Release of guests from encapsulated masked hydrophobic precursors by a phototrigger

Article abstract of DOI:10.1021/ol4019024

Examples of release of organic acids from encapsulated p-methoxyphenacyl esters provided here demonstrate the value of a phototrigger strategy to release chemicals of interest in water from hydrophobic precursors. In this study, a photochemical β-cleavage process centered on the p-methoxyphenacyl group is exploited to release the acid of interest from a water-soluble capsule made up of octa acid.

Full text of DOI:10.1021/ol4019024

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4374–4377
Release of Guests from Encapsulated
Masked Hydrophobic Precursors by
a Phototrigger
Nithyanandhan Jayaraj,† Pradeepkumar Jagadesan,† Shampa R. Samanta,†
‡
Jose P. Da Silva, and V. Ramamurthy*
,†
ꢀ
Department of Chemistry, University of Miami, Coral Gables, Florida 33124,
~
´
United States, and Centro de Investigac-ao em Quımica do Algarve, FCT,
Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
murthy1@miami.edu
Received July 7, 2013
ABSTRACT
Examples of release of organic acids from encapsulated p-methoxyphenacyl esters provided here demonstrate the value of a phototrigger
strategy to release chemicals of interest in water from hydrophobic precursors. In this study, a photochemical β-cleavage process centered on the
p-methoxyphenacyl group is exploited to release the acid of interest from a water-soluble capsule made up of octa acid.
Interest in synthesizing new hosts and exploring the
structure and characteristics of natural and synthetic
supramolecular hosts has continued unabated for over
five decades. Elegant examples where the excited-state
chemistry and physics of a guest have been altered by the
confinement and weak interactions provided by the hosts
have been reported.1ꢀ5 In this context, we have been
exploring a new host, commonly known as octa acid
(OA; Figure 1), to control the excited-state processes of
organic guest molecules.6
A distinct feature of the OA capsuleplex is its dynamic
character that assemblesꢀdisassembles in the time scale
of a second. When containing pyrene, the capsuleplex
disassembles in 2.7 s,7 and partial opening in microsecond
time scale has been established in several examples.8 The
dynamic capsuleplexes are thus suited to store and release
molecules of interest.
In this study, by exploiting the light activated β-cleavage
of a carbonyl compound (photorelease), we have explored
the feasibility of opening a capsuleplex “at will” and
releasing the contents to an aqueous exterior.9 We have
achieved this via a “phototrigger” mechanism utilizing the
p-methoxyphenacyl group as the “trigger” and the masked
acid the “load” to be released.10,11 Molecules 1ꢀ6 that we
† University of Miami.
‡ Universidade do Algarve.
(1) Ramamurthy, V. Tetrahedron 1986, 42, 5753.
(2) Supramolecular Photochemistry; Ramamurthy, V., Inoue, Y., Eds.;
John Wiley: Hoboken, 2011.
(3) Ramamurthy, V. Photochemistry in Organized & Constrained
Media; VCH: New York, 1991.
(4) Molecular Encapsulation; Brinker, U. H., Mieusset, J.-L., Eds.; John
Wiley & Sons: Chichester, 2010.
(7) Tang, H.; de Oliveira, C. S.; Sonntag, G.; Gibb, C. L. D.; Gibb,
B. C.; Bohne, C. J. Am. Chem. Soc. 2012, 134, 5544.
(8) Jayaraj, N.; Jockusch, S.; Kaanumalle, L. S.; Turro, N. J.;
Ramamurthy, V. Can. J. Chem. 2011, 89, 203.
(5) Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. Modern Molecular
Photochemistry of Organic Molecules; University Science Books:
Sausalito, CA, 2010.
(9) Klan, P.; Solomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.;
Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Chem. Rev. 2013, 113, 119.
(10) Givens, R. S.; Kueper, L. W., III. Chem. Rev. 1993, 93, 55.
(6) Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2004, 126, 11408.
r
10.1021/ol4019024
Published on Web 08/27/2013
2013 American Chemical Society

have investigated in this context are listed in Figure 1.
β-Cleavage (ꢀCOꢀ; with respect to the photoactive
carbonyl chromophore) in all these cases where the
p-methoxyphenacyl group is linked via an ester linkage
results in the release of the carboxylic acid. Although the
mechanism of the triggering process isyet tobe deciphered,
we have established that acids can be released from OA
capsule to the aqueous medium by a light initiated process.
Results of this study are presented below.
Figure 2. 1H NMR (500 MHz) spectra of (a) OA ([OA] = 1 mM)
in 10 mM Na2B4O7 buffer/D2O; (b) 1@(OA)2 ([OA] = 1 mM,
[1] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O; (c) 2@(OA)2
([OA] = 1 mM, [2] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O;
(d) 3@(OA)2 ([OA] = 1 mM, [3] = 0.5 mM) in 10 mM Na2B4O7
buffer/D2O; (e) 4@(OA)2 ([OA] = 1 mM, [4] = 0.5 mM)
in 10 mM Na2B4O7 buffer/D2O, (f) 5@(OA)2 ([OA] = 1 mM,
[5] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O and (g) 6@(OA)2
([OA] = 1 mM, [6] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O.
(* indicates the bound guest proton peaks; b indicates the
residual solvent peak of water.)
Figure 1. Structures of water-soluble cavitand, octa acid (OA),
and guests.
Capsular hostꢀguest complexes (2:1) of OA and 1ꢀ6
(see the Supporting Information for synthesis and spectral
data) were prepared by stirring an aliquot of DMSO stock
solution (5 μL) of 1ꢀ6 withOA in a 2:1 (host toguest) ratio
in borate buffer solution (0.6 mL; pH ∼ 9). In Figure 2,
1H NMR spectra of OA and 1ꢀ6 present in D2O in the
ratio of 2:1 are displayed. Inclusion of guests within OA
host was assumed from the evident upfield shift (note
in Figure 2 between δ 1 and ꢀ3 ppm and see Figure S1,
Supporting Information) of all methyl and methylene
signals of the guests with respect to that in CDCl3.12,13
1H NMR titration data (Figures S2ꢀS5 in the Supporting
Information) as well as the diffusion constants measured
by DOSY (diffusion-ordered spectroscopy) experiments
(Figures S6ꢀS11 and Table S1, Supporting Information)
suggested the formation of 2:1 hostꢀguest complexes
(capsuleplexes). 2D-COSY and NOESY spectra (Figures S12ꢀ
S23, Supporting Information) supported the conclusion
that the methoxy group anchored the guest molecules at
one tapered end of the capsule. The single set of upfield
shifted signals for the guest molecules in 1H NMR titration
experiments suggested there were no free molecules in
solution. The above studies established that guests 1ꢀ6
formed stable capsuleplexes in aqueous solution.
1
Supporting Information ). H NMR spectra of the irra-
diated 1@OA2, 2@OA2, and 3@OA2 presented in
Figures 3 and 4 confirmed the formation of acids as one
1
of the main products. Figure 3 also provides H NMR
spectra of 1@OA2 before (a) and after irradiation (b) and
that of independently prepared 1-adamantane carboxylic
acid@OA complex (c). Wehaveestablished1-adamantane
carboxylic acid forms a 1:1 cavitandplex in water.13 The
identical spectra shown in parts b and c of Figure 3 suggest
that upon irradiation the capsuleplex of 1 resulted in
cavitandplex of 1-adamantanecarboxylic acid. It is quite
likely that 1-adamantanecarboxylic acid released to the
aqueous exterior led tothe formation ofa 1:1 cavitandplex.
Observationsmade with2@OA2 and 3@OA2 establish the
potential of the “supramolecular photorelease” technique.
As illustrated in Figure 4b, d, independent experiments
suggested that o-toluic acid (product from 2) and 3,3-
dimethylacrylic acid (product from 3) preferred to reside
in water even in the presence of OA. They do not form
complexes with OA, for example, at δ 2.19 ppm (o-toluic
acid) and at δ 1.62 and in the absence of OA. Comparison
of the 1H NMR spectra of the irradiated samples
(Figure 4a, c) and signal at 1.76 due to 3,3-dimethylacrylic
acid both in the presence of OA and with independently
prepared samples of [acid þ OA] (Figure 4b, d) revealed
that upon irradiation of p-methoxyphenacyl esters 2 and 3
the corresponding product acids were released to aqueous
exterior. Products obtained (see the Supporting Information
for isolation procedures of products) and their yields as esti-
mated by GC and HPLC (with respect to the reacted material)
1H NMR spectral recordings of the progress of the
reaction from irradiation of capsuleplexes of 1ꢀ6 included
within OA indicated complete conversion within 90 min in
all cases except 3 which took ∼8 h (for details see the
(11) Falvey, D. E.; Sundararajan, C. Photochem. Photobiol. Sci.
2004, 3, 831.
(12) Porel, M.; Jayaraj, N.; Kaanumalle, L. S.; Maddipatla, M. V. S.
N.; Parthasarathy, A.; Ramamurthy, V. Langmuir 2009, 25, 3473.
(13) Jayaraj, N.; Zhao, Y.; Parthasarathy, A.; Porel, M.; Liu,
R. S. H.; Ramamurthy, V. Langmuir 2009, 25, 10575.
Org. Lett., Vol. 15, No. 17, 2013
4375

Figure 3. 1H NMR (500 MHz) spectra of (a) 1@(OA)2 ([OA] =
1 mM, [1] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O; (b) After
30 min irradiation (λ > 280 nm) and (c) 8@OA ([OA] = 1 mM,
[8] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O. (* indicates the
bound guest proton peaks; b and [ indicate the residual solvent
peak of water and DMSO-d6, respectively.)
Figure 5. Product distribution upon photolysis of guests 1ꢀ6@OA.
Structure of products shown below equations.
and 1875.4, respectively. The fragmentation behavior is
similar to the one observed for OA14 (Figure S26, Sup-
porting Information), while the isotope pattern simula-
tion indicates a singly charged ion with molecular formula
C105H73O34 under positive polarity. On the basis of the
m/z values, fragmentation behavior, and isotope distribu-
tions, we assign this product to a p-methoxyphenacyl-OA
adduct. Although ESIꢀMS confirmed the formation of
an adduct, the 1H NMRspectra werenot clean anddid not
permit identification of the exact structure of the adduct.
Based on the abstractable hydrogen present in the interior
of OA (Hg, Figure 1), we tentatively assign the structure as
shown in Figure 5. No attempt was made to look for OA
adducts from 4ꢀ6.
The UV absorption spectra of guests 1ꢀ3, p-methoxya-
cetophenone and OA shown in Figure S27 (Supporting
Information) suggested that under our irradiation condi-
tions (450 W medium pressure mercury lamp; Pyrex filter)
both OA and the guests would be excited. We have shown
previously OA to be an excellent triplet sensitizer with
Figure 4. 1H NMR (500 MHz) spectra of (a) Irradiated (λ >
280 nm, 1 h) sample of 2@(OA)2 ([OA] = 1 mM, [2] = 0.5 mM)
in 10 mM Na2B4O7 buffer/D2O; (b) Mixture of 11 and OA
([OA] = 1 mM, [11] = 1 mM) in 10 mM Na2B4O7 buffer/D2O;
(c) Irradiated (λ > 280 nm, 8 h) sample of 3@(OA)2 ([OA] =
1 mM, [3] = 0.5 mM) in 10 mM Na2B4O7 buffer/D2O; (d)
Mixture of 12 and OA ([OA] = 1 mM, [12] = 1 mM) in 10 mM
Na2B4O7 buffer/D2O. (“*” indicates the photoproducts).
(9 and * indicate the unbound proton peaks of o-toluic acid and
3, 30-dimethylacrylic acid, respectively; b and [ indicate the
residual solvent peak of water and DMSO-d6 respectively.)
triplet energy close to 73 kcal mol .
ꢀ1 15 Thus, independent
of which one absorbs light, we believe only the resulting
triplet of the guest would be the reactive species. On the
basis of the known characteristics of p-methoxyaceto-
phenone,16,17 we expect the lowest reactive triplet of 1ꢀ6
within the nonpolar capsule to have the ππ* configuration.
Several mechanisms have been proposed for the photo-
release of acids from phenacyl derivatives in organic
are listed in Figure 5. Conversion-independent product
distribution suggests the possibility of 100% conversion of
the guest without complications. p-Methoxyacetophenone
and the corresponding acid were consistently formed upon
irradiation of 1ꢀ6 included in OA. p-Methoxyphenacyl-
appended OA, one of several minor products identified by
ESIꢀMS and LCꢀMS, was isolated in the case of 1ꢀ3.
This product is readily seen under positive or negative
polarity (Figures S24 and S25, Supporting Information),
showing the first peak of the isotope series at m/z 1877.4
(14) Choudhury, R.; Gupta, S.; Da Silva, J. P.; Ramamurthy, V.
J. Org. Chem. 2013, 78, 1824.
(15) Jagadesan, P.; Mondal, B.; Parthasarathy, A.; Jayathirtha Rao,
V.; Ramamurthy, V. Org, Lett. 2013, 15, 1326.
(16) Srivastava, S.; Yourd, E.; Toscano, J. P. J. Am. Chem. Soc. 1998,
120, 6173.
(17) Wagner, P. J.; Kemppainen, A. E.; Schott, H. N. J. Am. Chem.
Soc. 1970, 92, 5280.
(18) Givens, R.; Conrad II, P. G.; Yousef, A. L.; Lee, J.-I. In CRC
Handbook of Photochemistry and Photobiology, 2nd ed.; Horspool, W.,
Lenci, F., Eds.; CRC Press: Boca Raton, 2004; p 69.1.
4376
Org. Lett., Vol. 15, No. 17, 2013

solvents which depend on polarity and hydrogen atom and
electron-donating ability of the medium.9,11,18ꢀ25 We spec-
ulate on the basis of the minor products isolated from the
encapsulated 1ꢀ6 that the primary process triggering the
release of acid depends on the structure of the guest. Lack
of formation of p-methoxyphenylacetic acid 13 (Figure 5)
from OA-encapsulated 1ꢀ4 suggested that the reaction did
not proceed via p-methoxy-assisted Favosrskii rearrange-
ment (Scheme 1).18,22 However, this process seemed
to occur to some degree in the case of 5 and 6 where
p-methoxyphenylacetic acid was isolated in small amounts
(11 and 14%). The difference in behavior between these
two sets of molecules (1ꢀ4 and 5 and 6) could be attributed
to the nature of their complexes with OA.
We speculate that with elongated guests, 5 and 6 cause
the capsule to be slightly expanded, generating some space
between the two caps. Consistent with this notion the
diffusion constants for 1ꢀ4 were slightly larger than for
5 or 6 suggesting that the latter capsuleplexes are slightly
larger. This expanded structure most likely allows the
reactant guest molecule to experience leakage of the polar
aqueous environment into the space and this is enough to
influence the formation of p-methoxyphenylacetic acid via
a polar intermediate.
Formation of p-methoxyacetophenone in all cases
(1ꢀ6) could be accounted for by a homolytic β-cleavage
process to yield p-methoxyphenylacyl and acyloxy radical
intermediates (Scheme 1); isolation of small amounts of
coupling products 9 and 14 resulting from the loss of CO2
(to yield stable adamantyl radical and benzyl radical,
respectively) in the case of 1 and 4 is consistent with
involvement of radical intermediates.19,21,26 Most likely,
p-methoxyphenacyl-appended OA isolated in the case of
1ꢀ3 derive via the homolytic β-cleavage process followed
by acyloxy radical abstracting the hydrogen (Hg) from
the host OA and the cage partner p-methoxyphenylacyl
Scheme 1. Possible Reaction Pathways for the Photolysis of
Guests 1ꢀ6@OA
radical coupling to the radical site resulting from the
hydrogen abstraction process. Given that OA is a good
hydrogen donor, we cannot rule out the possibility of
hydrogen abstraction by triplet ketone followed by homo-
lytic cleavage of the ester group to give the enol of the
acetophenone. Further work is needed to fully understand
the mechanism of the phototriggering process within the
above supramolecular capsule.
This presentation has brought to light that an OA cap-
suleplex could be photochemically disassembled to release
the contents. We have established “proof of principle”
of a supramolecular photorelease strategy that has the
potential to release chemicals of interest in water from
hydrophobic precursors. It is important to recognize that
without the aid of OA, these hydrophobic precursors could
not be solubilized in water. Further studies with phenacyl
and related systems as triggering agents9 within organic
capsules are currently underway in our laboratory. These
along with planned time-resolved studies, we hope, would
provide a better understanding of the mechanism of
photorelease of OA encapsulated guest molecules.
Acknowledgment. V.R. thanks the National Science
Foundation for generous support (NSF-CHE-0848017).
V.R. thanks Richard S. Givens, University of Kansas, for
encouragement, fruitful discussions, and careful reading of
the manuscript.
(19) Sheehan, J. C.; Umezawa, K. J. Org. Chem. 1973, 38, 3771.
(20) Anderson, J. C.; Reese, C. B. Tetrahedron Lett. 1962, 1.
(21) Laird, T.; Williams, H. J. Chem.Soc. C 1971, 1863.
(22) Givens, R. S.; Athey, P. S.; Matuszewski, B.; Kueper, L. W., III;
Xue, J.; Fister, T. J. Am. Chem. Soc. 1993, 115, 6001.
(23) Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R.
Tetrahedron 1997, 53, 16789.
(24) Banerjee, A.; Falvey, D. E. J. Org. Chem. 1997, 62, 6245.
(25) Banerjee, A.; Falvey, D. E. J. Am. Chem. Soc. 1998, 120, 2965.
(26) Epstein, W. W.; Garrossian, M. J. Chem. Soc., Chem. Commun.
1987, 532.
Supporting Information Available. Sample preparation
and irradiation procedures, isolation and characteriza-
tion of products, and additional NMR and absorption
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
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