R ES E A RC H

◥ other mechanistic paradigms, Cu(I) and Cu(II)

REVIEW SUMMARY substrate complexes can be directly excited
with visible light to instigate cross-coupling
reactions and homolytic cleavage, respectively.
ORGANIC CHEMISTRY
Recently, the oxoazidation of vinyl arenes has
been developed in which a Cu(II) complex
Copper’s rapid ascent in visible-light simultaneously acts as electron-transfer and
◥
aerobic oxygen-transfer
ON OUR WEBSITE
photoredox catalysis Read the full article
agent, obviating the re-
quirement of any ex-
at http://dx.doi. ogenous oxidants. An
Asik Hossain*, Aditya Bhattacharyya*, Oliver Reiser† org/10.1126/ enantioselective alkyla-
science.aav9713 tion of imines has also
..................................................
been achieved, showcas-
BACKGROUND: The recent resurgence and species in a rebound process. The resulting ing the capacity of chiral photoactive copper
dramatic evolution of visible-light photo- transitory Cu(III) intermediate can undergo complexes to act as asymmetric/photoredox
redox catalysis has led to a paradigm shift reductive elimination to furnish cross-coupled bifunctional catalysts. Various copper salts
in organic synthesis that encompasses acti- products. Alternatively, the Cu(II) interme- have also been used as cocatalysts alongside
vation of small molecules, unconventional diate can exchange ligands with the radical iridium or ruthenium photocatalysts. Owing
modes of bond formation, and access to to form cross-coupled products. Following to the persistent radical effect (PRE) demon-
heretofore elusive reaction pathways. Exoge- this paradigm, the monoalkylation of pri- strated by copper, organic radical intermedi-

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nous photocatalysts undergo single-electron mary amines with sterically hindered electro- ates generated by the visible light–induced
or energy transfer from their excited states philes becomes possible, an elusive process by photocatalytic cycles are efficiently trapped
to generate open-shell intermediates at the metal center and get stabilized.
that can participate in nontraditional, Many photochemical cross-coupling re-
low-energy reaction pathways comple- actions that forge C–C, C–N, C–O, and
mentary to more conventional thermal, C–S bonds have been developed. Cop-
high-energy, two-electron processes. per can also be used as a Lewis acid to
These mechanisms undergird elegant activate C–C multiple bond function-
synthetic methodologies for the rapid alities. Enantioselective transforma-
yet controlled construction of value- tions such as cyanoalkylation of styrenes,
added products with desired molecular decarboxylative cyanation of alkyl car-
complexity. Ru(II) or Ir(III)-polypyridyl boxylic acids, and C(sp3)-H arylation
complexes and organic dye sensitizers and alkynylation of tetrahydroisoqui-
have been the chromophores of choice nolines have been developed by exploit-
owing to strong absorption, long excited- ing copper’s innate capacity to form
state lifetimes, and high redox poten- chiral tetrahedral complexes with poly-
tials. However, the cost and adverse dentate N,O/P-ligands.
environmental impact of these com-
pounds, as well as their restrictive OUTLOOK: Although copper is currently
conformational constraints (both with enjoying signal success in photoredox
respect to inner-sphere substrate in- catalysis, a number of challenges re-
teractions and chiral ligand design for main to be addressed that warrant ex-
asymmetric transformations), limit their ploration of the oxidizing potential of
applications. Given the imperative need copper photocatalysts involving Cu(II)*
to develop ecologically benign, cost- to Cu(I) or Cu(I)* to Cu(0) transitions,
effective, multipurpose, and flexible further prolongation of the excited-
catalytic systems, copper has emerged state lifetime through sophisticated
as an appealing complement. Copper- Applications of copper in photoredox catalysis. ligand design, and enhancement of
based photocatalysts display highly scale-up efficiency. Broader use of cop-
tunable redox properties in their ex- per photocatalysts in asymmetric trans-
cited states, accommodate flexible ligand way of the classical nucleophilic substitution formations will enhance their value for the
architecture, allow stereoinduction, and offer approach. Alternatively, nucleophiles such as synthesis of drugs and natural products. The
multiple accessible oxidation states to achieve chlorosulfonyl anion or fluoride can be deliv- prospects are limited only by the ingenuity
rapid radical capture or facile reductive elim- ered to carbon-centered radicals. The redox underlying the design of catalytic reaction
ination, exerting exquisite control over the
photoredox processes occurring in their inner
potential of copper photocatalysts is highly
tunable with ligand variation in a broad array
prototypes.
▪
coordination sphere. of synthetically accessible homoleptic or
heteroleptic complexes. Sauvage’s complex
Institut für Organische Chemie, Universität Regensburg,
ADVANCES: Conspicuous features of Cu(I) {[Cu(dap)2]Cl} and other copper-based com- Universitätsstraße 31, 93053 Regensburg, Germany.
photocatalysts include the generation of plexes have found widespread applications *These authors contributed equally to this work.
radical species through the reduction of or- in photo-induced transformations, such as †Corresponding author.
Email: oliver.reiser@chemie.uni-regensburg.de
ganic substrates upon photoexcitation and bifunctionalization of olefins and various Cite this article as A. Hossain et al., Science 364, eaav9713
capture of the incipient radical and/or anionic C–C and C–N cross-coupling reactions. In (2019). DOI: 10.1126/science.aav9713

Hossain et al., Science 364, 450 (2019) 3 May 2019 1 of 1

R ES E A RC H

◥ labile ligands remains a substantial challenge.

REVIEW Catalysts that can straightforwardly direct pho-
toredox processes in their inner sphere, and
thereby control reactions through their ligand
ORGANIC CHEMISTRY environment, are desirable in this context. First-
row transition metal complexes hold the prom-

Copper’s rapid ascent in visible-light ise to meet this requirement (7). Consequently,
considerable advancements have been attained
by merging conventional Ir- or Ru-based photo-
photoredox catalysis catalysts with various nickel(II) salts or com-
plexes that are capable of effecting oxidative
addition to aryl, vinyl, and alkyl halides, leading
Asik Hossain*, Aditya Bhattacharyya*, Oliver Reiser†
to C- or N-arylation, -olefination, and -alkylation
(8). However, with very recent discoveries cop-
Visible-light photoredox catalysis offers a distinct activation mode complementary to
per has now come to the fore in the arena of
thermal transition metal catalyzed reactions. The vast majority of photoredox processes
photocatalysis (9), owing to its versatile redox
capitalizes on precious metal ruthenium(II) or iridium(III) complexes that serve as
characteristics that make it capable both of ini-
single-electron reductants or oxidants in their photoexcited states. As a low-cost alternative,
tiating a reaction by means of single electron
organic dyes are also frequently used but in general suffer from lower photostability.
transfer as well as directly interacting with sub-
Copper-based photocatalysts are rapidly emerging, offering not only economic and
strates in its coordination sphere. Moreover,
ecological advantages but also otherwise inaccessible inner-sphere mechanisms, which
copper complexes are highly dynamic; various
have been successfully applied to challenging transformations. Moreover, the combination
heteroleptic complexes with N- and P-based

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of conventional photocatalysts with copper(I) or copper(II) salts has emerged as an
multidentate ligands (Fig. 1) can be readily syn-
efficient dual catalytic system for cross-coupling reactions.
thesized to tune redox properties and enhance

T
excited-state lifetime (10–12). Here, we chron-
he recent resurgence and dramatic evo- orientation hinder their capacity to undergo icle the inception and evolution of copper as a
lution of visible-light photoredox cataly- oxidative addition with organic substrates. In visible-light photoredox catalyst.
sis has led to a paradigm shift in organic addition, although stereoselective transforma-
synthesis (1–3). The inventive yet intricate tions have been elegantly developed through Cu(I) complexes as standalone
design principles, accompanied by prac- the use of Ir- or Ru-based photocatalysts with photocatalysts
tical technological developments for ease of prefunctionalized substrates (6), synthesizing In 1977, McMillin et al. synthesized [Cu(dmp)2]BF4
implementation, have allowed chemists to acti- the appropriate chiral octahedral complexes with (dmp = 2,9-dimethyl-1,10-phenanthroline), which
vate small molecules, to contrive unconventional
modes of bond formation, and to access here-
tofore elusive reaction pathways by efficiently Fig. 1. Representa-
converting photonic energy into chemical energy. tive varieties
In order to circumvent the incapacity of small of commonly
organic molecules to absorb in the visible-light employed racemic
region of the electromagnetic spectrum, various and chiral ligands
external chromophores have been induced to for copper-based
undergo single-electron transfer (SET) or energy photocatalysts.
transfer processes from their photoexcited states,
generating radical species upon reduction or oxi-
dation of organic substrates. In turn, these inter-
mediates participate in nontraditional reaction
pathways complementary to common thermal
two-electron processes (4, 5). For this purpose,
appropriately ligated heavy transition-metal
catalysts such as Ru(II) or Ir(III)-polypyridyl
complexes or metal-free organic dye sensitizers
have been most commonly used, owing to their
favorable characteristics such as long excited-
state lifetimes, strong absorption in the visible
region, and high reduction or oxidation poten-
tials of the corresponding excited states (3).
However, organic dyes generally suffer from
lower photostability, and heavy transition metal–
based complexes are expensive as well as envi-
ronmentally unfriendly. Moreover, the high
oxidation states of conventional Ir- or Ru-based
photocatalysts and the inflexibility of their ligand

Institut für Organische Chemie, Universität Regensburg,

Universitätsstraße 31, 93053 Regensburg, Germany.
*These authors contributed equally to this work.
†Corresponding author. Email: oliver.reiser@chemie.
uni-regensburg.de

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R ES E A RC H | R E V IE W

can be excited at 454 nm; the resulting metal-to- 2,9-bis(p-anisyl)-1,10-phenanthroline; Ered = heteroleptic Cu(I)-phenanthroline-bisphosphine
ligand charge transfer (MLCT) state can reduce –1.43 V versus saturated calomel electrode (SCE) complexes (16) and palladium-free Sonogashira
Co(III) in K[cis-Co(IDA)2]·1.5H2O to the corre- in CH3CN], was shown to induce reductive cou- couplings by means of light-activated copper(I)-
sponding Co(II) complex (13). A decade later, pling of nitrobenzyl bromide to the correspond- alkyne complexes (17), set in motion the recent
Sauvage introduced an ingeniously designed ing bibenzylic coupling product. Surprisingly, proliferation of studies involving Cu(I)- and Cu(II)-
Cu(I) complex that rigidly confined the copper this catalyst went into hibernation until it was complexes as effective visible-light photocatalysts.
ion within the concave portions of two crescent- resuscitated in 2012 for a C–C bond-forming The general mechanistic paradigm of Cu(I)Ln
shaped phenanthroline ligands, considerably en- atom transfer radical addition (ATRA) transfor- complexes as standalone photocatalysts is de-
hancing the lifetime of its MLCT excited state mation (15). That study, along with concurrent picted in Fig. 2A. Upon excitation with visible
(≤270 ns) (14). The complex, [Cu(dap)2]Cl [dap = reports on electrocyclic 6p-reactions catalyzed by light, an appropriately ligated Cu(I)Ln complex

A Fig. 2. Cu(I) complexes as

standalone photocatalysts.
(A) The mechanistic paradigm of
Cu(I) photocatalysts for cross-
coupling reactions is depicted.
The transformation can proceed
either by means of a Cu(I)/Cu(II)
catalytic cycle involving sequen-
tial elementary steps—namely,
SET, ligand exchange, and ligand

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transfer—or a Cu(I)/Cu(II)/Cu(III)
catalytic cycle involving SET-
radical rebound, ligand exchange,
and reductive elimination steps
to yield the cross-coupled
product. L, ligand; R-X, electron-
accepting substrate (X = leaving
group); Nu, nucleophile; and
LED, light-emitting diode.
(B and C) Mechanistically
distinct copper-photocatalyzed
olefin-bifunctionalization
processes. OTf, Triflate.
B a
In the presence of 10 mole %
[Ru(bpy)3](PF6)2 photocatalyst
(yield in parenthesis).

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R ES E A RC H | R E V IE W

transfers a single electron to an electron-accepting that transfers the newly coordinated nucleophile to deliver the desired cross-coupled product
substrate, producing a radical species (R•) [which to R• to furnish the cross-coupled product (R–Nu) (R–Nu) and regenerate the initial Cu(I)Ln com-
can further be intercepted by an alkene or alkyne, and reverts to the initial Cu(I)L n complex by re- plex with L.
resulting in a more nucleophilic radical species uniting with the previously departed ligand (L);
(R′•)] and a transient Cu(II)Ln intermediate. At this and (ii) the incipient radical (R•) can rebind to the Bifunctionalization of olefins
stage, two possibilities emerge: (i) The Cu(II)Ln Cu(II)Ln intermediate to generate a high-valent A wide range of functionalities can coordinate
intermediate can exchange a ligand (L) with R-Cu(III)-Ln intermediate (18) that exchanges to the Cu(II)-intermediate generated by means
an incoming nucleophilic cross-coupling part- a ligand with Nu to form R-Cu(III)L(n−1)-Nu, of SET from the photoexcited Cu(I)*, and con-
ner (Nu) to generate a Nu-Cu(II)L(n−1) intermediate which undergoes facile reductive elimination sequently, the process of ligand transfer to the
intermediate radicals gets accelerated in vari-
ous ATRA reactions. The first such example was
A demonstrated in 2015 with the development of
vicinal trifluoromethylation/chlorosulfonylation
of olefins (Fig. 2B, i). Cognizant of the impor-
tance of fluorinated and trifluoromethylated
organic compounds in the pharmaceutical sec-
tor (19), when unactivated olefins were exposed
to triflyl chloride (CF3SO2Cl) in the presence
of 1 mole % [Cu(dap)2]Cl, the corresponding
trifluoromethyl-chlorosulfonylated products were
obtained in high yields (20), contrasting with
[Ru(bpy)3]Cl2, which yielded trifluoromethyl-

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chlorinated products (21). The formation of the
unexpected sulfonylchloride was attributed to
coordination between the chlorosulfonyl anion,
which is generated upon mesolysis of triflyl chlo-
ride after single-electron reduction by excited-
state [Cu(dap)2]Cl and the concurrently formed
Cu(II)-center. In a similar vein, the iodoper-
fluoroalkylation of styrenes fails with common
ruthenium or iridium-based photocatalysts but
proceeds efficiently with [Cu(dap)2]Cl, suggest-
B ing the intermediacy of an iodine-transferring
[CuII(dap)ClI] species (Fig. 2B, ii) (22). Along these
lines, Yu, Li, and co-workers have recently demon-
strated a remarkable fluorine atom-transfer (FAT)
capability of an innovative Cu(II)-F complex to ef-
ficiently promote carbofluorination of unactivated
olefins (Fig. 2B, iii) (23). The reaction proceeds in
the presence of CsF as the F-source, Umemoto’s
reagent, 5-(trifluoromethyl)dibenzothiophenium
tetrafluoroborate, as the CF3-source, and Cu(OTf)2
as the catalyst, with the assistance of two ligands:
bathocuproine (BC) to reduce Cu(II) to Cu(I) and
electron-deficient 4,4′-di(methoxycarbonyl)-2,2′-
bipyridine (bpydc) to accelerate FAT from the
LCu(II)-F complex. A similar dicopper complex has
been synthesized by Fu, Peters, and co-workers to
effect the transfer of a thiotrifluoromethyl (SCF3)
group in a three-component reaction between
electrophiles, olefins, and trifluoromethylthiolate
(Fig. 2B, iv) (24). The process is initiated with the
photoexcitation of a CuI(BINAP)(SCF3) complex
that reduces the electrophile, which is intercepted
by an olefin to generate a more nucleophilic
alkyl radical. Meanwhile, the newly formed
[CuII(BINAP)(SCF3)]2 complex effectively trans-
fers an SCF3 group to this radical species to
furnish the targeted trifluoromethyl thioether
with concurrent regeneration of the initial CuI-
complex with the SCF3 source.
Whereas all previously discussed examples
Fig. 3. Cu(I) complexes as standalone photocatalysts: Synthetic applications in carbon- can be explained either by ligand transfer or
heteroatom cross-coupling reactions. The mechanistic paradigms are similar to Fig. 2A. (A) Evolution rebound/reductive elimination of Cu(II) spe-
of copper in UV light–mediated photoreactions by means of a radical pathway. (B) Visible light– cies with a SET-generated radical, the three-
mediated reactions. W, watt; CFL, compact fluorescent light bulb; DBU, 1,8-diazabicyclo[5.4.0]undec-7- component cross-coupling protocol reported
ene; BTTP, tert-butylimino-tri(pyrrolidino)phosphorane. by Xiao and co-workers involving redox-active

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R ES E A RC H | R E V IE W

cycloketone oxime esters, styrenes, and aryl bo- mary aliphatic amines circumventing usual syn- amines with unactivated secondary alkyl iodides
ronic acids provides a strong case for the in- thetic problems such as overalkylation and steric for the exclusive synthesis of the corresponding
termediacy of Cu(III) species by means of a encumbrance. The same groups used a photo- mono-alkylated amine derivatices under mild
rebound pathway (Fig. 2C, i) (25). The proposed active Cu(I)-binaphtholate complex to mediate reaction conditions (Fig. 3B, iii) (33). The rac-
mechanism involves photoexcited Cu(I)(dtbbpy)– the desired cross-coupling between the primary BINOL ligand was found to be essential in this
catalyzed SET-assisted formation of a cyanoalkyl
radical that reacts with an olefin to generate
another intermediate radical. Simultaneously, A
the newly formed Cu(II) species undergoes trans-
metalation with aryl boronic acid to form an
aryl-Cu(II) intermediate; it subsequently cap-
tures the intermediate radical to form a new
aryl-Cu(III)(alkyl) species that undergoes re-
ductive elimination to yield the cross-coupled
product.

C(sp3/sp2)- heteroatom cross-coupling

A seminal report by Fu and Peters (26) in 2012
disclosing an ultraviolet (UV) light–mediated rad-
ical variant of the Ullmann C–N cross-coupling
protocol between a copper-carbazolide complex
and aryl halides and a succeeding report describ-

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ing the extension of the chemistry to alkyl electro-
philes (27) paved the way for developing various
other UV light–induced copper-catalyzed carbon-
B
heteroatom coupling reactions (Fig. 3A, i). The
authors have subsequently demonstrated that
other heteroatomic nucleophiles such as thio-
phenols (Fig. 3A, ii) (28) and phenols (Fig. 3A,
iii) (29) can also be viable coupling partners in
C(sp2)–S and C(sp2)–O cross-coupling reactions
advancing by means of the intermediacy of UV
light–absorbing Cu(I)-nucleophile species such
as [Cu(SPh)2]–, [Cu2(SPh)3]–, and [Cu(OPh)2]–,
respectively.
Shifting the classical pathway of nucleophilic
substitution to a radical regime under visible-
light irradiation conditions provides remark-
able solutions to longstanding challenges for
the (asymmetric) synthesis of amines, as pro-
gressively addressed by the pioneering contri-
butions from the groups of Peters and Fu. An
enantioconvergent cross-coupling of racemic
tertiary a-chloroamides with carbazoles and
indoles could be achieved in the presence of a
Cu(I)/Nu/(S)-SITCP complex (Nu = carbazole
or indole) that acts both as a photocatalyst and
as the source of enantioinduction (Fig. 3B, i)
(30, 31). The commercially available chiral
phosphine ligand (S)-SITCP controls the abso-
lute configuration of the products regardless of
the initial stereochemistry of the electrophiles.
A mechanistic inquest indicated toward the
plausible intermediacy of a photoactive {Cu(I)-
[(S)-SITCP]2-carbazolide} complex. Hence, with
a view to generalizing the protocol, a novel
tridentate bisphosphine/carbazolide ligand-
containing [Cu(CbzdiphosiPr )] photocatalyst was
later prepared and used in combination with
CuBr to accomplish C–N cross-coupling between
unactivated secondary alkyl halides and carba- Fig. 4. Cross-coupling reaction by means of photoexcitation of in situ–generated Cu(I)-
mates in an “out-of-cage” process (Fig. 3B, ii) (32). substrate complexes. (A) In situ–generated Cu(I) substrate complexes reduce an electrophilic
The use of Ru- or Ir-based photocatalysts instead coupling partner upon irradiation with visible light as a starting point for cross-coupling. FG,
of the aforementioned Cu(I) photocatalyst led to functional group; X, counter anion; EA, electron acceptor. (B) A few representative examples of the
<1% formation of the desired product. synthetic methodologies developed on the basis of this concept are shown, though (vi) differs in
The scope of nitrogen-containing cross-coupling that the in situ–formed [Cu(NCS)2]– complex acts as a sensitizer in the excited state and as a Lewis
counterpart could be further extended to pri- acid in the ground state. OAc, acetate.

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R ES E A RC H | R E V IE W

reaction. According to the proposed reaction with the Cu(II)-amine species, and subsequent esters are being widely exploited as superior
mechanism, the photoexcited Cu(I)/BINOL com- cross coupling furnishes the desired product. sources of alkyl radicals through a SET-reduction-
plex undergoes SET to generate an alkyl radical From the perspective of sustainability, carbox- decarboxylation process, leading to the devel-
and a Cu(II)/BINOL species that, upon ligand ylic acids are a more abundant, stable, and less opment of a wide variety of decarboxylative
exchange with an amine, forms the key Cu(II)- toxic chemical feedstock in comparison with cross-coupling methodologies (34). This prin-
amine species. Then, the alkyl radical combines alkyl halides. N-(hydroxy)phthalimide (NHPI) ciple was exploited for a decarboxylative C–N

A B

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C

Fig. 5. Photocatalysis with Cu(II) complexes (LMCT excitation). (A) Z, nucleophile; Y, heteroatom. Key steps are (B) [Cu(II)-N3]-species excitation.
(C) [Cu(II)-alkyl]-species excitation. Ar, 4′-(OMe)C6H4; X, counter anion.

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R ES E A RC H | R E V IE W

A coupling as an azide-free alternative to the Curtius

rearrangement (Fig. 3B, iv) (35). NHPI-esters
in the presence of a Cu(I) photocatalyst offered
a route to protected amines by means of initial
SET from a photoexcited Cu(I)/dmp/xantphos
complex to form a Cu(II) species and the radical
anion of the NHPI ester. Fragmentation produces
an alkyl radical, CO2, and the phthalimide anion,
which binds to Cu(II). The recombination of
the alkyl radical with this Cu(II)-phthalimide
species and subsequent cross coupling affords
the desired product, with regeneration of the
Cu(I) catalytic species.

Photoexcitation of in situ–generated
Cu(I) substrate complexes
B A mechanistically distinct class of reaction mani-
folds specific to copper has emerged in which suit-
able substrates can form visible light–absorbing
complexes by coordinating to Cu(I), obviating
the use of exogenous ligands. The excited Cu(I)
substrate complex reduces an electrophile by

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means of a SET process, and the resulting Cu(II)
substrate complex then participates in a diverse
range of synthetic transformations, including
cross-coupling reactions and functional group
modifications (Fig. 4A). By capitalizing on this
concept, Hwang and co-workers developed a
visible light–mediated, high-yielding Sonogashira
cross-coupling reaction between aryl halides and
alkyl- or aryl-substituted terminal alkynes in the
presence of catalytic amounts of CuCl (17).
This group has also applied this concept to a
three-component coupling of anilines, terminal
alkynes, and benzoquinones to regioselectively
synthesize functionalized indoles (Fig. 4B, i)
(36). The transformation advances with the in
situ formation of a Cu(I)-phenylacetylide species
that, upon excitation by blue LEDs, reduces ben-
zoquinone through SET (−2.048 V versus SCE
in CH3CN) to enable further reactions with
aniline. The visible light–absorbing properties
of Cu-acetylide species have also been applied
to denitrogenative oxidative C(sp2)–C(sp) cou-
pling between hydrazinylpyridines and terminal
alkynes (37), oxidative C–N coupling of anilines
with terminal alkynes to synthesize a-ketoamides
(38), oxidative C–N coupling of 2-aminopyridine
with terminal alkynes via C–C triple bond cleav-
age (39), and oxidative C(sp)–C(sp) homo and
cross-coupling of terminal alkynes (40, 41). An
intriguing example of this strategy entailed the
coupling of phenols and terminal alkynes in the
presence of molecular oxygen to produce aryl and
alkyl ketones. According to the proposed mechanism,
the excited state of the in situ–generated Cu(I)-
acetylide species reduces molecular oxygen through
SET to generate a Cu(II)-acetylide species and a su-
peroxide radical anion. Simultaneously, phenol is
also converted to benzoquinone by the Cu(II)-
superoxo intermediate. Sequential Paterno-Buchi-
type [2+2] cycloaddition of Cu(II)-phenylacetylide
Fig. 6. Cooperative photoredox dual catalysis. (A) The general mechanistic pathways are and benzoquinone, oxetane ring–opening, frag-
shown. The radical capture by Cu(II) species gives rise to a high-valent Cu(III) intermediate that mentation, formation of a peracid species, CO2
undergoes facile reductive elimination to furnish the cross-coupled product. (B) A series of extrusion, and keto-enol tautomerism furnish
nonstereoselective transformations involving C–C and C–N bond formations are shown. The wide the aryl ketone product (Fig. 4B, ii) (42, 43). By
variety of organic radicals captured by Cu(II) intermediates is highlighted. contrast, the coupling between phenylacetelyne

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R ES E A RC H | R E V IE W

and aliphatic alcohols in the presence of oxy- of an iminium species, which gets trapped by tion by ground state Cu(NCS)2–, is activated for
gen, stoichiometric 2-picolinic acid, and cata- Cu(I)-phenylacetylide to produce the desired the subsequent coupling with thiocyanide to
lytic copper(I) iodide furnished a-keto esters in product. Lalic and co-workers found that catalytic give rise to 2-aminothiazole derivatives.
high yields (44). Very recently, a CuCl-catalyzed amounts of CuCl in combination with a substi-
three-component reaction between N-alkylanilines, tuted terpyridine ligand can modulate the reac- Cu(II) complexes as standalone
terminal alkynes, and primary alcohols in the tivity of the photoexcited Cu(I)-acetylide complex photocatalysts
presence of stoichiometric benzoquinone as an to achieve the coupling of unactivated alkyl Very recently, the successful applications of
oxidant to furnish propargylamines is reported iodides and terminal alkynes (Fig. 4B, iv) (46). Wu Cu(II) complexes as visible light photoredox
by the same group (Fig. 4B, iii) (45). The photoex- and co-workers have reported a C–H functional- catalysts have been reported. Following the semi-
cited Cu(I)-phenylacetylide reduces benzoquinone, ization protocol in which Cu(II) salts can bind nal work of Kochi and co-workers, who dem-
and then the corresponding radical anion spe- 2-arylaminoacetates for the in situ formation of onstrated that CuCl2 undergoes homolysis to
cies triggers a hydrogen atom transfer process Cu(I) intermediates that can be excited with Cu(I)Cl and Cl• upon UV irradiation (49), the
with a primary alcohol to generate an a-oxy rad- visible light to promote the alkylation of enolates activation of Cu(II)X2 complexes endowed with
ical. It undergoes a radical-radical cross-coupling (Fig. 4B, v) (47). In situ–generated Cu(NCS)2– can suitable ligands to redshift absorption into the
with aminyl radical cation previously generated play the dual role of a photocatalyst and a Lewis visible region can produce radicals X• that ini-
upon ligand-to-metal charge transfer (LMCT) acid, as exploited by Liu and co-workers (Fig. tiate productive organic transformations (Fig. 5A).
excitation of a Cu(II)-amine species. Subsequent 4B vi) (48). Energy transfer from photoexcited Thus, rather than MLCT states fundamental to
intramolecular proton-transfer followed by elimi- Cu(NCS)2¯* to a vinyl azide effects rearrangement photoexcitation of Cu(I) complexes, Cu(II) com-
nation of water molecule results in the formation to an azirine intermediate that, upon coordina- plexes react from LMCT states (50, 51), which
oxidize the anionic nucleophile.
Following this concept, the synthesis of azido
ketones from vinyl arenes, TMSN3, and oxygen

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A was developed by use of the copper(II) complex
[Cu(dap)Cl2] as photoredox catalyst (Fig. 5B) (52).
The Cu(II) complex undergoes ligand exchange
with azide to give rise to a new LCu(II)azide-
bridged dimer. Upon visible light–induced ho-
molysis (VLIH), LCu(I) and an azido radical are
formed, and the latter can be intercepted by an
alkene followed by molecular oxygen. Rebound
of the O-centered radical with LCu(I) regenerates
the LCu(II) species, which upon elimination re-
leases the product and closes the catalytic cycle.
A second, notable example was reported shortly
after by Gong and co-workers (Fig. 5C) (53). In this
case, a chiral Cu(II)-bisoxazoline complex is alkyl-
ated through transmetallation from the corre-
sponding trifluoroborate salt, and once again, VLIH
generates an alkyl radical and a Cu(I) intermediate.
In a second catalytic cycle, this alkyl radical adds
to the substrate—here, a protected imine that is
activated by the same chiral Cu(II)-bisoxazoline
B complex. The newly generated N-centered radi-
cal is reduced by the previously formed Cu(I)
species in the first cycle to release the alkylated
imine with high enantioselectivity.
Very recently, [Cu(dap)Cl2] has been success-
fully used in a photochemical ATRA reaction be-
tween sulfonyl chloride and olefins (54). In line
with Kochi’s proposal, VLIH of LCu(II)–Cl bond
generates LCu(I) species for reduction of sulfonyl
chlorides. The presence of stoichiometric amount
Na2CO3 is necessary when unactivated olefins
(such as allylbenzene) are subjected to the afore-
mentioned reaction, in contrast to activated olefins
(such as styrene), for which no additive is required.
The role of Na2CO3 is proven to prevent the cat-
alyst poisoning during the reaction in case of a
less efficient radical trapping through the un-
activated alkene substrate.
Another report by Yuan and co-workers (55)
discloses the ability of CuCl2 salt to form photo-
active species with solvents (namely, acetonitrile
Fig. 7. Mechanistic paradigms are similar to Fig. 6A. (A) Efficient mergers of radical-capture or acetone), which can efficiently convert benzyl
and asymmetric induction by chiral Cu-complexes have been demonstrated. (B) Cross-coupling alcohol to benzaldehyde in the presence of molec-
through decarboxylation from Cu(II)-carboxylate intermediates has been demonstrated. BTMG, ular oxygen. Detailed mechanistic studies sug-
2-tert-butyl-1,1,3,3-tetramethylguanidine. gest that molecular oxygen helps only in the

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photocatalytic cycle by Cu(II)L(n−1)Z and forma-

A
tion of the high-valent transient Cu(III)R1L(n−1)Z
species; and (v) collapse of Cu(III)R1L(n−1)Z through
reductive elimination to generate the cross-coupled
product and to regenerate the initial Cu(I) spe-
cies to close the copper-catalytic cycle (Fig. 6A).
The carbophilic nature of copper allows access to
various Cu–C species, such as Cu-aryl and Cu-alkyl,
that in turn translate to several cross-coupling
strategies with the formation of a wide variety of
vital bonds, such as C(sp2)–C(sp3), C(sp2)–C(sp2),
C(sp3)–N(sp2), C(sp3)–N(sp3), C(sp3)–O, C(sp3)–
C(sp), and C(sp3)–C(sp3).
In a pioneering study published in 2012, Sanford
and co-workers revealed a mild synthetic method
for the preparation of perfluoroalkylated (hetero)
B aromatic compounds by the cross coupling of
(hetero)aryl boronic acids and perfluoroalkyl
iodides in the presence of [Ru(bpy)3]Cl2·6H2O
as the photocatalyst and copper(I) acetate as
the C(sp2)–C(sp3) bond-forming catalyst (Fig.
6B, i) (56).

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Although high-valent Cu(III) species undergo
facile reductive elimination, oxidative addition
of carbon-halogen bonds to low-valent Cu(I)
species was a longstanding problem in copper
C chemistry that had barred the widespread use
of Cu as an efficient cross-coupling catalyst.
MacMillan and co-workers have provided an ex-
cellent work-around by developing an efficient
cross-coupling strategy between aryl bromides
and a trifluoromethylating agent in the presence
of an Ir-based photocatalyst and copper cocatalyst
(57). The transformation proceeds through the
D initial formation of a reactive silyl radical from
tris(trimethylsilyl)silanol that abstracts bromine
from aryl bromide to generate an aryl radical.
Meanwhile, the Cu(I) complex combines with the
CF3 radical generated from the trifluoromethylat-
ing agent during the closure of the Ir-photocatalytic
cycle and forms a Cu(II)CF3 complex, which cap-
tures the aryl radical to subsequently reductively
eliminate the trifluoromethylated arenes in ex-
cellent yields (Fig. 6B, ii).
A different mechanistic manifestation of re-
ductive elimination from Cu(III) species has been
reported by Glorius and co-workers, entailing de-
carboxylative olefination of primary carboxylic
acids to produce terminal alkenes (58). Redox-
active esters were reduced by the excited photo-
Fig. 8. Miscellaneous roles of copper in photoredox catalysis. DEBM, diethyl bromomalonate; catalyst, and after the extrusion of carbon dioxide,
QUINAP, 1-(2-diphenylphosphino-1-naphthyl)isoquinoline. the corresponding alkyl radical was generated
and subsequently captured by the Cu(II) complex.
The newly formed Cu(III)alkyl species underwent
regeneration of the catalyst but does not act mediates display a wealth of prospective follow- b-hydride elimination to generate the desired
as a source of oxygen in benzaldehyde. up chemistry. The mechanistic paradigm involves terminal olefin in high yields concurrent with
the following generic steps (irrespective of order): regeneration of the Cu(I) complex, which was
Cooperative photoredox-copper (i) exogenous excited-state photocatalyst-assisted subsequently oxidized to the initial Cu(II) species
dual catalysis generation of a radical species by means of single- to close the photocatalytic cycle (Fig. 6B, iii).
Cu(I) and Cu(II) salts have also recently been electron reduction of an electrophile; (ii) simulta- Cognizant of the challenges associated with
applied in conjunction with traditional Ir- or neous single-electron oxidation of the initial Cu(I) amine synthesis from readily available chemical
Ru-based photocatalysts. Owing to the persistent species to the ligated Cu(II)Ln species by the feedstocks, Hu and co-workers have recently de-
radical effect (PRE) demonstrated by copper, or- oxidized state of the photocatalyst; (iii) anionic veloped an efficient cross-coupling method be-
ganic radical intermediates generated by the ligand (Z) substitution from one of the reaction tween activated carboxylic acids and nitrogen
visible light–induced photocatalytic cycles are counterparts and formation of Cu(II)L(n−1)Z (or nucleophiles for the synthesis of a wide range of
efficiently trapped and thus stabilized by the in some cases transmetallation); (iv) capture of alkyl amines (59). In the initial step, benzophe-
metal center. The resulting organocopper inter- the incipient radical (R1•) emanating from the none imine coordinates Cu(I), and subsequent

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R ES E A RC H | R E V IE W

deprotonation generates a Cu(I) amido complex. then undergo decarboxylation, radical recombi- Later, Li and co-workers substantially advanced
Efficient capture of the alkyl radical generated nation, and reductive elimination to furnish the the strategy with the development of its asym-
from the alkyl NHPI ester with the help of the cross-coupled product (Fig. 6A). In one such metric variant by using a chiral Cu-QUINAP com-
photocatalyst forms the alkyl Cu(II) species. The study, Liu and co-workers achieved difluoroacet- plex. It activates the terminal alkyne and forms
oxidized photocatalyst oxidizes this Cu(II) com- ylation of a,b-unsaturated carboxylic acids with a chiral Cu-QUINAP-acetylide species that acts
plex to a corresponding Cu(III) complex that ethyl iododifluoroacetate (Fig. 7B, i) (65). The as the active nucleophile toward the iminium
subsequently collapses through reductive elim- transformation proceeds by the Ru(II)*-catalyzed intermediate and furnishes the corresponding
ination to give the cross-coupled product, with initial oxidation of the Cu(I) cocatalyst to Cu(II), 1-alkynyl tetrahydroisoquinoline derivatives with
concurrent regeneration of the initial Cu(I) com- which accommodates two coordinated carbox- excellent enantioselectivity (Fig. 8B) (70). The
plex. The benzophenone imine group can be sub- ylates. In turn, upon reoxidation of Ru(I) to Ru(II), strategy has also been successfully extended to
sequently hydrolyzed or transaminated to give the difluoroacetyl radical is generated and adds to the functionalization of isochromans with b-keto
corresponding primary amines (Fig. 6B, iv). Hu’s the a-position of the olefinic double bonds of the esters in which a catalytic amount of Cu(OTf)2
group has further expanded the scope of the C–N Cu(II)-carboxylate species, which subsequently has been used to activate the nucleophiles for
bond-formation to anilines (Fig. 6B, v) (60) as well undergoes simultaneous elimination of Cu(I) and their addition to oxonium intermediates (71).
as to C–O bond-forming reactions with phenols CO2 to produce the desired difluoroacetylated A photocatalyzed decarboxylative alkynylation
(Fig. 6B, vii) (61). olefin derivatives in good yields. of NHPI esters of a-amino acids with terminal
MacMillan and co-workers further extended Along the same lines, MacMillan and co-workers alkynes has been achieved by Fu and co-workers,
the scope of the strategy by using a wide range have recently reported the decarboxylative tri- in which a catalytic amount of CuI was necessary
of primary, secondary, and tertiary alkyl carbox- fluoromethylation of aliphatic carboxylic acids to generate the active nucleophile in the form of
ylic acids through in situ iodonium activation (Fig. 7B, ii) (66). Initially, the free carboxylic acid copper acetylide (72).
with a broad range of nitrogen nucleophiles, such coordinates the Cu(II) cocatalyst, which is oxi- An improved Chan-Lam coupling reaction be-
as heteroaromatics, amides, sulfonamides, and dized by photoexcited Ir(III)* to the correspond- tween electron-deficient aryl boronic acids and

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anilines (Fig. 6B, vi) (62). The synthetic transfor- ing Cu(III)-carboxylate complex. Then, subsequent anilines has been developed by Kobayashi and
mation proceeds by means of the initial formation extrusion of carbon dioxide and recombination co-workers (Fig. 8C) by means of a combined
of the Cu(I)-amido species through sequential of the incipient alkyl radical generates the alkyl- copper/photocatalyst system. The reaction takes
binding of amine with Cu(I) and deprotonation. Cu(III) intermediate, which oxidizes Ir(II) to off with Cu(II) undergoing ligand exchange with
The excited Ir(III)* complex oxidizes this Cu(I)- ground-state Ir(III) to close the photocatalytic aromatic amine and transmetalation with aryl
amido species to the corresponding Cu(II)- cycle and generate an alkyl-Cu(II) intermediate. boronic acid to form an organo-Cu(II)-amide
amido species, and the resultant Ir(II) reduces This intermediate engages with Togni’s reagent, species. It subsequently gets oxidized by Ir(IV) to
the iodomesitylene dicarboxylate to generate the 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole, form a Cu(III) intermediate that, upon reductive
carboxyl radical and ultimately the alkyl radical to furnish the targeted alkyl-CF3 product in good elimination, generates the desired cross-coupled
(after CO2 extrusion). In contrast to Hu’s pro- yields and regenerates the Cu(II) cocatalyst to product (73). Aerobic oxidation of a wide range of
tocol, the Cu(II)-amido species captures the alkyl reenter the catalytic cycle. primary amines to the corresponding nitriles
radical to form the corresponding alkyl-Cu(III)- (Fig. 8D, i) could be accomplished by Tao’s group
amido species that collapses by means of reduc- Miscellaneous examples by use of a [Ru(bpy)3]Cl2/CuBr dual catalytic sys-
tive elimination to furnish the desired alkyl amine Apart from the aforementioned studies, copper tem. The mechanistic pathway involves an initial
product and regenerate the Cu(I) catalyst. has enriched the field of photoredox catalysis by ligand exchange of Cu(I) with amine to form a
Ligand modularity of the Cu complexes can adopting various other roles in a wide panoply of copper amide intermediate that undergoes single-
again greatly vary the chemistry and redox prop- synthetic applications. A regioselective halofunc- electron oxidation by a photoexcited Ru(II) cata-
erties in Cu/photocatalyst cooperative systems, tionalization of unsaturated carboxylic acids has lyst and subsequent hydrogen abstraction and
as reflected in the decarboxylative cyanation been accomplished by Nicewicz and co-workers neutralization by a superoxide radical anion and
reaction developed by Lin, Liu, and co-workers. (Fig. 8A, i). The transformation proceeds by hydrogen peroxide anion, respectively, to form a
Secondary benzylic NHPI esters were used along means of the initial oxidation of the alkene by an copper amido intermediate. Then, another sim-
with trimethylsilyl cyanide (TMSCN) in the pres- acridinium photocatalyst followed by the nucle- ilar catalytic cycle furnishes the desired nitrile
ence of [Ir(ppy)3], CuBr, and the chiral pyBOX ophilic addition of the internal carboxylate to the derivative (74). In another study, photoredox
ligand to produce benzyl nitriles (Fig. 7A, i) (63). radical cation intermediate. Then, Cu(II) cocata- catalyzed C4–H sulfonylation of 1-naphthylamides
The key step is the combination of the radical lyst transfers the halide from an external halide could be achieved by using Cu(OAc)2 catalyst,
obtained through photoreduction of the NHPI source to newly generated C-centered radical to which aided in single-electron oxidation of the
ester with the chiral L*Cu(II)CN complex, the furnish the corresponding product (67). Zhu and substrate in the presence of an oxidant (75).
latter stemming from oxidation of the initially co-workers have recently achieved remote C(sp3)- Copper’s Lewis acidity has also been leveraged
formed L*Cu(I)CN by the oxidized photocatalyst. H functionalization of N-alkoxypyridinium salts in activation of C≡C triple bonds through the
Reductive elimination from the resulting Cu(III) with silyl reagents through photoredox/copper formation of a p-complex between an internal
species provided the products in good yields with dual catalysis (Fig. 8A, ii). The transformation alkyne and Cu(II) to form a three-center two-
excellent enantioselectivities. Enantioselective takes place through the reductive generation of electron (3c-2e) system conducive to single-electron
bifunctionalization—cyanoalkylation of olefins— an alkoxy radical with Ir(III) photocatalyst and oxidation by an exogenous photocatalyst, as shown
has been accomplished as well with this strategy 1,5-hydrogen atom-transfer followed by function- by Guo and co-workers (Fig. 8D, ii). The newly
(Fig. 7A, ii) (64). alization of the C-centered radical with Cu(II)- formed 3c-1e system could then undergo an arene-
The aforementioned studies invariably re- catalyzed transfer of pseudohalide groups such yne cyclization reaction to produce phenanthrene
quired activation of the carboxylic acids either as azido, cyano, and isothiocyanato from their derivatives (76).
as their NHPI esters or through in situ iodonium corresponding trimethylsilylated precursors to Apart from the aforementioned studies, Cu(II)
formation. This potential drawback has recently furnish various d-functionalized alcohols (68). salts have been used in an intramolecular oxi-
been addressed in photoredox catalysis by using In 2012, Rueping et. al. developed a photo- dative cyclization/oxygen insertion of aromatic
copper as the cocatalyst to enable the direct de- catalytic oxidative alkynylation reaction of tet- enamines to furnish polysubstituted quinolines
carboxylation of the free carboxylic acids through rahydroisoquinolines using [Ru(bpy)3](PF6)2 under mild reaction conditions (77). Bode and
formation of Cu(II)-carboxylate complexes, which as a photocatalyst and a catalytic amount of co-workers have used stoichiometric Cu(OTf )2
can capture the photochemically generated radi- [Cu(MeCN)4]PF6 to generate copper acetylide as as the Lewis acid to lower oxidation potentials
cal to form Cu(III)(alkyl)-carboxylates. These can the active nucleophile from terminal alkyne (69). of demanding imine substrates that can then

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Copper's rapid ascent in visible-light photoredox catalysis
Asik Hossain, Aditya Bhattacharyya and Oliver Reiser

Science 364 (6439), eaav9713.

DOI: 10.1126/science.aav9713

Spotlight on copper
Photoredox catalysis relies on visible-light excitation to accelerate a burgeoning number of chemical reactions.
Initially, the technique relied primarily on complexes of precious metals, such as ruthenium or iridium, to absorb the light.
Hossain et al. review recent progress in the use of copper complexes as an alternative. In addition to its Earth
abundance, copper opens up a variety of distinct mechanisms involving electron transfer within the coordination sphere.
Science, this issue p. eaav9713

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