straightforward approach both facilitated the discovery and aided the development of new light-promoted reactions and suggests that mechanism-based screening strategies could become useful tools in the hunt for new reactivity. Enlightened! A mechanism-based screening approach can accelerate discovery in photocatalysis. It focuses on a single mechanistic step of a reaction class: the quenching step central to photocatalytic transformations. Luminescence spectroscopy was used to screen 100 compounds, identifying two promising substrate classes. A second, more-focused screen provided mechanistic insights for developing proof-of-concept reactions.

Full text of DOI:10.1002/anie.201600995

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Communications
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International Edition: DOI: 10.1002/anie.201600995
German Edition: DOI: 10.1002/ange.201600995
Screening Methods
Accelerated Discovery in Photocatalysis using a Mechanism-Based
Screening Method
Matthew N. Hopkinson, Adriµn Gómez-Suµrez, Michael Teders, Basudev Sahoo, and
Frank Glorius*
Dedicated to Professor Andreas Pfaltz
Abstract: Herein, we report a conceptually novel mechanism-
based screening approach to accelerate discovery in photo-
catalysis. In contrast to most screening methods, which
consider reactions as discrete entities, this approach instead
focuses on a single constituent mechanistic step of a catalytic
reaction. Using luminescence spectroscopy to investigate the
key quenching step in photocatalytic reactions, an initial screen
of 100 compounds led to the discovery of two promising
substrate classes. Moreover, a second, more focused screen
provided mechanistic insights useful in developing proof-of-
concept reactions. Overall, this fast and straightforward
approach both facilitated the discovery and aided the develop-
ment of new light-promoted reactions and suggests that
mechanism-based screening strategies could become useful
tools in the hunt for new reactivity.
Breaking up an overall reaction in this way can provide
deeper insight into the fundamental reactivity and, as
[3]
[4]
pioneered by Pfaltz and others, has proven beneficial for
[
1]
reaction optimization and mechanistic elucidation.
An outline of this “mechanism-based” screening
approach for the discovery of new reactivity is shown for
a representative catalytic process in Figure 1a. A mechanistic
step involving an interaction between a substrate (Sub) and
the catalyst (Cat) is crucial in this kind of reaction. If this
T
o a large extent, inspiration for the design of new chemical
transformations is rooted in deep understanding of reaction
mechanisms and the fundamental reactivity trends and
principles which underpin them. The scientific literature,
however, is full of ground-breaking reports where the key
advance was not planned but rather revealed as a result of
experimental serendipity. Speeding up the discovery of such
chance observations can be achieved through the use of
screening technologies, which seek to unveil new reactivity by
testing multiple substrates, reagents, and conditions in an
[
1,2]
efficient manner.
Regardless of the strategy employed,
assessment of the outcome is most often conducted by
analysis of the crude mixtures with the direct or indirect
observation of a new product signifying a “hit”. As such, these
methodologies consider chemical reactions as discrete pro-
cesses and can be loosely categorized as “reaction-based”. As
an alternative conceptual approach, we considered whether
screening methodologies could be devised, which rather than
looking for a new transformation as a whole, focus on a single
key mechanistic step common to a general reaction class.
Figure 1. a) Conceptual distinctions between “reaction-focused” and
“
mechanism-focused” screening. b) Outline of our “mechanism-
based” screening method applied to photocatalysis.
process can be directly investigated, screening different
compounds would reveal new potential substrates for this
kind of catalysis without requiring them to also be competent
at other steps in any specific transformation. In contrast to
[
*] Dr. M. N. Hopkinson, Dr. A. Gómez-Suµrez, M. Teders, Dr. B. Sahoo,
Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
“
reaction-based” approaches, a “hit” in this case corresponds
to the identification of a new substrate class rather than to
a successful overall reaction. Armed with this selection of pre-
identified suitable substrates, a range of many specific
reactions involving them could then be designed in a rational
sense. This endeavor could also benefit from mechanistic
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1
002/anie.201600995.
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[
11]
insights obtained during the screening process upon evaluat-
ing the effects of different substrates, catalysts and reaction
conditions. Alternatively, the discovered lead substrates could
be subjected to a more focused “reaction-based” high-
throughput screening method, thus combining the advantages
of both approaches to unveil new reactivity.
respectively. A library of one hundred potential quenchers
was compiled from stock compounds available in our
laboratory essentially at random, pre-selecting only on the
basis of solubility in acetonitrile. A cuvette containing
photocatalyst 1 (10 mm) and 2500 equivalents of a substrate
(25 mm) was then prepared under oxygen-free conditions in
degassed acetonitrile. The intensity of the luminescence
To validate the concept of “mechanism-based” screening,
our attention was drawn to the field of visible-light photo-
emission of 1 at 472 nm (l = 420 nm) under these conditions
(I) was measured using a standard fluorescence spectrometer
ex
[
5,6]
catalysis which has recently experienced a surge in interest.
A key mechanistic step common to all photocatalytic
reactions involves the quenching of an excited catalyst by
an organic substrate which leads to reactive radical species
capable of undergoing a wide-range of downstream reac-
and compared with that of the photocatalyst measured in
isolation (I ). A “quenching percentage” (F) defined as the
0
percentage decrease of the emission intensity at 472 nm
(100(1ÀI/I )) of higher than 25% was considered as worthy of
0
[
5,7]
tions.
This dynamic process, where energy from visible
further investigation so as to minimize the impact of
[
8]
light is effectively passed on from the catalyst to a non-
absorbing substrate, can be directly investigated using stan-
experimental errors and inner-filter effects.
An illustration of the procedure for this “quencher
discovery” screen is shown in Figure 2a and individual
luminescence spectra are provided in the Supporting Infor-
mation. Among the library of one hundred potential quench-
ers, a total of seven resulted in quenching fractions (F) of
greater than 25%. Two of the identified compounds were
already known to quench the excited state of 1; styrene
[
8,9]
dard luminescence spectroscopy. Simple comparison of the
emission spectrum of the catalyst in the presence of various
potential substrates with that of the photocatalyst in isolation
allows for fast assessment of the quenching abilities of those
compounds. As such, this approach provides direct exper-
imental data and does not require pre-knowledge of the
individual redox potentials or triplet-state energies of each
[
12]
(Q1)
and the tertiary amine N,N-diisopropylethylamine
which were deliberately planted to validate the
[
10]
[13]
compound. Simply changing the solvent also allows for an
easy assessment of the effect of the reaction medium on
quenching efficiency.
(Q2),
screen. The other five discovered quenchers were 1H-
benzotriazole (Q3), 1-methylindole (Q4), nitrobenzene
(Q5), 1-(trifluoromethanesulfonyl) benzotriazole (Q6), and
4-methoxyphenol (Q7, Figure 2b). At this stage, a literature
search was conducted to determine the novelty and potential
importance of each discovered substrate. Further investiga-
tions were not carried out with 1-methylindole (Q4) and
nitrobenzene (Q5) as these compounds have been widely
shown to act as quenchers in visible-light-mediated reac-
Based on this principle, we devised a two-stage screening
strategy to accelerate the discovery of new reactivity in
photocatalysis (Figure 1b). The first stage of the method is
a “quencher discovery” screen, which aims to identify new
potential substrate classes by screening the quenching abil-
ities of a range of organic compounds with a single repre-
sentative photocatalyst. For this purpose, we selected the
widely employed iridium(III) complex [Ir(dF(CF )ppy) -
[14,15]
tions.
The validity of our interpretation of the observed
3
2
(
dtbbpy)]PF6 (1, dF(CF )ppy = 2-(2,4-difluorophenyl)-3-tri-
luminescence intensity decreases as genuine dynamic quench-
ing was also evaluated. This led to the removal from
consideration of 1-(trifluoromethanesulfonyl)benzotriazole
(Q6) as the UV/Vis spectrum of this compound revealed
significant absorption of visible light by this compound (A > 3
at 420 nm). As such, the luminescence spectra obtained with
Q6 should be treated with caution owing to the non-linearity
between emission intensity and luminophore concentration at
3
fluoromethylpyridine, dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyri-
dine), which has excellent photophysical properties and is
chemically robust. Its excited state redox properties
III
II
IV
III
(
E (*Ir –Ir ) =+ 1.21 V vs. SCE, E (Ir –*Ir ) = À0.89 V
1
/2
1/2
vs. SCE. SCE = saturated calomel electrode) and triplet state
À1
energy (E (1) = 61 kcalmol ) are also attractive for the
development of new photoredox or photosensitized reactions,
T
Figure 2. a) Conceptual outline of the “quencher-discovery” screening stage used to accelerate the discovery of quenchers of visible light
photocatalysts. b) Structures of the seven compounds identified as quenchers (quenching fractions, F, are given in circles).
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[8,16]
high overall absorbance values.
The likelihood of the
remaining two substrates, Q3 and Q7, acting as dynamic
quenchers of visible light photocatalysts was then assessed
drawing on literature precedents and reported triplet-state
energies and redox potentials. Although benzotriazoles have
not previously been shown to act as quenchers of visible-light
photocatalysts, these compounds have demonstrated exten-
sive photoactivity upon ultraviolet light irradiation (e.g. the
[17]
Graebe–Ullmann reaction) while structurally similar azides
and diazo compounds have found many applications in
[5h,18]
photocatalysis.
On the other hand, direct reductive
quenching by phenols has been documented with some
[
19]
visible light photocatalysts,
while the redox activity of
[20]
tyrosine derivatives has been widely studied in vivo.
Previous applications of phenol derivatives as substrates in
visible-light photocatalysis are, however, surprisingly scarce,
with most examples not thought to involve direct quenching
[21]
by the phenols themselves.
With two lead compounds identified, we next turned our
attention to the second “quenching evaluation” screening
stage. Rather than concentrating on a single photocatalyst,
this screen instead examines the ability of each compound to
quench the excited states of a range of visible-light-active
complexes and thus allows for easy identification of promising
catalysts for reaction development. Moreover, through com-
parison of the quenching ability of the compound with the
excited state redox potentials and triplet energies of each
catalyst, insights that provide a good estimation of the
operating quenching mechanisms can be obtained. An outline
of the screen used to investigate the quenching by 1H-
benzotriazole (Q3) is shown in Figure 3a. In addition to Q3
itself, a selection of structurally varied analogues was
assembled. This approach can provide additional information
because trends in the quenching abilities of the substrates, as
a function of their electronic properties, may give further
insight into the operating quenching mode and allow for more
enlightened matching of the appropriate catalyst to a partic-
ular substrate. The luminescence spectra of six different
photocatalysts (1–6, 10 mm) were thus measured in the
presence of seven benzotriazole derivatives bearing a range
of nitrogen substituents (25 mm, 2500 equiv of each) under
oxygen-free conditions in degassed acetonitrile. The results of
this “quenching evaluation” screen are shown in Figure 3b,
while more detailed information is provided in the Supporting
Information.
Figure 3. a) Conceptual outline of the “quenching evaluation” screen-
ing stage. b) Results of the “quenching evaluation” screening stage
with benzotriazole derivatives (Fꢀ25% in red, Fꢁ70% in green).
[
22]
benzotriazole. The quenching of catalyst 1 by 1H-benzo-
triazole (Q3) could instead proceed through a different
triplet–triplet energy-transfer pathway involving the 2H
isomeric form, which has a triplet-state energy comparable
À1
to that of 1 (E (2H-benzotriazole) = 60 kcalmol , E (1) =
61 kcalmol ).
T
T
À1 [11,23]
Having obtained an overview of the quenching abilities of
benzotriazole derivatives, the next stage of the process
involves the development of new visible-light-promoted
transformations, which exploit the insights provided by
“mechanism-based” screening. As clearly demonstrated in
the “quenching evaluation” screen, benzotriazole derivatives
which bear electron-withdrawing N-substituents, act as effi-
cient oxidative quenchers of reducing photocatalysts. Upon
single-electron reduction, the resulting radical anions would
be expected to extrude a dinitrogen molecule and deliver aryl
radical anions in a similar fashion to that observed with widely
[
5h]
employed aryldiazonium salt quenchers.
Subsequent
Among the insights provided by this screen is the
observation that the original lead compound Q3 is a less-
efficient and overall more-limited quencher than several of
the N-substituted variants, with a significant decrease in the
emission intensity noted only with catalyst 1. By contrast, the
hydrogen-atom abstraction from the solvent or another
species present in the reaction mixture would then deliver
the corresponding protected aniline in an overall de-nitro-
genation process.
Selecting a substrate/catalyst combination shown by the
screen to result in efficient quenching, 1-(benzoyl)benzotria-
zole (7a) was irradiated with visible light from blue LEDs
(5 W, lmax = 455 nm) in a proof-of-concept experiment in the
iridium(III) complex fac-Ir(ppy) (6) was found to be the
3
optimum photocatalyst for most substrates bearing an elec-
tron-withdrawing carbonyl or sulfonyl group at the 1-position.
The activity of complex 6, which has the highest excited state
oxidation potential of all six tested photocatalysts, is highly
suggestive of an oxidative quenching pathway. Electron-
withdrawing nitrogen substituents may facilitate such a mech-
anism by reducing the reduction potentials of these com-
pounds by stabilizing the ring-opened diazonium form of the
presence of fac-Ir(ppy) (6, 5 mol%) in acetonitrile. After
3
13 h at room temperature, the corresponding anilide 8a was
generated in 28% GC yield, while control reactions in the
absence of light or 6 did not result in product formation
(< 2% GC yield). As expected from the screening results,
conducting the reaction with any of the other five photo-
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catalysts in place of 6 was similarly unproductive (< 2% GC
yield). The other six benzotriazole derivatives employed in
the “quenching evaluation” were also treated under the same
as direct quenchers. Upon single-electron oxidation by an
excited photocatalyst, the resulting radical cation could react
further in a halogen-transfer pathway to generate bromophe-
[25]
conditions with fac-Ir(ppy) (6). While most of the results
nol compounds useful as feedstocks for organic synthesis.
3
were in accordance with the screen, 1-sulfonyl-substituted
derivatives 1-(phenylsulfonyl)benzotriazole and 1-(methane-
sulfonyl) benzotriazole, however, did not react despite their
apparent activity as quenchers of photocatalyst 6. This
observation illustrates that the quenching process is only
one step in this specific reaction and that a particular
photocatalyst or substrate may not be suitable for other
steps in the catalytic cycle or indeed be stable under the
reaction conditions. An optimization study led to an improve-
ment in efficiency upon switching solvent to N-methyl-2-
pyrrolidone (NMP) and either adding the pre-formed 1-
An analogous visible-light-promoted phenol bromination has
been previously developed although this process does not
[21a]
involve direct quenching by phenols.
Taking a substrate
and catalyst combination shown by the screen to result in
efficient quenching, 4-methoxyphenol (Q7) was treated with
iridium(III) complex 1 (1 mol%) in the presence of dimethyl
bromomalonate (9, 1 equiv) in acetonitrile under irradiation
with visible light from blue LEDs (5 W, lmax = 455 nm). After
21 h at room temperature, the mono-brominated product 10a
was obtained as a single regioisomer in 62% GC yield while
control reactions in the absence of light or 1 resulted in only
recovered starting material (< 1% GC yield). An intriguing
disparity between the screening data and the reaction out-
comes was observed, however, upon performing the process
with [Ir(ppy) (dtbbpy)]PF (4) as the catalyst. Whereas the
(
benzoyl)benzotriazole slowly or generating it in situ from
1
H-benzotriazole (Q3) and benzoyl anhydride (see the
[24]
Supporting Information for more details).
Under these
conditions, anilide 8a was generated in 85% isolated yield,
while a range of derivatives bearing substituents on the
benzotriazole or benzoyl fragments were also successfully
transformed (Scheme 1).
2
6
excited state of this comparatively less-oxidising complex was
not quenched by Q7 in the screen, the bromination reaction
conducted with this catalyst delivered the product 10a in
a substantial 52% GC yield. This result would seem to imply
that an alternative mechanistic pathway is operating in this
case, with quenching occurring not with the phenol substrate
but with bromomalonate 9. Indeed, a full Stern–Volmer
luminescence-quenching analysis with both catalysts 1 and 4
supported this scenario with complex 1 being quenched only
by Q7 and catalyst 4 being quenched only by the bromomal-
[24,26]
onate (see the Supporting Information).
These results
clearly illustrate how “mechanism-based” screening can aid
understanding during the development of a new photocata-
lytic reaction by providing insightful mechanistic information
at the beginning of a study.
Scheme 1. Visible-light-promoted de-nitrogenation of benzotriazoles.
In this case, the possibility of two different photocatalytic
pathways allows an informed selection of the catalyst to be
made depending on the phenol substrate. For electron-rich
phenols, such as Q7, direct reductive quenching with catalyst
1 is the more efficient process, while the alternative, likely
oxidative quenching pathway accessible with catalyst 4, is
seemingly more effective for substrates such as phenol, which
is itself a poor quencher of 1 (Scheme 2). Interestingly, the
reactions with phenol, o-cresol, and m-cresol proceed with
very high selectivities for the para-functionalized products
(p:o/m > 20:1) and thus may prove synthetically useful as
As discussed above, visible-light-promoted reactions
involving phenols acting as quenchers are surprisingly
scarce considering that these compounds have been previ-
ously shown to act as reductive quenchers of some photo-
[
19]
catalysts. To obtain an overview of the quenching ability of
various phenols, the same “quenching evaluation” procedure
was conducted with a selection of eight structurally diverse
phenols (see the Supporting Information). As expected from
the literature, the trends in the quenching abilities observed in
the screen strongly support the involvement of reductive
quenching mechanisms for most substrates with the combi-
nation of highly oxidizing photocatalysts and electron-rich
phenols resulting in efficient quenching. An interesting
anomaly to this general trend, however, was the efficient
quenching observed with 2-naphthol and fac-Ir(ppy)3 (6),
which has the lowest excited-state reduction potential of all
six tested complexes. In this case, a triplet–triplet energy
[27,28]
routes towards para-halogenated aromatic compounds.
In summary, we have demonstrated that the application of
“mechanism-based” screening can help to accelerate the
discovery of new chemical reactivity. Using luminescence
spectroscopy, direct experimental data on the quenching step
transfer pathway is likely operative (E (2-naphthol) =
T
À1
À1
5
4 kcalmol and E (6) = 58 kcalmol ). Such detailed insight
T
demonstrates the power of this second “quenching evalua-
tion” screen to reveal individual quenching characteristics of
specific compounds in a fast and straightforward manner.
Armed with these results, we next sought to rationally
design a proof-of-concept transformation involving phenols
Scheme 2. Visible-light-promoted bromination of phenols.
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insights obtained during screening also aided the design and
optimization of new specific transformations involving each
of them. The method is fast, operationally simple, and
versatile, and provides direct experimental data without
requiring foreknowledge of redox potentials, triplet-state
energies, or other thermodynamic or kinetic parameters.
Looking beyond photocatalysis, we believe that “mechanism-
based” screening methodologies could be useful and comple-
mentary tools to accelerate discovery in many areas of
organic chemistry.
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Keywords: benzotriazoles · luminescence · phenols ·
photocatalysis · screening
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[
Received: January 28, 2016
Revised: February 16, 2016
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Angew. Chem. Int. Ed. 2016, 55, 4361 –4366