Development of Photoactivatable Nitroxyl (HNO) Donors Incorporating the (3-Hydroxy-2-naphthalenyl)methyl Phototrigger

Article abstract of DOI:10.1002/ejoc.201800092

A new family of photoactivatable HNO donors of general structure RSO₂NHO-PT [where PT represents the (3-hydroxy-2-naphthalenyl)methyl (3,2-HMN) phototrigger] has been developed, which rapidly releases HNO. Photogeneration of HNO was demonstrated using the vitamin B₁₂ derivative aquacobalamin as a trapping agent. The amount of sulfonate RSO₂^– produced was essentially the same as the amount of HNO released upon photolysis, providing a convenient method to indirectly quantify HNO release. Two competing pathways were also observed; a pathway involving O–N bond cleavage leading to release of a sulfonamide, and a pathway resulting in release of the parent Nhydroxysulfonamide RSO₂NHOH (for HNO donors with Me- and Ph-containing leaving groups only). Up to approximately 70 % of the HNO-generating pathway was observed with the CF₃-containing leaving group, with HNO generation favored for small percentages of aqueous buffer in the acetonitrile/pH 7.00 phosphate buffer solvent mixture. Characterization of the photoproducts obtained from steady-state irradiation by NMR spectroscopy showed that the desired HNO-generating pathway was less favored for HNO donors with Me- and Ph-containing leaving groups compared to the CF₃-containing leaving group, suggesting that the excellent CF₃-containing leaving group promotes HNO generation.

Full text of DOI:10.1002/ejoc.201800092

DOI: 10.1002/ejoc.201800092
Full Paper
Photoactivatable Nitroxyl Donors
Development of Photoactivatable Nitroxyl (HNO) Donors
Incorporating the (3-Hydroxy-2-naphthalenyl)methyl
Phototrigger
Yang Zhou,[a] Ruth B. Cink,[b] Zachary A. Fejedelem,[a] M. Cather Simpson,[c]
Alexander J. Seed,[a] Paul Sampson,*[a] and Nicola E. Brasch*[b]
Abstract: A new family of photoactivatable HNO donors of HNO donors with Me- and Ph-containing leaving groups only).
general structure RSO2NHO-PT [where PT represents the (3- Up to approximately 70 % of the HNO-generating pathway was
hydroxy-2-naphthalenyl)methyl (3,2-HMN) phototrigger] has observed with the CF3-containing leaving group, with HNO
been developed, which rapidly releases HNO. Photogeneration generation favored for small percentages of aqueous buffer in
of HNO was demonstrated using the vitamin B12 derivative the acetonitrile/pH 7.00 phosphate buffer solvent mixture.
aquacobalamin as a trapping agent. The amount of sulfonate Characterization of the photoproducts obtained from steady-
–
RSO2 produced was essentially the same as the amount of state irradiation by NMR spectroscopy showed that the desired
HNO released upon photolysis, providing a convenient method HNO-generating pathway was less favored for HNO donors with
to indirectly quantify HNO release. Two competing pathways Me- and Ph-containing leaving groups compared to the
were also observed; a pathway involving O–N bond cleavage CF3-containing leaving group, suggesting that the excellent
leading to release of a sulfonamide, and a pathway resulting in CF3-containing leaving group promotes HNO generation.
release of the parent Nhydroxysulfonamide RSO2NHOH (for
Introduction
HNO is unstable in aqueous solution, due to rapid dimerization
The development of new nitroxyl (HNO) donors has received
and further dehydration to yield nitrous oxide [equa-
tion (1)].[6] Therefore, HNO-containing molecules that decom-
pose to release HNO, also known as HNO donors, are required
to generate HNO in situ for chemical and biochemical studies
of HNO reactivity. Various HNO donors have been reported,[7]
including Angeli's salt (AS),[8] Piloty's acid (PA) and related deriv-
atives,[9] other N-substituted hydroxylamines,[10] primary amine-
based diazeniumdiolates,[11] acyloxy nitroso compounds,[12]
precursors of acyl nitroso species,[13] and metal nitrosyls.[14]
HNO donors are widely used in biochemical and biological
studies of HNO reactivity,[7c] but their utility is limited for some
applications, especially for use in kinetic and mechanistic
studies. For example, a mixture of HNO and NO is obtained
from the decomposition of some HNO donors at neutral
pH.[11d,12d,13a,13e] In addition, highly alkaline (pH > 9) conditions
are required for many donors to trigger HNO release.[9b,9e] Fur-
thermore, HNO generation from current HNO donors is typically
slow (t1/2 ≈ min-to-h).[13h] Therefore, the development of HNO
donors with fast HNO release profiles under neutral pH condi-
tions remains an important challenge.
increasing attention due to their promise for the treatment of
congestive heart failure,[1] a condition that adversely affects an
estimated 5.7 million people in the United States.[2] The vaso-
dilating properties of HNO donors have been demonstrated in
both normal and failing hearts,[3] and result from the ability of
HNO to improve Ca2+ handling and enhance myofilament Ca2+
sensitivity.[4] Recent studies with HNO donors in a pre-clinical
model of heart failure demonstrated that HNO greatly improves
cardiovascular performance of the failing heart by enhancing
the contractility and relaxation of the heart.[5]
[a] Department of Chemistry and Biochemistry, Kent State University,
Kent, OH 44242, USA
E-mail: psampson@kent.edu
www.kent.edu/sole/profile/paul-sampson
[b] School of Science, Auckland University of Technology
Private Bag 92006, Auckland 1142, New Zealand
E-mail: nbrasch@aut.ac.nz
www.brasch-group.com
[c] The Photon Factory, School of Chemical Sciences, The MacDiarmid
Institute for Advanced Materials and Nanotechnology, The Dodd Walls
Centre for Quantum and Photonic Technologies and Department of
Physics, The University of Auckland
(1)
Photochemical approaches have been widely explored for
the rapid in situ generation of molecules for chemical and bio-
chemical studies.[15] However, only a limited number of photo-
Private Bag 92019, Auckland, New Zealand
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800092.
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chemical approaches aimed at HNO generation have been re-
ported. Doctorovich et al. employed a pH photoactuator to spa-
tially and temporally increase the pH, resulting in HNO genera-
tion from decomposition of the 4-nitro derivative of Piloty's
acid.[9c] This approach would presumably be applicable to other
HNO donors that require alkaline solutions to decompose. An-
other approach is the use of photoactivatable HNO donors. Two
classes of photoactive HNO donors have thus far been devel-
oped, which decompose via retrocycloaddition of a 1,2,4-oxadi-
azole-4-oxide[13c,13d,13f] or a photomediated retro-Diels–Alder
reaction to generate acyl nitroso precursors of HNO.[13a,13d,13e]
Acyl nitroso intermediates generated from laser flash photolysis
of 1,2,4-oxadiazole-4-oxides were first reported to generate
HNO in the presence of amine and thiolate nucleophiles by
Toscano et al.[13c,13d] A series of related 1,2,4-oxadiazole-4-
oxides were shown to slowly yield HNO upon exposure to sun-
light.[13f] However, solutions of 1,2,4-oxadiazole-4-oxides are
sensitive to ambient light,[16] and secondary photochemical re-
actions occur.[17] Ethyl nitrodiazoacetate and phenylcyanonitro-
methane nitronate have also been investigated as photoactive
precursors of acyl nitroso species.[13d] Upon photolysis of
phenylcyanonitromethane nitronate, a competing pathway in-
volving a loss of nitrite ion also occurred. Hetero-Diels–Alder
cycloadducts generate acyl nitroso intermediates upon photoly-
(2)
The photolabile 3,2-HNM protecting group was selected
as the phototrigger due to its rapid photocleavage (krelease
≈
105 s–1) combined with good quantum and chemical yields.[19]
By attaching Piloty's acid and its analogues to a light-sensitive
3,2-HNM phototrigger, we hypothesized that concerted elimina-
tion could lead directly to HNO release without the formation
of an RSO2NHO– intermediate (Scheme 1). Rapid hydration of
the resulting o-naphthoquinone methide 4 would then afford
the alcohol 5. Since Piloty's acid (PhSO2NHOH) and Me-
SO2NHOH are both well-established HNO donors, we targeted
the corresponding HNM-based donors 2 (R = Me) and 3 (R =
Ph) (Scheme 1). A further derivative 1 (R = CF3) was also synthe-
–
sized, to investigate the role of the RSO2 moiety in facilitating
HNO release. We hypothesized that incorporation of the better
sulfinate leaving group in 1 may promote the desired elimina-
tion pathway. In this paper we present the synthesis of these
HNO donors, and steady-state irradiation experiments to deter-
mine the products of photolysis and the amount of HNO re-
leased.
sis, which subsequently hydrolyze to generate HNO (t1/2
≈
min).[13a,13e] A solvent-dependent mixture of HNO and NO was
obtained, via photoinduced homolytic cleavage.[13d] HNO gen-
eration was also observed in the absence of light. As the
authors point out, the proposed photochemical [4+2] cyclo-
Results and Discussion
Synthesis of HNO Donors 1–3
reversion is forbidden according to the Woodward–Hoffmann The synthesis of HNO donors 1–3 incorporating the 3,2-HNM
rules.[7d] Another retro Diels–Alder approach for HNO release phototrigger was achieved from commercially available methyl
has also been explored but the reaction instead was found to 3-hydroxy-2-naphthoate (6) via the route outlined in Scheme 2.
proceed via a thermal process.[13g] Hence, multiple issues com- The preliminary synthesis and photodecomposition of com-
promise the use of photochemical cycloreversion as an on- pound 1 have been reported in a recent communication.[18]
demand approach for HNO generation.
Following triisopropylsilyl (TIPS) protection of naphthol 6, the
reduction of the resulting ester 7 was attempted. The reduction
of 7 using LiAlH4 proved to be a highly capricious reaction and,
at best, only afforded alcohol 8 in low yields (ca. 20 %). A con-
siderable amount of deprotected diol 5 was also recovered,
consistent with cleavage of the silyl ether intermediate via intra-
molecular Al-Si hydride transfer from a hydridoaluminoxy inter-
mediate with release of triisopropylsilane.[20]
Recently, we communicated the first example of a new class
of photoactivatable HNO donors RSO2NHO-PT (PT = phototrig-
ger) incorporating the well-studied (3-hydroxy-2-naphthal-
enyl)methyl (3,2-HNM) phototrigger coupled to a trifluorometh-
anesulfonamidoxy moiety (R = CF3).[18] Herein, full details of this
investigation are provided alongside parallel studies with two
other related sulfohydroxamate analogues (R = Me and Ph). The
parent sulfohydroxamic acids (RSO2NHOH), Piloty's acid (PA, R =
Since the reactivity of a hydride reducing agent is influenced
Ph) and MSHA (R = Me), require deprotonation to give the con- by the Lewis acidity of the counterion, Hf(BH4)4 was considered
jugate base (RSO2NHO–) prior to HNO release, which occurs in as an alternate reducing agent. Although very rarely used as a
basic solution [equation (2)].[9a,9b,9d,9e] The release of HNO from reducing agent in organic synthesis, the hard oxophilic charac-
RSO2NHO– is slow (for R = Me, t1/2 = 488 min at pH 9.0 and ter of hafnium renders this reagent an extremely effective and
81 min at pH 12.0;[5b] for R = Ph, t1/2 = 90 min at pH 9.0 and chemoselective reducing agent that may be used under mild
29 min at pH 12.0[9b]).
conditions.[21] Hf(BH4)4 was prepared from the reaction of
Scheme 1. Proposed mechanism for release of HNO from HNO donors 1–3.
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Scheme 2. Synthesis of HNM-based HNO donors 1–3.
NaBH4 and HfCl4 in anhydrous THF. This reagent must be pre- the reaction time. Treating 12 with TBAF for approximately 1 h
pared under strictly anhydrous conditions due to the extremely gave target 1 in 49 % yield, which was readily characterized
hygroscopic nature of HfCl4; failure to ensure anhydrous condi- based on diagnostic signals in the 1H NMR and 19F NMR spectra
tions resulted in a significant lowering of reaction yields. Under at δ 5.28 (CH2) and –73.6 ppm, respectively. However, 12 was
rigorously anhydrous conditions, the reduction of ester 7 to 8 converted into another product at a shorter reaction time (ca.
1
using Hf(BH4)4 was achieved in 77 % yield and without any evi- 10 min), with signals in the H NMR and 19F NMR spectra at δ
dence of cleavage of the silyl ether.
5.00 (CH2) and –76.7 ppm, respectively.[29] The spectroscopic
data indicated that TIPS deprotection was accompanied by
N-O migration of the triflyl group to afford 16, an isomer of
target 1 (Figure 1). Interestingly, 16 can be converted into the
target 1 simply by subjecting it to silica column chromatogra-
phy using ethyl acetate as the eluant.
Nucleophilic attack on PBr3 by alcohol 8 gave 9, and the
hydroxylamine adduct 10 was subsequently generated in excel-
lent yield using N-hydroxyphthalimide via an SN2 reaction. The
more common tert-butyldimethylsilyl (TBS) group was initially
explored as the naphtholic O-protecting group. However, the
TBS ether analogue of 9 was not sufficiently robust when ex-
posed to the nucleophilic anion generated from N-hydroxy-
phthalimide in the presence of base catalysts including DBU,[22]
K2CO3,[23] and NaOAc,[24] and instead resulted in formation of
the desilylated derivative of 10.[25]
Alkoxyamine 11 was obtained after treating 10 with
hydrazine monohydrate. N-Sulfonylation of 11 using the appro-
priate sulfonyl chloride RSO2Cl (R = CF3, Me or Ph) afforded the
corresponding O-TIPS protected intermediates 12–14, respec-
tively.[26] TIPS deprotection using KF in tetraethylene glycol
generated the three target products 1–3.[27] Interestingly, the
1H NMR and 19F NMR spectra of the crude product 1 showed
that cleavage of the N–O bond of 12 (ca. 5 %) also occurs, to
give 3-hydroxy-2-naphthaldehyde (15) and trifluoromethane-
sulfonamide (CF3SO2NH2). These byproducts are most likely
generated by a fluoride-mediated elimination reaction, with ab-
straction of a benzylic proton by fluoride (Scheme 3) via a
mechanism analogous to a reaction observed by Overman et
al.[28] A similar elimination was not observed during removal of
the TIPS group from compounds 13 and 14, presumably due
to the higher barrier for these elimination pathways when a
less effective leaving group is present. Tetra-n-butylammonium
Scheme 3. Proposed mechanism for O–N bond cleavage of 12 by fluoride.
Figure 1. Isomer of target 1 obtained during the deprotection of 12 using
TBAF with short reaction times.
Characterization of the Photoproducts Obtained by
Steady-State Irradiation of HNO Donors 1, 2, and 3
fluoride (TBAF) was also used to remove the TIPS group, with HNO donors 1, 2, and 3 were found to be stable in ambient
the composition of the crude product mixture depending on room light [anaerobic phosphate buffer (pH 7.00, 5.0 m ) and
M
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CD3CN, 40:60 v/v, ≥ 1 d]. The compounds are stable in the pres- (1:0.74) as determined using 19F NMR spectroscopy (Figure 3).
–
ence of air for several months in the solid state. Upon photoly- Control experiments demonstrated that neither CF3SO2 nor
sis, the 3,2-HNM phototrigger was expected to yield 3-hydroxy- CF3SO2NH2 are photosensitive under the conditions of our ex-
2-naphthalenemethanol (diol, 5) through hydration of the inter- periments (data not shown).
mediate o-naphthoquinone methide (4), Scheme 1,[19] in addi-
–
tion to RSO2 and HNO.
Steady-state irradiation experiments of 1, 2, and 3 were per-
formed in a mixture of phosphate buffer (pH 7.00, 5.0 mM) and
CD3CN (40:60, v/v) using a Rayonet photochemical reactor
(RMR-600, 350 nm bulbs, 8 × 4 W bulbs) under strictly anaero-
bic conditions. The results for 1 have been reported in a recent
–
communication, with CF3SO2 [Pathway (a), Scheme 4] and
CF3SO2NH2 [Pathway (b), Scheme 4] generated in a approxi-
mately 40:60 ratio (determined from 19F NMR spectroscopic
analysis).[18] The observed rate constant for the photodecompo-
sition of 1 was determined by 19F NMR spectroscopy from a
plot of the peak area of the CF3 group of 1 vs. time, giving
kobs = 0.171 min–1 (t1/2 ca. 4.1 min; Figure 2).[18]
Figure 3. 19F NMR (top) and 1H NMR (bottom) spectra of the partial photolysis
products of HNO donor 1 (1.00 m , ca. 60 % conversion) in an anaerobic
mixture of phosphate buffer (pH 7.0, 5.0 m ) and CD3CN (40:60, v/v). Peaks
M
M
–
for 1 (δ –77.7 ppm), CF3SO2NH2 (δ –81.1 ppm), and CF3SO2 (δ –88.7 ppm)
are observed in the 19F NMR spectrum. In the 1H NMR spectrum, peaks for 1
[δ = 7.81 (d), 7.79 (s), 7.73 (d), 7.45 (t), 7.34 (t), 7.25 (s; used for integration)],
15 [δ = 8.43 (s), 8.02 (d; used for integration), 7.81 (d), 7.63 (t), 7.44 (t), 7.34
(s)] and 5 [δ = 7.82 (d), 7.81 (s), 7.71 (d), 7.42 (t), 7.34 (t), 7.22 (s; used for
integration)] are observed. Unidentified peaks are observed at δ = 8.49, 7.95,
7.88, 7.86, 7.77, 7.52, 7.50, 7.31, 7.29 ppm, probably arising from photo-
decomposition of the primary photoproducts. The 1H NMR spectrum is refer-
enced to TSP in the same solvent mixture (external standard used) and the
19F NMR spectrum is internally referenced to trifluorotoluene (–63.72 ppm).
Scheme 4. The major decomposition pathways observed upon photolysis of
HNO donors 1–3 [Note: Pathway (c) only occurs (in trace amounts) for 2 (R =
CH3) and 3 (R = Ph)].
The photodecomposition of HNO donor 2 (R = Me) was car-
ried out under the same conditions [anaerobic mixture of phos-
phate buffer (pH 7.00, 5.0 mM) and CD3CN (40:60, v/v)]. Three
1
methanesulfonyl-containing products were observed in the H
–
NMR spectra, with MeSO2 [δ = 2.23, 9 %; Pathway (a),
Scheme 4] MeSO2NH2 [δ = 3.08, 77 %; Pathway (b), Scheme 4]
and MeSO2NHOH [δ = 3.05, 14 %; Pathway (c), Scheme 4] ob-
tained after irradiating 2 for 40 min (Figure 4a). The observed
first-order rate constant for the photodecomposition of 2 was
0.110 min–1 (t1/2 ca. 6.3 min; Figure 4b).
The photodecomposition of HNO donor 3 was also moni-
tored by H NMR spectroscopy (Figure 5a). PhSO2NH2, PhSO2
Figure 2. Best fit of the 19F NMR peak area for the CF3 moiety of HNO donor
1
–
1 (3.89 m
(40:60, v/v) vs. time to
0.171 0.008 min–1
M
) in a mixture of phosphate buffer (5.0 m
M, pH 7.00) and CD3CN
and a trace amount of PhSO2NHOH were observed, with signifi-
cant overlapping of peaks. The PhSO2NH2/PhSO2– ratio was ap-
proximately 77:23 and, from the decrease in the peak area of
the benzylic CH2 group of 3, an observed rate constant for pho-
todecomposition, kobs = 0.096 min–1, was obtained [t1/2 ca.
7.2 min (Figure 5b)].
a
first-order rate equation, giving kobs
=
.
The products formed upon complete photodecomposition
of 1 in a mixture of phosphate buffer (pH 7.0, 0.10 ) and
M
1
CD3CN (40:60, v/v) were also characterized by H NMR spectro-
scopy (Figure 3).[18] In addition to the expected diol 5, aldehyde
To demonstrate that HNO is indeed released from HNO do-
15 was observed as a second major product [Pathway (b), nors 1–3, the HNO donors were photolyzed in the presence of
Scheme 4].[18] Substantial secondary photodecomposition of 5 the HNO trap aquacobalamin [H2OCbl(III)+], which reacts
and 15 occurs, as observed by Popik and co-workers for 5 and stoichiometrically with HNO to form bright orange nitrosyl-
related systems.[19b] Partial photolysis of 1 (60 % conversion) cobalamin [NO–-Cbl(III)].[18] Both H2OCbl(III)+ and NO–-Cbl(III)
shows that the ratio of 5 to 15 (1:0.69) is the same (within were shown to be stable upon irradiation with light under the
–
experimental error) as the CF3SO2 /CF3SO2NH2 product ratio experimental conditions, and a control experiment showed that
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Figure 4. (a) 1H NMR spectra for the photodecomposition of HNO donor 2
(4.68 m , 350 nm, 4 W) as a function of the total irradiation time in an
anaerobic mixture of phosphate buffer (5.0 m , pH 7.0) and CD3CN (40:60,
v/v). (b) Best fit of the peak area for the CH3 moiety of 2 vs. total irradiation
time to a first-order rate equation, giving kobs = 0.110 0.008 min–1
M
Figure 5. (a) 1H NMR spectra as a function of irradiation time for the photo-
M
decomposition of HNO donor 3 (3.08 m
M, 350 nm, 8 × 4 W bulbs) in an
anaerobic mixture of phosphate buffer (0.10
M, pH 7.0) and CD3CN (40:60,
.
v/v). Peaks for PhSO2NH2 [δ = 7.93–7.89 ppm (2 H), 7.70–7.65 ppm (1 H),
7.63–7.59 ppm (2 H)], PhSO2– [δ = 7.63–7.60 ppm (2 H), 7.52–7.43 ppm (3 H)]
and a trace amount of PhSO2NHOH [δ = 7.94–7.91 ppm (2 H), 7.78–7.74 ppm
(1 H), 7.67–7.63 ppm (2 H)] were observed, with significant overlapping of
peaks. (b) Best fit of peak area vs. time for the benzylic proton peak of 3 to
there is no reaction between aquacobalamin and 1 in ambient
room light.[18] Photolyzing HNO donor 1 in a solution of aqua-
cobalamin resulted in UV/Vis spectral changes and isosbestic
points characteristic of the conversion of H2OCbl(III)+ to
NO–-Cbl(III).[18] A similar experiment was carried out for HNO
donor 2. Figure 6 shows the UV/Vis spectral changes upon pho-
a first-order rate equation, giving kobs = 0.096 0.005 min–1
.
tolyzing a solution of 2 (1.50 × 10–4
H2OCbl+ (3.0 × 10–5
) using a Xe light source in a stopped-
M) in the presence of
M
flow instrument. Excess 2 was used since, under these condi-
tions, only approximately 20 % of the desired HNO-generating
pathway occurs. Once again H2OCbl(III)+ is converted to NO–-
Cbl(III), with an isosbestic point observed at 491 nm, character-
istic for the H2OCbl(III)+/NO–-Cbl(III) conversion.[18] Formation of
NO–-Cbl(III) was also observed upon irradiating HNO donor 3 in
the presence of aquacobalamin (Figure S1, Supporting Informa-
tion). The observed rate constant for NO–-Cbl(III) formation was
also estimated from the data, and found to be similar for all
HNO donors [2.7 × 10–3,[18] 1.1 × 10–3 (inset to Figure 6) and
2.3 × 10–3 s–1 (inset to Figure S1, Supporting Information) for 1,
2, and 3, respectively].
Figure 6. UV/Vis spectra for the reaction between H2OCbl(III)+ (3.0 × 10–5
and HNO donor 2 (1.50 × 10–4
) using xenon light (150 W, monochromator
slit width 3.0 mm) in an anaerobic mixture of phosphate
buffer (5.0 mm, pH 7.00) and CH3CN (40:60, v/v) at 25 °C. Inset: Fit of the
absorbance data at 530 nm vs. time to a first-order rate equation, giving
kobs = (1.1 0.1) × 10–3 s–1. Note: The stopped-flow instrument has a maxi-
mum data collection time of 1000 s.
M)
M
=
From Scheme 4, it can be seen that the percentage of sulf-
inate generated should be directly related to the percentage of
HNO released from the HNO donor. To investigate whether HNO try of the initial photoproducts. Unreacted H2OCbl(III)+ was sub-
generation can be directly inferred from sulfinate formation, a sequently converted to NO–-Cbl(III) by the addition of the
solution of H2OCbl(III)+ (200.0 μ
M
) and HNO donor 1 (200.0 μ
M
)
established HNO donor Angeli's salt (2.5 mol equiv.) without
was partially photolyzed, to minimize secondary photochemis- further irradiation. Based on the UV/Vis spectral changes at
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530 nm (Figure 7), approximately 10 2 % NO–-Cbl(III) was gen- from HNO donors 1, 2, and 3, other than seeing partial oxid-
–
–
erated, corresponding to the release of approximately 10 % ation of the MeSO2 product to MeSO3 (data not shown), sug-
–
HNO. The percentage of CF3SO2 formed was 16 3 %, which gesting that the pathways proceed through a singlet excited
is close to the percentage of NO–-Cbl(III) formed within experi-
mental error. Thus, the amount of sulfinate in the product solu-
tion is a useful indicator of the amount of HNO released upon
photodecomposition of this family of HNO donors.
state(s).
The leaving-group ability of sulfinates is correlated with the
pKa values for the related conjugated acids [pKa(MeSO2H) =
2.28,[30] pKa(PhSO2H) = 2.7[31] and pKa(CF3SO2H) = –0.6[31]]. The
amount of HNO generated (as measured by the sulfinate/sulf-
onamide ratio) during photolysis is approximately 1.5:1, 0.1:1,
and 0.3:1 for the photolysis of 1 (R = CF3), 2 (R = CH3), and 3
(R = Ph), respectively. The superior leaving-group ability of
CF3SO2– is therefore associated with increased HNO generation,
although the relative amount of HNO released from photolysis
of 2 and 3 does not closely correlate with the corresponding
sulfinic acid pKa values, suggesting that other factors are also
important. Interestingly, the leaving group had only a modest
effect on the observed rate of photodecomposition of the HNO
donor using a steady-state irradiation source (t1/2 0.17, 0.11, and
0.096 min–1 for 1, 2, and 3, respectively). We previously showed
that the rate of photodecomposition is dependent on the inten-
sity of the light source. Popik et al. have observed extremely
rapid release of the ethoxy leaving group in a closely related
3,2-HNM-based system excited using a nanosecond laser pulse
(krelease ≈ 105 s–1),[19b] suggesting that similar or faster release
of the better leaving groups in our system might be expected
under similar laser pulse conditions.
Figure 7. UV/Vis spectra for the partial photolysis of HNO donor 1 (200.0 μ
M)
in the presence of the HNO trap H2OCbl(III)+ (200.0 μ
M) in aqueous phosphate
buffer (pH 7.00, 5.0 mM) and CD3CN (40:60, v/v). Laser excitation at 266 nm,
ca. 5 ns pulse width, ca. 60 mJ/pulse. Inset: 19F NMR spectrum of the product
mixture. The peak at δ-77.70 ppm corresponds to 1, –81.42 ppm to
CF3SO2NH2, and –89.00 ppm to CF3SO2–. Approximately 28 % of 1 was photo-
–
lyzed, generating 16 3 % CF3SO2
.
The amounts of RSO2-containing products formed during
photolysis of 1–3 are summarized in Table 1. In addition to the
corresponding sulfinates and sulfonamides, MeSO2NHOH (14 %)
and trace amounts of PhSO2NHOH (PA) were also observed in
the product solutions derived from the photolysis of 2 and 3,
respectively [Pathway (c), Scheme 4]. In contrast, no traces of
the corresponding CF3SO2NHOH (or its conjugate base) were
seen as intermediates during the photolysis of 1. Control ex-
periments showed that, while MeSO2NHOH and PA are stable
in this solvent mixture, CF3SO2NHOH deprotonates to give
The effect of varying the ratio of acetonitrile to phosphate
buffer (5.0 mM, pH 7.0) in the solvent mixture was investigated
for 1 and 2. For 1, the photoproduct ratio was found to be
highly solvent dependent, with approximately 70 % CF3SO2
–
generation in a mixture of phosphate buffer (pH 7.0, 0.10
M)
–
and CD3CN (5:95, v/v), approximately. 60 % CF3SO2 in phos-
phate buffer:CD3CN (40:60 v/v), and only a trace amount of
CF3SO2– (ca. 4 %) in CD3CN in the absence of aqueous buffer.[18]
Increasing the volume percentage of water above 5 % resulted
–
CF3SO2NHO–, which then releases HNO and CF3SO2 upon de-
–
in a steady decrease in the amount of CF3SO2 (= HNO) gener-
composition (t1/2 ca. 11.0 min).[18] Since CF3SO2NHOH is photo-
stable[18] and decomposes in this solvent mixture significantly
more slowly than the observed rate of photodecomposition of
1 seen in the steady-state irradiation experiments (t1/2 ca.
4.1 min), it is clear that any CF3SO2NHO(H) generated as an
intermediate would be observed in the 19F NMR spectra during
the photolysis of 1. Given that it was not observed,[18] it is
highly unlikely that a pathway involving CF3SO2NHO(H) as an
intermediate [Pathway (c), Scheme 4] is important for the pho-
todecomposition of 1. Notably, the presence of oxygen in aque-
ous MeCN solutions had no effect on the photoproduct ratios
–
ated, with approximately 30 % CF3SO2 generated in aqueous
solution in the absence of CD3CN.[18] Whereas photolysis of 2
in 40:60 (v/v) phosphate buffer (pH 7.0, 0.10
in approximately 9 % MeSO2 , approximately 77 % MeSO2NH2,
and approximately 14 % MeSO2NHOH, irradiation of 2 in 95:5
(v/v) phosphate buffer (pH 7.0, 0.10
M
)/CD3CN resulted
–
M)/CD3CN produced ap-
–
proximately 8 % MeSO2 , 58 % MeSO2NH2 and approximately
34 % MeSO2NHOH, with the percentage of MeSO2NHOH dou-
bling. As observed for HNO donor 1, a near quantitative amount
of the sulfonamide (MeSO2NH2, ca. 97 %) was formed upon
photolysis of 2 in pure CD3CN; trace amounts of additional pho-
toproducts (δ = 3.02 and 3.48 ppm) were also seen that decom-
posed as photolysis proceeded. Formation of the aldehyde 15
was observed upon photolysis of 2 in anaerobic CD3CN. The
preceding results indicate that water is essential for Pathways
(a) and (c), consistent with a mechanism involving excited-state
proton transfer via water.[32] For both 1 and 2, HNO generation
is most favorable with small volume percentages of phosphate
buffer in acetonitrile. That said, water plays an essential role in
the photorelease of HNO from this family of HNO donors, re-
gardless of leaving group.
Table 1. Summary of RSO2-containing species generated from the photolysis
of 1–3 in a mixture of phosphate buffer (pH 7.00, 0.10 M) and CD3CN (40:60,
v/v).
–
HNO Donor
RSO2 [%]
RSO2NH2 [%]
RSO2NHOH [%]
1
2
3
60
9
23
40
77
77
0
14
[a]
–
[a] Small amounts were formed but were not precisely quantified due to the
overlapping of 1H NMR resonances of photolytic products.
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To further probe the mechanisms of photodecomposition for would then produce the observed aldehyde photoproduct. Di-
2, steady-state photolysis of 2 was monitored by 1H NMR spec- rect ESIPT from phenolic or naphtholic hydroxyl groups to nitro-
troscopy in anaerobic CD3CN and in an anaerobic mixture of gen atoms was proposed for related systems in aprotic sol-
deuterated phosphate buffer (0.10 M
, pH 7.0) and CH3CN (5:95, vents.[36] However, given that Pathway (b) also occurs upon
v/v) (Figures S2 and S3 in the Supporting Information). The ob- photoexcitation of the naphtholate conjugate base of 1, an-
served rate constant for photolysis was the same within experi- other mechanism for Pathway (b) is likely at least under these
mental error in both solvent mixtures (kobs = 0.38 0.07 and conditions.
0.43 0.03 min–1, respectively). In CD3CN, only Pathway (b) is
For R = Me and Ph, the parent sulfohydroxamic acid
observed; however, in aqueous CD3CN, Pathways (a), (b), and
(c) (Scheme 4) are observed. Taken together with data showing
that the percentages of the major photoproducts are un-
changed within experimental error under aerobic conditions,
these results are consistent with all pathways proceeding via
the singlet excited state of the parent molecule, with inter-
molecular bonding between excited state species and solvent
playing a key role in determining which photodecomposition
mechanism(s) dominate.[33]
RSO2NHOH was also observed as a minor product. It is likely
that water protonates the O atom of the leaving group in addi-
tion to removing a proton from the naphtholic hydroxyl group.
Time resolved spectroscopy experiments combined with theo-
retical calculations are required to confirm or refute these
mechanistic possibilities, although the former studies could be
complex, given that multiple pathways occur simultaneously.
Conclusions
The desired HNO generation pathway (a) is expected to pro-
ceed via the facile water-assisted deprotonation of the naphth-
olic hydroxyl group of the excited state molecule (Scheme 1).
The pKa of the hydroxyl group of 2-naphthol decreases from
9.30 in the ground state to approximately 2.6 ( 0.2) in the
excited state.[19a] Thus, the singlet excited state of the naphth-
olic chromophore in our 3,2-HNM-based HNO donors will rap-
idly deprotonate, with water acting as the proton acceptor.[34]
Subsequent elimination results in the formation of quinone
methide 4, which rapidly undergoes conjugate addition with
water to give diol 5 (Scheme 1). To probe the importance of
the parent (protonated) naphtholic hydroxyl group in the gen-
A novel family of photoactivatable HNO donors 1, 2, and 3 has
been developed. Release of HNO was demonstrated for donors
1, 2, and 3 using the HNO trap aquacobalamin. The selectivity
for release of HNO from the 3,2-HNM-photoprotecting group
was shown to be strongly dependent on the leaving group,
with the HNO donor containing the best leaving group (R =
CF3, 1), generating the most HNO (ca. 70 % under the optimal
solvent conditions). The solvent also plays a major role in deter-
mining the amount of HNO released, with maximum HNO re-
lease occurring with small volumes of buffer in the acetonitrile/
aqueous buffer solvent mixtures. Ongoing studies are focused
on improving the selectivity for the HNO generation pathway
versus the other two competing pathways through the synthe-
sis of analogues.
eration of HNO, the naphtholate conjugate base of 1 (1.00 m
M)
was irradiated in an anaerobic mixture of aqueous NaOH
–
(0.10 M) and CD3CN (40:60 v/v). CF3SO2NH2 (93 %) and CF3SO2
(7 %) were observed as products in this experiment (results not
–
shown). Given that approximately 60 % CF3SO2 is observed
when phosphate buffer (pH 7.0) is used as the aqueous compo-
nent of the 40:60 v/v solvent mixture,[18] this is consistent with
the protonated excited state parent molecule serving as a tran-
sient species in Pathway (a).
Experimental Section
General: All reactions were carried out using anhydrous solvents
under a nitrogen atmosphere. Unless otherwise noted, all commer-
cial chemicals were used directly without further purification. Anhy-
drous pyridine, DMF, and DMSO were purchased and used directly.
THF was freshly distilled from Na and benzophenone, and CH2Cl2
was freshly distilled from CaH2. Column chromatography was per-
formed on silica gel (60 Å, 40–63 μm) using ACS grade solvents
[ethyl acetate, petroleum ether (boiling point range: 30–60 °C) and
CH2Cl2] without further purification. All new synthetic compounds
Oxygen–nitrogen bond cleavage also occurs upon photo-
excitation of 1–3, Scheme 4, Pathway (b), to give the corre-
sponding sulfonamide RSO2NH2 and an aldehyde. Light-in-
duced O–N bond homolysis has been reported by others for
related systems.[35] O–N bond cleavage occurs for 1 regardless
of whether aqueous phosphate buffer is present in the aceto-
nitrile. Pathway (b), Scheme 4, could potentially occur via ex- were fully characterized using 1H, 13C, and 19F NMR spectroscopy,
and high-resolution mass spectrometry (HRMS) with a direct analy-
sis in real time (DART) ion source. 1H, 13C, and 19F NMR spectra
were recorded using a Bruker 400 MHz spectrometer with a 5 mm
probe at 25 1 °C. 19F NMR spectra were collected using a Bruker
spectrometer (400 MHz) operating at 376 MHz with D1 = 5 s at
cited-state intramolecular proton transfer (ESIPT) from the
naphtholic hydroxyl group to the nitrogen atom of the leaving
group (Scheme 5). Subsequent or concerted deprotonation of
the methylene carbon, presumably by a solvent molecule,
–
25 1 °C. The T1 values for CF3SO2 and CF3SO3NH2 were subse-
quently determined to be 4.0 and 4.6 s, respectively. We expected
that the relative amounts of CF3SO2– and CF3SO2NH2 could be esti-
mated from the peak areas even when a delay time of 5 s is used,
given that their T1 values are so similar. To confirm this assumption,
the 19F NMR spectrum of a mixture of CF3SO2– and CF3SO2NH2 was
measured using D1 = 5 s and D1 = 20 s. The ratios of the peak
areas for these spectra were the same within experimental error
[(peak area CF3SO2–):(peak area CF3SO2NH2) = 1:1.2 and 1:1.3, re-
Scheme 5. A proposed pathway for excited-state intramolecular proton trans-
fer to generate aldehyde 15 and the corresponding sulfonamide.
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spectively]. All NMR spectroscopic data were processed using
MestReC NMR software. Tetramethylsilane (TMS) was used as an
13.08 ppm. HRMS: m/z (DART): calcd. for MH+ 359.20370, found
359.20391.
1
internal reference in H and 13C NMR spectroscopy, and CFCl3 was
[3-(Triisopropylsilyloxy)naphthalen-2-yl]methanol (8): A suspen-
sion was made by mixing HfCl4 (1.5 g, 4.7 mmol) and NaBH4 (0.40 g,
11 mmol) in anhydrous THF (10 mL) under argon at 3 °C using an
ice/water bath. After stirring for 10 min, this mixture was warmed
to room temperature and was stirred for an additional 2 h. Then, a
solution of 7 (1.32 g, 3.68 mmol) in anhydrous THF (20 mL) was
added to the suspension at room temperature. After stirring for
22 h at room temperature, the reaction mixture was quenched with
chilled water (40 mL). The aqueous layer was extracted using ethyl
acetate (3 × 15 mL) and the combined organic extracts were
washed using saturated NaHCO3 (40 mL) and brine (40 mL). The
crude product was dried with Na2SO4 and the solvent was evapo-
rated in vacuo, before being purified by column chromatography
(silica gel/7:93 ethyl acetate/petroleum ether) to give the title com-
pound 8 as a yellow-tinted oil (0.94 g, 77 %). 1H NMR (400 MHz,
CDCl3): δ = 7.77 (s, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 8.4 Hz,
1 H), 7.40 (td, J = 7.6, 1.2 Hz, 1 H), 7.33 (td, J = 7.6, 1.2 Hz, 1 H), 7.14
(s, 1 H), 4.86 (s, 2 H), 2.26 (s, 1 H), 1.42 (sept, J = 7.6 Hz, 3 H), 1.16
(d, J = 7.6 Hz, 18 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 152.18,
used as an internal reference in 19F NMR spectroscopy. Melting
points were measured using a Stuart capillary melting point appara-
tus or an Electrothermal melting point apparatus.
In spite of careful purification, some very small impurities remained
in several early synthetic products as seen by additional signals in
the upfield region of the 1H NMR spectra, which appeared to be
due to some inseparable impurities found in all batches of the com-
mercial triisopropylsilyl chloride used. These small impurities were
readily removed in subsequent steps.
Phosphate buffer solution (0.10
M and 5.0 mM, pH 7.00) was pre-
pared using KH2PO4, and the pH of the buffer solution was adjusted
using H3PO4 and/or NaOH. pH measurements were performed us-
ing an Orion Model 710A pH meter equipped with Mettler-Toledo
Inlab 423 or 421 electrodes at room temperature. Phosphate buffer
solution was degassed by bubbling with argon for ca. 24 h, and
was stored under argon in an MBRAUN Labmaster 130 (1250/78)
glovebox equipped with O2 and H2O sensors.
Hydroxycobalamin hydrochloride (HOCbl·HCl, 98 %) was purchased 133.99, 132.60, 128.95, 127.65, 127.30, 126.24, 126.05, 123.92,
from Fluka. Solid HOCbl·HCl was dissolved in phosphate buffer
112.74, 62.59, 18.09, 13.04 ppm. HRMS: m/z (DART): calcd. for MH+
(0.100
M
, pH 7.00) to obtain an H2OCbl(III)+ stock solution. The 331.20878, found 331.20859.
concentration of H2OCbl(III)+ was determined by converting
H2OCbl(III)+ into dicyanocobalamin [(CN)2Cbl–] using KCN solution
[3-(Bromomethyl)naphthalen-2-yl]oxytriisopropylsilane (9): To a
stirred solution of compound 8 (2.23 g, 6.75 mmol) in anhydrous
CH2Cl2 (20 mL) at 0 °C in an water/ice bath was added PBr3
(0.962 mL, d = 2.88 g/mL at 20 °C, 10.2 mmol) in one portion. The
(0.10
mined using UV/Vis spectrometry (ε367 nm = 30400
M
). The concentration of the final product (CN)2Cbl– was deter-
M
–1 cm–1).[37]
All air-free UV/Vis spectrometric measurements were carried out us- reaction mixture was stirred at 0 °C for 30 min, and then was al-
ing either a Cary 5000 or 100 spectrophotometer with a thermostat- lowed to slowly warm to room temperature before being stirred for
ted (25.0 0.1 °C) cell changer and WinUV Bio software (version
an additional 3.5 h. The reaction mixture was poured into saturated
3.00). Schlenk cuvettes fitted with J-Young air-tight caps were used aq. NaHCO3 (50 mL), extracted using CH2Cl2 (3 × 80 mL), and the
for all air-free UV/Vis spectrometric measurements. The UV data
were analyzed using Microcal Origin version 8.0 software.
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The crude residue was purified by column chromatogra-
phy (silica gel/3:97 CH2Cl2/petroleum ether) to give the title com-
pound 9 as a white solid (2.41 g, 91 %). M.p. 77–79 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.73 (dd, J = 8.0, 0.4 Hz, 1 H),
7.64 (dd, J = 8.0, 0.4 Hz, 1 H), 7.40 (td, J = 7.2, 1.2 Hz, 1 H), 7.32 (td,
J = 7.2, 1.2 Hz, 1 H), 7.13 (s, 1 H), 4.71 (s, 2 H), 1.45 (sept, J = 7.6 Hz,
3 H), 1.19 (d, J = 7.6 Hz, 18 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
152.05, 134.78, 130.51, 129.66, 128.64, 127.66, 126.67, 126.23,
123.95, 112.89, 29.83, 18.17, 13.08 ppm. HRMS: m/z (DART): calcd.
for MH+ 393.12438, found 393.12416.
Air-tight J-Young NMR tubes (Wilmad, 535-JY-7) were used for all
the 1H/19F NMR experiments conducted under anaerobic condi-
tions. These NMR samples were freshly prepared using appropriate
phosphate buffer and CD3CN mixtures inside a glovebox. Sodium
3-trimethylsilylpropanoate (TSP) was used as an internal standard
for these 1H NMR experiments unless otherwise noted, and tri-
fluorotoluene (–63.72 ppm) in CD3CN prepared in a capillary tube
was used as an external standard (inserted into the NMR tube) for
19F NMR experiments.
2-[(3-Triisopropylsilyloxynaphthalen-2-yl)methoxy]isoindoline-
Synthesis of HNO Donors 1–3
1,3-dione (10): The procedure used followed a method reported
Methyl 3-(Triisopropylsilyloxy)-2-naphthoate (7): To a stirred so- by Zlotorzynska and Sammis.[22] To a stirred solution of N-hydroxy-
lution of 6 (4.00 g, 19.8 mmol), imidazole (2.01 g, 29.5 mmol) and
DMAP (181.52 mg, 1.4858 mmol) in anhydrous DMF (20 mL) at room amine (0.65 mL, d = 0.742 g/mL at 25 °C, 3.7 mmol) in anhydrous
temperature was added triisopropylsilyl chloride (8.5 mL, d = DMF (25 mL) was added all at once a solution of compound 9
0.901 g/mL at 25 °C, 40 mmol) in one portion. The reaction mixture (1.35 g, 3.43 mmol) in anhydrous DMF (5 mL) at room temperature.
phthalimide (613.67 mg, 3.7618 mmol) and N-ethyldiisopropyl-
was stirred for 24 h at room temperature and was then quenched
using saturated aqueous NaHCO3 (200 mL) and extracted with ethyl
acetate (3 × 100 mL). The combined organic extracts were washed
with brine (100 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by gravity column chromatography (silica gel/
The reaction mixture was stirred and heated at 70 °C for 7 h. The
cooled reaction mixture was partitioned between ethyl acetate
(50 mL) and water (200 mL), and the aqueous layer was extracted
with ethyl acetate (3 × 80 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo. The crude residue was
purified by column chromatography (silica gel/15:85 ethyl acetate/
1:9 ethyl acetate/petroleum ether) to give the title compound 7 as
1
a pale yellow oil (6.17 g, 87 %). H NMR (400 MHz, CDCl3): δ = 8.24 petroleum ether) to yield the title compound 10 as a white solid
(s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.44 (td,
J = 7.6, 1.2 Hz, 1 H), 7.31 (td, J = 7.6, 1.2 Hz, 1 H), 7.19 (s, 1 H), 3.91
(s, 3 H), 1.38 (sept, J = 7.6 Hz, 3 H), 1.14 (d, J = 7.6 Hz, 18 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 167.49, 151.80, 135.92, 132.40,
132.28, 128.57, 127.96, 127.85, 126.18, 124.30, 114.84, 52.02, 17.99,
(1.33 g, 81 %). M.p. 93–96 °C. 1H NMR (400 MHz, CDCl3): δ = 8.01 (s,
1 H), 7.79 (m, 2 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.71 (m, 2 H), 7.64 (d,
J = 8.4 Hz, 1 H), 7.41 (td, J = 8.4, 1.2 Hz, 1 H), 7.30 (td, J = 8.4, 1.2 Hz,
1 H), 7.15 (s, 1 H), 5.45 (s, 2 H), 1.43 (sept, J = 7.6 Hz, 3 H), 1.15 (d,
J = 7.6 Hz, 18 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 163.51,
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152.39, 134.86, 134.29, 130.97, 129.05, 128.57, 127.97, 126.62,
chromatography (silica gel/30:70 ethyl acetate/petroleum ether) to
126.26, 123.79, 123.44, 112.73, 75.16, 18.10, 13.08 ppm. (Note: One obtain the title compound 1 as a pale yellow solid (46.23 mg, 57 %).
1
aromatic 13C NMR signal was obscured due to accidental signal
M.p. 103–107 °C. H NMR (400 MHz, CDCl3): δ = 7.79 (s, 1 H), 7.79
equivalence). HRMS: m/z (DART): calcd. for MH+ 476.22516, found (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.47 (td, J = 7.6, 1.2 Hz,
476.22527.
1 H), 7.36 (td, J = 7.6, 1.2 Hz, 1 H), 7.21 (s, 1 H), 5.28 (s, 2 H),
(Note: The NH and OH signals were obscured due to rapid proton
exchange.) ppm. 13C NMR (101 MHz, CDCl3): δ = 152.28, 135.29,
132.12, 128.56, 128.02, 127.45, 126.15, 124.27, 121.85, 119.34 (q, J =
326 Hz), 110.83, 77.26 ppm. 19F NMR (376 MHz, CDCl3): δ = –73.50
ppm. HRMS: m/z (DART): calcd. for MH+322.03554, found 322.03549.
O-{[3-(Triisopropylsilyloxy)naphthalen-2-yl]methyl}-
hydroxylamine (11): To a stirred solution of compound 10 (1.33 g,
2.80 mmol) in anhydrous CH2Cl2 (10 mL) at 0 °C in a water/ice bath
was added hydrazine monohydrate (0.274 mL, d = 1.032 g/mL at
25 °C, 5.65 mmol) in one portion. The reaction mixture was slowly
warmed to room temperature and was stirred for an additional 4 h.
After the white suspension was filtered off, the filtrate was washed
with water (100 mL) and the aqueous layer was extracted with
CH2Cl2 (3 × 80 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to yield the title compound 11
N-{[3-(Triisopropylsilyloxy)naphthalen-2-yl]methoxy}methane-
sulfonamide (13): (The procedure used followed a method re-
ported by Gajewiak and Prestwich.[26]) To a stirred mixture of 11
(362.11 mg, 1.0479 mmol), DMAP (128.20 mg, 1.0494 mmol) and
anhydrous pyridine (0.084 mL, d = 0.978 g/mL at 25 °C, 1.04 mmol)
as a colorless oil (0.94 g, 97 %). The target product was used directly in anhydrous CH2Cl2 (20 mL) at - 20 °C was added dropwise a solu-
without any further purification. 1H NMR (400 MHz, CDCl3): δ = 7.81
(s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.40 (td,
J = 8.4, 1.2 Hz, 1 H), 7.32 (td, J = 8.4, 1.2 Hz, 1 H), 7.13 (s, 1 H), 4.93
(s, 2 H), 1.42 (sept, J = 7.6 Hz, 3 H), 1.16 (d, J = 7.6 Hz, 18 H), (Note:
The NH2 signal was obscured due to rapid proton exchange.) ppm.
13C NMR (101 MHz, CDCl3): δ = 152.41, 134.23, 129.26, 128.72,
tion of methanesulfonyl chloride (0.106 mL, d = 1.48 g/mL at 25 °C,
1.37 mmol) in anhydrous CH2Cl2 (4 mL). The reaction mixture was
slowly warmed to 10 °C over 30 min and was stirred for another
2 h. The reaction mixture was quenched using saturated aq. CuSO4
(100 mL), and the aqueous layer was extracted using CH2Cl2
(3 × 100 mL). The combined organic extracts were dried (MgSO4)
127.67, 126.19, 126.08, 123.71, 112.87, 109.98, 74.02, 18.11, 13.05 and concentrated in vacuo. The crude residue was purified by col-
ppm. HRMS: m/z (DART): calcd. for MH+ 346.21968, found
346.21971.
umn chromatography (silica gel/10:90 ethyl acetate/petroleum
ether), to give the title compound 13 as a colorless oil (346.55 mg,
78 %). 1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.78 (d, J = 8.4 Hz,
1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.43 (td, J = 8.8, 1.2 Hz, 1 H), 7.34 (td,
J = 8.8, 1.2 Hz, 1 H), 7.15 (s, 1 H), 6.80 (s, 1 H), 5.24 (s, 2 H), 3.05 (s,
3 H), 1.41 (sept, J = 7.6 Hz, 3 H), 1.15 (d, J = 7.6 Hz, 18 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 152.52, 134.81, 131.23, 128.52, 127.84,
126.92, 126.70, 126.25, 124.00, 113.02, 75.42, 36.98, 18.09, 13.03
1,1,1-Trifluoro-N-{[3-(triisopropylsilyloxy)naphthalen-2-yl]-
methoxy}methanesulfonamide (12): (The procedure used fol-
lowed a method reported by Gajewiak and Prestwich.[26]) To a
stirred solution of compound 11 (0.94 g, 2.7 mmol), DMAP
(331.26 mg, 2.7115 mmol) and anhydrous pyridine (0.218 mL, d =
0.978 g/mL at 25 °C, 2.70 mmol) in anhydrous CH2Cl2 (20 mL) at
–15 °C was added dropwise a solution of trifluoromethanesulfonyl
chloride (0.376 mL, d = 1.583 g/mL at 25 °C, 3.53 mmol) in anhy-
drous CH2Cl2 (5 mL). The reaction mixture was slowly warmed to
10 °C over 30 min and was stirred for another 2 h. The reaction
mixture was washed with saturated aq. CuSO4 (100 mL), and the
aqueous layer extracted with CH2Cl2 (3 × 80 mL). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo.
The crude residue was purified by column chromatography (silica
gel/50:50 CH2Cl2/petroleum ether) to yield the title product 12 as
a highly viscous colorless oil (0.75 g, 58 %). 1H NMR (400 MHz,
CDCl3): δ = 7.82 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz,
ppm. HRMS: m/z (DART): calcd. for M+ 424.19723, found 424.19725.
˙
N-[(3-Hydroxynaphthalen-2-yl)methoxy]methanesulfonamide
(2): (The procedure used followed a method reported by Song et
al.[27a]) To a stirred solution of compound 13 (187.43 mg,
0.44243 mmol) in anhydrous CH2Cl2 (0.5 mL) at room temperature
was added KF dissolved in tetraethylene glycol (5.80 mL, 0.15
M,
0.87 mmol) in one portion. After stirring for 30 min at room temper-
ature, the reaction mixture was poured into water (400 mL) and the
aqueous layer was extracted with ethyl acetate (3 × 50 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The crude residue was purified by column chromatogra-
1 H), 7.54 (s, 1 H), 7.43 (td, J = 7.2, 1.2 Hz, 1 H), 7.35 (td, J = 7.2, phy (silica gel/30:70 ethyl acetate/petroleum ether) to give the title
1.2 Hz, 1 H), 7.16 (s, 1 H), 5.24 (s, 2 H), 1.41 (sept, J = 7.6 Hz, 3 H),
1.15 (d, J = 7.2 Hz, 18 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
152.49, 135.02, 131.56, 128.43, 127.89, 126.96, 126.29, 125.79,
compound 2 as a white solid (96.31 mg, 81 %). M.p. 157–159 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 10.05 (s, 1 H), 10.02 (s, 1 H), 7.81 (s,
1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.40 (td, J =
124.14, 119.38 (q, J = 326 Hz), 113.09, 76.53, 18.03, 13.01 ppm. 19F 7.6, 1.2 Hz, 1 H), 7.28 (td, J = 7.6, 1.2 Hz, 1 H), 7.17 (s, 1 H), 5.04 (s,
NMR (376 MHz, CDCl3): δ = –73.44 ppm. HRMS: m/z (DART): calcd.
2 H), 3.04 (s, 3 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 153.61,
134.22, 129.37, 127.55, 127.26, 126.21, 125.52, 125.15, 122.81,
108.48, 73.50, 36.38 ppm. HRMS: m/z (DART): calcd. for MH+
268.06381, found 268.06376.
for MH+ 478.16897, found 478.16900.
1,1,1-Trifluoro-N-[(3-hydroxynaphthalen-2-yl)methoxy]meth-
anesulfonamide (1): (The procedure used followed a method re-
ported by Song et al.[27a]) A KF stock solution (0.15
M) was prepared
N-{[3-(Triisopropylsilyloxy)naphthalen-2-yl]methoxy}benzene-
sulfonamide (14): (The procedure used followed a method re-
ported by Gajewiak and Prestwich.[26]) To a stirred mixture of 11
(335.20 mg, 0.97005 mmol), DMAP (118.66 mg, 0.97127 mmol) and
anhydrous pyridine (0.078 mL, d = 0.978 g/mL at 25 °C, 0.96 mmol)
in anhydrous CH2Cl2 (20 mL) at - 20 °C was added dropwise a solu-
tion of benzenesulfonyl chloride (0.161 mL, d = 1.384 g/mL at 25 °C,
1.26 mmol) in anhydrous CH2Cl2 (4 mL) at –20 °C. The reaction
mixture was slowly warmed to room temperature over 30 min and
was stirred for another 2 h. The reaction mixture was quenched
using saturated aq. CuSO4 (200 mL), and the aqueous layer was
by dissolving spray-dried potassium fluoride (73.29 mg,
1.261 mmol) in anhydrous tetraethylene glycol (8.42 mL) under
sonication. To a stirred solution of compound 12 (119.56 mg,
0.25033 mmol) in anhydrous CH2Cl2 (0.5 mL) at room temperature
was added the KF stock solution (0.15
M, 5 mL, 0.8 mmol) in one
portion. The reaction mixture was stirred at room temperature for
2 h before being partitioned between water (300 mL) and ethyl
acetate (80 mL). The aqueous layer was extracted with ethyl acetate
(3 × 80 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The crude residue was purified by column
Eur. J. Org. Chem. 0000, 0–0
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9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
extracted using CH2Cl2 (3 × 50 mL). The combined organic extracts
were dried with MgSO4 and the solvent was removed in vacuo. The
crude residue was purified by column chromatography (silica gel/
10:90 ethyl acetate/petroleum ether) to yield the title compound
14 as a colorless oil (346.55 mg, 74 %). H NMR (400 MHz, CDCl3):
δ = 7.95 (m, 2 H), 7.77 (s, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.63 (m, 2
dissolving HOCbl·HCl in aqueous phosphate buffer (pH 7.00,
5.0 m
brate for 24 h. An HNO donor 1 stock solution in CD3CN was also
prepared. A solution of H2OCbl(III)+ (200.0 μ
) and HNO donor 1
(200.0 μ ) in a mixture of phosphate buffer (pH 7.00, 5.0 m ) and
CD3CN (4.0 mL, 40:60, v/v) was prepared in a cuvette fitted with a
M) and CD3CN (40:60, v/v) and the solution was left to equili-
M
1
M
M
H), 7.52 (m, 2 H), 7.41 (td, J = 7.6, 1.2 Hz, 1 H), 7.33 (td, J = 7.6, J-Young air tight cap inside a glovebox. The sample was irradiated
1.2 Hz, 1 H), 7.10 (s, 1 H), 6.86 (s, 1 H), 5.21 (s, 2 H), 1.33 (sept, J =
using a Q-smart 450 pulsed Nd:YAG laser fitted with 2nd and 4th
harmonic generators (1 Hz, ca. 5 ns pulse width, ca. 60 mJ/pulse)
7.6 Hz, 3 H) 1.08 (d, J = 7.6 Hz, 18 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 152.40, 136.81, 134.64, 133.69, 130.51, 128.99, 128.55, for three sets of 10 pulses and six sets of 10 pulses with mixing
127.80, 127.31, 126.54, 126.23, 123.91, 112.94, 75.23, 18.03, 12.95. between the sets of pulses. UV/Vis spectra and 19F NMR spectra
(Note: One aromatic13C NMR signal was obscured due to accidental
signal equvalence.) ppm. HRMS: m/z (DART): calcd. for MH+
486.21288, found 486.21296.
were periodically recorded at 25 °C.
Acknowledgments
N-[(3-Hydroxynaphthalen-2-yl)methoxy]benzenesulfonamide
(3): (The procedure used followed a method reported by Song et
al.[27a]) To a stirred solution of compound 14 (716.52 mg,
1.4752 mmol) in anhydrous CH2Cl2 (1.0 mL) at room temperature
The authors acknowledge the U.S. National Science Foundation
(CHE-1306644 and CHE-1545770), and AUT for funding support.
We are also grateful to Dr. Mahinda Gangoda for assistance with
NMR spectroscopy and Dr. Jacob Shelley for assistance with
HRMS experiments.
was added KF dissolved in tetraethylene glycol (19.8 mL, 0.15
M,
3.0 mmol) in one portion. After stirring for 30 min at room tempera-
ture, the reaction mixture was poured into water (400 mL) and the
aqueous layer was extracted with ethyl acetate (3 × 80 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The crude residue was purified by column chromatogra-
phy (silica gel/30:70 ethyl acetate-petroleum ether) to give the title
compound 3 as a white solid (394.82 mg, 81 %). M.p. 172–175 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 10.50 (s, 1 H), 10.00 (s, 1 H), 7.90
(m, 2 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.72 (m, 1 H), 7.64
(m, 3 H), 7.38 (td, J = 8.0, 1.2 Hz, 1 H), 7.27 (td, J = 8.0, 1.2 Hz, 1 H),
7.14 (s, 1 H), 5.05 (s, 2 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ =
153.60, 137.20, 134.21, 133.35, 129.57, 128.92, 127.92, 127.48,
127.18, 126.18, 125.45, 124.96, 122.76, 108.45, 73.55. (Note: Two aro-
matic 13C NMR resonances were obscured due to accidental signal
equvalence.) ppm. HRMS: m/z (DART): calcd. for MH+ 330.07946,
found 330.07941.
Keywords: Arenes · Sulfonamides · Bioinorganic
chemistry · Photolysis · Photochemistry
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Received: January 18, 2018
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Photoactivatable Nitroxyl Donors
A new family of photoactivatable HNO
donors (1–3) has been developed that
incorporate the (3-hydroxy-2-naphth-
alenyl)methyl (3,2-HNM) phototrigger.
The desired HNO-generating pathway
is favored only with the excellent
SO2CF3 leaving group (1).
Y. Zhou, R. B. Cink,
Z. A. Fejedelem, M. C. Simpson,
A. J. Seed, P. Sampson,*
N. E. Brasch* ..................................... 1–12
Development of Photoactivatable
Nitroxyl (HNO) Donors Incorporat-
ing the (3-Hydroxy-2-naphthalen-
yl)methyl Phototrigger
DOI: 10.1002/ejoc.201800092
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