Photochemistry of 2-nitrobenzylidene acetals

Article abstract of DOI:10.1021/jo901756r

(Figure Presented) Photolysis of dihydroxy compounds (diols) protected as 2-nitrobenzylidene acetals (ONBA) and subsequent acid- or base-catalyzed hydrolysis of the 2-nitrosobenzoic acid ester intermediates result in an efficient and high-yielding release of the substrates. We investigated the scope and limitations of ONBA photochemistry and expanded upon earlier described two-step procedures to show that the protected diols of many structural varieties can also be liberated in a one-pot procedure. In view of the fact that the acetals of nonsymmetrically substituted diols are converted into one of the corresponding 2-nitrosobenzoic acid ester isomers with moderate to high regioselectivity, the mechanism of their formation was studied using various experimental techniques. The experimental data were found to be in agreement with DFT-based quantum chemical calculations that showed the preferential cleavage occurs on the acetal C-O bond in the vicinity of more electron-withdrawing (or less electron-donating) groups. The study also revealed considerable complexity in the cleavage mechanism and that the structural variations in the substrate can significantly alter the reaction pathway. This deprotection strategy was found to be also applicable for 2-thioethanol when released from the corresponding monothioacetal in the presence of a reducing agent, such as ascorbic acid.

Full text of DOI:10.1021/jo901756r

pubs.acs.org/joc
Photochemistry of 2-Nitrobenzylidene Acetals†
ꢀ
Peter Sebej, Tomas Solomek, L’ubica Hroudna, Pavla Brancova, and Petr Klan*
ꢀ
ꢁꢀ
ꢁ
ꢁ
ꢁ
Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A8, 625 00 Brno,
Czech Republic
klan@sci.muni.cz
Received August 13, 2009
Photolysis of dihydroxy compounds (diols) protected as 2-nitrobenzylidene acetals (ONBA) and
subsequent acid- or base-catalyzed hydrolysis of the 2-nitrosobenzoic acid ester intermediates result
in an efficient and high-yielding release of the substrates. We investigated the scope and limitations of
ONBA photochemistry and expanded upon earlier described two-step procedures to show that the
protected diols of many structural varieties can also be liberated in a one-pot procedure. In view of the
fact that the acetals of nonsymmetrically substituted diols are converted into one of the correspond-
ing 2-nitrosobenzoic acid ester isomers with moderate to high regioselectivity, the mechanism of their
formation was studied using various experimental techniques. The experimental data were found to
be in agreement with DFT-based quantum chemical calculations that showed the preferential
cleavage occurs on the acetal C-O bond in the vicinity of more electron-withdrawing (or less
electron-donating) groups. The study also revealed considerable complexity in the cleavage mechan-
ism and that the structural variations in the substrate can significantly alter the reaction pathway.
This deprotection strategy was found to be also applicable for 2-thioethanol when released from the
corresponding monothioacetal in the presence of a reducing agent, such as ascorbic acid.
Introduction
employed in biochemistry,7,8 organic synthesis,9 and related
fields. Various authors investigated the mechanism of the leaving
group release.10-18 In general, the reaction is initiated by a light-
induced intramolecular 1,5-hydrogen shift in the primary step
yielding aci-nitro intermediates, followed by formation of benzo-
xazolidines and subsequent ring opening to give LG and
2-nitrosoacetophenone as a side product (Scheme 1).
Intramolecular photoreduction of the nitro group and sub-
sequent liberation of a leaving group (LG) from the benzylic
position of the 2-nitrobenzyl (o-nitrobenzyl; ONB) chromo-
phore belong among the most intensively studied transfor-
mations in photochemistry.1-5 Since its first use as a photo-
removable protecting group (PPG),6 the ONB moiety has been
(10) Zhu, Q. Q.; Schnabel, W.; Schupp, H. J. Photochem. 1987, 39, 317.
(11) Corrie, J. E. T.; Barth, A.; Munasinghe, V. R. N.; Trentham, D. R.;
Hutter, M. C. J. Am. Chem. Soc. 2003, 125, 8546.
(12) Dunkin, I. R.; Gebicki, J.; Kiszka, M.; Sanin-Leira, D. Spectrochim.
Acta, Part A 1997, 53, 2553.
† Dedicated to the memory of Professor Peter J. Wagner.
(1) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441.
(2) Goeldner, M.; Givens, R. S. Dynamic Studies in Biology; Wiley-WCH:
Weinheim, 2005.
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(14) Gaplovsky, M.; Il’ichev, Y. V.; Kamdzhilov, Y.; Kombarova, S. V.;
(3) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(4) Givens, R. S.; Conrad, P. G.; Yousef, A. L.; Lee, J.-I. In CRC
Handbook of Organic Photochemistry and Photobiology; Horspool, W. M.,
Lenci, F., Eds.; CRC Press: Boca Raton, 2004; p 1.
(5) Morrison, H. Biological Applications of Photochemical Switches; John
Wiley and Sons, Inc.: New York, 1993; Vol. 2.
€
Mac, M.; Schworer, M. A.; Wirz, J. Photochem. Photobiol. Sci. 2005, 4, 33.
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126, 4581.
(16) Laimgruber, S.; Schmierer, T.; Gilch, P.; Kiewisch, K.; Neugebauer,
(6) Kaplan, J. H.; Forbush, B.; Hoffman, J. F. Biochemistry 1978, 17,
1929.
J. Phys. Chem. Chem. Phys. 2008, 10, 3872.
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(17) Bley, F.; Schaper, K.; Gorner, H. Photochem. Photobiol. 2008, 84,
(7) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900.
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DOI: 10.1021/jo901756r
r
Published on Web 10/13/2009
J. Org. Chem. 2009, 74, 8647–8658 8647
2009 American Chemical Society

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SCHEME 1
SCHEME 2
The ONB moiety has been used to protect the hydroxy
group, for example, in some oligo- and polysaccharides,19-23
whereas 2-nitrobenzylidene acetals (ONBA, 1; Scheme 2)
can be utilized for protection of dihydroxy compounds
(diols). The earlier works of Tanasescu and co-workers
(e.g., refs 24 and 25) suggested that 2-nitrosobenzoic acid
esters (20 and 200 in Scheme 2) are obtained as primary
isolable products after photolysis of 1 and that the corre-
sponding free diols 3 can be liberated by subsequent acid
hydrolysis. Collins and co-workers later investigated the
photochemistry of various glycosides and pyranosides, in
which either the 1,2- or 1,3-dihydroxy functionality was
protected as an ONBA.22,26,27 The 2-nitrobenzylidene acet-
als of such nonsymmetrically substituted dihydroxy com-
pounds were reported to form preferentially one of two
possible 2-nitrosobenzoic acid esters upon photolysis.
Young and Deiters have recently used this strategy to control
activation of gene expression in bacterial cells.28 In this case,
photolysis of a galactoside acetal gave an ester that was
converted to the corresponding dihydroxy compound by
intracellular hydrolysis. An inverted procedure of diol re-
lease, according to which methylglucoside or methylmanno-
side ONBA derivatives were treated by boron trifluoride in
the first step to release a protected ONB ether followed by
photochemical release of the corresponding carbohydrates,
was introduced by Iwamura and co-workers.29 Photorelease
of organic diols has also been accomplished using different
PPGs, such as salicylaldehyde30 or coumarin-4-ylmethyl31
derivatives. In a reverse fashion, carbonyl compounds can be
liberated from 2-nitrophenylethylene glycol32 or bis(2-nitro-
phenyl)ethanediol33 precursors.
co-workers22,26,27 three decades ago. Furthermore, a simple,
one-pot photoinitiated procedure enabling diol release from
ONBA in high chemical yields is introduced.
Results and Discussion
Preparative Deprotection of Dihydroxy Compounds. The
2-nitrobenzylidene acetals 1a-f and the monothioacetal 4
(Table 1) were prepared from the corresponding dihydroxy
compounds 3a-f and 2-thioethanol (5), respectively, using
2-nitrobenzaldehyde and p-toluenesulfonic acid (PTSA) as a
catalyst under azeotropic reflux conditions in a Dean-Stark
apparatus (Scheme 3).34,35 The compounds were obtained
in very good chemical yields (88-95%) and purity. The
2-nitrobenzylidene acetal of methyl-R-D-glucopyranoside
1g was prepared from the corresponding glucopyranoside
3g and 2-nitrobenzaldehyde by stirring in dioxane with
H2SO4 as a catalyst at 20 °C.36,37
Diol liberation from the acetal 1 proceeds through two key
steps: the 2-nitrosobenzoic acid ester intermediate 2 is formed
upon acetal irradiation, and the corresponding diol 3 is
obtained in a subsequent hydrolysis of 2 (Scheme 2). For this
work, two different strategies of diol release have been used.
In stepwise procedures, a benzene solution of an acetal
(1a-g; ∼5 ꢀ 10-3 M) was irradiated at >280 nm (Pyrex
filter) to a nearly complete conversion (>95%). It was
apparent that formation of strongly absorbing nitroso inter-
mediates slowed down the observed rate of conversion as
their concentration increased as the result of an optical filter
effect. The solvent was then evaporated, the remaining
material was dissolved in methanol containing NaOH (0.2 M),
and the mixture was stirred at 20 °C for approximately 1 h.
A liberated diol was isolated by methanol evaporation and
subsequent extraction into ethyl acetate after addition of
Here we present a study that was aimed to find the scope
and limitations of 2-nitrobenzylidene acetal utilization as a
photoremovable group for 1,2- and 1,3-dihydroxy com-
pounds as well as for 2-hydroxythiols. A series of experi-
ments and DFT-based quantum chemical calculations were
performed to determine the key steps of the reaction and to
understand effects that lead to the remarkable regioselec-
tive acetal C-O bond cleavages reported by Collins and
(19) Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1993, 2161.
(20) Zehavi, U. Adv. Carbohydr. Chem. Biochem. 1988, 46, 179.
(21) Zehavi, U.; Patchornik, A. J. Org. Chem. 1972, 37, 2285.
(22) Collins, P. M.; Oparaeche, N. N. J. Chem. Soc., Perkin Trans. 1 1975,
1695.
(23) Collins, P. M.; Oparaeche, N. N.; Munasinghe, V. R. N. J. Chem.
Soc., Perkin Trans. 1 1975, 1700.
(24) Tanasescu, I.; Ionescu, M. Bull. Soc. Chim. Fr. 1940, 7, 77.
(25) Tanasescu, I.; Ionescu, M. Bull. Soc. Chim. Fr. 1940, 7, 84.
(26) Collins, P. M.; Munasinghe, V. R. N. J. Chem. Soc., Perkin Trans. 1
1983, 1879.
(27) Collins, P. M.; Munasinghe, V. R. N. J. Chem. Soc., Perkin Trans. 1
1983, 921.
(28) Young, D. D.; Deiters, A. Angew. Chem., Int. Ed. 2007, 46, 4290.
(29) Watanabe, S.; Sueyoshi, T.; Ichihara, M.; Uehara, C.; Iwamura, M.
Org. Lett. 2001, 3, 255.
(30) Kostikov, A. P.; Popik, V. V. Org. Lett. 2008, 10, 5277.
(31) Lin, W. Y.; Lawrence, D. S. J. Org. Chem. 2002, 67, 2723.
(32) Gravel, D.; Hebert, J.; Thoraval, D. Can. J. Chem. 1983, 61, 400.
(33) Blanc, A.; Bochet, C. G. J. Org. Chem. 2003, 68, 1138.
(34) Cole, E. R.; Crank, G.; Minh, H. T. H. Aust. J. Chem. 1980, 33, 675.
(35) Jin, T. S.; Zhang, S. L.; Wang, X. F.; Guo, J. J.; Li, T. S. J. Chem.
Res., Synop. 2001, 289.
(36) Collins, P. M.; Oparaeche, N. N. Carbohydr. Res. 1974, 33, 35.
(37) Collins, P. M.; Oparaeche, N. N.; Whitton, B. R. J. Chem. Soc.,
Chem. Commun. 1974, 292.
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TABLE 1. Synthesis and Photolysis of Acetals 1a-g and Monothioacetal 4
aNP = 2-nitrophenyl. bIsolated yields; an average of two experiments; two diastereomers were identified by NMR or/and GC in approximately 1:1
ratio in some cases. cA mixture of cis and trans isomers obtained from the commercially available starting material. dPhotolysis of 1a-g or 4 at >280 nm
in benzene (2-step procedure) or in methanolic NaOH solution (“one-pot” arrangement). Isolated chemical yields obtained using a triple extraction.
eIsolated yields obtained from a single extraction. fDetermined by NMR. gn.c. = not carried out. hBis(2-hydroxyethyl) disulfide (6) was the exclusive
product formed. 2-Thioethanol (5) was obtained in 90% yield only when ascorbic acid (>4 equiv) as a reducing agent was present during the photolysis;
see the text. iIrradiated in the presence of ascorbic acid (>4 equiv).
water. The aliphatic diols 3a-d are partially soluble in water;
therefore, at least a triple extraction protocol was necessary
to attain high chemical yields (Table 1). The sufficiently
lipophilic diol 3e was obtained in high yield by using a single
extraction. The quantum yields of 1a-e disappearance in
various solvents are listed in Table 2. Photodegradation of
simple 2-nitrobenzyl esters is known to be rather inefficient
(Φ is usually below 0.1).17,38 Yip and co-workers reported
that 2-nitrobenzaldehyde acetal of 2,2-dimethylpropane-1,3-
diol photoreacts more efficiently than 2-nitrobenzyl acetate
by a factor of 23.38 The larger disappearance quantum yields
of ONBA derivatives reported in Table 2 are in agreement
with this observation.
A more convenient one-pot procedure, in which the acetals 1
(∼5 ꢀ 10-3 M) were photolyzed in 0.2 M NaOH methanol
solutions at 20 °C, directly afforded the corresponding dihy-
droxy compounds 3. The course of the reaction was followed by
NMR to find optimum experimental conditions. The reaction
mixture was processed similarly to the second step of the
(38) Yip, R. W.; Sharma, D. K.; Giasson, R.; Gravel, D. J. Phys. Chem.
1985, 89, 5328.
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SCHEME 3
SCHEME 4
position to the nitroso group at þ55 °C in 2d (monomer) to
that in 2d (dimer) at -7 °C (Figure 1).
Photolysis of Nonsymmetric 2-Nitrobenzylidene Acetals.
More than 30 years ago, Collins and Oparaeche reported
that photolysis of ONBA derivatives of some glycosides or
pyranosides, which gave the corresponding ONB esters, can
be highly regioselective. Two examples are shown in
Scheme 5.22,23 The regioisomers were identified by 1H
NMR measurements either directly or after oxidation of
the products to the corresponding 2-nitrobenzoates by tri-
fluoroperacetic acid. These rather unexpected results were
attributed to steric and stereoelectronic effects.
TABLE 2. Disappearance Quantum Yields for 1a-e (Φdis) in Various
Solvents at 313 nm
a
compound
solvent
Φdis
1a
methanol
hexane
methanol
hexane
methanol
methanol
0.38 ( 0.04
0.39 ( 0.05
0.38 ( 0.08
0.31 ( 0.03
0.30 ( 0.08
0.44 ( 0.07
1b
One of the goals of our study was to determine the key steps
of the reaction and distinguish effects that lead to regioselec-
tive acetal C-O bond cleavage in nonsymmetric ONBA
derivatives. The structures of regioisomeric 2-nitrosobenzoic
acid esters photoreleased from the model ONBA derivatives
1c
1e
aThe quantum yields were obtained using 2-nitrobenzaldehyde (for
1a-c; Φ = 0.38 in methanol39) or valerophenone (for 1e, Φ of aceto-
phenone formation=0.33 in hexane40) as actinometers. The results are
based on at least three independent measurements; the relative standard
deviations are shown.
1
1d-g were analyzed by 2D NMR. The H NMR spectra
differentiated the aliphatic hydrogens of the ester group in
order to calculate the relative concentrations of the major and
1
minor isomers, while the H-1H COSY measurements (see
procedure described above. The chemical yields were compar-
able or better than those of the stepwise procedure (Table 1)
despite the fact that photolysis time to obtain sufficiently large
conversion (>95%) was somewhat longer (>2 h).
Supporting Information) established the relationships among
the neighboring hydrogens in the aliphatic part of the mole-
cule. In addition, 1H-13C HMBC experiments (see Support-
ing Information) provided an unambiguous correlation
between the aliphatic and aromatic parts of the molecule to
assign the correct structures. To work with less complex
spectra, the samples were analyzed at þ55 °C to ensure that
the concentration of the azodioxy dimers (Scheme 4) was
negligible. The relative concentrations of the regioisomers
2d-g obtained by irradiation of 1d-g are given in Scheme 6.
The diol substitution indeed affected the regioselective clea-
vage of the acetal C-O bonds: photolysis of 1d (R=methyl)
gave 2da as the major product, while an opposite regioisomer
2fb was formed from 1f (R=3-nitrophenyl). The phenyl sub-
stitution in 1e had no apparent affect on the reaction regio-
selectivity. The photoproduct concentration ratio was not
affected much by either changing the solvent polarity or by
addition of a strong acid. To authenticate our results with
those of Collins and Oparaeche,22,23 1g was irradiated in
methanol to release a 2.9-fold excess of the glucopyranoside
derivative 2ga. This was a very similar observation to that
found for the trimethoxy analogue 922,23 (Scheme 5).
We have also investigated the possibility that attack of a
nucleophile, such as methanol or water, can participate in an
acetal ring opening. No methanol adducts were identified in
the reaction mixtures after ONBA derivatives were photo-
lyzed in methanol. In addition, solutions of 1d in benzene-d6
or methanol-d4, containing either a small amount of D216O
or isotopically labeled D218O, were extensively irradiated
and the major reaction products were analyzed by LC-MS
TOF. The same mass spectra of the photoproducts were
obtained in both cases; that is, no incorporation of oxygen
from water occurred either during the initial photoreaction
or the subsequent dark steps.
Chemical Properties of 2-Nitrosobenzoic Acid Ester Inter-
mediates. To study properties and hydrolytic reaction of
2-nitrosobenzoic acid ester intermediates (2), a pentane
solution of 1 (5 ꢀ 10-3 M) was irradiated at >280 nm to
form 2 as a precipitate. For example, photolysis of 1a
gave the 2-nitrosobenzoic acid ester intermediate in ∼60%
chemical yield. Aromatic nitroso compounds are known to
exist in equilibrium with the corresponding azodioxy dimers
((E)- and (Z)-7; Scheme 4) in solutions.41,42 The monomer
and dimer species can be distinguished by NMR thanks to
the shielding anisotropy of the NO group.43,44 The popula-
tion of dimers are pronounced at lower temperatures and in
the solid state. Since nonsymmetrically substituted acetals,
such as 1d-g, give two different 2-nitrosobenzoic acid esters
(Scheme 2), a complex mixture of species was always obser-
ved after extensive photolysis.
1H NMR analysis of the monomer/dimer equilibrium of
2d (∼3 ꢀ 10-2 M) in CD3OD revealed that the concentration
of monomers is very small at -7 °C, whereas their popula-
tion increases considerably at þ55 °C (Figure 1). This
process was fully reversible over three cooling/heating cycles.
The isomer identification was accomplished by comparing
the characteristic peaks of the aromatic proton in the ortho
(39) George, M. V.; Scaiano, J. C. J. Phys. Chem. 1980, 84, 492.
(40) Wagner, P. J.; Kemppainen, A. E.; Kochevar, I. E. J. Am. Chem. Soc.
1972, 94, 7489.
(41) Azoulay, M.; Wettermark, G. Tetrahedron 1978, 34, 2591.
(42) Azoulay, M.; Stymne, B.; Wettermark, G. Tetrahedron 1976, 32,
2961.
(43) Fletcher, D. A.; Gowenlock, B. G.; Orrell, K. G. J. Chem. Soc.,
Perkin Trans. 2 1998, 797.
(44) Fletcher, D. A.; Gowenlock, B. G.; Orrell, K. G. J. Chem. Soc.,
Perkin Trans. 2 1997, 2201.
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FIGURE 1. Temperature-dependent 1H NMR spectra of 2d in CD3OD.
SCHEME 5. Results from References 22 and 23
SCHEME 6. Regioselectivity of Photorelease of 2d-g
Computational Studies: Protected Ethan-1,2-diol. The me-
chanism of ONB deprotection has also been subject of many
studies since its first application as PPG. An archetype
compound, 2-nitrotoluene, is known to undergo intramole-
cular hydrogen shift to form an aci-nitro tautomer upon
irradiation.45 This intermediate is a moderately strong acid,
and it recovers the ground state of the starting material upon
proton tautomerization.13 It is not clear yet whether the
reaction proceeds from the excited singlet or triplet state or
both, or whether H-atom transfer and conformational inter-
conversion occur in an electronic excited state. Similar initial
steps of the photoreaction have been proposed for various
2-nitrobenzyl moieties substituted in the benzylic position by
various leaving groups (Scheme 1).10-18 The decay of the aci-
nitro intermediates is often taken as the rate-limiting step of
the process, and it can proceed via different reaction path-
ways, the mechanisms of which depend considerably on pH
and polarity of a solvent. Although exhaustive computational
(45) Dunkin, I. R.; Gebicki, J.; Kiszka, M.; Sanin-Leira, D. J. Chem. Soc.,
Perkin Trans. 2 2001, 1414.
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studies by Il’ichev and Wirz have been devoted to explaining
the experimentally observed trends,14,15,46,47 the substituent
effects on the kinetics of the complete deprotection process
remain inadequately understood. None of the previous com-
putational studies included the nitrobenzylidene moiety.
In this work, a series of DFT-based quantum chemical
calculations48 were performed on the reactions of the ethan-
1,2-diol derivative 1i, the simplest model compound, to
understand the mechanism of ester 2 formation (Scheme 7;
red numbers). Our efforts have been centered on the reaction
steps that follow the photochemical formation of the aci-
nitro intermediate 10 (Scheme 7), which could be decisive
in determining the reaction regioselectivity observed. We
followed the methodology used previously for rearrange-
ments of 2-nitrobenzyl derivatives using the B3LYP/6-311þ
G(3df,2p)//B3LYP/6-31G(d) level of theory (with the scaling
factor of 0.9613 for vibrational frequencies)49 to compute
activation Gibbs energies (ΔGq).46,47 A polarizable conti-
nuum model (PCM) of Tomasi and co-workers was used to
mimic the solvation effects on the activation barriers.50,51 It
is known that the B3LYP functional underestimates the
activation barriers by more than 3 kcal mol-1 for most
reactions.52 Hence we considered the B3LYP results to be
a lower estimate for the energy requirements of all elemen-
tary steps. The structures, total energies (at 0 K), and total
Gibbs energies (at 298.15 K) together with Cartesian coor-
dinates for all species considered are given in Supporting
Information.
SCHEME 7. Reaction Mechanism Proposed for 1i and 1ja
Only the (E)-configuration on the CdN bond in 10i (trans-
aci-nitro tautomer) was considered because it was more
stable than the (Z)-isomer by 2.2 kcal mol-1 (>97.5%
trans-10i). The subsequent cyclization of 10i gives the tricyc-
lic N-hydroxy-2,3-dihydrobenzo[d]isoxazole 11i. The ΔGq
values of 8.2 kcal mol-1 in the gas phase and 6.6 kcal mol-1
in water as an implicit solvent were determined for this pro-
cess. The aci-tautomer is a moderately strong acid (pKa ∼3.6
for 2-nitrotoluene13) implying a more acidic character of 10i.
The anionic form of 10i, 10i-, should, therefore, prevail at
the neutral pH. Regarding the energy requirements for
cyclization (10i- f 11i-), the Gibbs energy of activation of
17.3 and 14.9 kcal mol-1 was found in the gas phase and in
water, respectively, which is in good agreement with the
value calculated by Il’ichev and Wirz for 2-nitrotoluene.47
aThe numbers (red = the reaction of 1i; blue = the reaction of 1j) are the
activation barriers (in kcal mol-1) in water and the pKa values.
Three different pathways for 11i decay were considered.
We initially assumed that an equilibrium is established
between 11i and 11i- and that both isomers are formed via
ring closure of 10i or 10i-, respectively. Unfortunately we
were unable to locate any minimum which corresponded to
11i-. The optimization process converged to 12i-. The
optimization process employing water as a solvent treated
as polarizable continuum (PCM) resulted essentially in the
same structure. These results suggest that there is a minimal
barrier between 11i- and 12i- at both the B3LYP/6-31G(d)
and B3LYP/6-31G(d) PCM potential energy surface (PES).
This indicates that no equilibrium can be described between
11i and 11i- because the latter structure decays immediately
to 12i-. Therefore, direct conversion of 11i- into the ester of
2-nitrosobenzoic acid 2i can also be excluded.
It is not surprising that no experimental pKa data for
compounds analogous to 11i are available. Previous compu-
tational work estimated the gas-phase deprotonation enthal-
pies of N-hydroxy-2,3-dihydrobenzo[d]isoxazole derived
from 2-nitrotoluene.47 To estimate a pKa of 11i, we adapted
the approach of Pliego and Riveros, predicting the experi-
mental values within 2 pKa units,53 which was previously
used in case of 2-nitrobenzyl alcohols.14 Thus, pKaapp=16.2
(app=apparent) was calculated for 11i. In addition, 11i can
also form 12i via an intramolecular proton transfer (or [1,3]-
H shift) from N-hydroxy group to the oxygen on the 2,3-di-
hydrobenzo[d]isoxazole ring, followed by the ring-opening.
The gas-phase ΔGq of 38.3 kcal mol-1 was found for this
(46) Il’ichev, Y. V. J. Phys. Chem. A 2003, 107, 10159.
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M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Kudin, T. V. K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, G.; Dapprich, S.; Daniels, A. D.; Strain, M.
C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, m. J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(49) Merrick, J. P.; Moran, D.; Radom, L. J. Phys. Chem. A 2007, 111,
11683.
(50) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett.
1996, 255, 327.
(51) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117.
(52) Boese, A. D.; Martin, J. M. L. J. Chem. Phys. 2004, 121, 3405.
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8652 J. Org. Chem. Vol. 74, No. 22, 2009

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process, which is considerably smaller than that reported for
2-nitrotoluene derivatives.47 The solvation showed only a
negligible effect on the barrier; its value increased only to
39.6 kcal mol-1 when water was included. We also per-
formed additional proton transfer to 11i that might lead
directly to 2. We assumed that the proton from the N-hydroxy
group could be transferred to one of the oxygen atoms
belonging to the protected diol. However, it made no sense
to optimize such a process in silico because the charge
separation would lead to exceedingly high energies. Instead,
an explicit molecule of water, which served as a proton car-
rier, was employed. We were able to locate a transition state
TS[11i f 2i] that corresponded to a one-step transformation
of 11i to the ester of 2-nitrobenzoic acid (2). The comparable
and relatively high ΔGq of 24.3 and 28.9 kcal mol-1 were
found for the reaction in the gas phase and water environ-
ment, respectively.
SCHEME 8
Computational Studies: Protected Substituted Nonsym-
metric Ethan-1,2-diols. Hypothetical 1,1-difluorethan-1,2-
diol (1j) was investigated by the same methods as those
described in the previous paragraph in order to explain the
acetal C-O bond cleavage priority in nonsymmetric 1,2-
diols. It was assumed that a strong inductive effect of the
fluorine atoms should considerably change the reactivity of
the key intermediates. The substituent effects on the aci-nitro
intermediates cyclization have been previously studied com-
putationally.46 We located two transition states TS[11jwa
f
The final step in the mechanism shown in Scheme 7 is the
transformation of the hemiortho ester 12i or its anionic form
12i- to 2. Two transition states with stable restricted wave
functions for 12i decay, differing by the angle contained
between the hemiortho ester hydroxy group and the benzene
ring, were found. The 30.1 and 31.3 kcal mol-1 values of ΔGq
in the gas phase were obtained, while the energy in the
water environment changed slightly to 30.3 kcal mol-1 and
30.9 kcal mol-1, respectively. A single transition state was
located for 12i- (TS[12i- f 2i-]). The computed ΔGq of 3.4
and 5.6 kcal mol-1 were obtained in the gas phase and water,
respectively. Both 12i and 12i- are in equilibrium. The pKa
values between 11 and 12 have already been reported for
common hemiortho esters.54 Here we used the method
of Riveros and Pliego53 to estimate the pKa of 12i to obtain
the value of ∼16 again. However, we assume that the
authentic value should be lower by several pKa units.
McClelland and co-workers described the hemiortho ester
anion 13- to be in equilibrium with its ring-opened form 14
(Scheme 8) and reported pKa of ∼10 for the neutral hemi-
ortho ester 13.55
A profile of the potential energy surface calculated for the
phototransformation of 1i is lucidly depicted in Figures 2
(neutral form) and 3 (deprotonated form). The Gibbs en-
ergies for various intermediates and transition states are
given relative to trans-10i and 10i-. The aci-nitro derivative
trans-10i cyclizes into 11i (or 11iw, with an explicit molecule
of water) with relatively low barrier of 6.6 kcal mol-1. The
anion 10i- possesses a considerably higher barrier for cycli-
zation (14.9 kcal mol-1 in water). Since aci-nitro intermedi-
ates are moderately strong acids (pKa ∼3.6 for 2-nitro-
toluene13), acid catalysis is expected to occur in this step
even at neutral pH. Three alternatives are possible for 11i
decay. Nevertheless, it is clear that the reaction barriers
connecting 11i (or 11iw) with 12ib (or 2 directly) are very
high. The last pathway considered involved the deprotona-
tion of 11i to give a hypothetical species 11i-, which is
transformed spontaneously to 12i-. Base catalysis is essen-
tial for this step. 12i is a relatively weak acid that prefers a
neutral form; therefore, we suggest that base catalysis is a
part of decay of the hemiortho ester 12i.
2ja] and TS[11jwb f 2jb] (for indexes, see Supporting Infor-
mation, page S10), the activation energies of which, 18.1 and
7.1 kcal mol-1, respectively, clearly suggest that the cleavage
of the C-O bond with the neighboring fluorine substitution
is largely favored (Scheme 7). The effect of fluorine atoms on
the transformation is enormous when compared to the
results for 11i. It is reasonable to assume that the pKa for
11j will drop below that of 11i as a result of the strong
inductive effect of fluorine atoms.
In addition, we explored the impact of this substitution on
the last reaction step, a decay of 12j. Two transition states
leading to each of the isomeric esters were located. The
cleavage of the C-OCF2 bond possessed a lower barrier of
18.5 kcal mol-1 (TS[12j f 2jb]) in water compared to that of
34.3 kcal mol-1 (TS[12j f 2ja]). 12j- was affected by the
substitution even more. The optimization process exclusively
converged to a structure reminiscent of 2jb (Scheme 9). We
tried to include the solvent or change the basis set by adding
diffuse functions (6-31þG*) in this optimization procedure
with the same conclusion.
Finally, we wished to confirm our experimental results
obtained from the HMBC spectra analyses of 2da (major)
and 2db (minor) formation (Scheme 6). The observed
(experimental) ratio of 3.7 corresponds to an activation
energy difference of less than 1 kcal mol-1 at 298 K. It is
clear that such small energy differences are on the edge of the
DFT performance; therefore, it cannot provide fully convin-
cing results. In addition, a stereogenic center in the molecule
of a nonsymmetric diol introduces a large amount of various
diastereomers essentially in each step of the reaction mecha-
nism. Modeling such a reaction mechanism is thus exceed-
ingly complex.
Nevertheless, here we considered the cyclization of the aci-
nitro form of all possible 10d diastereomers (the (E)-config-
uration of the CdN bond of the former nitro group was
assumed). All four species were found to be similar in energy.
The activation Gibbs energies varied only by 1.7 kcal mol-1
(see Table SI-3 and Figure SI-18 in Supporting Information).
None of the reactions was energetically disfavored and the
cyclization proceeded from all four diastereomers. We then
focused on the last step in the transformation, the dioxolane
ring opening in the hemiortho ester 12d or its anionic form
12d-. We were able to locate eight transition states with
stable restricted wave function for diastereomers of 12d
(54) Guthrie, J. P. J. Am. Chem. Soc. 1978, 100, 5892.
(55) McClelland, R. A.; Santry, L. J. Acc. Chem. Res. 1983, 16, 394.
J. Org. Chem. Vol. 74, No. 22, 2009 8653

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FIGURE 2. Profile of the potential energy surface for the transformation of the aci-nitro moiety 10i into 2i. The subscript (w) denotes an
explicit water molecule used in the calculation. Gibbs energies in water relative to trans-10i are given in kcal mol-1. The values relevant for the
gas phase are in parentheses. The barriers and the reaction energies for individual steps are shown near the corresponding dashed arrows. Red
color is used to highlight the preferred steps.
(two TS for each diastereomer). The results obtained pre-
clude creating a complete and all-inclusive picture of the
observed regioselectivity as expected. However, we would
like to illustrate that the energy differences in the activation
barriers are so small that the 2da/2db ratio must be close to 1.
The transition states and their energies are listed in Figure SI-
19 and Table SI-4 in Supporting Information.
interconnect the lowest energy minima with those of the
products. The transition states and their energies are sum-
marized in Figure SI-20, Figure SI-21, and Table SI-5 in
Supporting Information. The results suggest that each dia-
stereomer prefers formation of a different regioisomer of the
product. Hence the final product ratio could be affected by
another slow step in the mechanism, that is, by the rates of
the diastereomers 12d- formation. A similar trend can be
found for the neutral form 12d.
We located two transition states for each of the 12d-
diastereomers (12d- f 2da or 2db). However, they do not
8654 J. Org. Chem. Vol. 74, No. 22, 2009

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SCHEME 10. Data from Reference 22
SCHEME 11. Decay of 15-a
FIGURE 3. Profile of the potential energy surface for the transfor-
mation of the aci-nitro moiety 10i- into 2i-. The Gibbs energies in
water relative to 10i- are given in kcal mol-1. The barriers and reac-
tion energies for individual steps are shown near the corresponding
dashed arrows.
aendo C-O bonds highlighted in red (bond a) and blue (bond b). The
relative Gibbs energies for 16 and 17 are shown.
In addition, our calculations predicted that 17 was lower in
energy by at least 1.3 kcal mol-1 relative to the optimized
conformers of 16 (Scheme 11) at the B3LYP/6-311þG(2d,
p)//B3LYP/6-31G(d) level of theory. It suggests that more
strain energy of the five-membered ring in 15- is released
when 15- decays to 17, and it is in agreement with the results
of Collins and co-workers. Note that 2da (major) and 2db
(minor) were found equal in energy within 0.1 kcal mol-1
(the experimental ratio is 3.7:1 in methanol).
SCHEME 9
Photolysis of Monothioacetal 4. Photolysis of the mono-
thioacetal 4 in methanol followed by basic hydrolysis resul-
ted in high yields of bis(2-hydroxyethyl) disulfide (6;
Scheme 12; Table 1) instead of 2-thioethanol (5). In contrast,
5 was obtained in approximately 90% chemical yield when 4
was irradiated in the presence of more than 4 equiv of
ascorbic acid, a frequently employed reducing agent,56,57
following both stepwise and one-pot deprotection protocols
We have already shown that the regioselectivity of the
acetal cleavage in nonsymmetric ONBA derivatives, such as
1d or 1j, is, in principle, based on the leaving ability evalua-
tion of one of the terminal groups, although steric effects
should not be neglected. However, such a simple model
cannot unequivocally explain the regioselectivity observed
in some carbohydrate derivatives,23 such as 9 in Scheme 5.
To study a similar ONB structure, such as an acetal shown
in Scheme 10 previously studied by Collins,22 we selected a
model compound 15 (Scheme 11). We found that the two
endo C-O bonds of a hemiortho ester group in 15- differ
significantly in length. The a versus b length difference of
1
(Table 1). Both photoproducts were easily identified by H
NMR in situ thanks to the characteristic -CH2SH versus
-(CH2)S-S(CH2)- peaks.
SCHEME 12
˚
0.154 A was obtained using the B3LYP/6-31G(d) level of
theory. Improving the basis set by adding diffuse (6-31þ
G(d)) and polarization (6-31þG(d,p)) functions reduced
˚
the difference to 0.104 and 0.105 A, respectively. It appeared
that the solvation plays an important role here. The B3LYP/
6-31þG(d) geometry with PCM solvation model of water
˚
further attenuated the difference to 0.039 A. However, we
faced a problem with the convergence criteria in this case,
and hence we performed an MP2/6-31þG(d) geometry
optimization to obtain the same result with the difference
˚
of 0.066 A. All these findings suggest that the regioselectivity
in the 15- decay should be observed experimentally and they
indeed agree with the observation of Collins and co-workers
depicted in Scheme 10.
(56) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140.
(57) Liu, Q.; Han, B.; Liu, Z. G.; Yang, L.; Liu, Z. L.; Yu, W. Tetrahedron
Lett. 2006, 47, 1805.
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The formation of 6 was explored. 2-Thioethanol was
found to be photostable in methanol as well as in methanol
containing NaOH (0.2 M) even when purged with O2 in dark.
On the other hand, bis(2-hydroxyethyl) disulfide (6) was
formed in the presence of nitrobenzene in methanol under
irradiation (>280 nm, Pyrex filter; nitrobenzene itself is not
photoreduced in methanol under these conditions) as well as
in the presence of 2-nitrosobenzoic acid16,58 (Scheme 13) in
dark. Therefore, both photooxidation by the starting nitro-
benzyl acetal and oxidation by the nitroso intermediate
formed in the first step of photochemical deprotection could
be responsible for oxidative formation of a disulfide from a
thiol.
trans-Hexahydro-2-(2-nitrophenyl)benzo[d][1,3]dioxole (1a).
Prepared from 3a in 93% yield; light yellow viscous liquid. 1H
NMR (300 MHz, CDCl3): δ (ppm) 1.19-1.37 (m, 2H), 1.52 (dt,
2H, J1 = 11.0 Hz, J2 = 2 Hz), 1.85 (dd, 2H, J1 = 11.0 Hz),
2.14-2.28 (m, 2H), 3.16-3.25 (m, 1H), 3.41-3.50 (m, 1H), 6.67
(s, 1H), 7.49 (dt, 1H, J1 = 7.8 Hz, J2 = 1.2 Hz), 7.63 (dt, 1H,
J1=7.6 Hz, J2=1.0 Hz), 7.86 (dd, 1H, J1=8.0 Hz, J2=1.3 Hz),
7.93 (dd, 1H, J1 =8.3 Hz, J2 =1.0 Hz). 13C NMR (75.5 MHz.
CDCl3): δ (ppm) 23.3; 23.4; 28.4; 28.5; 79.7; 82.1; 98.9;
124.1; 127.3; 129.2; 132.7; 134.2; 148.5. MS (EI, m/z): 248,
232, 151, 134, 121, 104, 97, 79, 69, 51, 41. FTIR (KBr, cm-1):
3476, 3414, 2945, 2868, 1528, 1348, 1113, 1072, 963, 855, 749,
627. UV-vis: ε313 (acetonitrile) = 680 dm3 mol-1 cm-1; ε366
(acetonitrile)=180 dm3 mol-1 cm-1; ε313 (MeOH)=700 dm3
mol-1 cm-1; ε366 (MeOH) = 190 dm3 mol-1 cm-1; ε313
(cyclohexane) = 440 dm3 mol-1 cm-1; ε366 (cyclohexane) =
150 dm3 mol-1 cm-1. HRMS (EIþ) for C13H15NO4 (Mþ)
249.1001, found 249.1017.
SCHEME 13
cis-Hexahydro-2-(2-nitrophenyl)benzo[d][1,3]dioxole (1b).
Prepared from 3b in 95% yield; slightly yellow crystals. Mp
44.5-46.0 °C. 1H NMR (300 MHz, CDCl3): δ (ppm)
1.25-1.37 (m, 2H), 1.55-1.68 (m, 2H), 1.70-1.94 (m, 4H),
4.10 (p, 2H, J=4.6 Hz), 6.75 (s, 1H), 7.47 (dt, 1H, J1=7.9 Hz,
J2=1.3 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.79 (d, 1H, J=7.8 Hz),
7.88 (d, 1H, J=8.0 Hz) (diastereomer a; isolated); 1.25-1.38
(m, 2H), 1.46-1.57 (m, 2H), 1.72-1.81 (m, 4H), 4.22 (p, 2H,
J=5.1 Hz), 6.44 (s, 1H), 7.50 (t, 1H, J=7.8 Hz), 7.65 (t, 1H,
J=7.6 Hz), 7.98 (d, 1H, J=7.8 Hz), 7.92 (d, 1H, J=8.1 Hz)
(diastereomer b; isolated). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 20.8, 28.1, 75.1, 98.5, 124.2, 127.6, 129.5, 132.9, 134.0,
148.8 (diastereomer a) 20.9, 27.2, 74.5, 98.2, 124.4, 127.4,
129.2, 132.7, 135.2, 148.8 (diastereomer b). MS (EI, m/z): 248,
232, 150, 134, 121, 104, 91, 81, 69, 51, 41. FTIR (KBr, cm-1):
3425, 2937, 2864, 1533, 1448, 1367, 1209, 1105, 1068, 999,
Conclusions
Chemically stable and synthetically accessible 2-nitro-
benzylidene acetals (ONBA) can be utilized for protection
of dihydroxy compounds. The substrates are released in two
reactions: (1) a photochemical transformation to the 2-nitroso-
benzoic acid esters, and (2) their subsequent acid- or base-
catalyzed hydrolysis to yield the diol. Here we report that
substrates are liberated in excellent chemical yields by a one-
pot procedure that includes both steps. The study also
explored the scope and limitations of ONBA photochemis-
try, in particular, that of nonsymmetrically substituted acet-
als preferentially yielding the esters with moderate to high
regioselectivity. Both the experimental data and DFT-based
quantum chemical calculations favored preferential cleavage
of the acetal C-O bond in the vicinity of a more electron-
withdrawing (or a less electron-donating) group, which
reflects the better leaving-group ability of the corresponding
hydroxy group. The release mechanism involves a very
complex sequence through the aci-nitro intermediate 10 on
to the 2,3-dihydrobenzo[d]isoxazole intermediate 11 and
ultimately to the hemiortho ester 12. Structural variations
of the substrate will influence the partitioning of these
intermediates and will alter the ratios of the hydroxyester
photoproduct mixture for unsymmetrical acetals. Similar
deprotection strategy was also applied for 2-thioethanol
when released from the corresponding monothioacetal in
the presence of a reducing agent.
786, 730. UV-vis: ε313 (MeOH) = 650 dm3 mol-1 cm-1
,
ε366 (MeOH) = 190 dm3 mol-1 cm-1, ε313 (cyclohexane) =
400 dm3 mol-1 cm-1, ε366 (cyclohexane) = 150 dm3 mol-1
cm-1. Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62.
Found: C, 62.62; H, 6.10; N, 5.62.
3-(2-Nitrophenyl)-2,4-dioxa-bicyclo[3.3.1]nonane (1c). Pre-
pared from 3c in 95% yield; yellowish crystals. Mp 32-35 °C.
1H NMR (300 MHz, CDCl3): δ (ppm) 1.33-1.52 (m, 4H),
1.86-1.94 (m, 2H), 2.09-2.23 (m, 1H), 2.71-2.81 (m, 1H),
4.48 (t, 2H, J=3.4 Hz), 6.63 (s, 1H), 7.42 (dt, 1H, J1 =7.8 Hz,
J2=1.4 Hz), 7.59 (t, 1H, J=7.6 Hz), 7.77 (dd, 1H, J1=8.1 Hz,
J2=0.9 Hz), 8.00 (dd, 1H, J1=7.9 Hz, J2=0.9 Hz). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 16.0; 27.8; 32.2; 69.5; 86.8; 123.9;
128.4; 129.2; 132.8; 133.5; 148.6. MS (EI, m/z): 248, 232, 152,
134, 121, 104, 93, 81, 65, 51, 41. FTIR (KBr, cm-1): 3396, 3301,
2935, 2859, 1529, 1450, 1349, 1192, 1130, 1010, 786, 740.
UV-vis: ε313 (MeOH) = 600 dm3 mol-1 cm-1, ε366 (MeOH) =
190 dm3 mol-1 cm-1, ε313 (cyclohexane) = 410 dm3 mol-1
cm-1, ε366 (cyclohexane)=160 dm3 mol-1 cm-1. Anal. Calcd
for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.77;
H, 6.13; N, 5.52.
Experimental Section
4-Methyl-2-(2-nitrophenyl)-1,3-dioxolane (1d). Prepared from
3d in 88% yield; yellowish oil. 1H NMR (300 MHz, CDCl3): δ
(ppm) 1.28 (m, 6H), 3.36-3.56 (m, 2H), 4.00-4.14 (m, 2H), 4.20
(td, 1H, J1=5.9 Hz, J2=11.9 Hz), 4.32 (td, 1H, J1=6.1 Hz, J2=
6.8 Hz), 6.36 (s, 1H), 6.56 (s, 1H), 7.37-7.49 (m, 2H), 7.51-7.62
(m, 2H), 7.68-7.87 (m, 4H); a mixture of two diastereomers).
13C NMR (75.5 MHz, CDCl3): δ (ppm) 17.9; 18.0; 71.2; 71.6;
72.5; 73.8; 99.2; 99.4; 124.1; 124.3; 127.5; 127.9; 129.5; 129.6;
132.7; 132.9; 133.2; 133.7; 133.8; 134.0; 148.7; 148.8. MS (EI,
m/z): 208, 192, 162, 150, 135, 121, 104, 91, 79, 59, 51, 41. FTIR
(KBr, cm-1): 2977, 2883, 1702, 1531, 1531, 1201, 1105, 1065,
730. UV-vis: ε313 (MeOH)=600dm3 mol-1 cm-1, ε366 (MeOH)=
General Procedure for the Synthesis of Acetals 1a-f and
Monothioacetal 4. A solution of a dihydroxy compound
(3a-f; 7.2 mmol) or 2-thioethanol (5, 7.2 mmol), 2-nitrobenzal-
dehyde (7.2 mmol), and p-toluene sulfonic acid (PTSA; 0.5 mmol)
in toluene (150 mL) was refluxed under Dean-Stark conditions
until the starting material disappeared (TLC), usually for 4-10 h.
The reaction mixture was then washed with aqueous NaOH (40 mL;
10%) and water (2 ꢀ 50 mL), dried over MgSO4, and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography.
(58) Schaper, K. Magn. Reson. Chem. 2008, 46, 1163.
8656 J. Org. Chem. Vol. 74, No. 22, 2009
200 dm3 mol-1 cm-1, ε313 (cyclohexane) = 400 dm3 mol-1 cm-1
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ε366 (cyclohexane) = 140 dm3 mol-1 cm-1. HRMS (EIþ) for
C10H11NO4 (Mþ) 209.0688, found 209.0682.
purified by flash chromatography to give 1g in 36% yield.
Yellow crystals. Mp 168.8-172.3 °C. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.72 (b, 2H), 3.46 (s, 3H), 3.54 (t, 1H, J =
8.9 Hz), 3.64 (dd, 1H, J1=9.1 Hz, J2=3.8 Hz), 3.78 (d, 2H, J=
7.3 Hz), 3.92 (t, 1H, J=9.2 Hz), 4.27 (d, 1H, J=5.3 Hz), 4.81 (d,
1H, J = 4.0 Hz), 6.15 (s, 1H), 7.51 (dt, 1H, J1 = 7.8 Hz, J2 =
2-(2-Nitrophenyl)-4-phenyl-1,3-dioxolane (1e). Prepared from
3e in 95% yield; light yellow oil. 1H NMR (300 MHz, CDCl3): δ
(ppm) 3.86 (td, 2H, J1=7.8 Hz, J2=11.9 Hz), 4.41 (m, 2H), 5.14
(m, 1H), 5.23 (t, 1H, J=7.0 Hz), 6.63 (s, 1H), 6.85 (s, 1H), 7.38
(m, 10H), 7.53 (m, 2H), 7.65 (t, 2H, J = 7.5 Hz), 7.95 (td, 4H,
0.9 Hz), 7.63 (t, 1H, J = 7.1 Hz), 7.89 (t, 2H, J = 7.8 Hz). 13
C
J1=9.2 Hz, J2=16.9 Hz) (a mixture of two diastereomers). 13
C
NMR (75.5 MHz, CDCl3): δ (ppm) 55.9; 62.5; 69.4; 72.0; 73.2;
81.3; 97.6; 100.0; 124.4; 128.1; 130.1; 131.3; 133.0; 148.6. MS
(EI, m/z): 285, 224, 207, 194, 178, 152, 135, 121, 104, 73, 60.
FTIR (KBr, cm-1): 3400, 2940, 1535, 1375, 1354, 1340, 1070,
1040, 1024, 1001, 959, 852, 744, 696. ε313 (MeOH) = 650 dm3
mol-1 cm-1, ε366 (MeOH) = 200 dm3 mol-1 cm-1. HRMS
(EIþ) for C14H17NO8 (Mþ) 327.0954, found 327.0943.
NMR (75.5 MHz, CDCl3): δ (ppm) 71.8; 72.5; 77.9; 79.1; 100.0;
100.4; 124.3; 124.4; 125.9; 126.3; 127.5; 127.7; 128.2; 128.3;
128.5; 128.6; 129.6; 129.7; 132.8; 132.9; 138.1; 138.6. MS (EI,
m/z): 269, 208, 165, 150, 135, 119, 104, 91, 79, 65, 51. FTIR (KBr,
cm-1): 3064, 3033, 2941, 2887, 1955, 1734, 1529, 1352, 1107, 1066,
698. UV-vis: ε313 (MeOH) = 1000 dm3 mol-1 cm-1, ε366
(MeOH) = 300 dm3 mol-1 cm-1, ε313 (cyclohexane) = 720 dm3
Photolysis of Acetals 1a-f. Two general methods for the
release of the dihydroxy compounds 1a-f were carried out as
follows.
mol-1 cm-1, ε366 (cyclohexane) = 250 dm3 mol-1 cm-1
.
HRMS (EIþ) for
C
15H13NO4 (Mþ) 271.0845, found
271.0846.
2-(2-Nitrophenyl)-4-(3-nitrophenyl)-1,3-dioxolane (1f). Pre-
pared from 3f in 94% yield; yellowish crystals. Mp 62.5-
(A) Stepwise Deprotection. An acetal (1 mmol) was dissolved
in benzene (70 mL), purged with argon for 15 min, and irra-
diated with a 125-W Hg medium-pressure UV lamp through a
Pyrex filter. No starting material was observed usually after
60 min (TLC or GC). The solvent was removed under reduced
pressure, and the residue was dissolved in methanolic solution of
NaOH (250 mg of NaOH in 50 mL). The reaction mixture was
stirred for ∼1 h at 20 °C. Solvent was then removed under
reduced pressure, and the remaining solid was dissolved in ethyl
acetate (20 mL) and washed by water/brine mixture (1:1 v/v;
20 mL). The water layer was then washed with ethyl acetate (2 ꢀ
20 mL). Combined organic phases were dried (MgSO4), and
solvent was removed under reduced pressure. A crude dihy-
droxy compound was obtained and purified by column chro-
matography. Their identification was based on comparing the
NMR, GC, GC-MS data to those of the authentic compounds.
The chemical yields are reported in Table 1.
(B) One-Pot Deprotection. An acetal (1 mmol) was dissolved
in methanolic solution of NaOH (250 mg of NaOH in 50 mL).
The solution was purged with argon for 15 min and irradiated
with a 125-W Hg medium-pressure UV lamp through a Pyrex
filter for several hours (TLC). The solvent was then removed
under reduced pressure and the remaining solid was worked up
and the products were identified in the same way as described
above. The chemical yields are reported in Table 1.
Irradiation Experiments in NMR Cuvettes. A solution of an
acetal or the monothioacetal 4 (usually 2-10 mg) in deuterated
solvent (500 μL) in NMR tube was purged by argon for 10 min.
In some experiments involving 4, ascorbic acid (3-5 molar
equiv) was added. The samples were irradiated with a 125-W Hg
medium-pressure UV lamp through a Pyrex filter (>280 nm).
In some cases, a solution of NaOD in MeOD was added to
carry out the hydrolysis step (a stepwise protocol). 1H NMR
and 13C-APT NMR spectra were measured in the time
intervals as necessary (see Supporting Information). Identi-
fication of the (photo)products was based on comparing the
analytical data to those of the authentic compounds.
Quantum Yield Measurements. The quantum yield measure-
ments were performed on an optical bench consisting of high
pressure 350-W or 450-W UV lamps, a 1/8 m monochromator
with 200-1600 nm grating, set to 313 nm, and a 1.0-cm matched
quartz cell containing a solution degassed purging with argon
for 10 min. The sample temperature was maintained using a
Peltier thermo block set to 20 °C. The light intensity was
monitored by a Si photodiode detector (UV enhanced) with a
multifunction optical power meter. The concentration of all
sample solutions was approximately 5 ꢀ 10-3 M, containing
hexadecane (10-3 M) for GC analyses as internal standard.
2-Nitrobenzaldehyde or valerophenone were used as actin-
ometers (see the footnote in Table 2). The reaction conver-
sions were always kept below 10% to avoid the interference
1
67 °C. H NMR (300 MHz, CDCl3): δ (ppm) 3.91 (dd, 1H,
J1=8.1 Hz, J2=6.4 Hz), 4.49 (d, 1H, J1=8.1 Hz, J2=7.1 Hz),
5.35 (t, 1H, J=6.8 Hz), 6.65 (s, 1H), 7.54 (m, 1H), 7.61 (dd, 1H,
J1 =7.8 Hz; J2 =1.2 Hz), 7.65 (d, 1H, J=7.9 Hz), 7.71 (t, 1H,
J=7.8 Hz), 7.96 (d, 1H, J=8.9 Hz), 7.99 (d, 1H, J=7.9 Hz) 8.16
(m, 2H) (diastereomer a). 3.90 (dd, 1H, J=8.3 Hz), 4.49 (dd, 1H,
J1 =8.4 Hz, J2 =6.4 Hz), 5.25 (t, 1H, J=6.8 Hz), 6.89 (s, 1H),
7.60 (m, 2H), 7.69 (t, 1H, J=7.4 Hz), 7.79 (d, 1H, J=7.9 Hz),
7.89 (dd, 1H, J1=8.1 Hz, J2=0.5 Hz), 7.97 (dd, 1H, J1=7.4 Hz,
J2=0.5 Hz), 8.20 (d, 1H, J=7.3 Hz), 8.25 (s, 1H) (diastereomer
b). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 72.1; 78.0; 100.8;
121.6; 123.4; 124.8; 127.8; 129.9; 130.3; 132.1; 132.5; 133.4;
141.3; 148.6; 163.3 (diastereomer a). 72.4; 77.1; 101.1; 121.2;
123.4; 124.9; 127.7; 130.2; 132.1; 133.0; 133.2; 141.5; 148.7
(diastereomer b). MS (EI, m/z): 316 (Mþ), 299, 269, 166, 149,
135, 121, 104, 91, 79, 65, 51. FTIR (KBr, cm-1): 3089, 2925,
2889, 1525, 1348, 1205, 1097, 1064, 953, 735. ε313 (MeOH) =
1400 dm3 mol-1 cm-1, ε366 (MeOH) = 280 dm3 mol-1 cm-1
.
Anal. Calcd for C15H12N2O6: C, 56.96; H, 3.82; N, 8.86. Found:
C, 56.94; H, 3.81; N, 8.83.
2-(2-Nitrophenyl)-1,3-oxathiolane (4). Prepared from 5 in
95% yield; yellowish crystals. Mp 57.5-60.0 °C. 1H NMR
(300 MHz, CDCl3): δ (ppm) 3.12 (m, 2H), 4.03 (dd, 1H, J1 =
14.9 Hz, J2 = 8.8 Hz, J3 = 1.6 Hz), 4.58 (m, 1H), 6.57 (s, 1H),
7.44 (t, 1H, J=7.8 Hz), 7.64 (t, 1H, J=7.4 Hz), 7.86 (d, 1H, J=
7.9 Hz), 8.01 (d, 1H, J=7.9 Hz). 13C NMR (75.5 MHz, CDCl3):
δ (ppm) 33.2; 72.7; 82.1; 124.8; 127.4; 128.8; 134.0; 137.7; 146.8.
MS (EI, m/z): 210, 194, 166, 151, 136, 121, 104, 93, 77, 60, 51.
FTIR (KBr, cm-1): 2940, 2894, 1606, 1515, 1349, 1209, 1064,
977, 717, 674. UV-vis: ε313 (MeOH) = 600 dm3 mol-1 cm-1
,
ε
366 (MeOH)= 200 dm3 mol-1 cm-1, ε313 (cyclohexane) =410
dm3 mol-1 cm-1, ε366 (cyclohexane) = 160 dm3 mol-1 cm-1
HRMS (EIþ) for C9H9NO3S (Mþ) 211.0303, found 211.0338.
.
Synthesis of the Methyl-r-D-glucopyranoside 1g. Methyl-R-
D-glucopyranoside (0.70 g; 3.61 mmol) and 2-nitrobenzaldehyde
(0.55 g; 3.64 mmol) were dissolved in dry dioxane (20 mL) under
argon atmosphere and concentrated sulfuric acid (0.5 mL) was
added dropwise within few minutes according to the literature.36,37
The reaction mixture was vigorously stirred and the reaction
progress was monitored by TLC.
When the conversion reached the maximum (or reaction
stopped after 16 days), dichloromethane (20 mL) was added,
and the mixture was neutralized with solid Na2CO3 (∼1 g). The
mixture was filtered and the solvents were removed under
reduced pressure. The remaining matter was dissolved in di-
chloromethane (40 mL) and washed with water (20 mL). The
organic phase was dried over MgSO4, filtered, and the solvent
was evaporated under reduced pressure. Crude product was
J. Org. Chem. Vol. 74, No. 22, 2009 8657

ꢀ
Sebej et al.
JOCArticle
of photoproducts. The relative standard deviations for mul-
tiple (at least five) samples were found below 10% in all
analyses.
Humpa, Zdenek Kriz, Petr Kukucka, Romana Kurkova,
and Radek Marek for their help with the quantum-chemical
calculations and chemical analyses, and for fruitful discus-
sions. The University of Fribourg and CESNET association
are acknowledged for the computational resources.
Irradiation of 1e in D218O. A solution of 1e (10.0 mg) in C6D6
or CD3OD (1 mL) was transferred to two NMR tubes; one drop
of D216O was added into the first tube, and one drop of D218O
was added to the second tube. Both samples were purged by
argon for 10 min and were irradiated with a 125-W Hg medium-
pressure UV lamp through a Pyrex filter (>280 nm). When the
reaction reached a full conversion (NMR), the solutions were
analyzed by HPLC-MS.
Supporting Information Available: Experimental section
including materials, methods and quantum-chemical calcula-
tions; synthesis and photolysis of 5-tert-butyl-2-(2-nitrophenyl)-
benzo[d][1,3]dioxole; 1H-1H COSY and 1H-13C HMBC NMR
correlations; the total energies (including scaled ZPVEs) and the
total Gibbs energies (with scaled thermal corrections) of calcu-
lated neutral and anionic species discussed in the article; calcu-
lated optimized structures with the corresponding transition
states. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The project was supported by the
Grant Agency of the Czech Republic (203/09/0748) and by
the Czech Ministry of Education, Youth and Sport
(MSM0021622413). The authors express their thanks to
Thomas Bally, Michal Cajan, Richard S. Givens, Otakar
8658 J. Org. Chem. Vol. 74, No. 22, 2009