INSIGHTS | PERSPECTIVES
Oxidation of R-Y by Ir(III)*
releases highly reactive R•
Standard cross-coupling partner
(Ar = aromatic ring, including
heterocycles; X = Cl, Br, I)
Single-electron transfer
regenerates the nickel and
iridium catalysts,
synchronizing the
inner and outer cycles
Visible light
photoexcites
[IrIII] to [IrIII]*
Valuable Caryl-Csp3
cross-coupling products
Stable radical precursor
[IrIII]* [IrII]
[NiII]
e_
[Ni0]
[NiI][NiIII]
[IrII]
[IrIII]
[IrIII]*
Rapid capture by [Ni(II)]
avoids accumulation of R•
R-Y
R-Y
R-Ar
hν
Ar-X
= R-Y
G
ZY
G = H, alkyl
Z = aryl, N- or O-based
Y = BF3K, CO2Cs, H
R•+ Y+
R•
Driving chemistry with epicyclic gears. A schematic representation of cooperative iridium (outer) and nickel (inner) catalytic cycles for the cross-coupling of a stable radical
precursor (blue spheres, R-Y) with an aryl halide (purple spheres, Ar-X), driven by an external source of visible light (hν). Two points of contact (smaller cogs on the left and right
sides) synchronize the inner and outer cycles, ensuring autoregulated release of a highly reactive radical (red spheres, R·) to the awaiting nickel(II)-aryl intermediate.
Csp3 organometallic cross-coupling intermediate, it also generates a nickel(III) species that more readily undergoes reductive
elimination, avoiding competing decomposition. A single electron transfer then reoxidizes the spent iridium photocatalyst and
provides a nickel(0) species for addition to
the Ar-X, thereby closing and synchronizing the two cycles.
The whole process proceeds under re-
markably mild reaction conditions: The
iridium photocatalysis is driven by visible
light (simply using a household light bulb),
avoiding ultraviolet photodegradation of
the organic coupling partners. The organo-
radicals smoothly add to the nickel catalyst
at ambient temperature, and unlike most
couplings, there is no requirement for a
strong exogenous base. Overall, these mild
conditions suggest that the process can
be extended to a wider range of coupling
partners, including other unsaturated or
saturated halides, or their more environ-
mentally friendly equivalents (e.g., phenol
derivatives), as well as radical precursors
that do not benefit from a stabilizing group
(Z in the figure). An important target for fu-
ture development will be gaining access to
single-enantiomer products, via full stereo-
convergence of racemic radical precursors
(R-Y) (8), the feasibility of which Tellis et al.
preliminarily explored.
Consideration of the overarching mechanisms proposed for the couplings reveals
that this first example of the successful
confluence of iridium and nickel catalytic
cycles relies on more than just the relay
of an organoradical from one cycle to the
other. The single-electron transfer provides
a second point of contact between the two
cycles, as illustrated by the gear systems in
the figure. Neither cycle can operate independently of the other; the turnover of one
cycle both determines and is controlled by
the other. It is this “self-control” in the liberation of highly unstable radical reagents
from the Csp3 component that facilitates
their productive coupling, instead of their
decomposition, as would occur if they were
released en masse.
The system is an example of an under-
exploited approach in synthesis: “autoreg-
ulated release” of reactive intermediates
by synchronization of multiple catalytic
cycles, a phenomenon that is ubiquitous
in biochemistry. This analysis also shows
that, by modulating the relative concentra-
tions of the two catalysts and by judicious
choice of their initial point of entry into
the system, the distribution of catalytic in-
termediates can be constrained to be pre-
dominantly in one or the other hemisphere
of a cycle. This manipulation of the loca-
tion of the so-called “catalyst resting state”
provides wide-ranging opportunities for
the development of novel catalyst systems
for synthesis and for the installation of
new modes of selectivity into ones already
known (9). ■
REFERENCES
1. A.J.J.Lennox,G.C.Lloyd-Jones, J. Am. Chem. Soc. 134,
7431 (2012).
2. J.C. Tellis, D.N.Primer, G.A.Molander, Science 345, 433
(2014).
3. Z. Zuo et al., Science 345, 437 (2014).
4. D. M. Schultz, T. P. Yoon, Science 343, 1239176 (2014).
5. C. K. Prier, D. A. Rankic, D. W. C. Mac Millan, Chem. Rev. 113,
5322 (2013).
6. F.Lovering, J.Bikker, C.Humblet, J. Med. Chem. 52,6752
(2009).
7. R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 111, 1417
(2011).
8. C.J.Cordier, R.J.Lundgren,G.C.Fu,
J.Am.Chem.Soc.
135, 10946 (2013).
9. L. A. Evans, N. S. Hodnett, G. C. Lloyd-Jones,
Angew.Chem.
Int. Ed. 51, 1526 (2012).
10.1126/science.1256755
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