Induced diastereoselectivity in photodecarboxylation of 2-phenylpropionic acid in faujasite zeolites

Article abstract of DOI:10.1016/S0040-4020(01)00377-5

Irradiation of 2-phenylpropionic acid in various cation-exchanged faujasites leads to predominant formation of dl-2,3-diphenylbutane over the meso-isomer (in marked contrast to photolysis in isotropic media) and this zeolite-induced diastereoselectivity i

Full text of DOI:10.1016/S0040-4020(01)00377-5

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 4455±4459
Induced diastereoselectivity in photodecarboxylation of
2
-phenylpropionic acid in faujasite zeolites
a b,p
A. Lalitha, K. Pitchumani and C. Srinivasan
a,p
a
Department of Materials Science, Madurai Kamaraj University, Madurai-625 021, India
b
School of Chemistry, Madurai Kamaraj University, Madurai-625 021, India
Received 10 November 2000; revised 6 March 2001; accepted 22 March 2001
AbstractÐIrradiation of 2-phenylpropionic acid in various cation-exchanged faujasites leads to predominant formation of dl-2,3-diphenyl-
butane over the meso-isomer +in marked contrast to photolysis in isotropic media) and this zeolite-induced diastereoselectivity is attributed to
steric and electronic factors. q 2001 Elsevier Science Ltd. All rights reserved.
4
2
2
-Phenylpropionic acid +2-PPA) and its analogues are
photoreactive and undergo decarboxylation on exposure to
inside the cages of zeolites which are made up of [SiO ]
4
52
and [AlO4] tetrahedra resulting in a three-dimensional
network of cages/channels that can accommodate organic
molecules of the appropriate dimensions.
1
light. The non-steroidal anti-in¯ammatory arylalkanoic
acids such as ibuprofen, benoxaprofen, ketoprofen,
naproxen, carprofen, suprofen and tiaprofenic acid, which
are the structural analogues of 2-PPA are all labile in the
The generation of benzylic radicals in the steady state
photolysis of dibenzyl ketone and its methylated derivatives
2
±7
presence of light and are phototoxic.
The arylethyl
9
,10
radical, which is the key intermediate of photodecarboxyl-
ation, is partly responsible for the photobiological activity
of these drugs. In order to protect these drugs from the
action of light it is essential to study the photobehaviour
of the simplest analogue, namely 2-PPA in detail.
inside the cavities of zeolites has been reported. The life-
time of simple benzyl radicals generated inside the zeolite
cages in the photolysis of phenylacetic acid has been studied
using nanosecond diffuse re¯ectance spectroscopy and it has
been concluded that the benzyl radical decays in a fast
manner by a coupling reaction with a second benzyl radical
and the mobility decreases along the series from LiY to
8
1
The only reported study on the photolysis of 2-PPA +1) in
1
1
acetonitrile, methanol and benzene in a nitrogen atmosphere
leads to the formation of mainly the meso- and dl-2,3-
diphenylbutanes +3) and +4), respectively, in almost equal
amounts +non-stereoselective) in addition to the formation
of ethylbenzene +2), 1-+2-phenylethyl)-1-phenylethane +6)
and 1-+4-phenylethyl)-1-phenylethane +7) in small amounts
CsY.
9
Ghatlia and Turro have reported the generation of benzyl
radical and a-methylbenzyl radical +from diastereomeric
dibenzyl ketone and 2,4-diphenylpentan-3-one, respec-
tively) inside the cages of cation-exchanged faujasites X
and Y. LiY and NaY have shown greater diastereo-
selectivity. In the case of LiY and NaY the dl-isomer of
2,3-diphenylbutane is the major product +the dl/meso ratio
for LiY is ,1.8 and for NaY is ,1.9 and this decreases in
the case of KY) compared to that of LiX and NaX. The
+Scheme 1). Photolysis in the presence of cyclohexane and
carbon tetrachloride leads to solvent-derived products.
Irradiation in solution in aerated conditions results in
1
1
00% formation of acetophenone +5).
In the same study it was shown that the photolysis of 2-PPA
in the presence of b-cyclodextrin +b-CD) results in the
magnitude of diastereoselectivity is a function of
the substrate con®guration inside the zeolite cavity and
the observed zeolite-induced diastereoselection is more
signi®cant compared to other organized media such as
1
predominant formation of the meso-isomer by the
a,a-coupling of two long-lived a-methylbenzyl radical±
CD units, in which the methyl groups are antiperiplanar.
The in¯uence of this constrained medium on the photolysis
of 2-PPA prompted us to study its photochemical behaviour
9
,10
micelles and porous glass.
that the zeolites preferentially retained the dl-isomer of both
It is also interesting to note
9
2,3-diphenylbutane and 2,4-diphenylpentan-3-one.
Keywords: diastereoselectivity; photodecarboxylation; 2-phenylpropionic
acid; faujasite zeolites.
Corresponding authors. Tel.: 191-452-858246; fax: 191-452-859181;
e-mail: pit12399@yahoo.com
1
.Results and discussion
p
In the present study, 2-PPA, loaded into various
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00377-5

4456
A. Lalitha et al. / Tetrahedron 57 )2001ꢀ 4455±4459
Scheme 1.
cation-exchanged Y zeolites +Si/Al ratio 2.43) was
irradiated as a hexane slurry and the results are given in
Table 1. In all the cation-exchanged zeolites, remarkable
diastereoselectivity was observed. The dl-2,3-diphenyl-
butane was the major product with a small amount of
meso-isomer. Ethylbenzene was also formed as one of the
products and the amount of ethylbenzene increased with the
increase in the cation size. A reduction in cage free volume
with an increase in the cation size prevents the loading of
two molecules per cage and this facilitates the unimolecular
reaction pathway, namely hydrogen abstraction to yield
ethylbenzene. The ortho- or the para-coupled products of
the a-methylbenzyl radical were not formed in the zeolite-
mediated reactions.
In the photolysis of phenylacetic acid it has been stated that
the formation of toluene results from the benzyl anion
formed from the decarboxylation of the carboxylate group.
Likewise, here also the formation of ethylbenzene may be
due to the abstraction of a proton by the a-methylbenzyl
a
Table 1. Product distribution +%) in the photolysis of 2-PPA +1) inside zeolites
b
Loading level of 2-PPA +1)
c
Medium
Conversion +%)
Ethylbenzene +2)
2,3-Diphenylbutane
Acetophenone +5)
X
dl/meso ratio
meso-+3)
dl-+4)
CH
CH
CH
b-CD
LiY
NaY
KY
RbY
CsY
3
3
3
CN
CN
±
±
±
±
1.82
1.92
2.02
1.56
1.30
1.92
1.92
63
76
37
49
55
51
45
39
36
33
47
16
13
8.0
±
3.0
2.0
5.0
43
43
1.0
2.0
45
41
42
66
2.0
1.0
3.0
5.0
5.0
2.0
2.0
34
40
40
34
95
97
92
52
52
78
52
±
±
±
±
±
±
±
±
±
5.0
6.0
10
±
±
±
±
±
±
±
0.76
0.98
0.95
0.52
48
97
31
10
10
d
d
OH
d
e
NaY
NaY
19
44
39
26
f
±
a
Irradiated as hexane slurry in nitrogen atm. for 6 h.; analysed by GC. Error limit ^5%. In all the experiments, retention time of 2-PPA is taken as the internal
standard.
b
c
d
e
f
Loading level refers to the number of 2-PPA molecules/cage.
X: ortho-+6) and para-+7) coupled products of the a-methylbenzyl radical.
Literature data ; +b-CD is b-cyclodextrin: irradiated in water under argon atm.).
1
Irradiated as hexane slurry in oxygen atm.
Irradiated as solid complex in oxygen atm. for 25 h.

A. Lalitha et al. / Tetrahedron 57 )2001ꢀ 4455±4459
4457
Figure 1. Dependence of unimolecular/bimolecular reactivity and loading level on zeolite size.
anion, which is likely to be formed along with the a-methyl-
benzyl radical.
groups and this pushes the hydrocarbon part into the
interior. This factor along with the higher electrostatic
®
eld present in LiY and NaY zeolites results in a hydro-
A careful analysis of the data in Table 1 displays an inter-
esting dependence of reactivity +unimolecular/bimolecular)
on the loading level +Fig. 1). In the cases of LiY, NaY and
KY about two molecules can be accommodated inside a
supercage whereas in RbY and CsY the loading level
decreases to 1.5 and 1.3, respectively. The mobility of the
a-methylbenzyl radical inside the cages of LiY and NaY is
also greater compared to RbY and CsY. This higher
mobility inside the smaller LiY and NaY zeolites coupled
with the higher loading level lead to a faster a,a-coupling
with another radical as evident by the higher percentage
conversions in LiY and NaY in relation to RbY and CsY.
In the cases of larger cations, the lower loading level and
decreased mobility of the a-methylbenzyl radical promotes,
in addition to coupling, signi®cant unimolecular hydrogen
abstraction to give ethylbenzene and oxidation to aceto-
phenone.
phobic association between the phenyl rings of adjacent
2-PPA molecules +Fig. 2). Thus, the preferred geometrical
arrangement in zeolite cages is one in which the methyl
groups are anti to each other [Fig. 2+a) and +b)]. The syn
arrangement of methyl groups will have considerable steric
hindrance [Fig. 2+c)] and hence may not be energetically
favoured. Dimeric association, which is commonly
encountered in carboxylic acids, may not be signi®cant
here due to:
1. the spatial constraints imposed by the cavity on the
formation of the eight-membered ring in the dimer; and
2. the intrinsic polarity of the inner walls of the zeolite,
which attract the carboxyl group towards them +more
pronounced in a hydrocarbon solvent as in the present
study).
With RbY and CsY zeolites, a combination of lower loading
and decreased elecrostatic ®eld results in a weaker pre-
association +hydrophobic interaction) between the adjacent
aryl rings and this leads to a decrease in diastereoselective
induction.
Acetophenone is the only product in the homogeneous
photolysis of 2-PPA in an oxygen atmosphere due to the
abstraction of oxygen by the a-methylbenzyl radical. But
1
the photolysis of 2-PPA in zeolite slurry and as a solid
complex in an oxygen atmosphere gives only a minor
amount of acetophenone along with considerable amounts
of the dl-isomer +4). This observation is presumably due to
the preassociation of the 2-PPA molecules inside the cage in
such a way that the radicals are not completely free. The
dl/meso ratio is very high compared to that obtained in the
When the results are compared with the photolysis of
2,4-diphenylbutan-3-one +which also involves the
generation and subsequent coupling of a similar a-methyl-
benzyl radical), the induced diastereoselectivity is very high
and this may be attributed to the preassociation in a
preferred geometrical arrangement of the 2-PPA molecules
inside the zeolite cavities +Fig. 2). The results are also
remarkable in that the dramatic diastereoselectivity is
achieved from a racemic mixture of 2-PPA. A closer look
at Fig. 2 points to an interesting observation. Preassociation
of a d-isomer with another d-isomer [Fig. 2+a)] is sterically
favoured while with an l-isomer it leads to considerable
repulsion [Fig. 2+c)]. Similarly an l-isomer associates only
9
irradiation of 2,4-diphenylpentan-3-one +,2.0) where also
the same a-methylbenzyl radical is identi®ed as the
intermediate.
The predominant formation of the dl form of 2,3-diphenyl-
butane over the meso-isomer is explained on the basis of
steric and elecronic factors. Binding to the walls of the
zeolite cage takes place through the more polar carboxyl

4458
A. Lalitha et al. / Tetrahedron 57 )2001ꢀ 4455±4459
Figure 2. Packing of 2-PPA molecules inside the faujasite cage and the preferred modes of coupling of a-methylbenzyl radicals.
with another l-isomer [Fig. 2+b)] and this enatioselection is
largely responsible for the observed zeolite-induced
diastereoselectivity in decarboxylation.
The high diastereoselectivity observed with 2-PPA has
prompted us to extend these studies to ibuprofen [2-+4-iso-
butylphenyl)propionic acid] and the methyl ester of
naproxen [2-+6-methoxy-2-naphthyl)propionic acid]. These
are common non-steroidal anti-in¯ammatory drugs and
the arylethyl radicals produced from them upon irradiation
are mainly responsible for their phototoxicity. In isotropic
solution, cleavage products are obtained in both cases
+.50% conversion). However, when irradiated in faujasites,
both ibuprofen and naproxen are photostable under the
conditions employed indicating that the zeolite environment
offers better protection to these drugs from the action of
light.
It is interesting to note that while the meso-2,3-diphenyl-
butane +3) is the predominant product in b-cyclodextrin
1
+
+
with a hydrophobic cavity), the corresponding dl-isomer
4) is the exclusive product in zeolite cages. This striking
reversal of diasteroselectivity, in comparison to b-CD, is
attributed to:
1
2
. the polar environment inside the zeolite cage, wherein
more ef®cient binding by the carboxyl moiety may be
visualised; and
. the larger cage size in the zeolite ensures packing of
approximately two 2-PPA molecules, thereby facilitating
preassociation.
2.Experimental
2-Phenylpropionic acid was purchased from Fluka and used
as such. NaY was obtained from Aldrich. The cations of
1
2
Thus, it is clear that the photodecarboxylation of 2-PPA is
controlled not only by the con®ning spaces inside the zeolite
cages/cyclodextrin cavities, but also by their polarities.
interest were exchanged into the NaY powder by stirring
with the corresponding nitrate +10%) solution at 708C for
about 12 h. The exchange was repeated at least four times.

A. Lalitha et al. / Tetrahedron 57 )2001ꢀ 4455±4459
4459
Each time, after exchange, the zeolite powder was washed
repeatedly with distilled water and then dried. Based on an
93 +SR-I)], New Delhi is gratefully acknowledged. A. L.
thanks CSIR, New Delhi for the award of a Senior Research
Fellowship.
1
2
earlier literature report, exchange levels are assumed to be
between 62% and 84%. All these cation-exchanged zeolites
were activated at 5008C for about 10 h prior to use. From the
amounts of zeolite and 2-PPA taken, the loading level is
calculated. +This is based on unit-cell composition of zeolite
Y and hence the number of supercages present in the given
amount of zeolite.)
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8
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9
+
10% phenylmethylsilicone) column and ¯ame ionization
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1
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1
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1
3
acteristic NMR spectra. The NMR for dl d are 1.26 +m, 6,
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meso d 1.05 +m, 6, 2CH Z), 2.80 +m, 2, 2CHZ), 7.25 +m,
6
4%, KY 84%, RbY 68% and CsY 62%).
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2
3
6
5
3
4
1
0, 2C H ).
6 5
Acknowledgements
Financial assistance from UGC [Major Project No. F.12-57/