Light-induced decarboxylation of (o-Acylphenyl)acetic acids

Article abstract of DOI:10.1021/ol0170758

(Matrix Presented) Near-UV irradiation of both o-acetylphenyl-and o-benzoylphenylacetic acids in benzene solution results in their efficient decarboxylation. Their meta and para isomers do not undergo this process. The O-deuterated acids yield deuterated

Full text of DOI:10.1021/ol0170758

ORGANIC
LETTERS
2002
Vol. 4, No. 3
379-382
Light-Induced Decarboxylation of
(o-Acylphenyl)acetic Acids
Martin Sobczak and Peter J. Wagner*
Chemistry Department, Michigan State UniVersity, East Lansing, Michigan 48824
wagnerp@pilot.msu.edu
Received November 20, 2001
ABSTRACT
Near-UV irradiation of both o-acetylphenyl- and o-benzoylphenylacetic acids in benzene solution results in their efficient decarboxylation.
Their meta and para isomers do not undergo this process. The O-deuterated acids yield deuterated o-acyltoluene products, suggesting the
possibility of an intramolecular proton transfer step in the decarboxylation process, although intermolecular deuteration would achieve the
same result. The corresponding esters and amides are essentially photoinert and, like the acids, do not undergo the benzocyclobutenol
formation expected of o-alkylphenyl ketones.
The light-induced decarboxylation of various R-arylcarboxy-
lic acids has received a good deal of attention, especially
since several NSAIDs are R-arylpropionate salts.1 In the case
of the parent phenylacetic acid, two mechanisms have been
identified that involve the π,π* excited singlet state of the
aromatic moiety:2
ently also by internal electron transfer to the n,π* singlet
and/or triplet states of its ketone chromophore.4
(1) In polar protic solvents, electron transfer from the
carboxylate anion site to the benzene ring is followed by
rapid loss of CO2 from the carboxy radical site, the resulting
benzyl anion then being protonated by solvent.
We now report another such photodecarboxylation of
(acylphenyl)acetic acids, one that proceeds by a different
mechanism that may include but is not initiated by electron
transfer. UV-irradiation of both (o-acetylphenyl)acetic acid
1 and (o-benzoylphenyl)acetic acid 2 in benzene causes loss
of CO2 and leaves o-acyltoluenes as products. Our discovery
of this process resulted from studies of substituent effects
on the Yang photoenolization of o-alkylphenyl ketones.5
Having shown that a variety of o-acyltoluenes substituted
on the benzylic carbon undergo stereoselective photocycliza-
tion to benzocyclobutenols via γ-hydrogen abstraction by
excited n,π* states,6 we were disappointed to find that neither
(2) In less polar solvents photoionization induces ho-
molytic cleavage, which generates benzyl radicals that both
dimerize and abstract hydrogen atoms from solvent.
Ketoprofen, sodium R-(3-benzoylphenyl)propionate, also
undergoes decarboxylation only in protic solvents,3 appar-
(1) Kochevar, I. E.; Hoover, K. W.; Gawienowski, M. J. InVest. Dermatol.
1984, 82, 214. Ljunggren, J. J. Photodermatol. 1985, 2, 3. Navaratman, S.;
Hughes, J. L.; Parsons, B. J.; Phillips, G. O. Photochem. Photobiol. 1985,
41, 375. Encinas, S.; Miranda, M. A.; Marconi, G.; Monti, S. Photochem.
Photobiol. 1998, 67, 420.
(2) Budac, D.; Wan, P. J. Photochem. Photobiol., A 1992, 67, 135. Epling,
G. A.; Lopes, A. J. Am. Chem. Soc. 1976, 99, 2700.
(3) Bosca, F.; Miranda, M. A.; Carganico, G.; Mauleon, D. Photochem.
Photobiol. 1994, 60, 96. Constanzo, L. L.; DeGuidi, G.; Condorelli, G.;
Cambria, A.; Fama, M. Photochem. Photobiol. 1989, 50, 359.
(4) Martinez, L. J.; Scaiano, J. C. J. Am. Chem. Soc. 1997, 119, 11066
and references therein.
(5) Yang, N. C.; Rivas, C. J. Am. Chem. Soc. 1961, 83, 2213.
10.1021/ol0170758 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

esters nor amides of 1 and 2 do so. (They do form some as
yet unidentified products in very low chemical and quantum
yields.) Knowing the rapidity of γ-hydrogen abstraction in
o-alkylphenyl ketones7 and the 10- to 30-fold extent to which
γ cyano and carboxy groups lower rates of Norrish type II
hydrogen abstraction,8 we were certain that the esters and
amides of 1 and 2 should undergo very efficient triplet state
γ-hydrogen abstraction to form o-xylylenols. Knowing that
the o-xylylenol intermediates undergo rapid acid-catalyzed
reketonization,9 we suspected that trace amounts of acid in
the esters and amides might be responsible for the lack of
cyclization products, and so we studied 1 and 2 themselves.
NMR tubes containing benzene-d6 solutions 0.01 M in 1
or 2 were irradiated for 20-30 min at 40 °C in a Rayonet
solvents. The knowledge that cyclization of any o-xylylenol
would be prevented by the acid can be combined with
revealing studies on the behavior of o-acetylphenylacetoni-
trile 3. Park found that upon irradiation in methanol 3 forms
its amide; he proposed hydrogen abstraction as the first step.10
Agosta and co-workers studied this process independently
and showed convincingly that in methanol triplet 3 undergoes
the expected γ-hydrogen abstraction, which is followed by
a very plausible series of ionic reactions of the resulting
o-xylylenol.11
1
reactor with 300-nm lamps, after which H NMR analysis
revealed that the 3.5 or 3.8 ppm methylene singlet of the
reactant had disappeared to be replaced by a 2.2 or 2.5 ppm
singlet characteristic of the benzylic methyl of o-acyltoluenes.
The acyltoluene products were isolated from preparative scale
irradiations; their NMR spectra, mass spectra, and GC
retention times were identical to those of pure samples. The
time required for complete conversion, when compared to
that for the photocyclizations of similar compounds, indicated
quantum yields in the 50% range. A benzene solution of 1
in a sealed IR cell was irradiated, after which the sample
contained a bubble and showed an intense new peak at 2340
cm-1 characteristic of CO2 and greatly diminished intensities
of the acid carbonyl and hydroxyl peaks.
The key revelations that the above facts provide are (1) if
3 forms an o-xylylenol, then so should 1 and 2, which in
the case of their esters and amides mainly revert to ketone;
and (2) if traces of 1 or 2 can cause o-xylylenols to revert to
starting material by intermolecular catalysis, then intra-
molecular protonation of xylylenols might also occur. To
test the validity of these conclusions, we prepared and
irradiated the O-deuterated versions of 1 and 2. In both cases
the benzylic methyls of the acyltoluene products were
2
deuterated, as indicated by both H NMR peaks and split
1H NMR peaks at 2.2 or 2.5 ppm and by large M + 1 and
M + 2 mass spectral peaks in the case of 2. This alone does
not prove intramolecular benzylic deuteration.
We propose the mechanism for decarboxylation depicted
in Scheme 1. First the n,π* excited ketone chromophore
Scheme 1
As with the esters and amides, no trace of a benzocy-
clobutenol could be observed. Unreacted ketoacid must
catalyze reketonization of any o-xylylenol products before
they can cyclize. Apparently even the low concentration of
ketoacid reactant remaining after >95% complete reaction
is sufficient to prevent any photocyclization of the acyltolu-
ene products, which form benzocyclobutenols quite ef-
ficiently in the absence of acid.6a
As for the mechanism of this decarboxylation, it clearly
cannot be due to electron transfer from carboxyl to excited
carbonyl, for several reasons. First, we found no such
decarboxylation by the meta and para isomers of 1, which
should undergo electron transfer as readily as their ortho
isomer. (We have not yet studied their behavior in protic
solvents but do not anticipate behavior much different from
that of ketoprofen.) Second, for other R-aryl acids, including
ketoprofen, electron transfer does not occur in hydrocarbon
abstracts a hydrogen atom from the ortho benzylic carbon
to generate an excited xylylenol BR1 that relaxes via
rearranged BR2 to a ground-state xylylenol X1, the well-
known mechanism for photoenolization of o-alkylphenyl
(6) (a) Wagner, P. J.; Subrahmanyam, D.; Park, B.-S. J. Am. Chem. Soc.
1991, 113, 709. (b) Wagner, P. J.; Sobczak, M.; Park, B.-S. J. Am. Chem.
Soc. 1998, 120, 2488.
(7) kH > 109 s-1: Wagner, P. J.; Chen, C.-P. J. Am. Chem. Soc. 1976,
98, 239.
(8) Wagner, P. J.; Kemppainen, A. E. J. Am. Chem. Soc. 1972, 94, 7495.
(9) Scaiano, J. C.; Wintgens, V.; Netto-Ferreira, J. C. Tetrahedron Lett.
1992, 33, 5905.
(10) Park, B.-S., Ph.D. Thesis, Michigan State University, 1992.
(11) Lu, A. L.; Bovonsombat, P.; Agosta, W. C. J. Org. Chem. 1996,
61, 3729.
380
Org. Lett., Vol. 4, No. 3, 2002

ketones.6,12 Next a carboxyl group protonates the xylylenol
to generate a zwitterionic species Z, which then can
decarboxylate by one of two pathways: a one-electron
transfer to generate a biradical BR3 that undergoes the rapid
decarboxylation expected of carboxyl radicals, generating
xylylenol X2 via the singlet biradical BR4, or a two-electron
decarboxylation that generates X2 directly. X2 then under-
goes, from any proton source, acid-catalyzed ketonization
to final product.
Scheme 3
With a ∼103 M-1 s-1 rate constant for protonation of
o-xylylenols by acetic acid,9 the pseudo-unimolecular rate
constant for bimolecular protonation of X1 by 0.01 M
ketoacid is 10 s-1. Thus formation of Z probably involves
some protonation of X1 by a second ketoacid molecule,
followed by rapid proton exchange. However, reprotonation
of the ketocarboxylate anion by the hydroxy-carbocation is
more likely and would explain the formation of doubly
deuterated acyltoluenes, as shown in Scheme 2. It is not clear
to what extent the dimerization of acids in hydrocarbon
solvents would affect bimolecular protonation; how rapid
intramolecular 1,3-proton transfer might be also awaits
determination.
further behavior, one very relevant example being the nearly
complete lack of photoreactivity of o-benzylacetophenone.6b
The biradical it forms by γ-hydrogen abstraction relaxes to
a geometry with the OH pointed in and both xylylenols
formed from it maintain that feature, which results in rapid
and exclusive reversion to starting ketone.14 It struck us that
similar behavior by the various o-acylphenylacetic acid
derivatives could provide another explanation for their lack
of benzocyclobutenol formation. That would be the case if
carboxyl and cyano groups were better than a methyl/
hydroxyl combination at stabilizing one radical site on these
triplet biradicals, a possibility that seemed reasonable enough
to investigate.
Scheme 2
We performed computations at a variety of levels,15 all of
which indicate that the lowest energy geometry of triplet BR2
from both 1 and 2 is that drawn in Scheme 1, with the
R-hydroxyl radical site twisted 90° out of conjugation with
the center benzene ring and the enolate radical site conjugated
with the benzene ring. As shown in Scheme 4, this geometry
Scheme 4
We do not have specific experimental evidence for an
electron-transfer step, other than knowledge of the facility
with which carboxylate anions undergo one-electron oxida-
tion by excited states. Precedent for the Z f BR3 pathway
for decarboxylative electron transfer is afforded by earlier
reports of sensitized decarboxylation of carboxylic acids, but
only those containing readily oxidizable groups. The process
is induced by one-electron transfer to excited ketones, as
shown in Scheme 3.13 Direct hydrogen atom abstraction from
a carboxyl group cannot be involved.
collapses to two ground-state o-xylylenols with the carboxyl
group pointing out, Xoo with the OH pointing out, Xio with
OH in.6b The latter reverts rapidly to starting ketone by a
1,5-sigmatropic H shift, whereas the former lives long
enough to undergo protonation either by its own or another
molecule’s carboxyl group.
A key feature of Scheme 1 is the geometry of BR2, which
determines which isomers of X1 are formed and thus the
selectivity of further reactions. We have already noted how
the geometric preferences of such biradicals dominate their
It is noteworthy that the methyl/hydroxyl combination is
predicted to stabilize a radical site better than does a cyano
(12) Small, R. D., Jr.; Scaiano, J. C. J. Phys. Chem. 1977, 81, 2126.
(13) (a) Davidson, R. S.; Harrison, K.; Steiner, P. R. J. Chem. Soc. C
1971, 3480. (b) Cohen, S. G.; Ojampera, S. J. Am. Chem. Soc. 1975, 97,
5633.
(14) Haag, R.; Wirz, J.; Wagner, P. J. HelV. Chim. Acta 1977, 60, 2595.
(15) UHF/PM3, 6-31G*, Dft.
Org. Lett., Vol. 4, No. 3, 2002
381

or carbonyl group. The calculations indicate a 2.8 kcal/mol
gap between the energies of BR1 and BR2, which would
provide only 1% population of BR1 at thermal equilibrium.
It thus appears that the lack of cyclization of the various
derivatives of 1 cannot be blamed on exclusive xylylenol
formation from the initial BR1 geometry. If the triplet
biradical preferred the BR1 geometry with the carboxyl
radical site twisted, only xylylenols with the OH in would
be formed6b and most or all would revert to starting ketone,
in which case the decarboxylation of 1 and 2 could not
display anything close to the measured ∼50% quantum
efficiency.
Scheme 5
A thoughtful referee has suggested that the benzylic
deuteration could be due to an inter- or intramolecular H/D
exchange between a carboxyl and an enolic hydroxyl group
on xylylenol Xii or Xio, followed by internal protonation
by the ennolic OD group. Such a process would indeed
deuterate the benzylic carbon but in doing so would merely
regenerate reactant and thus prevent decarboxylation, which
requires total loss of the carboxyl proton. The idea is doubly
unlikely given that the computations suggest that xylylenol
Xii is not formed.
lecular processes are probably at least partially involved in
all protonations of these photoproduced xylylenols.
Since o-alkylacetophenones react from both singlet and
triplet excited states,7,14 it is likely that both biradical
conformers are populated enough to form all possible
xylylenols. However, we found little difference in the
behavior of 1 and 2, although benzophenones react only from
their triplet states. We shall perform more quantitative
measurements on these compounds in order to provide better
information about intermediates and the extent of bimolecular
protonations in these reactions.,
Internal protonation of the Xii xylylenol from 3 has been
suggested to initiate amide formation.11 It is hard to picture
this happening unless xylylenols are formed mainly from
the BR1 geometry. Scheme 5 shows both intra- and
intermolecular protonation processes that may compete in
the xylylenols formed from 3. Xio can only revert to 3
intramolecularly. It is not clear how well a 1,7-proton transfer
to nitrogen would compete with the known rapid 1,5-transfer
to carbon in Xii. However, both Xio and Xoo can protonate
another xylylenol by the bimolecular process that causes the
slow reversion of other Xoo xylylenols to ketone.14 Bimo-
Acknowledgment. This work was supported by NSF
grants CHE95-08308 and CHE98-11570.
OL0170758
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Org. Lett., Vol. 4, No. 3, 2002