Highly reactive or unstable chemical reagents are challenging to prepare, store, and safely handle, so chem- ists frequently generate them in situ from convenient precursors. In an ideal case, the rate of release of the
reagent would be matched to the rate of
its “capture” in the desired chemical reaction, thereby preventing the reagent from
accumulating and minimizing any opportunity for decomposition. However, this
synchronization is rarely achieved or even
attempted: The rate of release is usually dictated by the conditions of the reaction (1),
rather than being regulated by capture of
the reagent. In this issue, Tellis et al. (2) on
page 433 and Zuo et al. (3) on page 437 independently report the use of iridium photocatalysis (4, 5) to supply highly reactive
radical coupling partners (R·) to a nickel-catalyzed carbon-carbon bond-forming process (see the figure). Intriguingly, the two
points of contact between the iridium and
nickel cycles enforce autoregulated release
of the radical, ensuring its efficient capture
by nickel rather than its decomposition via
other pathways.
Transition metal catalysts for the car-bon-to-carbon coupling of complementary
pairs of appropriately functionalized molecular building blocks are now a mainstay
in modern organic synthesis, at least for
unsaturated carbon sites (ones with double or triple bonds). Efficient coupling at
saturated sites (“Csp3” where the carbon has
four single bonds) remains troublesome.
An important difference between these
processes is that Csp3 coupling generates
three-dimensional molecular architectures
that are of key importance to the pharmaceutical, agrochemical, and materials industries (6).
There are three primary reasons that
Csp3 reaction centers are ill-suited to cross-coupling. The first is that the organic component transfers sluggishly to the metal
catalyst. This problem precedes two more—
the resulting organometallic species are
frequently unstable, and also only slowly
undergo the desired C-C bond formation
(“reductive elimination”), exacerbating the
Self-control tames the
coupling of reactive radicals
By Guy C. Lloyd-Jones and Liam T. Ball
Iridium complexes use two points of contact to control
carbon-carbon bond formation
CATALYSIS
instability problem (7). Cases of successful
Csp3 couplings typically must address all
three issues. The slow transfer is tackled by
use of highly reactive Csp3 nucleophiles (the
electron-rich component), which are inherently hard to control. The other two issues
are suppressing side reactions at the metal
center and accelerating the reductive elimination, which can be addressed through
careful tuning of the metal catalyst (for example, altering its ligand sphere).
The reports of Tellis et al. and Zuo et al.
offer an alternative and innovative solution to all three issues. The authors report
high-yielding and selective formation of a
new bond between an aromatic (
benzene-like) ring and a Csp3 moiety (“R”) with an
aromatic halide (“Ar-X”) coupling partner,
and convenient precursor sources of the
Csp3 component, in reactions that are simple
to conduct and of substantial scope. At the
heart of the new process is a photoexcited
iridium complex ([Ir(III)]*) that oxidizes
stable Csp3 precursors (R-Y, where Y is BF3K,
CO2Cs, or H) to their corresponding organoradicals (R·), highly reactive species in
which the sp3 carbon now bears an unpaired
electron. The radical does not accumulate,
but instead is captured by an aryl-nickel(II)
complex that “awaits” its arrival. Not only
does the use of an organoradical overcome
the usual reluctance for formation of the
School of Chemistry, University of Edinburgh, Edinburgh EH9
3JJ, UK. E-mail: guy.lloyd-jones@ed.ac.uk; liam.ball@ed.ac.uk
‘The system is an example
of an underexploited
approach in synthesis:
“autoregulated release”
of reactive intermediates
by synchronization of
multiple catalytic cycles,
a phenomenon that is
ubiquitous in biochemistry.’
that drive DNA ejection into the host are
likely to be smaller than those resisting packaging, which may limit the role of pressure
in DNA ejection. Berndsen et al. propose that
relaxation of confined DNA may occur by a
reptation-like mechanism, the time scales of
which depend on the cube of genome length.
If so, relaxation time scales would be even
longer for bacteriophages and viruses with
genomes longer than that of φ29 (e.g., λ, T4,
T7, and herpes virus) (9). Because the time to
complete packaging is expected to be similar for many of these systems (10), this potentially presents an even bigger challenge to
their packaging motors. Interestingly, under
certain conditions, T4 is also known to “
un-package” DNA (11), allowing its genome to
exit the capsid in a controlled and reversible
manner. It is tantalizing to speculate that this
mechanism could allow the motor to “unjam”
DNA.
A number of issues remain to be addressed.
More precise measurements of relaxation
times as a function of filling fraction will aid
theoretical models of polymers, because such
models often lack accurate relaxation time
scales. It will also be important to connect the
observed slow relaxation to the mechanism
of the packaging motor and to the organization of the DNA inside the capsid. Another
recent optical trap study (12) showed that
the motor rotates DNA as it packages it, and
that the rotation pitch changes as the capsid
becomes filled. This is potentially related to
the spool structure proposed for packaged
DNA (13, 14). It may be possible to study the
prerelaxation conformations of the packaged
DNA with the help of recent advances in
cryoelectron microscopy. Direct visualization
of confined DNA motion by single-molecule
imaging may shed additional light on the
packaging process. This system illustrates
how biological processes exist far from equilibrium and how their study can provide an
unexpected testing ground for the underlying physical theories. ■
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