7-Methoxy-3-nitro-2-naphthalenemethanol - A new phototrigger for caging applications

Article abstract of DOI:10.1016/j.tetlet.2011.07.043

Synthesis, photochemistry and photorelease properties of 7-methoxy-3-nitro-2-naphthalenemethanol (MNNM) are described. Photoirradiation (≥370 nm) of MNNM covalently linked to hippuric acid causes efficient release (～90%) of hippuric acid.

Full text of DOI:10.1016/j.tetlet.2011.07.043

Tetrahedron Letters 52 (2011) 4899–4902
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
7-Methoxy-3-nitro-2-naphthalenemethanol—a new phototrigger for
caging applications
⇑
Anil K. Singh , Prashant K. Khade
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 March 2011
Revised 9 July 2011
Accepted 12 July 2011
Available online 6 August 2011
Synthesis, photochemistry and photorelease properties of 7-methoxy-3-nitro-2-naphthalenemethanol
(MNNM) are described. Photoirradiation (P370 nm) of MNNM covalently linked to hippuric acid causes
efficient release (ꢀ90%) of hippuric acid.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
7-Methoxy-3-nitro-2-naphthalenemethanol
2-Nitrobenzyl
Phototrigger
Caging
Phototriggers allow rapid liberation of bioactive molecules from
their inactive caged precursors upon photolysis.1,2 Widespread
applications of these phototriggers in many fields of science and
technology have led to numerous attempts toward the synthesis
of ideal phototriggers. The ideal phototrigger properties for biomo-
lecular applications comprise photoactivation in physiological con-
ditions, photolysis in the visible region, high quantum yield and
the rate of photoreaction, etc. One of the most extensively utilized
classes of phototrigger is based on the 2-nitrobenzyl chromophore.
This is mainly because of its compatibility with various functional
groups. With a view to improve biomolecular caging properties of
this chromophore, attempts have been made to modify the known
2-nitrobenzyl compounds3 and design other related compounds
like 1-(2-nitro)phenyl ethanol2a (1), (4,5-dimethoxy-2-nitro-
phenyl)methanol2b (2) and 3-nitro-2-naphthalenemethanol4a (3).
Herein we propose a new phototrigger viz. 7-methoxy-3-nitro-
2-naphthalenemethanol (9, MNNM), which can be used for caging
of a carboxyl functional group of amino acids and is efficiently
photoactivable with visible light.
and 6a was reacted with lithium aluminum hydride in tetrahydro-
furan to obtain the respective diols from which diol 7 was
separated by column chromatography. Diol 7 was oxidized under
Swern oxidation conditions to obtain 4-methoxy phthaldehyde
(8). Condensation of 8 with ethyl-3-nitro propionate in the pres-
ence of sodium ethoxide/ethanol and further hydrolysis by 1 N
H2SO4 yielded the acid, which on reduction by BF3-etherate and
sodium borohydride in diglyme yielded 9 (major) and 9a (minor)
products.5,6 The ester derivative 10 was prepared by DCC/DMAP
mediated condensation of 9 with hippuric acid in dichloromethane
at ambient temperature in good yield.7,8 All products were satisfac-
torily characterized by the melting point, FT-IR, 1H NMR and mass
spectral analyses.
MNNM (9) in ethanol shows absorption bands at 225, 256 and
at 339 nm, which is extended up to 420 nm. Similar absorption
bands were obtained in other solvents like 1,4-dioxane, acetoni-
trile and 0.153 M NaCl. These results showed that the absorption
spectrum of 9 largely remains insensitive to the dielectric constant
of the solvent medium studied. For comparison, the UV–Vis
absorption spectra of compounds 1, 2, 3 and 9 are shown in Figure
1. Extinction coefficient values of compounds 1, 2, 3 and 9 in
ethanol at 350, 380, 400 and 420 nm are given in Table 1. It is note-
worthy that in 350–420 nm range, the extinction coefficient of
compound 9 is larger than the extinction coefficient of compounds
1–3.
Synthesis of 1,2a 24b and 34a was done following literature pro-
cedures. MNNM (9) was synthesized according to the steps shown
in Scheme 1. 3-Hydroxy benzoic acid (4) was alkylated with di-
methyl sulfate in 1 M aqueous sodium hydroxide by heating the
reaction mixture at 60–80 °C to obtain 3-methoxy benzoic acid
(5). Compound 5 was lactonized using conc. HCl and formaldehyde
at 70–80 °C, when a mixture of two inseparable (silica gel column
chromatography) lactones 6 and 6a was obtained. The mixture of 6
Compound 9 was irradiated at 370 nm and the progress of the
photoreaction was monitored by UV–Vis spectroscopic measure-
ments. This revealed a uniform and clean photoconversion of 9,
with isosbestic points at 312 and 362 nm. Typical UV–Vis spectra
of 9 during its photolysis in ethanol at different time intervals
⇑
Corresponding author. Tel.: +91 22 2576 7167; fax: +91 22 2576 7152.
E-mail address: Retinal@chem.iitb.ac.in (A.K. Singh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.043

4900
A. K. Singh, P. K. Khade / Tetrahedron Letters 52 (2011) 4899–4902
COOH
COOH
a
O
b
+
H3CO
O
H3CO
OH
OCH3
O
O
4
5
6a
6
c
CHO
CHO
H3CO
NO2
OH
OH
OH
e
d
H3CO
H3CO
9a
7
8
+
NO2
OR
NO2
OH
f
O
H3CO
H3CO
10
N
H
9
R =
O
Scheme 1. Synthesis of MNNM (9) and caged hippuric acid (10). Reagents and conditions (a) (Me)2SO4, 1 M NaOH, 60–80 °C; (b) HCHO, conc. HCl, 70–80 °C; (c) LiAlH4, THF,
80 °C; (d) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C; (e) (i) NO2CH2CH2COOEt, EtOH/EtONa; (ii) 1 N H2SO4, 60 °C; (iii) Diglymne, NaBH4 BF3.OEt2, 0 °C; (f) DCC/DMAP, Hippuric acid.
Table 1
Molar absorptivity of phototriggers in ethanol
Compound
NO2
e
(molÀ1 cmÀ1 L at 350 nm)
e
(molÀ1 cmÀ1 L at 380 nm)
e
(molÀ1 cmÀ1 L at 400 nm)
e
(molÀ1 cmÀ1 L at 420 nm)
OH
497
150
No absorbance
No absorbance
H
CH3
1
MeO
MeO
NO2
OH
7362
3000
11327
1808
1350
6508
822
100
180
611
2
NO2
OH
505
3
NO2
OH
2580
H3CO
9
are shown in Figure 2. FTIR analysis of the photomixture of 9
showed generation of IR band at 1689 cmÀ1 corresponding to the
aldehyde group and at 1525 and 1347 cmÀ1 corresponding to the
nitroso group. The 1H NMR spectrum of the photomixture of 9
showed a peak at d 11.20 due to the aldehyde group, confirming
the formation of an aldehyde photoproduct. The mass spectrum
also revealed the formation of a nitroso aldehyde photoproduct
[ES-MS: m/z found 216.0671 (M++1), calculated for C12H9NO3
216.0661 (M++1)]. However, prolonged irradiation of 9 results in
the disappearance of the aldehyde group as evidenced by 1H
NMR spectrum, and attempts to purify this photoproduct were
unsuccessful. This can be due to the secondary photoreactions of
the primary photoproduct nitroso aldehyde. Such secondary
photoreactions of nitroso aldehydes are known in literature.9
Irradiation of 9 in ethanol, 1,4-dioxane and in 0.153 M NaCl at
380 nm showed a similar product profile as indicated by HPLC
analysis. Similar results were obtained when 9 was irradiated in
acetonitrile at different wavelengths of 300, 350, 380 and
400 nm. These results indicate that 9 undergoes a similar
photochemical reaction when irradiated in different solvents and
at different photolysis wavelengths in the range of 300–400 nm.
The primary photochemical process in this reaction can be intra-
molecular hydrogen abstraction by the excited nitro group
followed by electron redistribution to the aci-nitro form, which
rearranges to the nitroso aldehyde derivative.2b
To examine the caging property of 9, carboxylic group of hippu-
ric acid was protected by 9 under mild conditions. Caged hippuric
acid (10) shows absorption similar to the parent chromophore (9).
Photolysis of 10 at 370 nm in CH3CN–H2O (3:2 v/v) and photore-
lease of hippuric acid from 10 was followed by HPLC.10 The time
course of photorelease of hippuric acid is shown in Figure 3. The
maximum percent of photorelease was 90%. The quantum yield
of chromophore disappearance (i.e., uncaging efficiency of the
phototrigger) at 380 nm and 420 nm is 0.145 and 0.031
respectively.11 Further, 10 is stable to the reported photolysis
conditions as evidenced by HPLC analysis by keeping its solution

A. K. Singh, P. K. Khade / Tetrahedron Letters 52 (2011) 4899–4902
4901
100
3
2
1
0
80
60
40
20
0
0.0
2.5
5.0
7.5
10.0
12.5
200
250
300
350
400
450
Time (hours)
Wavelength (nm)
Figure 3. Time course for photolysis of the caged hippuric acid (10). Caged hippuric
acid (10, 1 Â 10À3 M) was irradiated at P370 nm in CH3CN–H2O (3:2 v/v). Release
of hippuric acid monitored by HPLC; caged hippuric acid 10 (d) and released
hippuric acid (o).
Figure 1. UV–Vis absorption spectra of phototriggers 1(.), 2(N), 3(j) and 9(d) in
ethanol (1.0 Â 10À4 M).
3
2
1
0
polarity, good quantum yield, good % release of the caged molecule,
and better absorption in the visible region than the known 2-nitro-
benzyl systems make 9 a good phototrigger for caging applications.
The versatility of 9 in various applications also including biomolec-
ular caging and aqueous solubility can be extended by modifying
its phenolic position.
Acknowledgment
A research grant [01/1509/98-EMR-II] from the Council of
Scientific and Industrial Research, New Delhi, Government of India
is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.043.
References and Notes
200
300
400
500
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Wavelength (nm)
Figure 2. Absorption spectral changes during photolysis of MNNM (9) in ethanol
(1.0 Â 10À4 M) at P370 nm. Arrows indicate the changes of absorbance during the
irradiation time.
in CH3CN–H2O (3:2 v/v) in dark for about one day. However, it is
also observed that the nitroso aldehyde undergoes secondary reac-
tion or photoreaction, although it does not affect the recovery of
the released hippuric acid, as the release is due to the primary
photochemical process.
These results show that MNNM (9) undergoes the desired
photochemistry when irradiated at around 400 nm and releases
caged hippuric acid in good yield. Mild reaction conditions to pre-
pare the caged compound, photochemical insensitivity to solvent

4902
A. K. Singh, P. K. Khade / Tetrahedron Letters 52 (2011) 4899–4902
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% release of hippuric acid is calculated by HPLC. 2 mL of
1.0 Â 10À3 M solution of 10 in CH3CN–H2O (3:2 v/v) was photolyzed using a
400 W medium pressure Hg lamp in a quartz cuvette. The desired wavelength
was obtained by using P370 nm glass filter having 47% and 96% transmittance
at 370 and 420 nm, respectively. The distance between the sample and the
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hippuric acid (10) and the percent appearance of hippuric acid aliquots of
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20 lL of the photomixture was removed periodically and analyzed by HPLC.
6. Compound 9: Yield: 15%; Mp: 165–167 °C (Lit.5 Mp: 166–167 °C); UV–Vis
The photochemical deprotection yields were calculated by comparing the HPLC
trace (peak area) due to released hippuric acid with the corresponding peak
area due to the standard hippuric acid. HPLC analysis were performed on a
Hitachi instrument consisting of a L-6250 intelligent pump and a U-2000
(CH3CN): mmax, 339 nm (e
, 13184 molÀ1 cmÀ1 L); IR (KBr) vmax (cmÀ1): 3454
(OH), 1532 and 1334 (NO2); MS, m/z (% rel int): 233 (M+, 41), 216 (9), 172 (33),
156 (100), 145 (72), 128 (72), 115 (86), 89 (19), 77 (18) and 63 (20); 1H NMR
(400 MHz, CDCl3): d 8.67 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 7.88 (d, J = 9.2 Hz, 1H,
H–C8), 7.28–7.19 (m, 2H, Ar-H), 5.08 (s, 2H, CH2) and 3.97 (s, 3H, OCH3).
7. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475–4478.
8. Compound 10: Yield: 60%; Mp: 152–154 °C; FTIR (KBr) vmax (cmÀ1): 1749
(OCO), 1668 (NHCO), 1545 and 1398 (NO2); ES-MS: m/z Found 417.1053
(M++Na) calculated for C21H18N2O6 417.1063 (M++Na); 1H NMR (300 MHz,
CDCl3): d 8.69 (s, 1H, Ar-H), 7.90–7.80 (m, 4H, Ar-H), 7.54–7.43 (m, 4H, Ar-H),
7.28–7.21 (m, 1H, Ar-H), 6.72 (br s, 1H, NH), 5.78 (s, 2H, CH2), 4.42 (d, 2H, CH2)
and 3.97 (s, 3H, OCH3).
spectrophotometer under the following conditions: column, ALTEX ODS (5 l,
4.6 mm  25 cm), solvent, CH3CN–H2O (3:2 v/v) and 0.1% phosphoric acid, flow
rate, 0.8 mL/min, detection k 226 nm.
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The quantum yield of 10 disappearance (UPR) at 380 and 420 nm is determined
using Applied Photophysics photoreactor and the number of quanta absorbed
are calculated by ferrioxalate actinometry.