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Design of Diradical-based Hydrogen Abstraction Agents.

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Design of Diradical-based Hydrogen Abstraction Agents**
Peter Chen*
Interest in the chemistry of diradicals has undergone a vigorous resurgence over the last decade, in large part due to the
putative intermediacy of arene diradicals in the DNA-cleaving
activity of the enediyne family of antitumor antibiotics. There
were early indications from the Masamunel'] and Sondheimerc2]groups, but the first unambiguous demonstration of
the presence of arene diradicals produced by the cyclization of
enediynes was reported by Bergman and co-worker~.[~]
The field
lay fallow for many years until the discovery of the remarkable
polyunsaturated ring structures for esperamicin, dynemicin,
and cali~heamicin.[~]
ical function, which may or may not bear much relationship to
the constraints or function that the enediynes find as therapeutic
agents. It is therefore highly desirable to understand the ways in
which organic chemists may re-engineer the functionalities of
the natural products to effect a rational modification in properties."] The modular design of the enediyne series of compounds
makes this enterprise particularly attractive. In this report, perspectives on the redesign of the "warhead" part of the enediyne
drugs are discussed with an emphasis on recent developments in
the field of arene diradicals that provide handles for alteration
of function.
The diradicals that form from the natural products are all
1,4-diradicals: either substituted p-benzynes or 3,7-dehydroindenes. The functional significance of this restricted range of
structures is not altogether clear, although suggestions (see below) can be made. Arene diradicals for which spectroscopic,
thermochemical, and/or kinetic data have recently appeared include p - b e n z ~ n e , ['1 ~ <9,1O-dehydroanthra~ene,[~~,
12] and the
larger condensed species, which form by tandem cyclizat i o n s . ~ 1 3 . 141
It became evident that the enediyne antitumor antibiotics
cycloaromatized to form a substituted 1,4-didehydrobenzene
(p-benzyne) diradical, which could initiate D N A cleavage by
hydrogen abstraction from the sugar phosphate backbone of
duplex DNA. Further studies have elucidated the design principles behind the various functional domains of the natural
products : the triggering by the trisulfide
calicheamicin and esperamicin, the D N A recognition function
of the pendant oligosaccharide chains,''] the control of cycloaromatization through complexation by the apoprotein in
kedarcidinU6Iand neocarzinostatin,"~ etc. One marvels a t the
elegance and modular design of the natural products. Nevertheless, it is almost a truism to state that the natural products are
highly optimized under some set of constraints for some biolog-
Prof. Dr. P. Chen
Lahoratorium fur Organische Chemie
der Eidgenossischen Technischen Hochschule
Universitiitstrasse 16, CH-8092 Zurich (Switzerland)
Fax: Int. code +(1)632-1280
e-mail: peter(#
This work was supported financially by the ETH Zurlch and the Kontaktgruppe fur Forschungsfragen (Basel).
Q VCH Verlugsgeseiischafl mbH. 0-69451 Weinhelm, 1996
9.10-dehydroanthracene 3,7-dehydroindene
In the older literature, there are also structures such as the
presumed cyclization product of Sondheimer's tetrayne.[21
While there are many reasons to study diradicals, the key questions in the present context are: What would happen if one were
to use one of the nonnaturally occurring diradicals in a DNAcleaving agent? What would the advantages and disadvantages
be relative to p-benzyne, for example? What handles does one
have, from an engineering point-of-view, to modify the chemistry?
In this light, the preparation and characterization of arene
diradicals with connectivity or substitution different from those
occurring in the natural products is of high interest. The recent
report of the clean preparation, under matrix-isolation conditions, of 1,3-didehydrobenzene (m-benzyne) ]'1I,
opens the way
to the physical characterization of an arene diradical which,
while never implicated in the activity of a natural product, may
have desirable properties from the engineering point-of-view.
A comparison of the results obtained by IR spectroscopy with
those from a b initio calculations confirms the identity of the
common product that is formed from different precursors by
flash vacuum pyrolysis (FVP) and photolysis (Scheme 1). Noteworthy is the survival of in-benzyne under the conditions
employed for FVP, which is in marked contrast to p-benzyne,
which has been trapped, but never isolated. The earlier reports
that pyrolysis of 1,3-diiodobenzene['"] or isophthaloyl diiodide'' 'I produced hex-3-ene-I ,5-diyne d o indicate that there
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Angew. Chem. Int. Ed Engl. 1996, 35. No. 13/14
Scheme 1 Formation of m-benzyne.
is a rearrangement/ring-opening pathway, but with an
activation energy that must be higher than the barrier of
19.8 kcal mol-lL'olfor the ring-opening ofp-benzyne. One can
write plausible mechanisms, based on carbene isomers of the
enediyne, which rationalize the rearrangement (Scheme 2).
Scheme 2
However, given that m-benzyne has a heat of formation
15 kcal mol - ' lower[91 than p-benzyne, and the vinylidene
isomer of the enediyne, for example, should lie perhaps
40 kcal mol- above the enediyne, the greater kinetic stability of
m- versus p-benzyne is not difficult to understand. With information gleaned from the experiment. one is almost in a position
to make a prediction as to the effect of replacing p-benzyne by
m-benzyne as a hydrogen abstraction agent. To close the argument. one needs only to know something about 1,4-diradicals as
abstraction agents.
We have reported the absolute rates of hydrogen abstraction
from acetonitrile and isopropyl alcohol by the 9,lO-dehydroanthracene diradical['21as a model for the reaction by p-benzyne
or any other 1,4-arene diradical. The second-order rate constants for the hydrogen abstraction obtained at room temperature by measuring the transient absorption after flash photolysis
and trapping of the reactive intermediate are kMeCN
(1.1 k 0 . 3 ) ~
1 0 3 ~ - ' s - ' and kiPrOH
= (6.5i0.6)~
and thus 100- 100 times lower than the corresponding rate constants for the phenyl radical['*] or the 9-anthryl radical.["]
A reduced rate in hydrogen abstraction reactions for p-benzyne
relative to that for the phenyl radical was also found by a b initio
calculations at the CASPT2N/6-31 G** level.[201The lowered
reactivity of a singlet ground-state diradical relative to that of
a reference monoradical was rationalized by a valence-bond
promotion energy argument that correlated the singlet -triplet
splitting in the diradical to the magnitude of rate reduction.
The singlet - triplet splitting in the arene diradicals, in turn, is
determined primarily by the extent of through-bond coupling
between the two radical sites. Accordingly, by choosing a
diradical whose structure favors or disfavors through-bond
coupling. or by tuning the energies of the o and/or u* orbitals
by way of substituents on the o-framework, it should be possible to tune the rate of hydrogen abstraction to optimize the
process for a particular set of constraints. The heats of forma-
A n g w . (%em. I n [ . Ed. Engl. 1996. 35, N o 13/14
tion for 0-,m-, and p-benzyne, determined experimentally within the last two year^,[^.'^] indicate a much larger coupling in
m-benzyne than in p-benzyne. Ab initio calculations confirm the
effect as manifested by a larger singlet- triplet splitting.["] One
would expect, therefore, that the rate of hydrogen abstraction
by m-benzyne should be even lower than that by p-benzyne.
Conversely, the diradicals formed by tandem cyclizations, by
virtue of greater separation of the two radical centers, should be
more reactive than p-benzyne.
Accordingly, the substantial stabilization from the 1,3through-bond interaction in m-benzyne should impose both
thermodynamic and kinetic barriers to hydrogen abstraction
which could be very useful. From the heat of formation,"] it is
clear that abstraction of hydrogen by m-benzyne from donors
with C-H bonds stronger than 94 kcalmol-' would be endothermic. Even for those donors with a weak enough C-H
bond, the promotion energy argument above suggests that there
should be a substantial additional component to the activation
energy which would nevertheless slow the hydrogen abstraction.
The diradical should be long-lived, and presumably, selective in
its attack.
It remains only to consider the possible functional significance of arene diradicals in the natural products, given their
rather low rate of hydrogen abstraction, and the possible modification in that function upon replacement by a different diradical. Of course, it is conceivable that there is no special reason
at all for the occurrence of such diradicals in Nature, but given
that there are now many examples of radical-based biological
processes,[221one can imagine that, if it were to be advantageous
to have a better abstraction agent, it would have been possible
to have one. Greater selectivity, associated in general with lower
reactivity, is one possible reason for the choice of a diradical
agent versus a monoradical one. A more interesting possibility
comes from the differential reactivity between an arene diradical
and the phenyl radical. The first hydrogen abstraction by a
p-benzyne-type diradical proceeds rather slowly (and presumably selectively) and yields the two-hundredfold more reactive phenyl radical. Reaction at the same target site is then likely,
in this case meaning that two hydrogen atoms are abstracted
from closely spaced positions, rather than from widely separated locations. For DNA cleavage, one would presume that this
would lead to more double-stranded breaks, as has been shown
to be the case in D N A cleavage by c a l i c h e a m i ~ i n . The
[ ~ ~ ~exploitation of the differential rates of hydrogen abstraction between diradicals and monoradicals to enhance the likelihood for
double-stranded breaks represents an elegant use of intrinsic
reactivity to achieve a functional goal. The differential is further
enhanced if m-benzyne is substituted for p-benzyne. While the
former should be even slower and more selective than the latter
in the first hydrogen abstraction, both diradicals produce the
same phenyl radical for the second abstraction. DNA need not
even be the target. The general motif associated with diradicalbased hydrogen abstractions would be the use of an activated
C - H bond, for example benzylic, allylic, etc., to direct the attack on a neighboring, unactivated C-H bond.
Some consequences of recent studies of the chemistry of arene
diradicals have been discussed with an view to identifying the
factors responsible for the particular choice of diradicals in natural products, and the advantages and disadvantages that
Verlugsgesellsrhufr mbH, D-69451 Weinhrim. 1996
0570-0833/96/3513-1479$15.00 t .25/0
would be incurred if an alternative structure were to be substituted. Important structural features for rational modification of
the diradical “warhead” have been suggested.
German version: Angen-. Chem. 1996, 108. 1584-1586
Keywords: diradicals
- DNA cleavage - enediynes
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