A Redox-Active Nickel Complex that Acts as an Electron Mediator in Photochemical Giese Reactions

Article abstract of DOI:10.1002/anie.201814497

We report a simple protocol for the photochemical Giese addition of C(sp³)-centered radicals to a variety of electron-poor olefins. The chemistry does not require external photoredox catalysts. Instead, it harnesses the excited-state reactivity of 4-alkyl-1,4-dihydropyridines (4-alkyl-DHPs) to generate alkyl radicals. Crucial for reactivity is the use of a catalytic amount of Ni(bpy)₃²⁺ (bpy=2,2′-bipyridyl), which acts as an electron mediator to facilitate the redox processes involving fleeting and highly reactive intermediates.

Full text of DOI:10.1002/anie.201814497

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: A Redox Active Nickel Complex that Acts as an Electron Mediator
in Photochemical Giese Reactions
Authors: Thomas van Leeuwen, Luca Buzzetti, Luca Alessandro
Perego, and Paolo Melchiorre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814497
Angew. Chem. 10.1002/ange.201814497
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10.1002/anie.201814497
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Synthetic Photochemistry
A Redox Active Nickel Complex that Acts as an Electron Mediator in
Photochemical Giese Reactions**
Thomas van Leeuwen, Luca Buzzetti, Luca Alessandro Perego, and Paolo Melchiorre*
Abstract: We report a simple protocol for the photochemical Giese
addition of C(sp3)-centered radicals to a variety of electron-poor
olefins. The chemistry does not require external photoredox catalysts.
Instead, it harnesses the excited-state reactivity of 4-alkyl-1,4-
dihydropyridines (4-alkyl-DHPs) to generate alkyl radicals. Crucial
intermediates may suffer from short lifetimes and low electron-
transfer rates, thus rendering the SET interactions with other reagents
kinetically challenging.[8]
2+
for reactivity is the use of a catalytic amount of Ni(bpy)3 (bpy =
2,2’-bipyridyl), which acts as an electron mediator to facilitate the
redox processes involving fleeting and highly reactive intermediates.
T
he venerable field of photochemistry is re-gaining a central role in
synthetic endeavors.[1] For example, the fast-moving area of
photoredox catalysis is providing modern chemists with the
possibility of generating radical species under mild conditions and
from bench-stable reagents.[2] A more classical photochemical
approach exploits the ability of substrates or reaction intermediates to
harvest the energy of the photons and access an electronically excited
state (direct photochemistry). The chemical reactivity of excited
molecules[3] can then be used to unlock reaction manifolds
unavailable to conventional ground-state pathways. In this context,
our laboratory recently reported[4] how selective excitation with violet
light turns 4-alkyl-1,4-dihydropyridines (alkyl-DHPs, 1) into strong
reducing agents, which can activate reagents via single-electron
transfer (SET) manifolds while undergoing a homolytic cleavage to
generate C(sp3)-centered radicals (Figure 1a).[5] This dual
photochemical reactivity was used to trigger radical-based C-C bond-
forming processes.
Figure 1. (a) The excited-state reactivity of 4-alkyl-1,4-dihydropyridines (R-
DHPs, 1): on excitation, they become both photoreductants and precursors of
alkyl radicals. (b) Proposed strategy to realize the Giese reaction by combining
the photochemistry of 1 and the action of a catalytic nickel complex, which
facilitates the redox processes by acting as an electron mediator (EM); Ni(II)
rapidly oxidizes the short-lived, excited R-DHPs (1*) while the ensuing Ni(I)
species reduces the highly reactive intermediate A, which has a high tendency
to undergo side reactions. The overall sequence affords product 3.
In general, the direct excitation of substrates or intermediates can
create new synthetic opportunities for radical chemistry[3,6] while
bypassing the need for photoredox catalysts, which are often based
on precious transition-metals. However, there are some challenges
intrinsic to this photochemical strategy. The excitation of organic
molecules provides strong oxidants and/or reductants.
Thermodynamically speaking, this makes it easy to activate reagents
via an SET manifold.[7] However, these highly reactive excited-state
We recently wondered if electron mediators (EMs) could be used
to alleviate these limitations, thus expanding the synthetic
applicability of the direct photoexcitation approach. Electron
mediators have found widespread use in different areas of chemistry,
including dye-sensitized solar cells,[9] CO2 reduction,[10] and
electrochemical synthesis.[11] They have also been sporadically
applied in photoredox catalysis.[12] This is because, by acting as
electron shuttles, they can facilitate exergonic redox processes that
are kinetically slow. They can also mitigate the occurrence of a back-
electron transfer (BET) and competitive side-reactivity.
[]
Prof. Dr. P. Melchiorre
IIT - Istituto Italiano di Tecnologia
Laboratory of Asymmetric Catalysis and Photochemistry
via Morego 30 –16163, Genoa, Italy
Dr. T. van Leeuwen, Dr. L. Buzzetti, Dr. L. A. Perego, and Prof. Dr.
P. Melchiorre
However, to date, there has been little exploration of the potential
of EMs to accelerate a thermodynamically feasible but kinetically
unfavorable SET event involving the direct excitation of organic
intermediates. Herein, we demonstrate the feasibility of this strategy.
By combining the excited-state reactivity of alkyl-DHPs 1 with the
ability of a nickel complex to act as an electron mediator, we have
developed a Giese addition process[13] without the need for an
external photoredox catalyst.[14] Figure 1b details the idea behind our
synthetic plan: photoexcitation turns 1 into a strong reductant (1*).
The EM facilitates the SET oxidation of this short-lived electronically
ICIQ - Institute of Chemical Research of Catalonia
the Barcelona Institute of Science and Technology,
Avenida Països Catalans 16 – 43007, Tarragona, Spain
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/
[]
Financial support was provided by MICIU (CTQ2016-75520-P), the
AGAUR (Grant 2017 SGR 981), and the European Research
Council (ERC-2015-CoG 681840 - CATA-LUX).
1
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10.1002/anie.201814497
Angewandte Chemie International Edition
excited intermediate 1* to afford the radical cation 1•+, which
fragments into a carbon-centered radical (R·). Interception by the
electron-poor olefin 2 leads to intermediate A, which is a highly
reactive radical prone to side-reactions, including β-scission and
polymerization.[15] The reduced form of the EM rapidly engages in a
second SET, reducing intermediate A to B while bringing the EM
back to the original oxidation state. The SET reduction of A is critical
for an effective Giese reaction leading to product 3. Overall, the EM
provides a catalytic manifold to secure an efficient SET between 1*
and intermediate A. The EM acts as a reservoir for the electron
donated by 1*, prolonging its availability for the reduction of A.
These redox processes involve two short-lived intermediates, so they
would be problematic without EM.
SCE),[17b] had only a negligible effect (entry 3). We then turned our
attention to transition metal complexes. Based on the aforementioned
criteria, Ni(bpy)3(BF4)2 was identified as a promising EM.[18] This
readily available and bench-stable Ni(II) complex, which is soluble
in acetonitrile, is reduced at Ep(NiII/NiI) = −1.35 V vs. SCE,[19] and
absorbs weakly at 405 nm. Gratifyingly, 10 mol% of Ni(bpy)3(BF4)2
increased the yield of product 3a significantly (up to 85%, entry 4),
and secured full conversion of 1a and 2a. Further control experiments
showed that the reaction requires light, and does not proceed
thermally (entry 5). The yield of 3a was greatly diminished in the
presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 1 equiv.),
and we detected the adduct generated upon isopropyl radical trap
(53% yield, entry 6).
To validate our proposal, we studied the Giese-type radical
conjugate addition to dimethyl fumarate (2a) using 4-isopropyl-DHP
1a as the radical precursor (Table 1). We conducted our experiments
in CH3CN under irradiation by a single high-power light-emitting
diode (LED, λmax = 405 nm, see the Supporting Information for
details).
Having identified Ni(bpy)3(BF4)2 as a suitable EM, we evaluated
the synthetic potential of the photochemical Giese reaction (Figure 2).
We first demonstrated that a high efficiency was maintained when
running the reaction on a 2 mmol scale. This experiment required the
use of commercially available LEDs (see section B5 in the Supporting
Information) and it afforded product 3a in 78% yield (294 mg).
Concerning the reaction scope, a variety of α,β-unsaturated nitriles
and esters can be successfully functionalized using 4-isopropyl-DHP
1a as the radical precursor (products 3a-3f). We then explored the
possibility of using substrates 1 bearing alkyl fragments other than
isopropyl at the C4-position. Secondary alkyl (3g-h), benzyl (3i-j),
and α-heterosubstituted primary radicals are tolerated well in this
transformation. Noteworthy examples include the addition of α-
oxygen (3k-n) and α-nitrogen radicals (3o-t), which bring about the
facile introduction of synthetically interesting motifs such as
benzotriazoles (3s-t), phthalimides (3o-p), and dioxolanes (3k-l).
Appealing features of this protocol include the need for a slight excess
(1.5 equiv.) of the radical precursor 1. In contrast to other Giese
addition protocols, there is no need for stoichiometric amounts of
additional reagents, such as bases, reductants or hydrogen-atom
donors, or for photoredox catalysts.[14]
Table 1. Optimization and control experiments[a]
Entry
Conditions
Yield [%][b]
1
2
3
4
5
6
No mediator
32
57
p-Dicyanobenzene (0.2 equiv.)
Methyl viologen dichloride (0.2 equiv.)
Ni(bpy)3(BF4)2 (0.1 equiv.)
41
85
Same as entry 4, no light, 50 °C
<5
26[c]
Same as entry 4, TEMPO (1 equiv.)
We next conducted extensive mechanistic investigations to
clarify the role played by the nickel catalyst and to establish its ability
to act as an EM. The first crucial step of the mechanism proposed in
[a] Reactions performed at ambient temperature on a 0.1 mmol scale using 1.5
equiv. of 1a under illumination by a single high-power (HP) LED (λmax = 405 nm)
.
with an irradiance of 50 mW cm−2 [b] Yield determined by 1H NMR analysis of
the crude mixture using trichloroethylene as internal standard. [c] The TEMPO-
2+
Figure 1b requires Ni(bpy)3 to oxidize the excited state of DHP
(1a*). Based on UV-vis and electrochemical data, the redox potential
of 1a* (E (1a•+/1a*) was estimated to be −1.9 V vs. SCE according
to the Rehm-Weller approximation.[20] Therefore, the reduction of
trapped intermediate (TEMPO-iPr) was obtained in 53% NMR yield.
Performing the model reaction in the absence of an electron
mediator afforded product 3a in low yield, while a large amount of
reagents 1a and 2a remained unreacted (entry 1). We ascribed this
low reactivity to the inefficiency of the redox events underlying the
overall process.[16] We then tested our hypothesis that, by behaving
alternately as a donor and an acceptor, an EM could effectively shuttle
electrons between the key fleeting intermediates (1a* and the radical
of type A, Figure 1b). An effective EM must here meet several
requirements: (i) it should easily oxidize 1*; (ii) its reduced form
should selectively reduce intermediate A, but not substrate 2 or the
alkyl radical resulting from the fragmentation of 1*; and (iii) it should
not strongly absorb at 405 nm to avoid inner-filter effects.
In consonance with our design, the presence of organic EMs (20
mol%) substantially improved the efficiency of the Giese process. p-
Dicyanobenzene (Ep/2 (EM/EM•−) = −1.64 V vs. SCE)[17a] increased
the yield of 3a to 57% (entry 2), while another common redox
mediator, methyl viologen dichloride (E1/2 (EM2+/EM•+) = −0.41 V vs.
Ni(II) (Ep(NiII/NiI)
=
−1.35 V vs. SCE)[19] by 1a* is
thermodynamically feasible. We further investigated this
photoreduction using the following experiment: direct illumination of
a CH3CN solution of 4-isopropyl-DHP 1a at 405 nm in the absence
of the nickel (II) complex led to very low conversion of 1a into the
corresponding pyridine (Scheme 1a). The relative photostability of 1a
implies that the redox processes underlying the generation of the
isopropyl radical from 1a* are inefficient in the absence of an EM.
The addition of Ni(bpy)3(BF4)2 (10 mol%) greatly increased the
degradation of 1a (Scheme 1b). In this experiment, because of the
lack of an oxidation mechanism to regenerate the Ni(II) complex, we
observed the formation of Ni0 particles, which otherwise were never
observed during the progress of the catalytic reaction. When repeating
the experiment (Scheme 1c) in the presence of dimethyl fumarate 2a,
which provides a mechanism for regenerating the EM (see Figure 1b),
we recovered Ni(bpy)3(BF4)2 in 90% yield.
2
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10.1002/anie.201814497
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Figure 2. Survey of the electron-poor olefins 2 and the dihydropyridines 1 that can participate in the photochemical Giese addition. Reactions performed at 0.1 mmol
scale using 1.5 equiv. of 1; yields refer to isolated products 3 after purification (average of two runs per substrate). [a] Yields obtained in the absence of
Ni(bpy)3(BF4)2. [b] Conducted in a 1:1 CH3CN:CH2Cl2 (0.25 M) solvent mixture due to the low solubility of the corresponding radical precursor 1.
The identity of the nickel(II) complex, which crashed out from
the reaction mixture upon dilution with Et2O, was confirmed by UV-
vis and IR spectroscopy. In addition, the recovered Ni(bpy)3(BF4)2
was successfully reused to promote another Giese reaction, affording
product 3a in high yield (Scheme 1d).
based EM in the original oxidation state, is supported by the redox
potentials of the key intermediates involved (Scheme 2).
Scheme 1. Mechanistic experiments; NMR yields are reported.
Scheme 2. Redox potentials of the species involved in the proposed
mechanism.
Overall, the experiments detailed in Scheme 1 suggest that
Ni(bpy)3(BF4)2 can effectively mediate the SET oxidation of 1a* and
that its regeneration is only possible in the presence of olefin 2
(Schemes 1c and d). The latter observation is very relevant to the
overall mechanism (Figure 1b): to act as an effective EM, it is
essential that the Ni(I) complex reduces the highly reactive
intermediate A, emerging from the radical addition to 2. The
feasibility of this crucial redox step, which turns back the nickel-
The data in Scheme 2 indicate that the excited 1a* can reduce
Ni(bpy)32+. The resulting Ni(I) complex is not able to reduce typical
radicals generated upon fragmentation of 1a* (for example E1/2
(Bn•/Bn−) = –1.45 V[21] and Ecalc (iPr•/iPr−) = –2.42 V vs. SCE).[22]
However, it can easily reduce radicals α to electron withdrawing
groups, such as intermediate A. This mechanistic possibility is
3
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10.1002/anie.201814497
Angewandte Chemie International Edition
supported by the reduction potential of the radical resulting from the
addition of iPr· to 2a, estimated by DFT calculations (Ecalc (A•/A−) =
−0.54 V vs. SCE).[22] An alternative scenario, based on a self-
propagating radical manifold, could be envisaged in an SET reduction
of A from the ground state of 1a, but this pathway can be excluded
based on the redox potential of 1a (Ep/2 (1a+•/1a) = +1.04 V vs. SCE).
The quantum yield measured for the model reaction (Φ = 0.014) is
also incongruent with a radical chain process.
Scheme 4. Reactivity/wavelength correlation for substrate 4.
We also obtained evidence to support the intermediacy of the
anionic intermediate B, arising from the SET reduction of A (Scheme
2). We performed deuteration experiments by adding CD3OD to the
reaction medium. A high deuterium incorporation (>80%) was
observed at the α-carbon of product 3a (Scheme 3). No deuterium
incorporation took place at the β-carbon, indicating that deuteration
occurs solely via the in-situ-generated anion.
In conclusion, we have reported a photochemical strategy to
perform the Giese addition of C(sp3) radicals to a variety of electron-
poor olefin. Mechanistic investigations suggest that readily available
2+
Ni(bpy)3 acts as an electron mediator to facilitate the redox
processes between fleeting and highly reactive intermediates. These
findings could be relevant in the design of other photochemical
strategies based on the direct excitation of organic molecules or
intermediates. In addition, they may have mechanistic implications in
the context of the combination of nickel and photoredox catalysis,[23]
since nickel complexes could be involved in kinetically enhancing
electron-transfer processes.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Scheme 3. Deuteration experiments.
Keywords: dihydropyridines • electron mediator • photochemistry •
We deem it very unlikely that the reaction proceeds via the
intermediacy of organonickel species. The trapping of
photogenerated alkyl radicals with Ni complexes has been the subject
of recent studies.[23] While the majority of these procedures employ a
metal-to-ligand ratio of 1:1 or 1:1.5, the present chemistry works
when Ni is coordinatively saturated. The addition of extra bpy (up to
10 equiv. with respect to Ni(bpy)32+) did not result in a significant
drop of yield. Additional observations are incongruent with the
involvement of organometallic intermediates: (i) Ni(bpy)3(BF4)2 can
be recovered almost quantitatively at the end of the reaction and
reused; (ii) in situ monitoring of the reaction by the Evans NMR
method (see Section C5 in the Supporting Information for details)
reveals no significant change in the magnetic susceptibility of the
reaction mixture, suggesting that the resting state of the catalyst is
Ni(bpy)32+; (iii) organic electron mediators (Table 1, entries 2-3)
promote the model reaction in the absence of nickel.
nickel catalysis • synthetic methods
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[6] M. Silvi, P. Melchiorre, Nature 2018, 554, 41–49.
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We finally considered the possibility that Ni(bpy)32+ could act as
photoredox catalyst. The irradiation of the model reaction at 530 nm,
where only the Ni complex absorbs, did not result in the conversion
of 1a or the formation of 3a. This result is not surprising, given that
the electronic structure and photophysical properties of Ni(bpy)32+ (a
d8, high spin complex, paramagnetic) are very different from those of
2+
typical photoredox catalysts, including Ru(bpy)3 (d6 low spin,
diamagnetic).[2a] This is why the sporadic applications of nickel-based
photoredox catalysts have required meticulous engineering of the
ligands to ensure a low-spin Ni(II) centers in a square planar
coordination environment.[24] We also observed that, in consonance
with the notion that the reaction is triggered by direct excitation of
2+ [25]
alkyl-DHP 1 and not of Ni(bpy)3
,
the optimal irradiation
wavelength changes depending on the nature of the substrate. For
example, dihydropyridine absorbs at significantly shorter
4
wavelength (λmax = 323 nm) than esters 1 (λmax = 335 nm for 1a).
Irradiation at 405 nm does not promote the formation of the Giese
addition product 5 at all, while a high yield is obtained using a 365
nm LED (Scheme 4).
[8] a) Electron Transfer in Chemistry, (Ed: V. Balzani), Wiley-VCH,
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Electron Transfer, VCH Publishers, 1993.
[9] M. Grätzel, J. Photochem. Photobiol. C Photochem. Rev. 2003, 4,
145–153.
4
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10.1002/anie.201814497
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electrochemical data and according to the Rehm-Weller
approximation, see Section C3 of the Supporting Information.
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[19] P. N. Bartlett, V. Eastwick-Field, Electrochim. Acta 1993, 38, 2515–
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110, 132–137.
[22] Estimated by DFT computations at the B3LYP/6-
311++G(2d,2p)//B3LYP/6-31+G(d) level, with PCM solvation. See
the Supporting Information for computational details (Section D1) and
validation of the theoretical approach (Section D2).
[23] J. A. Milligan, J. P. Phelan, S. O. Badir, G. Molander, Angew. Chem.
Int. Ed. 2018, DOI: 10.1002/anie.201809431; Angew. Chem. 2018,
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[25] For additional mechanistic discussion, including triplet quenching
experiments, see the Supporting Information, Section C6.
[14] Previous methods for Giese-type additions required the use of an
external photoredox catalyst, see for examples: a) G. L. Lackner, K.
W. Quasdorf, L. E. Overman, J. Am. Chem. Soc. 2013, 135, 15342–
15345; b) L. Chu, C. Ohta, Z. Zuo, D. W. C. MacMillan, J. Am.
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2017, 56, 260–265; Angew. Chem. 2017, 129, 266 –271.
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H. Thang, Macromolecules 1999, 32, 7700–7702.
[16] The reduction of 2a (Ep/2 (2a/2a•−) = −1.39 V vs. SCE) by the excited
1a* is exergonic but apparently slow, given that only a fraction of 1a
and 2a reacted after 16 h of irradiation. The reduction potential of 1a*
was estimated to be −1.9 V vs. SCE based on UV-vis and
5
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10.1002/anie.201814497
Angewandte Chemie International Edition
Synthetic Photochemistry
Thomas van Leeuwen, Luca Buzzetti, Luca
Alessandro Perego, and Paolo Melchiorre*
__________ Page – Page
A Redox Active Nickel Complex that Acts as
an Electron Mediator in Photochemical Giese
Reactions
A time to get, and a time to lose electrons. Electron mediators can
alleviate limitations associated with the photochemistry of excited-state
intermediates, including short lifetimes and low electron transfer rates.
Here, the ability of a nickel complex to act as an electron shuttle assists
the excited-state reactivity of dihydropyridines 1 to enable a photochemical
Giese addition of C(sp3)-centered radicals to electron-poor olefins.
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