Photorelease of incarcerated guests in aqueous solution with phenacyl esters as the trigger

Article abstract of DOI:10.1021/acs.orglett.5b00252

We report the clean, efficient photorelease of a series of carboxylic acids embedded in octa acid (OA) host and protected by a p-hydroxyphenacyl cage. A key role is played by the cage by providing hydrophobicity for entry into the OA enclosure and yet readily removable as a photoactivated protecting group for release from the host. The rapid photo-Favorskii rearrangement of the departing chromophore does not react with the host OA but diminishes hydrophobicity of the OA contents, leading to their facile release into the solvent.

Full text of DOI:10.1021/acs.orglett.5b00252

Letter
pubs.acs.org/OrgLett
Photorelease of Incarcerated Guests in Aqueous Solution with
Phenacyl Esters as the Trigger
Pradeepkumar Jagadesan,† Jose P. Da Silva,‡ Richard S. Givens,*,§ and V. Ramamurthy*,†
́
†Department of Chemistry, University of Miami, Coral Gables, Florida 33124, United States
‡Meditbio, FCT, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
§Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: We report the clean, efficient photorelease of a
series of carboxylic acids embedded in octa acid (OA) host and
protected by a p-hydroxyphenacyl cage. A key role is played by
the cage by providing hydrophobicity for entry into the OA
enclosure and yet readily removable as a photoactivated
protecting group for release from the host. The rapid photo-
Favorskii rearrangement of the departing chromophore does
not react with the host OA but diminishes hydrophobicity of
the OA contents, leading to their facile release into the solvent.
Scheme 1. Structures of Water-Soluble Octa Acid (OA)
Cavitand, p-Hydroxyphenacyl (pHP) Esters (1a, 2a, and 3a),
p-Methoxyphenacyl (pMP) Esters (1b, 2b, and 3b), and
Photoproducts
upramolecular chemistry has caught the interest of
Sscientists in fields as diverse as fluorescence spectroscopy,
chemical dynamics, biochemistry, drug delivery, and “catch and
release” sequestration methodology.1,2 Likewise, the photo-
chemistry of host−guest (H−G) assemblies has attracted
considerable interest for three decades with recent studies
focused on the effects of confinement on dynamical behavior of
the guest in organized H−G assemblies. Molecules irradiated in
an enclosed assembly have displayed varied, sometimes
unanticipated, behavior. Some hosts, such as micelles, cyclo-
dextrins, cucurbiturils, or organometallic nanoclusters, partially
expose the guest to the aqueous exterior2b complicating the
environmental effects on the photochemistry. In contrast, we
have focused our interests on the behavior of the water-soluble
cavitand octa acid (OA, Scheme 1), which forms an enclosed
capsule of either a 2:1 or 2:2 H−G complex,2c,3,4 fully
protecting the encapsulated guest from the aqueous media. In
principle, encapsulated guests can be transported from site to
site in aqueous media and then deposited at a selected location,
provided there is a mechanism for opening the capsule, e.g., by
a spatially or temporally controlled photorelease processes.
This Letter addresses the release by photolysis of encapsulated
carboxylic acids that have been coupled to photoremovable
protecting groups (PPGs). The photoproducts are incompat-
ible with the host, freeing them into the solvent.
chemistry includes a concomitant photo-Favorskii rearrange-
ment of the chromophore,7 a process that should test the
robustness of the photochemistry, the relative rates of OA
opening,8 and the vulnerability of the host and guest to
environmental changes within and outside the H−G complex.
Scheme 1 gives the structures of OA, the three pHP esters
(1a−3a) of acids 6−8, and two anticipated photochemical
byproducts. This study contrasts with earlier results employing
While there are a plethora of known PPGs or cages available
as candidates that could assist in opening the OA host, we have
selected p-hydroxyphenacyl (pHP)5,6 as the chromophore to
cage the guest. We anticipate that the release of caged
carboxylic acids will occur upon irradiation of OA encapsulated
pHP esters. The well-established mechanism of pHP photo-
Received: January 26, 2015
Published: February 23, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00252
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Letter
p-methoxyphenacyl (pMP)4 as protected esters 1b−3b (see
Scheme 1).
sequestered (Figure 2d; see Figures S24(v),(vi)). The π,π*
transitions of the conjugate bases absorb at 330 nm, so Pyrex
filters employed for the photolysis reactions ensure that the
absorbing chromophores are the pHP conjugate bases and not
OA (Figure 2e, for comparison, see Figures S37 and S38 for the
corresponding pMP ester 1b). A difference spectrum of 1a at
pH <2 subtracted from one at pH 8.7 shows that excitation
dominates at >300 nm, the Pyrex filter cutoff (Figure S36). It
should be noted that all three esters, 1a−3a, were stable to
hydrolysis as their encapsulated OA complexes.
The pHP esters were synthesized by methods reported
earlier4,9 (Supporting Information (SI)). For H−G titration
experiments, DMSO-d6 solutions of the esters were incremen-
tally added to D2O solutions of OA at pH 8.7 with Na2B4O7
1
buffer and monitored by H NMR (Figure 1). The upfield
shifts of the ester aliphatic protons were used to measure the
extent of the OA:pHP ester H−G complex.3,4
Photolysis of 1a@(OA)2 in aqueous borate buffer for 30 min
at >300 nm with a 450 W medium pressure lamp through a
Pyrex filter was tracked by the appearance of 1H NMR singlets
at 0.5, −0.3, −0.45, and −1.1 ppm that are assigned to the
conjugate base of 1-adamantane carboxylic acid (6) in OA (6@
OA, 67% yield) and a singlet at 3.3 ppm assigned to the
chromophore’s rearrangement product, p-hydroxyphenyl ac-
etate (5) in OA (5@OA), both as 1:1 OA cavitand complexes
(see Figure 1(iv),(v)). The conversion to products increased to
100% by irradiating the sample an additional 20 min (Table 1).
Table 1. Percent Comparisons of Photolysis Conversions
and Yields Based on Consumed pHP ester for 1a, 2a, and 3a
with or without OA Encapsulation in Aqueous Borate Buffer
at pH 8.7; Error Limits Are 10%
Figure 1. 1H NMR (500 MHz) spectra of (i) 1a in DMSO-d6; (ii) OA
([OA] = 1 mM) in 10 mM Na2B4O7 buffer/D2O, pH = 8.7); (iii)
1a@(OA)2 ([OA] = 1 mM and [1a] = 0.5 mM) in 10 mM Na2B4O7
buffer/D2O); (iv) after 40 min irradiation of (iii) at λ ≥ 300 nm; and
(v) a mixture of 5 (0.5 mM), 6 (0.5 mM), and OA (1 mM) in 10 mM
Na2B4O7 buffer/D2O. Symbols (red *) and (blue *) indicate aliphatic
■
protons of OA incarcerated 1a and 6, respectively, (green ) the
◆
●
−CH2− of 5, and (blue ) and (green ) the residual solvent peak of
H2O and DMSO-d6, respectively.
Addition was continued until there was no further spectral
change or the solution became turbid. For pHP ester 1a
(shown in Figure 1 (iii)) as well as esters 2a and 3a (Figures
S19(ii) and S20(ii)), the molar ratios of OA to pHP esters were
2:1 H−G complexes, i.e., 1a@(OA)2. The esters 1a−3a, which
slowly hydrolyze in aqueous base, are very stable as their
conjugate bases when encapsulated in the OA devoid of water,
consistent with our observations that the OA cavity interior is
hydrophobic.
a
UV−vis spectra of 1a at pH <2, 7, and 8.7 (Figure 2a−c)
demonstrate the pH dependence of the pHP chromophore
indicating that the conjugate base of the pHP ester is
1-Adamantanecarboxylic acid, o-toluic acid, and 3,3-dimethylacrylic
b
acid from pHP esters 1a, 2a, and 3a, respectively. After a 30 min
c
irradiation of the OA. After 50 min irradiation.
Product identifications were confirmed by liquid chromatog-
raphy coupled to a diode array detector and to a mass
spectrometer (LC-DAD-MS) or by gas chromatography (GC)-
MS. Progress of the reaction was followed at 275 nm (DAD)
and under single ion monitoring (SIM) in the negative polarity
(MS). Product 8 was analyzed by GC-MS in the SIM mode
(see SI). A minor photoproduct, 2,4′-dihydroxyacetophenone
(4), was also detected (<10%). The time-dependent product
yields of the released acid approached 100% (Figure 3).
Irradiations of the OA encapsulated conjugate bases of the pHP
esters 2a and 3a (Figures S17 and S20) in aqueous borate
buffer gave the expected carboxylic acids 7 and 8, the
rearranged chromophore 4-hydroxyphenylacetic acid (∼90%,
5) (see Figure S14), and the minor photosolvolysis product
2,4′-dihydroxyacetophenone (4, ∼7%) detected by LC.
Figure 2. Absorption spectra of 1a ([1a] = 10 μM) (a) in 70%
aqueous HClO4 (pH <2); (b) in water (pH ≈ 7); (c) in 10 mM
Na2B4O7 buffer/H2O (pH = 8.7); (d) 1a@(OA)2 in 10 mM Na2B4O7
buffer/H2O ([1a] = 10 μM and [OA] = 20 μM (pH = 8.7)); and (e)
transmission spectrum of Pyrex filter. Inset: absorption spectrum of
OA ([OA] = 50 μM) in 10 mM Na2B4O7 buffer/H2O (pH = 8.7).
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Scheme 2. Suggested Mechanism for the Photorelease of
Carboxylic Acids from Their pHP Esters 1a, 2a, and 3a
within OA Capsules
Figure 3. Product distribution for the time-dependent photolysis of
pHP ester 1a at λ > 300 nm (xenon lamp, Pyrex filter) as a 2:1 octa
acid complex (1a@(OA)2, [1a] = 25 μM) in aqueous borate buffer (10
mM; pH = 8.7) to 1-adamantanecarboxylic acid (6), p-hydroxyphenyl-
acetic acid (5), and 2,4′-dihydroxyacetophenone (4).
produce no decarboxylation byproducts from the carboxylic
acids released, and give no radical coupling byproducts, three
reactions that are observed for methoxyphenacyl cage reactions,
strongly indicate that the encapsulated conjugate bases of the
pHP esters proceed exclusively via heterolytic cleavage. A short-
lived, neutral triplet biradical 123 is initially formed, which
intersystem crosses10 then closes to 13 following the
established photo-Favorskii pathway for the protonated pHP
chromophore. Currently, we are pursuing additional studies to
extend the variety of substrates released and to examine the
mechanism for release from pHP substrates confined within an
OA host.
The time-dependent photolyses of the three pHP esters
yielded nearly identical product distributions and rates of
conversion, independent of the ester’s encapsulation by OA
host or not (Table 1). While the reaction appears to be slightly
more efficient when encapsulated within OA, the photorelease
reactivities of the three esters appear to be essentially
independent of both the nature of the leaving carboxylate
moiety and the presence of OA as shown by the reaction
profiles (Figures 3, S18, and S21).
The minor photosolvolysis product 4 has been observed in
prior studies of pHP esters when neutral aqueous media were
employed, but the effect of pH had not been examined. For
1a−3a, the photolyses were carried out in aqueous borate
buffer (pH 8.7) and at neutral pH in aqueous MeCN in the
absence of OA host. LC−MS analyses confirmed the release of
the carboxylic acids 6−8 in all cases as well as the chromophore
rearrangement product 5 and the solvolysis product 4 (Table 1
and Figure S15).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, 1H and 13C NMR, and ESI-MS
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
A comparison of the time-dependent 1H NMR spectra of the
photolysis mixtures in the OA encapsulated and free,
unencapsulated caged esters indicates that decaged acids 7
and 8 are released into the aqueous base, whereas, in the case of
1a, the released acid 6 remains within an OA hemisphere. We
attribute this difference between 6 and 7/8 to the increased
hydrophobicity of 6.
Furthermore, the photoproduct mixtures from pHP esters
1a, 2a, and 3a show no evidence of reaction between the ester
and the host OA contrasting with earlier results with OA
enclosed p-methoxyphenacyl esters 1b, 2b, and 3b. The p-
methoxyphenacyl esters react by a homolytic release mecha-
nism for the leaving group leading to reactive radical
intermediates.4,6b,7c Thus, the absence of radical attack on the
OA by pHP ester photolysis as evidenced by the lack of OA
adducts and the high yield of p-hydroxyphenyl acetic acid 5
(>90%) suggests that the photorelease mechanism for OA
encapsulated pHP esters differs from that of the p-
methoxyphenacyl esters.6,7,10 In isotropic solutions, the
conjugate base of p-hydroxyphenacyl esters proceeds through
the photo-Favorskii rearrangement from their pHP triplet state
forming a short-lived (0.5 ns) triplet biradical (Scheme 2).
While we lack sufficient evidence to unequivocally assign a
mechanistic pathway, the facts that release of acids from pHP
esters 1a−3a show no evidence of radical attack on OA,
*E-mail: murthy1@miami.edu.
*E-mail: givensr@ku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.R. thanks the National Science Foundation (CHE-1411458
and CHE-1111392) for financial support. R.S.G. thanks the
Kansas University Endowment Association for partial financial
support.
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