Photolytic release of carboxylic acids using linked donor-acceptor molecules: Direct versus mediated photoinduced electron transfer to N-alkyl-4-picolinium esters

Article abstract of DOI:10.1021/ol050744n

(Chemical Equation Presented) Efficient photorelease (Φ = 0.7) of carboxylic acids is achieved with a covalenlly linked mediator (benzophenone) protecting group (N-alkyl-4-picolinium ester) molecule. The mechanism involves initial photoreduction of the mediator, followed by rapid electron transfer to the protecting group.

Full text of DOI:10.1021/ol050744n

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2631-2634
Photolytic Release of Carboxylic Acids
Using Linked Donor Acceptor
−
Molecules: Direct versus Mediated
Photoinduced Electron Transfer to
N-Alkyl-4-picolinium Esters
Chitra Sundararajan and Daniel E. Falvey*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
falVey@umd.edu
Received April 6, 2005
ABSTRACT
Efficient photorelease (Φ ) 0.7) of carboxylic acids is achieved with a covalently linked mediator (benzophenone) protecting group (N-alkyl-
4-picolinium ester) molecule. The mechanism involves initial photoreduction of the mediator, followed by rapid electron transfer to the protecting
group.
The controlled photochemical release of functional molecules
is a general goal in photochemistry. In the past decade a
series of useful molecular systems known as “phototriggers”,
“photoremovable protecting groups” (PRPGs), or “caged
molecules” have been developed.1 In these systems a
functional molecule is deactivated through covalent attach-
ment to a protecting group. The latter is then released at a
specified time and located through UV or visible irradiation.
Successful PRPGs include various ester derivatives of
2-nitrobenzyl alcohol,2 benzoin,3 and phenacyl alcohol,4 as
well as various aryl ketone derivatives.5 Such PRPGs have
been used in diverse applications such as multistep synthesis,1b
the fabrication of combinatorial libraries,6 time-resolved
X-ray crystallographic studies of enzymatic reactions,7 and
the temporal or spatial manipulation of cellular process.8
Despite this remarkable progress, several problems remain
to be addressed. One of these is controlling the light
wavelengths required for photorelease. With most PRPGs,
the triggering photon is absorbed directly by the protecting
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Goody, R. S. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7687-7690. (b)
Schlichtig, I.; Almo, S. C.; Rapp, G.; Wilson, K.; Petratos, K.; Lentfer, A.;
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10.1021/ol050744n CCC: $30.25
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group and the requisite wavelengths are determined by its
chromophore. As a rule it is difficult to extend the conjuga-
tion of PRPG chromophores without adversely affecting the
bond cleavage rates and selectivity, although some recent
progress has been reported.9
Herein we report photochemical studies on linked donor-
NAP molecules. Attempts to achieve efficient photorelease
with a simple sensitizer, 9-alkylcarbazole, are unsuccessful.
It is argued that this is due to rapid BET. However, efficient
photorelease is achieved using mediated electron transfer.
In particular, it is shown that a covalently tethered ben-
zophenone chromophore can, upon photoexcitation, abstract
an electron from an external donor. The resulting benzophe-
none anion radical then transfers an electron to the NAP
group, triggering release of a carboxylate ion.
Mediated electron transfer (also called electron-transfer
cosensitization)15 has been shown to substantially increase
the quantum yields of a variety of PET-initiated processes.16
In our embodiment of this scheme, initial electron transfer
occurs between a donor and an excited-state mediator. The
reduced mediator then relays an electron to the substrate in
a subsequent ground-state electron-transfer process. This
approach avoids the problem of having a rapid, exergonic
back electron transfer reaction compete with the desired bond
scission process.
Our approach to the issue of wavelength control has been
to decouple the light absorption and bond-breaking steps in
PRPGs through the use of electron-transfer sensitization.10
In these systems, light is absorbed by an electron-donor
sensitizer. The excited-state sensitizer then encounters and
transfers an electron to the protecting group, triggering a
bond-breaking event, releasing the protected molecule. It was
demonstrated that phenacyl esters could be used in this way.11
Photoinduced one-electron reduction with a variety of
sensitizers was shown to promote rapid and high yield release
of carboxylic acids. However the very negative reduction
potential (ca. -2.2 V vs SCE) of the phenacyl group limits
the range of sensitizers that can be employed. Subsequent
efforts have focused on the N-alkyl-4-picolinium esters
(NAP) (1, Scheme 1).12 The NAP group is reduced at less
Scheme 2 shows the linked mediator-acceptor systems
that we studied. Benzophenone (BP) was chosen as the
Scheme 1. Release of Carboxylate Ions from NAP Group
Scheme 2. Synthesis of Linked Mediator-NAP Molecule
negative potentials (-1.1 V vs SCE) than the phenacyl group,
allowing activation by a wider variety of photoreductants.
In fact a recent report shows that the NAP group can be
activated using high-wavelength laser dyes.13
One limitation imposed by the sensitization approach is
that the quantum yields for deprotection depend on the
concentration of the NAP ester. This is because the bimo-
lecular electron transfer step competes with unimolecular
relaxation of the excited sensitizer. A potential solution to
this problem is to covalently tether the sensitizer to the
protecting group. However, the problem then becomes
competition between back electron transfer (BET) and the
desired bond-breaking step. In fact, this problem was
encountered in our attempts to create a useful PRPG by
linking an anthracene donor to a phenacyl ester group. This
PRPG was found to be stable to prolonged irradiation, despite
the fact that unlinked analogues of this system release
carboxylates with high efficiencies.14
mediator for the following reasons. (1) Its reduction potential
(-1.68 V) is more negative than that of the picolinium
esters.17 Thus electron transfer is expected to occur rapidly
and irreversibly to the acceptor. (2) BP is a very well
characterized chromophore with a relatively high wavelength
absorption maximum (380 nm). (3) BP undergoes rapid
intersystem crossing. This means that the geminate radical
ion pair formed following electron abstraction from the donor
will be in the triplet state as well. That, in turn, should reduce
BET and make the overall photorelease process more
efficient.18
(9) Wo¨ll, D.; Walbert, S.; Stengele, K.-P.; Albert, T. J.; Richmond, T.;
Norton, J.; Singer, M.; Green, R.; Pfleiderer, W.; Steiner, U. HelV. Chim.
Acta 2004, 87, 28-45.
The linked mediator-acceptor synthesis is fairly straight-
forward (Scheme 2). Friedel-Crafts acylation of 1-phenyl-
(10) Sundararajan, C.; Falvey, D. E. Photochem. Photobiol. Sci. 2004,
3, 831-838.
(14) Lee, K.; Falvey, D. E. J. Am. Chem. Soc. 2000, 122, 9361-9366.
(15) Gould, I. R.; Ege, D.; Moser, J. E.; Farid, S. J. Am. Chem. Soc.
1990, 112, 4290-4301.
(16) (a) Rinderhagen, H.; Mattay, J. Chem. Eur. J. 2004, 10, 851-874.
(b) Morkin, T. L.; Turro, N. J.; Kleinman, M. H.; Brindle, C. S.; Kramer,
W. H.; Gould, I. R. J. Am. Chem. Soc. 2003, 125, 14917-14924.
(17) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochem-
istry, 2nd ed.; Marcel Dekker: New York, 1993.
(11) (a) Banerjee, A.; Falvey, D. E. J. Org. Chem. 1997, 62, 6245-
6251. (b) Banerjee, A.; Lee, K.; Yu, Q.; Fang, A. G.; Falvey, D. E.
Tetrahedron Lett. 1998, 39, 4635-4638. (c) Banerjee, A.; Lee, K.; Falvey,
D. E. Tetrahedron 1999, 55, 12699-12710.
(12) Sundararajan, C.; Falvey, D. E. J. Org. Chem. 2004, 69, 5547-
5554.
(13) Sundararajan, C.; Falvey, D. E. J. Am. Chem. Soc. 2005, 127,
published ASAP.
(18) Peters, K. S.; Kim, G. J. Phys. Chem. A 2004, 108, 2598-2606.
2632
Org. Lett., Vol. 7, No. 13, 2005

2-bromoethane 5 forms 4-(2-bromoethyl)benzophenone 6.
The latter is combined with the appropriate 4-picolylester
7 to form the linked system 9. Three of these ions were
synthesized: a phenylacetate ester (9a), a diphenylacetate
ester (9b), and a nonreactive system having no leaving group
(9c).
Results from photolysis of 9a and 9b are shown in Table
1. In these experiments the linked esters were dissolved in
Table 1. Photolysis of Mediator-NAP Molecules with DMA
linked
ester
% acid
formed
% 9
consumed
% 9c
formed
conditions
2 h, MeOH
2 h, MeOH
2 h, MeOH, CHD
9a
9b
9a
70
63
41
76
62
46
40
CH3OH along with an electron donor, N.N-dimethylaniline
(DMA, 10-15 mM). These solutions were purged with N2
and then irradiated with wavelengths >320 nm. The product
mixtures were then analyzed by 1H NMR spectroscopy. As
shown in Table 1, the acids are formed cleanly and account
for all, or nearly all, of the consumed esters. To confirm the
identity of the product, photolysis of 9a was carried out on
a larger (3×) scale. The product, PhCH2CO2H, was isolated
Figure 1. Transient absorption spectra from pulsed laser photolysis
of 9a (top) and 9c (bottom) in MeOH with added DMA. Times
indicated are in µs.
1
in pure form (73% yield), and its H NMR spectrum was
found to be indistinguishable from that of an authentic
sample. With only DMA added, we could not identify any
byproduct associated with the picolinium benzophenone
portion of the molecule. However, when photolysis was
carried out with a radical scavenger, 1,4-cyclohexadiene
(CHD), quantitative yields of the expected byproduct 9c were
observed. For compound 9a the quantum yield of acid release
was determined using monochromatic irradiation at 380 (
10 nm to be Φ ) 0.72.
is transferred from the benzophenone anion radical to the
NAP group, occurs too rapidly (<100 ns) to be observed
with our instrument. Electron-transfer reactions between
DMA and BP triplet state have been studied in some detail.19
The geminate radical ion pair partitions between solvation,
forming the ion radicals, and proton transfer, forming
benzophenone ketyl radical. It is interesting to note that with
9a and b, no ketyl radical is detected. This implies that relay
electron transfer and the subsequent C-O bond scission
occur more rapidly than geminate proton transfer. Although
rate of this process in CH3OH has not been characterized,
rates of ca. 5 × 108 s-1 have been determined in other polar
solvents.20
The proposed mechanism, shown in Scheme 3, is sup-
ported by LFP experiments, as well as the product studies,
Scheme 3. Photorelease through Mediated Electron Transfer
The nonreactive model system, 9c, shows different be-
havior. In this case, LFP results in the formation of the
DMA+ •, along with BP- • and ketyl radical. Indeed, the
transient spectra immediately following LFP of 9c are very
similar to those from unlinked DMA/BP. In the case of 9c,
each of these transients decay in a non-first-order way and
each shows a different half-life. The BP anion radical decays
with the shortest half-life (0.61 µs), the DMA cation radical
decays with a somewhat longer half-life (2.7 µs), and BPH•
shows a still longer half-life (5.6 µs). There are two reasons
why the reduced BP intermediates are longer lived with this
and thermodynamic considerations described above. Figure
1a shows transient spectra taken following pulsed laser
photolysis of 9b with DMA in MeOH. The peak at 470 nm
is assigned to the well-known absorption of the DMA cation
radical. Not detected are the peaks for the H-bonded BP
anion radical (640 nm) or the BP ketyl radical (545 nm).19
Thus, we conclude that the relay step, in which an electron
(19) (a) Devadoss, C.; Fessenden, R. W. J. Phys. Chem. 1990, 94,
4540-4549. (b) Simon, J. D.; Peters, K. S. J. Am. Chem. Soc. 1982, 104,
6542-6547.
(20) Dreyer, J.; Peters, K. S. J. Phys. Chem. 1996, 100, 19412-19416.
Org. Lett., Vol. 7, No. 13, 2005
2633

model system. First, simple picolinium ions are more difficult
to reduce than the corresponding NAP esters, presumably
because of the inductive effect of the acyloxy substituent.12
Thus relay electron transfer is expected to be less exergonic
in this system and perhaps reversible (the redox potentials
were characterized in CH3CN rather than CH3OH). Second,
in the esters, the relay electron transfer is coupled to an
irreversible C-O bond heterolysis. On the other hand, with
the model system, proton transfer from DMA cation radical
to the BP- • constitutes the only irreversible process. A more
detailed kinetic study of these reactions is underway.
Also examined were linked systems, designed to undergo
direct photoinduced electron transfer. As shown in Scheme
4, the electron donor, carbazole, was covalently tethered to
Scheme 5. No Bond Scission in Donor-NAP Molecule
react with high efficiencies under these conditions.12 LFP
experiments on 11a-c show none of the anticipated charge-
transfer intermediates 12, whereas the corresponding radical
intermediates were easily detected in the unlinked cases.12
Thus, we conclude that back electron transfer in 11 occurs
much more rapidly than the C-O bond scission that would
give the carboxylate anion. In the absence of any direct
detection of the charge-transfer intermediates, it is difficult
to estimate the rates of any of these processes. However,
the lack of significant fluorescence from the linked systems
and the fact that we could not detect reduced picolinium ion
or carbazole cation radical by nanosecond LFP imply that
both PET and BET are occurring on a subnanosecond time
scale
Scheme 4. Synthesis of Linked Donor-NAP Molecule
These experiments emphasize the importance of addressing
the issue of BET when designing linked donor-acceptor
PRPGs. That 11b would show rapid BET is, perhaps,
unsurprising given that similar linked donor-acceptor mol-
ecules typically exhibit subnanosecond charge recombination
lifetimes.21 The successful and highly efficient photorelease
with 9 illustrates the promise of using mediated electron
transfer as a way of activating PRPGs, although practical
applications have yet to be explored. In principle, this
approach could be extended to visible light absorbing
mediators.
the NAP group. These include two propyl-linked esters, one
of phenylacetic acid 11a and one derived from 4-tolylacetic
acid 11b. A butyl-linked phenylacetic ester, 11c, was also
synthesized. These compounds were all prepared by nucleo-
philic substitutions of carbazole on 1,3-dibromopropane or
1,4-dibromobutane, followed by coupling of the resulting
compound (10) with a 4-picolyl ester (7). These bromide
-
salts were converted to the ClO4 salts (11) by treatment
with AgClO4.
Although the unlinked chromophore, 9-methylcarbazole,
shows very efficient fluorescence, the linked systems 11a-c
show no measurable fluorescent emission. The free energy
change for the excited state electron transfer is expected to
be significantly exergonic (∆GCT ) -33.2).12 On this basis,
we infer that the desired intramolecular electron-transfer
process occurs very rapidly. On the other hand, prolonged
photolysis (8 h with a 300 W Hg lamp) of esters 11a-c
results in no measurable release of the corresponding acids.
In contrast, analogous unlinked systems (e.g., Scheme 1)
Acknowledgment. This work was supported by the
Chemistry Division of the NSF.
Supporting Information Available: Detailed procedures
for synthesis of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050744N
(21) Bleisteiner, B.; Marian, T.; Schneider, S.; Brouwer, A. M.; Verho-
even, J. W. Phys. Chem. Chem. Phys. 2001, 3, 5383-5392.
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