A new caging phototrigger based on a 2-acetonaphthyl chromophore

Article abstract of DOI:10.1016/j.tetlet.2007.07.155

Irradiation (λ ～ 350 nm in an aqueous environment) of carboxylic acid esters derived from the reaction between carboxylic acids and 2-bromo-1-(naphthalene-2-yl)ethanone affords the parent carboxylic acid in good yield, making the 2-acetonaphthyl chromophore a good phototrigger for caging applications, including biomolecular caging.

Full text of DOI:10.1016/j.tetlet.2007.07.155

Tetrahedron Letters 48 (2007) 6920–6923
A new caging phototrigger based on a 2-acetonaphthyl chromophore
Prashant K. Khade and Anil K. Singh*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
Received 19 June 2007; revised 18 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Irradiation (k ꢀ 350 nm in an aqueous environment) of carboxylic acid esters derived from the reaction between carbox-
ylic acids and 2-bromo-1-(naphthalene-2-yl)ethanone affords the parent carboxylic acid in good yield, making the 2-acetonaphthyl
chromophore a good phototrigger for caging applications, including biomolecular caging.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Molecular caging is a technique in which a bioactive
compound is rendered inactive by covalently linking it
to a photolabile group. The caged molecule can be
released in its active form by photoirradiation of the
cage.1–4 The caging technique is used in many areas such
as analytical chemistry, biochemistry, combinatorial
chemistry, materials chemistry, medicine, organic syn-
thesis, and physiology, and it offers numerous practical
applications. For instance, while biomolecular arrays
based on photocleavable cages are of central importance
in the field of nanotechnology, the possibility of pro-
drug photoactivation and site-, time- and concentra-
tion-controlled photorelease of drugs is important in
the field of medicine and healthcare. Further, it presents
a novel strategy for in vivo investigation of a wide range
of cellular activities.
of photoreaction, a biologically benign photoproduct
and the photoactivation of the chromophore should
occur under physiological conditions. Recently, novel
phototriggers based on a phenacyl chromophore have
attracted much attention.8–15 The phenacyl chromo-
phore has found varied caging applications, for exam-
ple, in caging of phosphates,8 excitatory amino acids9
and peptides,10 and photoreversible covalent inhibition
of protein tyrosine phosphatases.11 Noteworthy
attempts have been made to develop improved photo-
triggers based on an acetophenone chromophore.8,16
Herein, we report a new phototrigger based on a
2-acetonaphthyl chromophore, which can find applica-
tions in caging of bioactive compounds through a
carboxylic functional group (Scheme 1).
In order to investigate the phototrigger properties of
the 2-acetonaphthyl chromophore, we first prepared
2-bromo-1-(naphthylen-2-yl)ethanone (2) by brominat-
ing 2-acetonaphthalene following a previously described
procedure.13,17 Subsequently, esters 5a–5e were obtained
in good yields by treating various carboxylic acids with 2
in the presence of triethylamine in dry acetonitrile at
ambient temperature for 12 h. Additionally, 2-bromo-
1-(4-methoxyphenyl)ethanone (4), a known phototrig-
ger was prepared for comparison purposes from 4-meth-
oxyacetophenone (3) as described elsewhere.17 All
compounds were characterized by IR, 1H NMR and
mass spectroscopy.18
Many phototriggers have been developed for caging
applications. While phototriggers that are photoactiv-
able in organic media employing UV light can be used
in synthesis, combinatorial chemistry, analytical chemis-
try, and in many other non-biological situations, such
phototriggers are of limited use in biological and medi-
cal applications. In this context, we have recently
synthesized and examined the efficacy of phototriggers
based on nitronaphthyl and anthryl frameworks.5–7
For biological and medical caging applications, the
phototrigger should have a high rate and quantum yield
A solution of 2 in THF–H2O (1:1, v/v) showed absorp-
tion up to 380 nm (e, 220 M LÀ1 cmÀ1) with an absorp-
tion maximum (kmax) at 346 nm (e, 2992 M LÀ1 cmÀ1).
However, 4 in the same solvent showed kmax at
284 nm (e, 17433 M LÀ1 cmÀ1) with no significant
Keywords: 2-Acetonaphthalene; Phototrigger; Carboxylic acid esters;
Photolysis; Caging.
*
Corresponding author. Tel.: +91 22 2576 7167; fax: +91 22 2576
7152; e-mail: Retinal@chem.iitb.ac.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.155

P. K. Khade, A. K. Singh / Tetrahedron Letters 48 (2007) 6920–6923
6921
Figure 1 and the photochemical data for esters 5a–5e
are summarized in Table 1. Maximum photorelease
yields of 88% and 90% were observed for 5a and 5e
when photolyzed at P337 nm in THF–H2O (1:1, v/v)
mixture, with the time taken for complete consumption
of the starting material being 2–4 h. Good photorelease
yields were also obtained in the case of ester 5c. How-
ever, in the cases of esters 5b and 5d, the photorelease
yield was moderate. The quantum yield (U) for the
starting esters varied in the range 0.068 to 0.180 at
350 nm.22 When a solution of 5a in THF–H2O (1:1)
O
O
Br2 , AlCl3
THF, 0 oC
CH3
Br
Br
2
1
3
O
O
Br2 , AlCl3
THF, 0 oC
CH3
H3CO
H3CO
4
O
OX
N(Et)3, CH3CN
2
+ HOX
5
3.0
2.0
1.0
0.0
O
Cl
O
X =
N
H
O
5a
5b
O
NO2
O
5c
5d
OCH3
OH
OCH3
O
O
5e
6
200
300
400
Scheme 1.
Wavelength / nm
Figure 1. UV–vis absorption spectral changes during photolysis of
ester 5a at 350 nm in THF–H2O (1:1, v/v, 1.0 · 10À4 M).
absorption beyond 350 nm (e, 192 M LÀ1 cmÀ1). The
photocleavable protecting group properties of the esters
derived from 4 are known, and besides release of the
protected moiety, reduced and rearrangement photo-
products are known to form.8,16,19 Photo-debromina-
tion of 2 is known and after debromination it
subsequently undergoes a neophenyl-like rearrange-
ment.20 The photolysis of 2 in THF–H2O (1:1, v/v,
1.0 · 10À3 M) at P337 nm yielded three products, two
Table 1. Photochemical properties of esters 5a–5e in THF–H2O (1:1,
v/v)
Ester Carboxylic acid
Photorelease Photolysisb UPR
c
yielda (%)
time (h)
O
HO
5a
88
2.3
0.117
N
1
H
O
of which were characterized by HPLC and H NMR
analysis as the reduced 2-acetonaphthone (1) and the
Cl
rearrangement
photoproduct naphthalene-2-acetic
5b
5c
42
67
5
3
0.068
0.180
HO
acid21 (6). HPLC analysis of the photomixture of 2
obtained after photolysis at P337 in 1,4-dioxane–H2O
(1:1, v/v) and in CH3CN–H2O (1:1, v/v) showed a
similar profile of photoproducts. Thus, the photochem-
istry of 2 did not change significantly with solvent
systems.
O
O
HO
HO
HO
5d
5e
44
90
5
4
0.080
0.120
NO2
O
O
The UV–vis absorption spectra of esters 5a–5e were
similar to that of the parent chromophore (2-aceto-
naphthyl) present in 2. Photolysis of 5a in THF–H2O
(1:1, v/v) released the parent acid and 1 along with a
few other minor photoproducts, which could not be
characterized. Similar results were observed when esters
(5b–5e) were photolyzed. Typical absorption spectral
changes during the photolysis of ester 5a is shown in
OCH3
OCH3
a Based on HPLC.
b Time for complete disappearance of starting ester (1.0 · 10À3 M).
c Quantum yield of disappearance of the starting ester at 350 nm at
ambient temperature.

6922
P. K. Khade, A. K. Singh / Tetrahedron Letters 48 (2007) 6920–6923
O
O
OX
h
THF-H O
2
v,
OX
CH2
Homolytic cleavage
O
H-abstraction
e.g., X=
N
H
O
O
CH3
XOH
+
1
Scheme 2.
5. Singh, A. K.; Khade, P. K. Bioconjugate Chem. 2002, 13,
1286.
6. Singh, A. K.; Khade, P. K. Tetrahedron Lett. 2005, 46,
5563.
7. Singh, A. K.; Khade, P. K. Tetrahedron 2005, 61, 10007.
8. Givens, R. S.; Athey, P. S.; Matuszwski, B.; Kueper, L.
W., III; Xue, J.-Y.; Fister, T. J. Am. Chem. Soc. 1993, 115,
6001.
9. Givens, R. S.; Jung, A.; Park, C.-H.; Weber, J.; Bartlett,
W. J. Am. Chem. Soc. 1997, 119, 8369.
was photolyzed at longer wavelength (P370 nm), simi-
lar photoproducts were obtained, with a maximum
photorelease yield of 94%. Parallel dark reactions were
conducted for all the esters and it was found that no
thermal reaction occurred under the photolysis condi-
tions. To find the best solvent system for the photolysis,
5a was photolyzed in different solvent systems including
THF–H2O (7:3, v/v), THF–H2O (3:7, v/v), CH3CN–
H2O (1:1, v/v) and 1,4-dioxane–H2O (1:1, v/v). The best
photorelease yield of 88% was obtained in THF–H2O
(1:1, v/v).
10. Sheehan, J. C.; Umezawa, K. J. Org. Chem. 1973, 21,
3771.
11. Arabaci, G.; Guo, X.-C.; Beebe, K. D.; Coggeshall, K. M.;
Pei, D. J. Am. Chem. Soc. 1999, 121, 5085.
12. Contrad, P. G., II; Givens, S. R.; Weber, J. F. W.;
Kandler, K. Org. Lett. 2000, 2, 1545.
13. Park, C.-H.; Givens, R. S. J. Am. Chem. Soc. 1997, 119,
2453.
14. Givens, R. S.; Park, C.-H. Tetrahedron Lett. 1996, 37,
6259.
15. Falvey, D. E.; Sundararajan, C. Photochem. Photobiol.
Sci. 2004, 3, 831.
16. Givens, R. S.; Kueper, L. W., III Chem. Rev. 1993, 93, 55,
and references cited therein.
During the photolysis of esters 5a–5 e, the release of car-
boxylic acid was accompanied by the appearance of the
reduced photoproduct 1. Based on a literature prece-
dence, a plausible mechanism for the observed photo-
chemistry of the esters is outlined in Scheme 2.8,16,19
Thus, homolytic cleavage of the C–O bond leads to
the formation of a radical pair, which, among many
other possible reactions, on subsequent hydrogen atom
abstraction gives 1 and the carboxylic acid.
17. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S.
Bull. Chem. Soc. Jpn. 1987, 60, 1159.
In conclusion, esters bearing a 2-acetonaphthyl chromo-
phore can be photoexcited in aqueous medium at
350 nm, releasing the corresponding carboxylic acids in
good chemical yields. This work introduces a new poten-
tial phototrigger, which is useful for various caging
applications.
18. A typical procedure for the preparation of esters 5a–5e: A
solution of 2 (0.8 mmol) and carboxylic acid (0.9 mmol) in
dry CH3CN (10 mL) was cooled to 0 ꢁC. The cooled
solution was treated with triethylamine (0.9 mmol) drop-
wise over 15 min and then stirred at ambient temperature.
The progress of the reaction was monitored by TLC (silica
gel). After completion, the reaction mixture was neutral-
ized with aq. HCl and then poured into water, extracted
with ethyl acetate and dried. Removal of the solvent under
reduced pressure yielded a solid, which was further
purified by column chromatography. Compound 5a:
Yield: 60%; mp: 79–81 ꢁC; FTIR (KBr) vmax (cmÀ1):
3392 (NH), 1720 (CO), 1666 (OCO) and 1633 (NHCO);
ES-MS: m/z Found 348.1219 (M++H) calculated for
C21H18NO4 348.1236 (M++H); 1H NMR (300 MHz,
CDCl3): d 8.42 (s, 1H, Ar-H), 7.99–7.82 (m, 6H, Ar-H),
7.67–7.42 (m, 5H, Ar-H), 6.79 (br s, 1H, NH), 5.60 (s, 2H,
CH2O) and 4.51 (d, J = 5.1 Hz, 2H, CH2). Compound 5b:
Yield: 69%; mp: 79–81 ꢁC; FTIR (KBr) vmax (cmÀ1): 1743
(OCO) and 1710 (CO); ES-MS: m/z Found 347.0453
(M++Na) calculated for C19H13O3ClNa 347.0451
(M++Na); 1H NMR (400 MHz, CDCl3): d 8.50 (s, 1H,
Ar-H), 8.10–7.90 (m, 5H, Ar-H), 7.67–7.36 (m, 5H, Ar-H)
and 5.74 (s, 2H, CH2). Compound 5c: Yield: 57%; mp:
Acknowledgements
A research grant [01/1509/98-EMR-II] from the Council
of Scientific and Industrial Research, New Delhi, Gov-
ernment of India, is gratefully acknowledged.
References and notes
1. Caged compounds; Marriot, G., Ed.; Methods Enzymol;
Academic Press: New York, 1998; p 291.
2. Pillai, V. N. R. Synthesis 1980, 1.
3. Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
4. Pelliccioli, A. P.; Witz, J. Photochem. Photobiol. Sci. 2002,
1, 441.

P. K. Khade, A. K. Singh / Tetrahedron Letters 48 (2007) 6920–6923
6923
96–98 ꢁC; FTIR (KBr) vmax (cmÀ1): 1743 (OCO) and 1696
(CO); ES-MS: m/z Found 327.1013 (M++Na) calculated
for C20H16O3Na 327.0997 (M++Na); 1H NMR
(400 MHz, CDCl3): d 8.40 (s, 1H, Ar-H), 7.97–7.87 (m,
5H, Ar-H), 7.64–7.57 (m, 3H, Ar-H), 7.39–7.27 (m, 3H,
Ar-H), 5.49 (s, 2H, CH2) and 3.85 (s, 2H, CH2).
Compound 5d: Yield: 65%; mp: 136–138 ꢁC; FTIR (KBr)
vmax (cmÀ1): 1743 (OCO), 1710 (CO), 1532 and 1354
(NO2); GC–MS, m/z (% rel int): 335 (M+, 0.5), 305 (9), 155
(100), 127 (47) and 92 (20); 1H NMR (400 MHz, CDCl3): d
9.01 (s, 1H, Ar-H), 8.49 (m, 3H, Ar-H), 8.01–7.91 (m, 4H,
Ar-H), 7.73–7.60 (m, 3H, Ar-H) and 5.80 (s, 2H, CH2).
Compound 5e: Yield: 60%; mp: 110–112 ꢁC; FTIR (KBr)
vmax (cmÀ1): 1737 (OCO) and 1690 (CO); ES-MS: m/z
Found 373.1035 (M++Na) calculated for C21H18O5Na
20. Hall, M.; Chen, L.; Pandit, C. R.; McGimpsey, W. G. J.
Photochem. Photobiol. A: Chem. 1997, 111, 27.
21. Giordano, C.; Castaldi, G.; Casagrande, F.; Belli, A. J.
Chem. Soc., Perkin Trans. 1 1982, 11, 2575.
22. Photolysis, HPLC and quantum yield measurements:
Photolysis was accomplished using a 400 W medium
pressure mercury lamp and the desired wavelengths were
obtained with the aid of either a f/3.4 monochromator or
appropriate glass filters (P370 nm having 47% and 96%
transmittance at 370 and 420 nm, respectively, and P337
having 100% and 52% transmittance at 365 and 337 nm,
respectively). The distance between the sample and the
lamp was 2 cm. All photolyses were performed in a quartz
cuvette containing 2 mL samples of concentration
1.0 · 10À3 M. The quantum yield of disappearance is
defined as the ratio of ester molecules disappeared to the
amount of photons absorbed, employing the potassium
ferrioxalate actinometer. Rabek, J. F., Radiometry and
actinometry. In Experimental methods in photochemistry
and photophysics; Wiley: New York, 1982; Vol. 2, pp 944.
The percent photorelease of carboxylic acids from the
corresponding esters was determined from the HPLC, by
comparison with the standard peak area of the respective
carboxylic acid.
1
373.1052 (M++Na); H NMR (400 MHz, CDCl3): d 8.51
(s, 1H, Ar-H), 8.05–7.88 (m, 4H, Ar-H), 7.64–7.55 (m, 2H,
Ar-H), 7.32–7.28 (m, 1H, Ar-H), 6.56 (d, 2H, J = 8.4 Hz,
Ar-H), 5.65 (s, 2H, CH2) and 3.80 (s, 6H, 2 · OCH3).
19. Dynamic Studies in Biology: Phototriggers, Photoswitches
and Caged Biomolecules, Goeldner, M.; Givens, R., Eds.;
Chapter 2. Mechanistic Overview of Phototriggers and
Cage Release, Givens, R. S.; Kotala, M. B.; Lee, J.-I., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: 2005; pp 55–75.