Intramolecular electron transfer initiated cation and radical formation through carbon-carbon bond activation

Article abstract of DOI:10.1021/ol070850k

Radical cations can be formed in a spatially and temporally controlled manner by appending a sacrificial photooxidant to an easily oxidized substrate, leading to intramolecular electron transfer upon irradiation. The anthraquinone carboxyl group is an effective photooxidant that can promote single electron oxidation from an appended arene. The resulting intermediates undergo a cleavage reaction through carbon-carbon bond activation to provide either cations or radicals that react to form a range of products.

Full text of DOI:10.1021/ol070850k

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2389-2392
Intramolecular Electron Transfer Initiated
Cation and Radical Formation through
Carbon−Carbon Bond Activation
Wangyang Tu and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received April 12, 2007
ABSTRACT
Radical cations can be formed in a spatially and temporally controlled manner by appending a sacrificial photooxidant to an easily oxidized
substrate, leading to intramolecular electron transfer upon irradiation. The anthraquinone carboxyl group is an effective photooxidant that can
promote single electron oxidation from an appended arene. The resulting intermediates undergo a cleavage reaction through carbon
bond activation to provide either cations or radicals that react to form a range of products.
−carbon
Photoinitiated deprotection reactions1 are powerful tools for
liberating molecules in a spatially and temporally precise
manner on surfaces2 and in cells.3 Developing new methods
that employ photocleavage reactions to yield synthetically
versatile reactive intermediates rather than stable functional
groups would expand the structural diversity that can be
accessed in this manner. In this regard, utilizing photoinitiated
electron-transfer processes is attractive because of the wealth
of reactions that proceed through radical ion intermediates.4
We have developed a series of transformations based on
carbon-carbon bond-cleavage reactions of radical cations
that arise from bimolecular single electron-transfer pro-
cesses.5 These reactions, however, cannot be applied to
spatially and temporally controlled syntheses because of the
potential for photooxidant diffusion and, for biological
applications, the statistical improbability of bimolecular
electron transfer. Tethering a photooxidant to the cleavage
substrate would solve these problems by promoting reactions
through intramolecular electron transfer rather than inter-
molecular electron transfer. Herein we report that anthra-
quinone carboxylates are suitable photooxidants for effecting
intramolecular single electron oxidations of homobenzylic
alcohols and ethers, that the resulting charge separated
intermediates undergo carbon-carbon bond cleavage reac-
tions, and that, in addition to the expected cationic intermedi-
ates, radicals can be formed from electron transfer following
the initial cleavage.
We envisioned a modular design for cleavage substrates
in which a photooxidant is appended to an electroauxiliary
that is attached to a cargo unit by a cleavable linker (Scheme
1).6 Photoirradiation will yield a charge-separated intermedi-
ate through intramolecular electron transfer. Provided that
the radical cation fragment of the molecule reacts in an
analogous manner to related species that arise from inter-
molecular electron transfer, the cargo will be released as a
(1) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(2) (a) Pirrung, M. C. Chem. ReV. 1997, 97, 473. (b) McGall, G. H.;
Barone, A. D.; Diggelmann, M.; Fodor, S. P. A.; Gentalen, E.; Ngo, N. J.
Am. Chem. Soc. 1997, 119, 5081.
(3) (a) Adams, S. R.; Tsien, R. Y. Annu. ReV. Physiol. 1993, 55, 755.
(b) Dorma´n, G.; Prestwich, G. D. Trends Biotechnol. 2000, 18, 64. (c)
Dynamic Studies in Biology: Phototriggers, Photoswitches, and Caged
Biomolecules, Goeldner, M., Givens, R., Eds.; Wiley-VCH GmbH and
Co.: Weinheim, Germany, 2005.
(4) (a) Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 2550. (b) Baciocchi, E.; Bietti, M.; Lanzalunga, O. Acc. Chem. Res.
2000, 33, 243.
(5) (a) Kumar, V. S.; Floreancig, P. E. J. Am. Chem. Soc. 2001, 123,
3842. (b) Aubele, D. L.; Floreancig, P. E. Org. Lett. 2002, 4, 3443. (c)
Wang, L.; Seiders, J. R., II; Floreancig, P. E. J. Am. Chem. Soc. 2004, 126,
12596.
(6) For a related approach, see: Majjigapu, J. R. R.; Kurchan, A. N.;
Kottani, R.; Gustafson, T. P.; Kutateladze, A. G. J. Am. Chem. Soc. 2005,
127, 12458.
10.1021/ol070850k CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/17/2007

products. To confirm that intramolecular electron transfer is
feasible in this system we prepared noncleavable analogue
5. The characteristic fluorescence emission bands from the
anthraquinone carboxylate group at 466 and 500 nm were
completely quenched by arene substitution, consistent with
efficient photoinitiated intramolecular electron transfer.10
To test the capacity of these structures to undergo bond
cleavage, we prepared substrates 6-9 based on observations
that related substrates smoothly undergo cleavage upon
bimolecular oxidation.8 These substrates were irradiated
(medium-pressure mercury lamp, Pyrex filtration) in aqueous
CH3CN to provide carbonyl-containing products11 as sum-
marized in Table 1. Several observations from Table 1 are
Scheme 1. Strategy for Intramolecular Electron Transfer and
Bond Cleavage
Table 1. Bond Cleavage through Intramolecular Electron
Transfera
cation that can either engage in a cyclization reaction or be
quenched by solvent.
For this approach to be effective, return electron transfer
in the charge-separated intermediate must be sufficiently slow
to allow bond cleavage to be a competitive process. Because
a spin flip must precede return electron transfer, enhanced
lifetimes of charge-separated states are observed7 when
photooxidants react through triplet excited states rather than
singlet states. Whitten has reported8 that the anthraquinone
carboxylate group is a suitable photooxidant for promoting
long-lived charge separated intermediates. Substituted arenes
are exceptionally versatile electroauxiliaries and function
even when appended to complex structures through ether
linkages.9 Incorporating these elements into a composite de-
sign led to prototypical substrate 1 (Scheme 2). Photoexci-
tation of the anthraquinione group in 1 is expected to provide
charge separated intermediate 2, which will cleave to form
3 and 4. Subsequent reactions of 4 can lead to a range of
entry
1
substrateb
time (h)
1.5
product(s)
yield (%)c
6
10
11
12
12
13
61
6
89
97
77
2
3
4
7
8
9
1
1
2
a AQC ) anthraquinone carboxylate. Reaction conditions: hν (medium-
pressure Hg lamp, Pyrex filter), NaOAc, CH3CN, H2O (20:1). b See the
Supporting Information for synthetic schemes to prepare the substrates.
c Yields are reported for isolated, purified materials.
noteworthy. Weakening the benzylic carbon-carbon bond,5c
either by using a tertiary alcohol rather than a secondary
alcohol or by introducing alkyl groups at the benzylic
position, enhances both the rate and the efficiency of the
cleavage reaction. Remarkably effective ketone formation
was noted when both strategies were employed (entry 3).
Free hydroxyl groups are not required for cleavage, as
demonstrated by the reaction of acetal 9, though the process
is slower (entry 4). Baciocchi has observed12 that alcohols
undergo cleavage faster than ethers in the presence of base,
presumably reflecting heightened electron donation. Acetal
substrates yield esters, thereby broadening the range of
oxidation states that can be accessed through this protocol.
To the best of our knowledge entry 4 depicts the first report
of ester formation through photochemical cleavage in a
Scheme 2. Anthraquinone Carboxylate Substrates
(7) Jones, G., II; Haney, W. A.; Phan, X. T. J. Am. Chem. Soc. 1988,
110, 1922.
(8) Leon, J. W.; Whitten, D. G. J. Am. Chem. Soc. 1993, 115, 8038.
(9) Liu, H.; Wan, S.; Floreancig, P. E. J. Org. Chem. 2005, 70, 3814.
(10) See the Supporting Information for fluorescence quenching data.
(11) For other examples of photoinitiated ketone and aldehyde release,
see: (a) Blanc, A.; Bochet, C. G. J. Org. Chem. 2003, 68, 1138. (b) Lu,
M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003, 5, 2119.
(12) Baciocchi, E.; Bietti, M.; Putignani, L.; Steenken, S. J. Am. Chem.
Soc. 1996, 118, 5952.
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Org. Lett., Vol. 9, No. 12, 2007

nonalcoholic solvent. Cleaving secondary alcohol 6, in
addition to the expected aldehyde 10, provided a small
amount of carboxylic acid 11. This result was unexpected
on the basis of related bimolecular reactions8 that did not
result in overoxidation. All of these reactions were conducted
in 5% aqueous acetonitrile, demonstrating that water does
not have a deleterious effect on the process. A control
substrate in which the anthraquinone carboxylate and linker
groups were replaced by a methyl group underwent photo-
initiated cleavage at a rate that was approximately 2 orders
of magnitude slower than that of the parent structures (data
not shown), confirming the importance of intramolecular
electron transfer in promoting the reaction.
Scheme 4. Reaction Pathways Following Cleavage
While no direct comparison of these cleavage reactions
to similar reactions that proceed through intermolecular elec-
tron transfer is possible, a general comparison of reactivity
patterns is instructive. Notably, for reactions that proceed
through intermolecular electron transfer the presence of a
para-alkoxy group on the arene completely suppresses oxida-
tive cleavage unless substituents are appended to the benzylic
position to weaken the carbon-carbon bond. Benzylic sub-
stituents promote smoother cleavage for reactions that utilize
intramolecular electron transfer, but they are not necessary.
This effect can most likely be attributed to an inherently en-
hanced reactivity for the charge separated intermediates rela-
tive to simple radical cations and/or to intramolecular electron
transfer producing higher concentrations of reactive inter-
mediates than the corresponding intermolecular processes.
dominant pathway (Scheme 4). However, the radical anion-
cation pair from the cleavage reaction (16) can undergo an
electron-transfer reaction to form radicals 17 and 18 when
the reaction with water is slow because neutral product
formation through proton loss is not a viable pathway (as
for 14) or because the driving force for reducing a relatively
unstabilized intermediate oxocarbenium ion is high (as for
6). The enhanced production of peroxyacetal 15 in anhydrous
conditions supports this hypothesis. We have not previously
observed this process because the driving force for cation
reduction by the benzylic radical leaving groups that we
normally employ is significantly lower than for reduction
by the radical anion in 16. The resulting oxyalkyl radical
(18) can react with O2 to form peroxy radical 19. The peroxy
radical can either recombine with the benzylic radical to form
a peroxy acetal, collapse to form a carbonyl group, or lose
superoxide to regenerate the oxocarbenium ion intermediate.
In further exploration of radical intermediates on this
pathway, and in an attempt to use these intermediates in
productive bond formation, we prepared substrate 20 with
the expectation that alkoxyalkyl radical formation would
result in a cyclization through addition into the electron
deficient alkene. Indeed, irradiating 20 (Scheme 5) in the
absence of added water resulted in the formation of peroxide
21 as a mixture of stereoisomers. This process proceeded
To explore the scope of the process further, we prepared
secondary ether 14 to determine whether oxocarbenium ions
could be generated in this manner as an entry to cyclization
reactions. Direct irradiation of 14 under the standard condi-
tions (Scheme 3) indeed provided aldehyde 10 in 54% yield,
Scheme 3. Cleavage of a Secondary Ether
Scheme 5. Photoinitiated Radical Cyclization
though the reaction was slower (5.5 h) than the reactions in
Table 1 and the unusual peroxyacetal 15 was formed in a
7% yield. Interestingly, when the reaction was conducted in
the absence of water but in the presence of O2, 15 was formed
in 21% yield while the yield of 10 dropped to 40%. These
results suggest that the intermediacy of alkoxyalkyl radicals
is possible in these cleavage reactions.
Isolating acid 11 from 6 and peroxyacetal 15 from 14
indicates that the reaction pathways following intramolecular
electron transfer and bond cleavage can diverge from those
that are observed when cleavage is initiated by intermolecular
electron transfer. Reaction of the intermediate carbocations
with water either through nucleophilic addition or deproto-
nation to form the expected products appears to be the
Org. Lett., Vol. 9, No. 12, 2007
2391

through cleavage and electron transfer to form alkoxyalkyl
radical 22 followed by cyclization into the pendent alkene
to form 23. Radical trapping by O2 to form peroxy radical
24 and hydrogen abstraction completed the sequence to form
21. Product characterization was facilitated by converting
the multiple diastereomers of 21 to keto ester 25,13 which
was isolated as a 2:1 mixture of stereoisomers. While the
yield for this reaction was modest, the results are consistent
radical formation through oxocarbenium ion reduction since
reaction between the electron deficient alkene and a cationic
intermediate is unlikely, particularly given the observed
regiochemical outcome.
We have developed a method for cleaving carbon-carbon
bonds through photoinitiated intramolecular electron-transfer
processes. These fragmentations proceed to form oxocarbe-
nium ions and radical anions, and are most efficient when
the intermediate cations are highly stabilized or when a
neutral product can be formed through deprotonation.
Ketones, aldehydes, and esters can be released in good to
excellent yields. When the cationic fragment cannot form a
neutral molecule through deprotonation, radical formation
through electron transfer from the radical anion to the
oxocarbenium ion becomes a competitive process, as evi-
denced by the isolation of peroxide and radical cyclization
products. In principle the modular substrate design will allow
for the incorporation of a wide range of photooxidants and
electroauxiliaries in response to the needs of a particular
application, such as altered excitation wavelength or elec-
trophore oxidation potential. The ability to access reactive
intermediates rather than stable molecules should substan-
tially broaden the range of structures that can be accessed
in a spatially and temporally controlled manner. Further
studies directed toward these objectives are currently in
progress
Acknowledgment. This work was funded by generous
support from the NIH (Grant GM-62924) and the NSF (Grant
CHE-0606757). We thank Professor Billy Day (University
of Pittsburgh, Department of Pharmaceutical Sciences) for
assistance with mass spectrometry and Professor Stephane
Petoud (University of Pittsburgh, Department of Chemistry)
for assistance with fluorescence quenching studies.
Supporting Information Available: Synthetic schemes
for all cleavage substrates and experimental procedures and
characterization data for all cleavage reactions. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Matsushita, Y.; Sugamoto, K.; Matsui, T. Chem. Lett. 1992, 2165.
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