Controlled photochemical release of nitric oxide from O2-naphthylmethyl- and O2-naphthylallyl-substituted diazeniumdiolates

Article abstract of DOI:10.1021/ja027957h

The photochemistry of O²-naphthylmethyl- and O²-naphthylallyl-substituted diazeniumdiolates has been investigated. Electron-donating methoxy group substitution is shown to have a significant effect on the observed photochemistry, with the appropriate substitution pattern resulting in efficient diazeniumdiolate photorelease. Observed nitric oxide release rates from these photoprecursors are consistent with those expected for normal thermal dissociation of the diazeniumdiolate in aqueous solutions and show the same pH dependence. Copyright

Full text of DOI:10.1021/ja027957h

Published on Web 10/04/2002
Controlled Photochemical Release of Nitric Oxide from O2-Naphthylmethyl-
and O2-Naphthylallyl-Substituted Diazeniumdiolates
K. Mani Bushan, Hua Xu, Patrick H. Ruane, Raechelle A. D’Sa, Christopher M. Pavlos,
Joseph A. Smith, Tevye C. Celius, and John P. Toscano*
Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street, Baltimore, Maryland 21218
Received July 31, 2002
Scheme 1
Anions such as 1-(N,N-dialkylamino)diazen-1-ium-1,2-diolates
(1) are stable as solid salts, but release up to 2 mol of the important
bioregulatory molecule nitric oxide (NO) when dissolved in aqueous
solution at physiologically relevant conditions.1 The rate of NO
release can be varied by modifying the substituents R, pH, or
temperature.1 To extend the usefulness and applications of diaz-
eniumdiolates as NO donors, we have been developing efficient
photosensitive protecting groups for these anions.2,3 Our previous
work has demonstrated that the photochemistry of O2-alkyl- and
O2-benzyl-substituted diazeniumdiolates can be severely compli-
cated by a reaction that produces potentially carcinogenic nitros-
amine and an oxynitrene intermediate4 (see Scheme 1, Path A).
More recently, we have shown that for a series of meta-substituted
O2-benzyl-protected diazeniumdiolates, the desired photorelease of
1 (see Scheme 1, Path B) competes more effectively with this
undesired reaction pathway for those derivatives with stronger
π-donating meta substituents.5 Near quantitative release of 1 is
obtained with the 3,5-dihydroxybenzyl derivative, but only at pH
values above 10. The highest contribution from the photorelease
reaction pathway observed at neutral pH is 50%, obtained with the
3,5-bis-dimethylamino derivative. An additional shortcoming of
these benzyl derivatives is the complication caused by potential
secondary photolysis of photoreleased 1, which has λmax ) ca. 250
nm and tails out to A ) 0 at approximately 320 nm.6 Reported
herein is an extension of our previous work to O2-naphthylmethyl-
and O2-naphthylallyl-substituted diazeniumdiolates 2-10 that ad-
dresses these deficiencies.
Table 1. Yields of Productsa Following Photolysis of
O2-Naphthylmethyl- and O2-Naphthylallyl-Substituted
Diazeniumdiolates
nitros-
amine
11
alcohol rearranged diazenium- quantum
c
reactant
oximes aldehyde
12
alcohol 13
diolate 1b
yield
2
3
4
5
6
7
8
9
74
75
72
53
16
53
62
10
14
35
d
31
23
d
42
d
4
0
d
d
20
0
14
d
8
42
26
36
34
14
16
-
-
1
1
0.007
d
24
-
25
40
95
32
20
50
50
0.12
0.12
0.66
0.055
0.025
0.15
0.10
53
-
d
35
16
3
-
52
46
10
2
a Average of at least three measurements, estimated error (5%; based
on the percent reactant converted (30-40%). Photolyses (typically for ca.
15 s) were carried out in a Rayonet reactor (300 nm for compounds 2-4
and 8, 350 nm for compounds 5-7, 9, and 10) in argon-purged 90-95%
aqueous acetonitrile. Secondary photochemistry is negligible under these
conditions. b Based on percent reactant converted (determined by HPLC
analysis), the yield of NO measured, and the observation that diazenium-
diolate 1 (R ) Et) gives 1.5 equiv of NO for compounds 2-9 and
diazeniumdiolate 1 (NR2 ) piperidinyl) gives 1.8 equiv of NO for compound
10.8 c For reactant photodecomposition, using the azobenzene actinometer;9
photolysis at 300 nm (Rayonet) for compounds 2-4 and 8, and at 355 nm
(Nd:YAG laser) for compounds 5-7, 9, and 10. d Not determined.
provide substantial amounts of nitrosamine 11 and very little
photorelease of diazeniumdiolate 1 (Table 1).
Following the recent report of Rao and co-workers showing that
arylallyl acetates undergo efficient ionic photodissociation in polar
solvents,10 we also examined naphthylallyl derivative 4. Here, we
observe approximately 25% photorelease of diazeniumdiolate 1
(Table 1).
Although photolysis of the parent O2-benzyl-substituted deriva-
tive results in negligible release of 1, we were able to enhance this
process significantly with electron-donating meta substitution. This
substitution pattern was examined on the basis of the well-
established meta effect of electron-donating groups favoring the
Since Pincock and co-workers have examined the photochemistry
of a series of 1-naphthylmethyl esters and demonstrated efficient
carboxylate photorelease for the 4-methyl derivative as well as for
the unsubstituted parent compound,7 we initially examined 1-naph-
thylmethyl derivatives 2 and 3. Unfortunately, these derivatives
* To whom correspondence should be addressed. E-mail: jtoscano@jhu.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 12640-12641
10.1021/ja027957h CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
diazeniumdiolate photorelease is not pH-dependent and can be
initiated by long-wavelength (g350 nm) light, making this diaz-
eniumdiolate precursor potentially well-suited for a range of
biological applications.14
Since the rate of NO release from diazeniumdiolate 1 can be
controlled by factors such as the substituents R, pH, and temper-
ature, an additional advantageous feature of 6 (and of the other
derivatives reported here) is that the flux of NO can be controlled
(and varied) by these factors. Figure 1 demonstrates that the NO
release rate observed following photolysis of 6 is exactly analogous
to that observed for thermal dissociation of the sodium salt of 1 (R
) Et) and, moreover, shows the same pH dependence. In addition,
the inset of Figure 1 shows that the rate of NO release following
photolysis at a particular pH can be varied by simply changing the
nature of the released diazeniumdiolate, for example, from a
diethylamine derivative (1 (R ) Et)) to a piperidine derivative
(1 (NR2 ) piperidinyl)).
Figure 1. NO release rates observed following photolysis (Xe-arc lamp
with a 324-nm long pass filter) of 6 (0.5 µM in 99% aqueous acetonitrile
at 25 °C) at varying solution pH’s (in blue) compared with the corresponding
rates observed for the thermal dissociation of the sodium salt of diazeni-
umdiolate 1 (R ) Et) at the same pH’s (in red). The inset shows an
analogous comparison for (a) the photolysis of 10 (in blue) with the thermal
dissociation of 1 (NR2 ) piperidinyl) (in red) and (b) the photolysis of 9
(in blue) with the thermal dissociation of 1 (R ) Et) (in red) at pH 6.8.
Acknowledgment. We gratefully acknowledge the National
Institutes of Health (R01 GM58109) for generous support of this
research. J.P.T. also acknowledges a Camille Dreyfus Teacher-
Scholar Award and an Alfred P. Sloan Research Fellowship. J.A.S.
acknowledges a Jean Dreyfus Boissevain Undergraduate Scholar-
ship. We also thank Professor Jakob Wirz for helpful discussions.
formation of ionic products in photochemical reactions of benzylic
systems.7,11 To determine what substitution patterns might enhance
the photorelease of 1 in naphthylmethyl and naphthylallyl systems,
we examined reported substituent effects on the excited-state acidity
of 1- and 2-naphthols.12 Electron-withdrawing substituents in the
5 and 8 positions and in the 3, 5, and 8 positions for 1- and
2-naphthol, respectively, enhance the excited state acidity. We
reasoned, therefore, that these positions transmit electronic effects
most effectively in the excited states of naphthalene derivatives
and that electron-donating substituents in these positions would
enhance the formation of a naphthylmethyl or naphthylallyl cation,
resulting in the desired photorelease of diazeniumdiolate anion 1
(Path B, Scheme 1).
To test this hypothesis, methoxy-substituted compounds 5-9
were synthesized and, along with the parent compounds 2 and 4,
were analyzed for products following photolysis. Yields of organic
products, quantified by HPLC analysis, are given in Table 1.13
Quantification of NO released upon photolysis was performed as
described previously5 and was used to derive yields of photoreleased
1 (see also Supporting Information).
The diazeniumdiolate yields presented in Table 1 indicate that
the appropriate methoxy group substitution pattern has a significant
effect on the efficiency of the photorelease of 1, for example, 2
(1% release) versus 5 (40% release) and 4 (25% release) versus 6
(95% release). In addition, naphthylallyl derivatives perform better
than their naphthylmethyl analogues, for example, 5 (40% release)
versus 6 (95% release) and 8 (20% release) versus 9 (50% release).
This latter trend may be the result of production of a more stable
naphthylallyl cation or may reflect greater transfer of electron
density in the excited states of the naphthylallyl systems as
suggested by simple Hu¨ckel calculations. These calculations, at least
qualitatively, reproduce the general trends observed for diazeni-
umdiolate photorelease from compounds 2-9 (Supporting Informa-
tion).
Supporting Information Available: Experimental details concern-
ing the synthesis of 2-10 and of authentic products, quantification of
photoreleased diazeniumdiolate 1, and Hu¨ckel calculations on the first
excited states of 2-10 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For a recent review of the chemistry of diazeniumdiolate derivatives,
see: Hrabie, J. A.; Keefer, L. K. Chem. ReV. 2002, 102, 1135-1154.
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diazeniumdiolates 1, see: Makings, L. R.; Tsien, R. Y. J. Biol. Chem.
1994, 269, 6282-6285.
(3) For a recent review of NO-donor chemistry, see: Wang, P. G.; Xian, M.;
Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J. Chem. ReV. 2002,
102, 1091-1134.
(4) Srinivasan, A.; Kebede, N.; Saavedra, J. E.; Nikolaitchik, A. V.; Brady,
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(5) Ruane, P. H.; Bushan, K. M.; Pavlos, C. M.; D’Sa, R. A.; Toscano, J. P.
J. Am. Chem. Soc. 2002, 124, 9806-9811.
(6) A full characterization of the photochemistry of diazeniumdiolates 1 will
soon be reported: D’Sa, R. A.; Ruane, P. H.; Kumar, N. A.; Relyea, H.
A.; Toscano, J. P. Manuscript in preparation.
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(13) The observed aldehydes are not primary products of either Path A or B
(Scheme 1). They likely arise from secondary photolysis of primary oxime
products as has been observed,4,5 or via a reaction pathway involving the
extrusion of nitrous oxide (N2O) that has also been observed.4
(14) Compound 6 has a UV-vis absorption band centered at 336 nm (ꢀ )
9780 M-1 cm-1) that tails out to A ) 0 at approximately 400 nm. It is
soluble up to 20 µM in 95% aqueous acetonitrile and is stable at room
temperature in pH 2, 7, and 11 solutions for at least 24 h. We are currently
developing derivatives of 6 with enhanced water solubility; these results
will be reported in due course.
The most efficient NO-releasing compound of those examined
in this study, both in terms of diazeniumdiolate photorelease and
quantum yield of photodecomposition, is naphthylallyl derivative
6. Importantly, this precursor overcomes the shortcomings of the
previously studied benzyl derivatives.5 The high efficiency of
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