A remarkably long-lived benzyl carbanion

Article abstract of DOI:10.1021/ol036313r

(Equation presented) The photochemistry of ketoprofen, a widely used nonsteroidal antiinflammatory drug (NSAID) has been the subject of several studies as a result of its known phototoxicity. Photolysis of ketoprofen leads to 3-ethylbenzophenone, a proces

Full text of DOI:10.1021/ol036313r

ORGANIC
LETTERS
2004
Vol. 6, No. 6
873-875
A Remarkably Long-Lived Benzyl
Carbanion
Marie Laferrie`re, Carlos N. Sanrame´, and J. C. Scaiano*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa,
Ontario, K1N 6N5, Canada
tito@photo.chem.uottawa.ca
Received November 26, 2003
ABSTRACT
The photochemistry of ketoprofen, a widely used nonsteroidal antiinflammatory drug (NSAID) has been the subject of several studies as a
result of its known phototoxicity. Photolysis of ketoprofen leads to 3-ethylbenzophenone, a process that is mediated by a short-lived carbanion.
We have found that under carefully controlled conditions in THF, the lifetime of the carbanion can be extended to several hours, thus providing
a powerful tool for studying the mechanism of its formation and subsequent reactions.
Ketoprofen (1) and related benzophenone derivatives have
proven to be convenient photochemical sources of carban-
ions.1 Carbanion 2 has a lifetime of ca. 200 ns in water and
can be readily detected in laser flash photolysis experiments
as a result of its characteristic absorption at ∼600 nm.2 The
short lifetime in aqueous solution is not unexpected, since
rapid protonation leads to the quantitative formation of
3-ethylbenzophenone (3). The carbanion lifetime can be
extended by about 1 order of magnitude by isolation in dry
zeolites.3
Despite purification and drying efforts, lifetime enhancements
in DMSO are marginal. In this communication, we report
that the lifetime of 2 in dry, basic THF can be enhanced to
many minutes at room temperature, thus allowing a more
detailed characterization of this species.
To provide a basic environment, sodium hydride was
added to samples of 1 in THF, freshly distilled over metallic
sodium. The samples also had a small excess of solid NaH.
It is likely that in addition to providing a basic environment
(decarboxylation is a characteristic reaction of the carboxylate
form of ketoprofen),2 NaH acted as a sacrificial drying agent
for small traces of moisture.
Carbanion 2 and related species can also be detected in
organic solvents, such as dimethyl sulfoxide, DMSO, which
has been employed for mechanistic and kinetic studies.4
Laser irradiation (355 nm) of solutions of 1 in dry, basic
THF led to the formation of a distinct blue coloration in the
exposed region. We attribute this color to the formation of
carbanion 2, which under these experimental conditions has
a lifetime of several minutes (hours in a freezer at -20 °C).
Typical concentrations generated in this manner are in the
(1) (a) Cosa, G.; Llauger, L.; Scaiano, J. C.; Miranda, M. A. Org. Lett.
2002, 4, 3083-3085. (b) Borsarelli, C. D.; Braslavsky, S. E.; Sortino, S.;
Marconi, G.; Monti, S. Photochem. Photobiol. 2000, 72, 163-171. (c) Xu,
M.; Wan, P. Chem. Commun. 2000, 2147-2148.
(2) (a) Bosca, F.; Marin, M. L.; Miranda, M. A. Photochem. Photobiol.
2001, 74, 637-655. (b) Cosa, G.; Martinez, L. J.; Scaiano, J. C. Phys. Chem.
Chem. Phys. 1999, 1, 3533-3537. (c) Martinez, L. J.; Scaiano, J. C. J.
Am. Chem. Soc. 1997, 119, 11066-11070. (d) Monti, S.; Sortino, S.; De
Guidi, G.; Marconi, G. J. Chem. Soc., Faraday Trans. 1997, 93, 2269-
2275.
(3) Chre´tien, M. N.; Cosa, G.; Garcia, H.; Scaiano, J. C. Chem. Commun.
2002, 2154-2155.
(4) Llauger, L.; Cosa, G.; Scaiano, J. C. J. Am. Chem. Soc. 2002, 124,
15308-15312.
submillimolar range. It is worth noting that for a 10-4
M
solution of carbanion, 2 ppm of water would be sufficient
to destroy it quantitatively. It is possible that 2 may be
stabilized by ion-pairing in the nonpolar environment;
resonance forms containing a benzyl radical center and a
ketyl radical-anion may also contribute to the stability,
10.1021/ol036313r CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004

photoinduced formation of the blue color, although it does
have some effect on the transient phenomena observed under
these conditions (vide infra). It has been proposed that
carbanion formation proceeds from the singlet state of
ketoprofen.2b Our observations are consistent with this
proposal.
Scheme 1
Laser flash photolysis of 1 in basic THF yields the
characteristic signals from the ketyl radical of the benzophe-
none-like moiety, with a maximum at ca. ∼550 nm (see
Figure 2).
although it should be noted that this biradicaloid form may
have a triplet ground state.
Having some experience drying THF over sodium, our
first reaction was to assume that the blue color was due to
the benzophenone-like radical-anion from ketoprofen, formed
photochemically by some unknown mechanism. Benzophe-
none is frequently used as a dryness indicator, since the
formation of blue radical-anion 4 shows that the solvent is
dry, Scheme 2.
Scheme 2
Figure 2. Laser flash photolysis with a 355 nm laser, spectra of
KP in THF with NaH (O, 2.4 µs; 0 46.7 µs, ], 78.7 µs, and 4174.7
µs after the laser pulse).
Our experiments show that the blue color formed upon
irradiation of ketoprofen in THF is not due to a radical-anion
similar to 4. The visible spectrum of the species formed upon
355 nm laser excitation of 1 in THF is shown in Figure 1.
We attribute ketyl formation to a triplet state reaction, since
benzophenone triplet readily abstracts hydrogen from THF.
Our results cannot establish if ketyl formation involves the
acid or carboxylate forms of ketoprofen. Consistent with this
hypothesis, ketyl radical formation is suppressed by addition
of triplet quenchers. For example, addition of 0.07 M
1-methylnaphthalene is sufficient to quench completely the
formation of ketyl radical signals. The decay of the ketyl
radical occurs in the microsecond time scale, as illustrated
in Figure 3. These signals are therefore not expected to be
detected in the “minute” time scale.
Figure 1. Visible spectra, after baseline correction, of a solution
of KP in basic THF after irradiation with a 355 nm laser.
The long lifetime of this blue color allowed several
reactivity tests that reflect the basic and nucleophilic character
of this species. Thus, water, methanol, acetone, and methyl
iodide all bleached the blue color immediately following
addition to freshly prepared samples.
We note that identical samples that contain benzophenone
instead of ketoprofen do not yield the long-lived blue species
upon 355 nm laser excitation. This strongly suggests that
color formation involves the side chain in ketoprofen, rather
that just the benzophenone moiety.
Figure 3. Decay of the signal at 550 nm, without (a) and after
adding 2.5 mM (b) and 5 mM (c) 1-methylnaphthalene to 9 mM
KP in THF and NaH.
When the transient signals are monitored in the 650 nm
region, one observes a jump and a distinct growth in the
microsecond time scale. This is illustrated in Figure 4.
Addition of 1-methylnaphthalene (a well-known triplet
quencher) to samples of 1 in THF has no effect on the
874
Org. Lett., Vol. 6, No. 6, 2004

mentioned before confirm not only the reactive nature of
the blue species but also its ability to compete with hydride.
Further, in the case of methyl iodide as a substrate, the
product of carbanion scavenging (3-isopropylbenzophenone)
was detected by GCMS; its concentration was about twice
as large as that for 3-ethylbenzophenone. The products of
trapping by carbonyl compounds have been characterized
previously in the case of carbanion reaction in zeolites.3
We were surprised by the long lifetimes observed, since
both the carbanion and its precursor are carbonyl compounds
themselves and therefore possible reactants (i.e., addition to
give the carbinol). We rationalize this observation in terms
of (a) the submillimolar concentrations involved disfavoring
second-order reactions; (b) Coulombic repulsion, since both
reactants are negatively charged; and (c) the low dielectric
constant of THF (7.6) tending to maximize repulsive
interactions. It is also possible that in samples preserved for
long times the excess hydride may have consumed some of
the initial ketoprofen present.
Product studies were performed following laser or CW
exposure (355 or 350 nm) of samples of 1 in basic THF.
Both an acid and a basic workup were performed on the
samples (see Supporting Information for details). Basic
workup followed by extraction in ether eliminates all base-
soluble products, retaining only nonpolar products. Under
these conditions the major product detected is 3-ethylben-
zophenone, consistent with carbanion involvement. Acid
workup was followed by treatment with diazomethane in
order to produce the methyl ester of products retaining the
carboxylic acid. In addition to 3-ethylbenzophenone, these
studies revealed the formation of typical photoreduction
products, ketoprofen-THF adducts, presumably formed by
recombination of radical products. Unfortunately, these
products are formed in submillimolar concentration rendering
their full characterization difficult. However, their mass
spectrum is consistent with the radical reactions observed
by laser flash photolysis.
Figure 4. Kinetic traces showing absorbance change at 650 nm
before and after adding 1-methylnaphthalene (1-MeNp) to 9 mM
KP in dry THF with excess NaH.
It is clear that absorption in the 650 nm region would yield
a characteristic blue color. Addition of 1-methylnaphthalene
results in a reduction and eventually the total elimination of
the growth component in the traces recorded at 650 nm
(Figure 4). Thus, this observation suggests that the “jump”
in Figure 4 is due to a singlet reaction, while the quenchable
growth reflects a triplet-mediated process. We believe that
the growth component is due to radical-anion formation by
deprotonation of the ketyl radical, Scheme 3.
Scheme 3
Since 5 is the product of a triplet reaction with the solvent,
one anticipates that its formation will be quenched by
1-methylnaphthalene. Thus, the growth component is at-
tributed to formation of a radical anion, while the singlet-
mediated “jump” is attributed to carbanion 2.
While the formation of 6 can be perceived as a complica-
tion in the process, in fact it provides a clear distinction
between radical anion and carbanion signals. Thus, two blue
signals are formed. One, due to the radical anion, can be
readily quenched by 1-methylnaphthalene and under our
experimental conditions does not survive for minutes. The
other, due to carbanion 2, is singlet-derived, is not quenched
by triplet quenchers, and under careful water exclusion it
survives for minutes.
In summary, our studies reveal that under dry, basic
conditions the carbanion derived from ketoprofen can have
very long lifetimes, presumably unlimited under ideal
experimental conditions. This carbanion is produced in a
singlet-state reaction, at least in non-hydroxylic media. Its
chemistry is in agreement with that anticipated from well-
known nucleophilic reactivity patterns.
Acknowledgment. This work has been generously sup-
ported by a discovery grant from the Natural Sciences and
Engineering Research Council of Canada (NSERC). M.L.
thanks NSERC for a PGS-B scholarship.
Unfortunately, product studies could not be carried out
with typical substrates for SN2 reactions (methanol, ketones,
alkyl halides) present during the irradiation, since the hydride
(present in excess in all samples) readily reacts with them
before exposure. However, the decoloration experiments
Supporting Information Available: Experimental pro-
cedures and additional graphs and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL036313R
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