Chromoselective Photocatalysis: Controlled Bond Activation through Light-Color Regulation of Redox Potentials

Article abstract of DOI:10.1002/anie.201602349

Catalysts that can be regulated in terms of activity and selectivity by external stimuli may allow the efficient multistep synthesis of complex molecules and pharmaceuticals. Herein, we report the light-color regulation of the redox potential of a photocatalyst to control the activation of chemical bonds. Light-color control of the redox power of a photocatalyst introduces a new selectivity parameter to photoredox catalysis: Instead of changing the catalyst or ligand, alteration of the color of the visible-light irradiation adjusts the selectivity in catalytic transformations. By using this principle, the selective activation of aryl–halide bonds for C?H arylation and the sequential conversion of functional groups with different reduction potentials is possible by simply applying different colors of light for excitation of the photocatalyst.

Full text of DOI:10.1002/anie.201602349

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International Edition: DOI: 10.1002/anie.201602349
German Edition: DOI: 10.1002/ange.201602349
Photocatalysis
Hot Paper
Chromoselective Photocatalysis: Controlled Bond Activation through
Light-Color Regulation of Redox Potentials
Indrajit Ghosh* and Burkhard Kçnig*
Abstract: Catalysts that can be regulated in terms of activity
and selectivity by external stimuli may allow the efficient
multistep synthesis of complex molecules and pharmaceuticals.
Herein, we report the light-color regulation of the redox
potential of a photocatalyst to control the activation of
chemical bonds. Light-color control of the redox power of
a photocatalyst introduces a new selectivity parameter to
photoredox catalysis: Instead of changing the catalyst or
ligand, alteration of the color of the visible-light irradiation
adjusts the selectivity in catalytic transformations. By using this
colors of light. The use of different redox states generated by
different colors of visible light for photocatalyst excitation
enables selective and sequential catalytic transformations of
À
aryl–halide bonds in synthetically important C H arylation
reactions.
Rhodamine 6G (Rh-6G), a widely applied fluorescent
xanthene dye,[11] yields the stable radical anion[12,13] Rh-6GCÀ
upon photoirradiation under nitrogen with visible light in the
presence of N,N-diisopropylethylamine (DIPEA, an electron
donor; Figure 1). The absorption spectra of Rh-6G and Rh-
6GCÀ differ significantly (Figure 2):[12,13] Rh-6G absorbs both
À
principle, the selective activation of aryl–halide bonds for C H
arylation and the sequential conversion of functional groups
with different reduction potentials is possible by simply
applying different colors of light for excitation of the photo-
catalyst.
S
elective activation of chemical bonds in catalytic trans-
formations is of key importance for the efficient production of
fine chemicals and pharmaceuticals.[1] In enzyme catalysis,
such selectivity is achieved by the confined molecular
environment of active site of the enzyme, whereas in
homogeneous transition-metal-based catalysis, the nature of
the metal, and the electronic and steric features of the
coordinating ligands, provide such selectivity.[1,2] However,
sequential activation of chemical bonds requires either the
use of different catalysts possessing different reactivity (and
thus selectivity),[3] or a multifunctional catalyst, the reactivity
of which can be altered by changing the reaction conditions,
for example, through the use of additives or by changing the
temperature or pH. In recent years, external-stimuli-respon-
sive structural alterations (e.g., photoinduced ligand isomer-
izations)[4–10] that allow partial modification of the catalyst
reactivity have been shown to tune catalyst function, but this
approach is limited by the need for specific ligand design.
Instead of altering the molecular structure of the catalyst,
we envisioned that stimuli-induced alteration of its redox
potential could be an effective approach to control the
reactivity. Among different external stimuli, for example,
temperature or magnetic fields, visible light is of particular
interest since it is easily available and applied. Herein, we
report a strategy to control the reactivity of a redox-active
photocatalyst by regulating its redox potential using different
Figure 1. Light-color-selective generation of the redox active species
Rh-6GCÀ and Rh-6GCÀ*, which provide drastically different reduction
potentials for photocatalysis.
in the green and blue regions of the visible-light spectrum,
whereas Rh-6GCÀ absorbs significantly only in the blue region
(Figure 2 and Figure S2 in the Supporting Information).[12,13]
This provides access to different redox states of Rh-6G
through external control:
1) The excited state of Rh-6G (Rh-6G*) has a reduction
potential of ca. À0.8 V vs. SCE (see the Supporting
Information) in the absence of any electron donor
molecule under visible-light irradiation, irrespective of
the excitation wavelength.
[*] Dr. I. Ghosh, B. Kçnig
Universität Regensburg, Fakultät für Chemie und Pharmazie
93040 Regensburg (Germany)
E-mail: burkhard.koenig@ur.de
2) The ground-state reduction potential of the Rh-6GCÀ
radical anion, formed upon photoirradiation in the
presence of an electron donor (e.g., DIPEA) under
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602349.
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An application of this photocatalytic system is the
sequential activation of carbon–bromine bonds (see
Figure 1) in aromatic and heteroaromatic compounds for
À
C H arylation reactions. Irradiation of 1,3,5-tribromoben-
zene or 1,4-dibromo-2,5-difluorobenzene, aryl bromide sub-
strates with three or two bromine atoms, respectively, in
DMSO in the presence of Rh-6G and DIPEA (2.2 equiv) as
an electron donor, with green light (l = 530 nm) yields the
corresponding radical anions, which fragment with loss of
a bromide anion to generate aryl radicals.[21,22] Trapping of the
reactive intermediates with N-methylpyrrole and subsequent
rearomatization gives the monosubstitution products 1a and
2a in good yields. The reduction potential of Rh-6G (ca.
À1.0 V vs. SCE) is not sufficient under these reaction
conditions for subsequent activation of the remaining bro-
mide substituents, even with higher catalyst loading. How-
ever, if the reactions are performed under blue-light irradi-
ation (l = 455 nm), which increases the available reduction
power of the photoredox catalyst to ca. À2.4 V vs. SCE, the
reactions proceed to the two-fold-substituted products 1b and
2b. The two-fold-substituted products are obtained directly
by irradiating the reaction mixtures with l = 455 nm light
from the beginning. Representative examples of such sequen-
À
tial C H arylation reactions with commercially available aryl
bromide substrates with different trapping reagents are
depicted in Scheme 1. Most importantly, if a new reaction
partner for trapping of the aryl radical is added before the
irradiation wavelength is switched, two different substituents
are introduced sequentially in a controlled manner in one pot
(Scheme 1, sequential substitutions). 2,4,6-Tribromopyrimi-
dine, a commercially available substrate with a core structure
found in many biologically active compounds and drug
molecules,[23] was selectively functionalized depending on
the light color. Control experiments confirmed that Rh-6G,
DIPEA, and light irradiation are necessary for the catalytic
Figure 2. Spectroscopic investigation: A) Changes in the fluorescence
spectra (in this case intensity, lEx =455 nm) of Rh-6G upon the
addition of DIPEA in DMSO. Insets: Stern–Volmer quenching plot of
Rh-6G in the presence of DIPEA (i), and changes in the absorption (ii)
and fluorescence (iii) spectra of Rh-6G in the presence of DIPEA and
4-bromobenzonitrile (as the test substrate). Unchanged absorption
and fluorescence spectra of Rh-6G in the presence of DIPEA and 4-
bromobenzonitrile, respectively, demonstrate that Rh-6GCÀ accumulates
in the reaction mixture only in the presence of DIPEA upon photo-
irradiation. B) Formation of the Rh-6G radical anion upon photoirradia-
tion (lEx =455Æ15 nm) in the presence of DIPEA in DMSO under
nitrogen. Inset: generation of the Rh-6G radical anion with l=530-
(Æ15) nm irradiation. See the Supporting Information for further
spectroscopic investigation and larger versions of the inset graphics.
À
photoredox C H arylation reactions to proceed (see
Tables S1,S2 in the Supporting Information).
Functional groups with different reduction potentials are
selectively activated with Rh-6G in the presence of DIPEA
when using different light colors as an external control. The
reaction of ethyl 2-bromo-(4-bromophenyl)acetate,[24] which
requires the reduction potential of Rh-6GCÀ[14] to form the
radical in benzylic position, proceeds under green-light
irradiation, whereas the subsequent activation of the aryl–
bromide bond requires blue-light irradiation (see Table S3).
Similarly, aryl radicals are generated selectively by activating
the diazonium group (reduction potential ca. À0 V vs.
SCE)[25] of 4-bromobenzene diazonium tetrafluoroborate in
DMSO using photoexcited Rh-6G* in the absence of a base,
which leaves the aryl–bromide bond intact. Reaction of the 4-
bromoaryl radical with isopropenyl acetate gives 1-(4-bromo-
phenyl)-propan-2-one.[26] Blue-light irradiation of Rh-6G in
the presence of DIPEA leads to activation of the remaining
bromine substituent. The resulting aryl radical reacts with
pyrrole derivatives with sp2–sp2 carbon bond formation to
yield 8b and 8c. The excited-state redox potential of Rh-6G
(see Supporting Information for the estimated excited-state
reduction potential of Rh-6G)[14] is sufficient for the reduction
of diazonium salts[27] but not for the aryl bromide[21] (see
green-light irradiation, corresponds to ca. À1.0 V vs.
SCE.[14]
3) The excited-state reduction potential of the radical anion
Rh-6GCÀ* under blue-light irradiation[12,13] reaches more
than À2.4 V vs. SCE.
Such wavelength-dependent excitation of different redox
states of dye molecules, particularly for xanthene dyes, have
gained enormous importance in biological applications, for
example to control the non-fluorescent “dark-state” and
fluorescent “on-state” of a dye molecule in biomolecular
imaging.[12,13,15–17] However, to the best of our knowledge, it
has not been applied to control the selective activation of
chemical bonds in synthetic catalytic photoredox transforma-
tions[18–20] using visible light.
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À
Scheme 2. Photocatalytic C H arylation reactions. Reaction condi-
tions: starting material (in all cases the corresponding aryl bromide;
0.1–0.6 mmol), Rh6G (10–15 mol%), DIPEA, DMSO, 258C,
lEx =455 nm; reaction time 20–96 h; 5–25 equiv of the aryl radical
trapping reagent. The amount depends on the reactivity of the reagent;
1,1-diphenylethylene was found to be more reactive than pyrroles. For
detailed reaction conditions for all compounds, see the Supporting
Information. [a] Yield for 0.6 mmol scale (76%). [b] Incomplete con-
version of the starting material. [c] Addition product; the unsaturated
substitution product was obtained in only 7%.
reaction partners for substituted aryl bromides possessing
electron-withdrawing (e.g., -CN, -CO2Et, -COMe, -CF3, -Cl)
as well as electron-donating (e.g., -Me, -Ph, -OMe) groups.
The reduction potentials of aryl bromide substrates with
several electron-donating groups are too high to be reduced[21]
À
and define the limit of the method. However, the C H
arylation of N-methylpyrrole with 4-bromoanisole does
proceed, although with a low yield of isolated product.
Alkaloids such as b-nicotyrine and its derivatives
(entry 10m,n in Scheme 2) are obtained in good yields by
simply mixing commercially available 3-bromopyridine, trap-
ping reagents, Rh-6G, and DIPEA, followed by photoirra-
diation with visible light under nitrogen.
Scheme 1. Chromoselective one- and two-fold or sequential substitu-
tion reactions. [a] Yield of isolated product. [b] Yields in parenthesis
are based on the conversion of starting materials calculated by taking
the recovered isolated and quantified staring material into account.
[c] Yield of isolated product over two steps in one pot; starting
material is completely consumed, but monosubstituted products were
isolated (27% for 1b and 33% for 5b). [d] Incomplete conversion of
the monosubstituted intermediates. In the synthesis of compounds
7b, 8b,c and 9b, the intermediates 7a, 8a and 9a were isolated. All
other reactions were performed in one pot by changing only the light
source.
Based on spectroscopic and experimental results and
recent reports, we propose mechanisms for the photocatalytic
cycles involving Rh-6GCÀ and Rh-6GCÀ* as the active redox
species (Figure 3). For aryl bromides, a radical mechanism is
supported by the formation of products 7b,c and 10o in the
presence of the radical trap 1,1-diphenylethylene.[28] The Rh-
6GCÀ radical anion is not stable in the presence of oxygen
Table S3 for control reactions). The conversion of 1,3-
dibromobenzene into the corresponding aryl radical requires
the reduction power of the excited Rh-6GCÀ, but since the
activation of the second bromide of the resulting compound
(9a) is kinetically slower owing to the increased reduction
potential,[21] a stepwise sequential substitution with N-meth-
ylpyrrole and pyrrole is possible.
(Figure 2),[12,13] which leads to the inhibition of C H arylation
À
(entry 6 in Tables S1,S2). Upon photoexcitation with green or
blue light, Rh-6G takes an electron from DIPEA to give
+
a radical anion/radical cation pair: Rh-6GCÀ and DIPEAC .
À
Additional examples of C H arylation reactions with Rh-
The ground-state radical anion Rh-6GCÀ can activate aryl
bromide substrates with relatively low reduction potentials.
However, if the irradiation wavelength is set to l = 455 nm,
Rh-6GCÀ is excited again[12,13] and is able to activate aryl
6G photocatalysis under visible-light irradiation with bench-
stable aryl halides are shown in Scheme 2. Biologically
important pyrrole derivatives and styrenes are suitable
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How to cite: Angew. Chem. Int. Ed. 2016, 55, 7676–7679
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the neutral Rh-6G to complete the catalytic cycle. Fragmen-
tation of Ar BrC gives the aryl radical, which reacts with
unsaturated compounds to yield C C coupling products after
À
À
À
reoxidation and loss of a proton. In a competing pathway, the
aryl radical abstracts a hydrogen atom either from DIPEAC+
(see Section 6 in the Supporting Information) or from the
solvent DMSO to give the reduction products and diisopro-
pylamine, which were detected by gas chromatography mass
spectrometry (GC-MS) analysis of the crude reaction mix-
tures (Figure S28 in the Supporting Information).[22,29]
In conclusion, the reduction potential of the xanthene dye
Rh-6G can be tuned over a range of approximately 2.4 V by
changing the irradiation wavelength for excitation. This light-
color-guided formation of different redox states of Rh-6G
À
enables chromoselective C H arylations to yield functional-
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and bench-stable starting materials. The reaction conditions
are exceptionally mild and operationally simple, and the
functional-group tolerance is large. Rh-6G is commercially
available in kilogram amounts and enables economic photo-
redox catalytic reactions for the synthesis of complex
molecules, as well as late-stage functionalization of drugs
and pharmaceuticals under metal-free conditions.
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Acknowledgements
[29] The amount of the reduction product depends on the aryl halide.
À
We thank the Deutsche Forschungsgemeinschaft (GRK 1626)
for financial support, and Dr. R. Vasold and Ms. R. Hoheisel
for GC-MS and CV measurements, respectively.
Substrates with electron-withdrawing groups give mainly C
arylated products, whereas substrates with electron-donating
groups lead to reduction products in notable amounts.
H
À
Keywords: C H arylation · dyes · photocatalysis · radicals ·
radical anions
Received: March 7, 2016
Published online: May 20, 2016
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