Efficient photodecarboxylation of trifluoromethyl-substituted phenylacetic and mandelic acids

Article abstract of DOI:10.1111/j.1751-1097.2010.00737.x

A total of eight CF₃-substituted phenylacetic and mandelic acids are shown to undergo efficient photodecarboxylation (PDC; Φ = 0.37-0.74) in basic aqueous solution to give the corresponding trifluoromethyltoluenes or trifluoromethylbenzyl alcohols. The products are consistent with the almost exclusive formation of benzylic carbanions that subsequently react with water, with minor amounts (≤5%) of radical-derived products detected. Quenching studies indicate that the reaction likely proceeds from the singlet excited state. This work demonstrates that the CF₃ group greatly facilitates the excited state ionic PDC of phenylacetic acids.

Full text of DOI:10.1111/j.1751-1097.2010.00737.x

Photochemistry and Photobiology, 2010, 86: 821–826
Efficient Photodecarboxylation of Trifluoromethyl-substituted
Phenylacetic and Mandelic Acids
Misty-Dawn Burns and Matthew Lukeman*
Department of Chemistry, Acadia University, Wolfville, NS, Canada
Received 25 September 2009, accepted 6 March 2010, DOI: 10.1111 ⁄ j.1751-1097.2010.00737.x
contain the strongly electron withdrawing keto or nitro groups
ABSTRACT
attached to the aromatic ring follow a heterolytic pathway
similar to that in Eq. 1, and produce carbanion intermediates
with high quantum yield (10–13). Heterolytic PDC reactions
are of particular current interest as they have been exploited in
the design of new photoremovable protecting groups (PPGs)
with very promising properties (14,15). Benzophenone and
xanthone-based arylacetic acids (4) with leaving groups
substituted b to the benzylic carbon undergo heterolytic
PDC to generate carbanion 5, which rapidly eliminates the
leaving group (k > 10 s ) to give alkene 6 (Eq. 2). In
addition to the fast rates of substrate release, other advantages
associated with carbanion-mediated PPGs are high quantum
yield (F > 0.6), good aqueous solubility and good absorption
above 300 nm. They have been shown to be capable of
releasing a variety of leaving groups, including halides,
carboxylic acids, amines (via the carbamate) and alcohols.
3
A total of eight CF -substituted phenylacetic and mandelic acids
are shown to undergo efficient photodecarboxylation (PDC;
F = 0.37–0.74) in basic aqueous solution to give the corre-
sponding trifluoromethyltoluenes or trifluoromethylbenzyl alco-
hols. The products are consistent with the almost exclusive
formation of benzylic carbanions that subsequently react with
water, with minor amounts (£5%) of radical-derived products
detected. Quenching studies indicate that the reaction likely
proceeds from the singlet excited state. This work demonstrates
9
)1
3
that the CF group greatly facilitates the excited state ionic
PDC of phenylacetic acids.
INTRODUCTION
Photodecarboxylation (PDC) reactions have been of interest
for decades, partly because of the central role they play in the
photodecomposition of a number of pharmaceutical and
agricultural compounds (1). For example, ketoprofen (1), a
nonsteroidal anti-inflammatory drug (NSAID), undergoes loss
of CO when irradiated in neutral aqueous solution to give a
2
short-lived carbanion (2) that reacts with water to produce 3-
ethylbenzophenone (3) (Eq. 1) (2–7), a reaction that has been
linked to the phototoxic effects of this drug (8).
We are interested in finding new chromophores capable of
undergoing efficient heterolytic PDC, primarily so that they
might be exploited in the design of future PPGs related to 4 but
also because of our fundamental interest in the mechanism of
PDC reactions in general. Because nitro and keto functional
groups are well known to mediate efficient heterolytic PDC
(
and several other excited state reactions that produce benzylic
carbanions [16–20]), we became interested as to whether the
trifluoromethyl (CF ) group, another ground state EWG,
The mechanism of PDC for arylacetic acids such as
ketoprofen is strongly dependent on the nature of the other
substituents on the aryl ring (1). Arylacetic acids that lack a
strong electron withdrawing group (EWG) on the ring (a good
example is ibuprofen, another NSAID), will generally undergo
PDC via an inefficient homolytic pathway that produces
radical intermediates (9). However, arylacetic acids that
3
might also be able to promote ionic excited state reactions. The
CF group would represent an attractive alternative to the keto
and nitro substituents in PPG applications, as these latter
groups have a tendency to undergo competing photoinduced
hydrogen abstraction (especially when substituted in the ortho
3
3
position), and electron transfer chemistry. While CF substit-
uents are reasonably strong EWGs in the ground state
*
ꢀ
Corresponding author email: mlukeman@acadiau.ca (Matthew Lukeman)
2010 The Authors. JournalCompilation. The AmericanSocietyofPhotobiology 0031-8655/10
(rm = 0.43, r = 0.54) (21), it was not initially clear whether
p
8
21

8
22 Misty-Dawn Burns and Matthew Lukeman
this would translate into good electron withdrawing ability in
the excited state. EWGs that engage in conjugation with aryl
rings (such as the nitro and keto groups) generally experience
an enhancement of their ability to withdraw electron density
via resonance on excitation, producing an excited state that is
much more polar than the corresponding ground state.
Because the CF3 group is saturated and cannot engage in
direct conjugation with aryl rings to which it is attached, it
might not experience a sufficient enhancement of its electron
withdrawing properties to mediate ionic excited state reactions.
While there are no reports available to our knowledge that
of this solution to a quartz NMR tube. The solution was then bubbled
with N or argon via a stainless steel needle for 5 min and capped
2
tightly. Typically, four to eight such tubes were prepared and
irradiated simultaneously for periods of 3–20 min in a merry-go-
round apparatus to ensure that all tubes received the same light dose.
Quantum yield measurements were made by comparison of integra-
1
tions of the peaks in the H NMR spectra for samples of 7–14 with
those of ketoprofen (1) (3) irradiated simultaneously. For solubility
reasons, photolyses of ketoprofen were carried out in 1:1 CD
(
3 2
CN-D O
containing 0.16 NaOH) rather than in purely aqueous solution in
which its quantum yield is reported. We have measured the quantum
yield for PDC of ketoprofen under these modified conditions to be
87% of that in pH 7 buffer, or 0.65, and we used this value to
determine the quantum yields of 7–14. Reported quantum yields are
the average of three to five runs.
clearly demonstrate that the CF
state ionic reactions, Seiler and Wirz showed that ortho, meta
and para trifluoromethylphenols have pK * values (in S ) that
3
group can mediate excited
a
1
RESULTS
are around two units more acidic than that of unsubstituted
phenol (22), a fact which could be taken as evidence for the
existence of enhanced electron withdrawing ability of the CF3
Product studies
1 3
group in S . To explore whether the CF group is capable of
mediating heterolytic PDC of phenylacetic acids, the photo-
chemistry of five CF substituted phenylacetic acids (7–11) and
3
3
three CF substituted mandelic acids (12–14) was investigated
in aqueous solution. In this work we demonstrate that all eight
derivatives undergo PDC efficiently to give products consistent
with the initial formation of benzylic carbanions.
Carbanions generated from ionic PDC of 7–14 were expected
to react rapidly with water to give the corresponding trifluo-
romethyl-substituted toluenes (15–19 from 7–11, respectively)
or benzyl alcohols (20–22 from 12–14, respectively). Due to the
expected volatility of some of these products, photolyses of 7–
14 were carried out in quartz NMR tubes which allowed
identification and quantification of the photoproducts without
workup, thereby eliminating product loss. Irradiation of 7
(
lamps, argon bubbled) for 3 min in 1:1 CD CN-D O (con-
50 mM, LuzChem LZC-ORG photochemical reactor, 10 UVC
3
2
taining 0.16 M NaOH) resulted in 22% conversion to trifluo-
romethyltoluene 15 with one benzylic hydrogen replaced with
deuterium (i.e. 15-D, Eq. 3), as evidenced by the appearance of
1
a new peak at 2.45 ppm in the H NMR spectrum (Fig. S1,
Table S1). Photolysis for longer periods of time led to higher
conversions, with >90% conversion reached after 20 min
(
Fig. 1), and with no other primary or secondary photoprod-
1
ucts observed by H NMR spectroscopy. The formation of the
monodeuterated trifluoromethyltoluene 15-D is entirely con-
sistent with the initial formation of a carbanion intermediate
that subsequently reacts with the D O solvent. No other
2
1
products (such as dimers) (10,12) were observed in the
H
NMR spectra, suggesting a clean ionic reaction pathway rather
than a radical pathway. Irradiation of 8–11 gave similar
results, each giving efficient conversion to its corresponding
trifluoromethyltoluene photoproduct (i.e. 16-D–19-D from 8–
Structure 1.
1
1, respectively). Irradiation of 12–14 was carried out in the
MATERIALS AND METHODS
same manner in order to determine the effect of the a-hydroxyl
group on the reaction efficiency. Each of 12–14 underwent
efficient PDC as well, with the corresponding deuterium
containing trifluoromethylbenzyl alcohol (20-D–22-D) ob-
All phenylacetic and mandelic acids (7–14) were purchased from
Oakwood Chemicals and used as received. Authentic samples of 15,
17, 20 and 21, and 19 were also purchased from Oakwood Chemicals
and used for comparison in GCMS studies. NMR experiments were
performed on a Bruker AVANCE 300 (300 MHz) spectrometer using
deuterated solvents purchased from Norell, Inc. All other fine
chemicals were purchased from Sigma Aldrich Canada. Photolyses
were carried out in a LuzChem LZC-Org photochemical reactor
equipped with 10 low-pressure mercury lamps (254 nm output,
dose = 75 W m) ), in most cases in quartz NMR tubes (also
purchased from Norell). UV–Vis spectra were recorded on a CARY
1
tained as the only reaction product (Eq. 4) observable by H
NMR spectroscopy. Photolyses were repeated for 7–14 under
conditions identical to those described above, but with the base
(NaOH) omitted. Under these conditions, the carboxylic acid
functionality is expected to exist primarily in its undissociated
form. Even after irradiation for 20 min, no evidence for
2
100 spectrometer.
The photolysis procedure involved making a solution of the
1
product formation was apparent in the H NMR spectra,
indicating that the carboxylic acid group must be ionized in
order for the reaction to take place. Also, samples of 7–14
requisite phenylacetic or mandelic acid in a 1:1 (vol ⁄ vol) mixture of
CD CN and D O containing NaOH (0.16 M), and transferring 0.8 mL
3
2

Photochemistry and Photobiology, 2010, 86 823
dissolved in neutral or basic solution showed no observable
decarboxylation (by NMR spectroscopy) when kept in the
dark for a period of 2 h.
Table 1. Quantum yields for photodecarboxylation (in neutral or
basic aqueous solution) of 7–14 and for selected arylacetic acids for
comparison. Estimated errors are ± 10%.
Substrate
FPDC
Reference
7
8
9
1
1
1
1
1
0.46
0.41
0.37
0.74
0.56
0.53
0.37
0.69
0.04*
0.4
0
1
2
3
4
Phenylacetic acid
Mandelic acid
(24)
(25)
(10)
(10)
(10)
(10)
(11)
(11)
(12)
(12)
(13)
(13)
(13)
In order to probe for trace side products not visible by
H NMR analysis, higher conversion photolyses were car-
1
2
3
-Nitrophenylacetic acid
-Nitrophenylacetic acid
0.04
0.63
0.59
0.04
0.66
0.62
0.6
0.22
0.67
0
ried out for 7–14 (same conditions as above, irradiation
time = 20 min), and the photolysates were analyzed by
GC-MS. For 7–14, the major products observed via this
method of analysis in all cases were the corresponding toluenes
and benzyl alcohols 15–22, as indicated by their mass spectra.
We also ran authentic samples of 15, 17, 20 and 21 by GCMS
for comparison, and they matched those produced photo-
chemically in both their retention times and mass spectra. In
addition to these primary product peaks, small peaks were
observed in the photolysis runs for all cases that had retention
times and mass spectra consistent with dimeric photoproducts.
4-Nitrophenylacetic acid
2
3
4
3
,4-Dinitrophenylacetic acid
-Benzoylphenylacetic acid
-Benzoylphenylacetic acid
-Acetylphenylacetic acid
4-Acetylphenylacetic acid
2-Xanthoneacetic acid
3
4
-Xanthoneacetic acid
-Xanthoneacetic acid
0.61
*
In basic methanol.
1
Due to our inability to detect these by H NMR spectroscopy,
and because of their small relative peak integrations in the GC-
MS chromatograms, we estimate that they account for £5% of
the product obtained in all cases. The presence of dimeric
products in the photolysate suggests that in addition to the
primary heterolytic PDC, a much less efficient homolytic
pathway is available that produces benzylic radicals. These
dimeric photoproducts are unlikely to be secondary photo-
products resulting from excitation of primary products 15–22;
the photochemistry of trifluoromethyltoluenes has been exam-
ined in detail, and the major reaction is phototransposition
Quantum yields for PDC of 7–14 in basic D
0.16 M NaOH) were measured using the PDC reaction of
ketoprofen (F = 0.75) (3) as a secondary reference standard.
The results appear in Table 1 along with selected examples of
quantum yields for PDC reactions of other arylacetic acids.
The quantum yields measured for 7–14 span the range from
2 3
O-CD CN
(
0
3
.37 to 0.74, demonstrating that the CF group is able to
mediate the PDC reaction nearly as well as a nitro or keto
group (Table 1), placing it among the very best excited state
3
activating groups. All arrangements of the CF group gave
(
with low F) which does not lead to dimer formation (23).
high quantum yields, whereas the keto and nitro groups give
low yields when the EWG is in the ortho position due to
competing intramolecular hydrogen abstraction (Table 1).
To gather information regarding the multiplicity of the
reactive excited state, two samples for each of 7–14 were
simultaneously irradiated as before in which one sample per
pair contained 10 mM potassium sorbate, and the extents of
conversion were determined by H NMR spectroscopy. The
sorbate ion is a potent triplet quencher, and is known to
quench the triplet states of other arylacetic acids with
1
rate constants approaching the diffusion limit (k
q
= 7 ·
for ketoprofen) (6). Assuming a similar quenching
rate constant for the triplet states of 7–14, the presence of
9
)1 )1
1
0
M
s
1
5
0 mM sorbate in our samples was expected to quench at least
0% of triplet states with lifetimes 14 ns or longer. Due to
competitive absorption of the 254 nm incident light by sorbate
ions, some reduction in the photodecarboxlyation yields of 7–
1
4 was expected, and this expected drop was calculated from
the extinction coefficients and concentrations employed. For
all of 7–14, the presence of 10 mM sorbate caused no
additional drop in reaction efficiency beyond that expected
because of competitive absorption, suggesting that the PDC of
all derivatives proceeds either through the singlet state or
through a very short-lived triplet (ꢀ10 ns). In an effort to
sensitize the reaction, and thus provide evidence for a triplet
Figure 1. Plot of percent decarboxylation of 7 (50 mM in 1:1 [vol ⁄ vol]
CD CN-D O, 0.16 M NaOH) with irradiation time. The error asso-
ciated with each point is estimated to be ± 5%. The curve was drawn
to run through the points and is not the result of a least-squares fitting
analysis.
3
2

8
24 Misty-Dawn Burns and Matthew Lukeman
pathway, solutions of 7–14 were irradiated in a basic 1:1 D
acetone-d solution at 300 nm, where the solvent absorbs
strongly, but 7–14 do not. Even after extended photolysis
>20 min) under these conditions, complete recovery of
starting material was realized for all compounds, lending
further support for a singlet pathway.
2
O-
when they are located at the meta position than when located
in the para position. If the small difference in reactivity
between 7–9 does result from the meta effect, it certainly is not
as pronounced as it is in the case of xanthone acetic acids, in
which case the meta derivative undergoes PDC with a
quantum yield of 0.64 and the para derivative does not
undergo PDC at all (13). Further, on comparison of 10 and 11,
6
(
3
both of which contain two CF groups, the di-meta derivative
DISCUSSION
undergoes PDC with an efficiency which is less than the ortho-
para derivative, which would run contrary to expectations
based on the meta effect.
The proposed mechanism for the PDC of 7 based is presented
in Scheme 1. Direct excitation of the acid form of 7 does not
lead to any observable reaction, indicating that the carboxylate
form is required for efficient PDC. Excitation of the carbox-
ylate form in aqueous solution (pH > 7) produces a singlet
excited state which undergoes C–C bond heterolysis to generate
Comparing the PDC efficiency of 12–14 with the corre-
sponding phenylacetic acids 7, 9 and 11, it is apparent that the
presence of the a-hydroxyl group modestly increases the
reaction efficiency for all but the para arrangement, presum-
ably because the electronegative oxygen atom can assist in
stabilizing the incipient carbanion on the a-carbon. However,
the enhancement offered by the a-hydroxyl group is very
modest when one considers its effect on unsubstituted phen-
ylacetic acid. While the PDC efficiency of phenylacetate in
basic solution is marginal (F ꢁ 0.04, Table 1) (24), addition of
the hydroxyl group to the benzylic position to give the
mandelate ion leads to a 10-fold increase in PDC quantum
yield (F = 0.40, Table 1) (25). A similarly large enhancement
is not observed for 12–14, and the PDC quantum yield of 13 is
essentially the same as that of unsubstituted mandelic acid.
This result seems to indicate that the enhancements in PDC
efficiency provided by the trifluoromethyl substituents and a-
hydroxy substituents are not additive, particularly in the para
2
a benzylic carbanion and CO . Our inability to quench the
reaction with sorbate or to sensitize the reaction with acetone
argues against PDC occurring from a triplet state. While we
cannot definitively rule out the reaction occurring from a very
short-lived triplet state, singlet reactivity has the added appeal
of enabling production of the singlet carbanion directly in one
step via a spin-allowed process. The carbanion produced can
then react with water (or D
2
O) to give the toluene product 12
(
GC-MS, we propose a second minor pathway from the excited
or 12-D). Because trace amounts of dimer were observed by
)
carboxylate 7 *: ejection of an electron to produce the radical
7· (and a solvated electron), which then loses CO to generate
2
the trifluoromethyl-substituted benzyl radical which subse-
quently dimerizes. The eventual fate of the solvated electron is
unknown, although it represents a minor pathway. Related
derivatives 8–14 are assumed to follow the same mechanism as
7 due to their similarity in reaction products, quenching and
sensitization behavior.
case. Derivatives 10, 11, and 14 containing two CF groups
3
show the highest yields of the eight studied, suggesting that
multiple CF groups do act cooperatively in the excited state to
give an overall additive effect.
3
3
We propose that the CF group is able to enhance the PDC
efficiency of phenylacetic acids to which it is attached because
of enhanced resonance electron-withdrawing capabilities of
this group in the excited state. For EWGs that are directly
conjugated with an aromatic system, an increase in their
1
electron withdrawing abilities in S can be rationalized with
HMO theory (26). HMO calculations predict a larger electron
density on the EWG in the LUMO compared to the HOMO
for substituted benzyl anions, so when an electron is excited
from the HOMO to the LUMO, electron density shifts onto
the EWG, increasing its apparent withdrawing ability. Despite
being saturated, the CF
R = 0.16, ref. 21) via hyperconjugation, and its electron-
withdrawing ability via resonance may be greater in S due to a
3
group does exert resonance effects
Scheme 1.
(
1
A major conclusion from this work is that the CF
clearly able to mediate the ionic PDC of phenylacetic acids in
aqueous solution (pH > pK ), regardless of whether it is
3
group is
similar electron-density shift. This would allow a portion of the
developing negative charge on the benzylic carbon during the
transition state of the PDC step to be delocalized onto the CF3
group, thus facilitating the reaction.
a
positioned ortho, meta or para to the acetic acid functional
group. On comparing the PDC efficiencies of 7–9, there is only
a small difference in reaction efficiency between the three
isomers, although the meta derivative gives the most efficient
reaction, followed by ortho, and with the para position being
least reactive. The enhanced reactivity from the meta isomer is
mirrored in the reaction efficiency of mandelic acids 12 and 13,
and is reminiscent of the ‘‘meta effect’’ proposed by Zimmer-
man and Sandel (26), which is simply the observation that
substituents on aromatic rings will exert a much greater
influence on the reaction center in photochemical reactions
Hydrogen bonding is likely to be of significant importance
in at least some PDC reactions, although its role is not well
understood. Keto-substituted phenylacetic acids typically
show a strong solvent dependence, with efficient reaction
often only observed in aqueous solution (2–7,11–13). A
notable exception to this generalization is the efficient PDC
of 2-acetylphenylacetic acid in benzene (27), although this
reaction is believed to be assisted by intramolecular hydrogen
bonding, only available in this example because of the
proximate positioning of the ketone and acetic acid function-

Photochemistry and Photobiology, 2010, 86 825
1
Figure S1. H NMR spectra of irradiated samples of 7–14.
alities (28). The PDC efficiencies of several keto-substituted
phenylacetic acids show significant solvent isotope effects
when D O is used in place of water, in some cases as high as
1
Table S1. Summary of H NMR data for 7–14.
Please note: Wiley-Blackwell are not responsible for the
content or functionality of any supporting information sup-
plied by the authors. Any queries (other than missing material)
should be directed to the corresponding author for the article.
2
4
.2 (29), indicating that the decarboxylation step is very
sensitive to the surrounding solvent, and that in some cases, a
formal proton transfer might occur to the substrate on loss of
CO . In such cases, it is probable that solvent hydrogen
2
bonding with the carbonyl group of the keto substituent is the
important interaction, as it is well established that aromatic
ketones become more basic in the excited state (30,31).
Discrete proton transfer to the keto group during the PDC
step would also favor the reaction by avoiding a carbanion
intermediate altogether and directly generating a neutral enol.
The PDC reactions of 7–14 collectively provide an interesting
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