Synthesis of cyclic selenenate/seleninate esters stabilized by ortho-nitro coordination: Their glutathione peroxidase-like activities

Article abstract of DOI:10.1002/asia.201000858

The syntheses of selenenate/seleninate esters and related derivatives by aromatic nucleophilic substitution (S_NAr) reactions of 2-bromo-3-nitrobenzylalcohol (13) and 2-bromo-3-nitrobenzaldehyde (17) with Na₂Se₂/nBuSeNa are

Full text of DOI:10.1002/asia.201000858

DOI: 10.1002/asia.201000858
Synthesis of Cyclic Selenenate/Seleninate Esters Stabilized by ortho-Nitro
Coordination: Their Glutathione Peroxidase-Like Activities
Vijay P. Singh,[a] Harkesh B. Singh,*[a] and Ray J. Butcher[b]
Abstract: The syntheses of selenenate/
seleninate esters and related deriva-
tives by aromatic nucleophilic substitu-
tion (SNAr) reactions of 2-bromo-3-ni-
trobenzylalcohol (13) and 2-bromo-3-
nitrobenzaldehyde (17) with Na2Se2/
nBuSeNa are described. The reaction
of 13 with Na2Se2 at room temperature
with in situ generated nBuSeNa. The
bromination reaction of selenide 19 did
not afford the expected arylselenenyl
bromide 20, instead, it resulted in the
formation of the unexpected 7-nitro-
Se···O interactions in esters 15, 18, 21,
22, and selenenic anhydride 29 has
been confirmed by single-crystal X-ray
diffraction studies as well as computa-
tional studies. The presence of an intra-
molecular Se···O interaction in esters
4b, 8, 15, 18, 21, and 22 has been fur-
ther proved by natural bond orbital
(NBO) and atoms in molecules (AIM)
calculations. Glutathione peroxidase-
like (GPx) antioxidant activities of 15,
18, 21, 22, and related heterocycles
1,2-benzisoselenol
3,3’-oxybis(7-nitro-1,2-benzisoselenole-
AHCTUNGTRENNG(UN 3H)) (22), respectively. The facile for-
ACHTUNGTREN(NUGN 3H)-3-ol (21) and
afforded
7-nitro-1,2-benzisoselenole-
mation of heterocycles 21 and 22 is ra-
tionalized in terms of the aromatic ring
strain in selenenyl bromide 20. The
presence of intramolecular secondary
ACHTUNGTRENNUNG(3H) (15) instead of the desired diaryl
diselenide 14. Oxidation of selenenate
ester 15 with hydrogen peroxide af-
forded the corresponding selenium(IV)
derivative, 7-nitro-1,2-benzisoselenole-
(3H) selenium oxide (18). 2-(Butylse-
lanyl)-3-nitrobenzaldehyde (19) was
synthesized by treating compound 17
such as 7-nitro-1,2-benzisoselenol
3-one selenium oxide (4b), 7-nitro-1,2-
benzisoselenol(2H)-3-one (8), and 29
ACHTUNGTRENNUNG(2H)-
Keywords: antioxidants · aromatic
substitution · esters · glutathione
peroxidase · selenium
ACHTUNGTRENNUNG
have been determined by the coupled
reductase assay.
Introduction
the synthetic enzyme selenosubtilsin.[7] Recently, organosele-
ꢀ
nium compounds with Se O/Se···O bonds have attracted an
Organoselenium compounds that mimic the activity of sele-
noenzyme glutathione peroxidase (GPx) have attracted
much attention.[1] Ebselen (PZ 51, 2-phenyl-1,2-benzisosele-
nazol-3-(2H)-one), a selenium-nitrogen heterocycle is a
useful antioxidant and GPx mimetic.[2] Several other mimet-
ics have been reported including ebselen analogues,[3] benzo-
selenazolinones,[4] selenenamide,[5] and related derivatives
such as diaryl diselenides,[1c–g] tellurides, ditellurides,[6] and
immense interest as GPx mimics. Wirth was the first to
report the GPx-like activities of diaryl diselenides 1, which
contain an oxygen atom in close proximity to the selenium
atom and concluded that the intramolecular secondary
Se···O interactions play an important role in enhancing the
GPx-like activity (Figure 1).[1d] Back and co-workers have
reported a series of cyclic seleninate esters 2–3, 4a, and spi-
ꢀ
rodioxaselenanonane 5–7 with a Se O bond that showed
good GPx-like activities.[8] Heterocycles 3a and 6a were also
investigated by our group.[9a] Related cyclic esters 4b and 8,
stabilized by intramolecular coordination of an ortho-nitro
group, have been known for a long time,[10] however, their
GPx-like activities have not been investigated.
[a] V. P. Singh, Prof. H. B. Singh
Department of Chemistry
Indian Institute of Technology Bombay, Powai
Mumbai-400 076 (India)
Fax : (+91)022-2572-3480
E-mail: chhbsia@chem.iitb.ac.in
Bis(2,6-diformyl-4-tert-butylphenyl)diselenide (9) with
two formyl ortho coordinating groups showed good GPx-
like activity.[9b,c] An attempted halogenation reaction of 9
led to the isolation of novel selenium(II) ester 10, which is
stabilized by intramolecular secondary Se···O interactions
with ortho formyl groups. It was observed that selenenate
ester 10 showed significant GPx-like activity. Okazaki et al.
[b] Prof. R. J. Butcher
Department of Chemistry
Howard University
Washington DC 20059 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000858.
Chem. Asian J. 2011, 6, 1431 – 1442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1431

FULL PAPERS
zene (12) instead of the expected corresponding disele-
nide.[12]
In view of the interesting reactivity and GPx-like activities
of the diselenides with two ortho coordinating
groups,[9b–d,12,13] we envisaged to prepare similar diselenides,
which have two different coordinating groups ortho to the
selenium atom from substrates such as 2-bromo-3-nitroben-
zylalcohol (13) containing nitro and benzylalcohol
ꢀ
( CH2OH) groups and 2-bromo-3-nitrobenzaldehyde (17)
with nitro and formyl groups (see below). The attempted
synthesis of diselenides afforded new cyclic selenenate
esters. In this study, we report a convenient synthesis of
stable selenenate esters/lactols without a carbonyl group by
using a Meisenheimer displacement of the aryl bromides
with Na2Se2/nBuSeNa. The GPx-like activities of esters are
compared with the related selenenate/seleninate esters stabi-
lized by intramolecular secondary Se···O interactions.
Results and Discussion
Syntheses
Compound 13 was prepared by following the reported pro-
cedure.[14a] The synthesis of diselenide 14 was attempted by
treating 13 with Na2Se2 (Scheme 1). The reaction of 13 with
Na2Se2 at 08C in tetrahydrofuran (THF) afforded selenenate
ester 15. It is worth noting that ester 15 is the first stable
Figure 1. Some diaryl diselenides with ortho coordinating oxygen donors
ꢀ
and cyclic organoselenium compounds with a Se O bond.
have reported the synthesis of
3,3-bis(trifluoromethyl)-1,2-
benzisoselenoleACHTUNGTRENNUNG(3H) (11) con-
taining a sp3 carbon.[11] Though
the related selenium(II) ester
contained an electron-with-
ꢀ
drawing group ( CF3) in place
of the carbonyl group, it was
found to be susceptible to hy-
drolysis and partially decom-
posed to give the corresponding
selenenic acid. The selenenic
acid underwent a self-redox re-
action and afforded the corre-
sponding diselenide as well as
the seleninic acid.[11a] It is worth
noting that most of the seleni-
nate esters/spirocyclic com-
pounds studied have either se-
lenium(IV) as part of the ring
Scheme 1. Synthesis of selenenate esters 15, 16, and seleninate ester 18.
or contain a carbonyl group
(C=O). Selenenate esters without a carbonyl group and with
selenium(II) as part of the heterocyclic ring are rare. Esters
structurally characterized selenenate ester (see below) with
a CH2 group present in the five-membered heterocyclic ring.
Ester 15 is stabilized by coordination of the ortho-nitro
group to the selenium atom. The formation of 15 involves
the disproportionation of in situ generated diselenide 14
owing to the presence of two different ortho coordinating
groups (see below). When the reaction mixture was re-
fluxed, a new selenenate ester 16 was afforded. In this reac-
ꢀ ꢀ
with Se O CH2 linkage are expected to show different
ꢀ
GPx-like activities owing to the weak Se O bond. In this
regard, the work of Wirth and co-workers is a notable ex-
ception, wherein the reaction of 1-(2-bromo-3-nitrophenyl)
ethanol with Na2Se2 afforded an interesting new cyclic se-
lenenate ester, bis(3-methyl-2-oxa-1-selenaindan-7-yl)dia-
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Synthesis of Cyclic Selenenate/Seleninate Esters
tion, presumably, the nitro group of 15 has coupled to form
a symmetrical diazo-containing ester 16. Though, ester 16
showed a molecular-ion peak in ES-MS and HRMS spectra,
its elemental analysis varied from preparation to prepara-
tion due to its decomposition in solution during crystalliza-
tion and silica-gel column chromatography. Also the 77Se
NMR spectrum of 16 showed several peaks (see Figure S25
in the Supporting Information).
Alternatively, the reaction of 13 with Na2Se2 may also
lead to the formation of 15 with the elimination of NaSeH
by the disproportionation of ArSeSeNa (Scheme 2).
Scheme 2. A possible mechanism for the formation of 15.
In an alternative approach to synthesize the desired diaryl
diselenide 14, when compound 13 was treated with in situ
prepared LiAlHSeH,[15a] the reaction again afforded 15 in
low yield in addition to 17.[14a,c] The unreacted 13 is probably
oxidized into 17 by the mild-oxidizing agent, potassium
iodide and iodine, present in the system. The mixture of po-
tassium iodide and iodine has been used as a mild-oxidizing
agent for the oxidation of the alcohol into the aldehyde.[15b]
Oxidation of selenenate ester 15 with an excess of H2O2 at
room temperature afforded seleninate ester 18 (Scheme 1).
Given that our attempts to prepare diselenide 14 with two
different ortho coordinating groups failed, we next set out to
synthesize selenide 19, which could provide the desired sele-
nenyl halides. Precursor 19 was synthesized again by a facile
aromatic nucleophilic substitution (SNAr) reaction of 17
using in situ prepared nBuSeNa in deoxygenated ethanol at
08C (Scheme 3). Further treatment of 19 with one equiva-
lent of bromine in the presence of triethyl amine (Et3N) af-
forded selenenate esters 21 (35%) and 22 (7%) instead of
the expected arylselenenyl bromide (20). Under slightly dif-
ferent conditions, the reaction afforded selenenate ester 22
(30%) in higher yield. In the modified procedure, triethyl
amine was added after the complete addition of bromine.
Also selenenate ester 21, on keeping in a chloroform solu-
tion at room temperature for sometime turns into an orange
precipitate of selenenate ester 22. The formation of 21 and
22 takes place via the elusive intermediate selenenic acid 23
generated from the hydrolysis of 20. Selenenate esters 21
Scheme 3. Synthesis of selenenate esters 21, 22, and selenoxide 24.
Selenenate ester 21 is the first example of a lactol, which
has been structurally characterized, and 22 is only the sec-
ond[9b] dimeric compound to be reported. All these selenen-
ate esters are stable in air and moisture at room tempera-
ture over a period of time except for ester 21, which under-
goes condensation to give 22. The stability of selenenate
esters 15, 21, and 22 is due to intramolecular secondary
Se···O interactions (see below).
To delineate the structure and GPx-like activity correla-
tion of the newly synthesized esters 15 and 18 containing a
ꢀ
CH2 group, and 21 and 22 with OH or C=O functions, re-
lated esters 4b, 8, and acyclic 29 were also prepared. Se-
lenenate ester 8 was prepared in a higher yield of 95% (see
Ref. [10a], 75%) by a slight modification of the reported
method. In our modification, methyl(2-(butylselanyl)-3-ni-
trobenzoate) (25b) was used as the precursor instead of 2-
methylseleno-3-nitrobenzoic acid (Figure 2).[10a] Compound
ꢀ
and 22, which have a Se O direct bond can be assumed as
the protected form of 23. Selenenic acid is known to be an
unstable and reactive intermediate that is implicated in the
catalytic cycle of glutathione peroxidase.[1] It is worth men-
tioning that during the preparation of selenenate ester 10,[9b]
the intermediate lactol selenenate ester of type 21 could not
be isolated. When compound 19 was treated with H2O2 in
chloroform, the reaction afforded 2-(butylseleninyl)-3-nitro-
benzoic acid (24).
Figure 2. Precursors 25a–b and some ortho-nitro coordinating organose-
lenium compounds 26–29.
Chem. Asian J. 2011, 6, 1431 – 1442
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1433

H. B. Singh et al.
FULL PAPERS
25b was prepared by treating methyl(2-bromo-3-nitroben-
zoate) (25a) with the in situ generated nBuSeNa (see the
Experimental Section). Selenide 25b after further bromina-
tion afforded selenenate ester 8.[10a,16] Seleninate ester 4b[10a]
was obtained by the oxidation of 25b with H2O2.[17]
chemical shift of 18 (d=1367 ppm) is shifted slightly more
downfield compared to that of 3a (d=1352 ppm).[9a] This
15 ppm increase in the chemical shift of 18 is probably due
to the presence of an intramolecular secondary Se···O inter-
action with the ortho-nitro group.
Attempts to prepare the known acyclic selenenate ester
26 were made by treating ortho-nitrobenzeneselenenyl bro-
mide (27) with CH3COOAg/MeOH following the literature
method (Figure 2).[18] Compound 27 has been characterized
by single crystal X-ray diffraction studies (see below). The
attempted preparation of 26 afforded a mixture of products,
which could not be purified. When crude 26 was treated
with a mixture of HClO4/1,4-dioxane to isolate ortho-nitro-
benzeneselenenic acid (28),[19] the reaction afforded selenen-
ic anhydride 29.[20] Compound 29, presumably, resulted from
the condensation of 28. Compound 29 was characterized by
comparing the spectroscopic data with the reported litera-
ture values.[20a] The structure of 29 was unambiguously con-
firmed by single-crystal X-ray crystallographic analysis (see
below).
To delineate the role of the ortho-coordinating groups on
the 77Se NMR chemical shifts, density functional theory
(DFT) calculations were carried out.[1m,21] The geometries
were fully optimized at the B3LYP level of theory by using
the 6–31G(d) basis set and taking the coordinates of 4b,[10b]
8,[10c] 15, 18, 21, 22, 27, and 29 from their crystal structures.
The calculated and the experimental 77Se NMR chemical
shifts are in good agreement (Table 1). The chemical shifts
for cyclic selenenate esters 8, 15, 21, and 22 are shifted
downfield compared to the reported acyclic selenenate
esters (d=1224 and 1269 ppm).[22] The remarkable down-
field shift is mainly due to the presence of the intramolecu-
lar secondary Se···O interactions (see below). Interestingly,
the 77Se NMR chemical shift (d=1332 ppm) for 29 was
quite downfield compared with the reported 77Se NMR
chemical shift (d=1095 ppm) in deuterated acetone. How-
ever, the chemical shift (d=1332 ppm) observed is in good
agreement with the calculated value (d=1317 ppm). The
difference in the chemical shift might be due the use of dif-
ferent deuterated solvents. The 77Se chemical shift for 29
when recorded in deuterated acetone was found to be d=
1051 ppm, which is close to the literature value (see Fig-
ure S77 & Figure S78 in the Supporting Information). The
deuterated acetone carbonyl group would compete with the
nitro group to interact with the selenium centre.
1
The H NMR spectrum of 21 exhibited a doublet for the
alcoholic proton at d=3.24 ppm and a doublet for the ben-
zylic proton at d=6.84 ppm. The assignment of the alcoholic
proton peak was confirmed by the deuterium oxide ex-
change studies. The peak disappeared completely upon addi-
tion of deuterium oxide and only a singlet was observed for
the benzylic proton at d=6.83 ppm (see Figure S44 in the
Supporting Information). Selenenate ester 22, which has two
chiral centers can exist in meso form and as a dl pair. Ini-
1
tially, two sets of signals were observed for 22 in the H, 13C,
and 77Se NMR spectra corresponding to the meso (minor
isomer) and the dl pair (major isomer), as reported for
compound 10. Further crystallization of 22 with hot dimeth-
yl sulfoxide (DMSO) led to isolation of the major isomer
(DL pair). All the characterization data were obtained from
X-ray Crystallographic Studies
Molecular Structure of 15
1
the purified sample of 22. The H and 13C NMR spectra of
The molecular structure of 15 (Figure 3) indicates a T-
shaped geometry around the selenium atom with the O1
Se···O3 bond angle of 157.07(10)8. The Se···O3 distance
22 show a single set of signals for the DL pair. The 77Se
NMR spectrum of 22 also exhibits only one major signal at
d=1302 ppm (see the Experimental Section).
ꢀ
The 77Se NMR chemical shifts of seleninate esters 4b, 18,
and selenenate esters 8, 15, 21, and 22 are in the range of
d=1303–1367 ppm (Table 1). The 77Se NMR chemical shift
of 27 is in the range of arylselenenyl bromides (see Fig-
ure S76 in the Supporting Information). The 77Se NMR
Table 1. Summary of DFT calculations at the B3LYP/6-31G(d), GIAO
77Se NMR chemical shifts calculated in the gas phase at the B3LYP/6-
31G(d)//B3LYP/6-311+GACTHNUTRGNE(NUG d,p) along with the experimental values.
Compounds
77Se NMR[a]
Experimental
Solvents
Calcd
4b
8
1301
1286
1341
1340
1346
1341
1317
1365
1364
1360
1367
1342
1302
1332
[D6]DMSO
CDCl3
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
15
18
21
22
29
Figure 3. The molecular structure of 15. Thermal ellipsoids are set at
ꢀ
ꢀ
50% probability. Significant bond lengths [ꢁ] Se O1 1.832(3), Se C7
ꢀ
ꢀ
ꢀ
1.862(3), Se···O3 2.579(6), and angles [8] O1 Se C7 87.65(12), O1
[a] The values are referenced with respect to Me2Se (d=0 ppm).
Se···O3 157.07(10).
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Chem. Asian J. 2011, 6, 1431 – 1442

Synthesis of Cyclic Selenenate/Seleninate Esters
(2.579(6) ꢁ) is shorter than the sum of the van der Waals
radii (3.4 ꢁ).[23] The Se···O3 distance is greater than that re-
ported for 8 (2.35(1) ꢁ),[10c] thereby indicating a weak Se···O
interaction in 15. However, the Se···O distance is close to
that observed for selenenate ester 10 (2.604 ꢁ), which has
an ortho formyl coordinating group.[9b] The calculated dis-
tance for the Se···O3 interaction is 2.474 ꢁ and is close to
the experimental value (see below; (Table 2).
Molecular Structure of 21
The geometry around selenium is quite similar to that ob-
ꢀ
served for 15 with a O1 Se···O4 bond angle of 157.948
(Figure 5). The Se···O4 distance (2.538(4) ꢁ) is close to that
observed for selenenate ester 15. The packing diagram of
ester 21 clearly reveals an intermolecular hydrogen-bonding
interaction (O···H 1.972 ꢁ) between the oxygen atom of the
alcohol group and the hydrogen atom of the other alcohol
group of the other molecule. The packing diagram also
shows an intermolecular Se···O interaction (2.911 ꢁ; see Fig-
ure S90 in the Supporting Information).
Table 2. Summary of DFT calculations at the B3LYP/6-31G(d), NBO
analysis at B3LYP/6-311+G
analysis (NPA) charges and lone pair occupancies on selenium and
oxygen atoms at the B3LYP/6-31G(d)//B3LYP/6-311+G(d,p).
ACHTUNGTRENUN(NG d,p) level. Calculated natural population
AHCTUNGTRENNUNG
Entry rSe···O [ꢁ]
(Calcd)[a]
rSe O [ꢁ]
G
ESe···O
NPA Occupancies[b]
ꢀ
G
(Calcd)[a]
(kcalmolꢀ1
)
qSe nSe nO
4b[10b] 2.733 (2.636) 1.920 (1.928) 6.78
+1.637 1.98 1.79
+0.861 1.74 1.79
+0.828 1.75 1.94
+1.637 1.98 1.91
+0.829 1.75 1.91
+0.821 1.75 1.91
8[10c]
15
2.442 (2.351) 1.893 (1.981) 20.04
2.474 (2.579) 1.874 (1.832) 17.16
2.774 (2.747) 1.859 (1.795) 5.17
2.464 (2.538) 1.884 (1.850) 18.30
2.463 (2.562) 1.886 (1.836) 18.37
18
21
22
27
29
2.307 (2.420)
2.352 (2.416)
–
–
36.01
28.04
+0.551
+0.820
–
–
–
–
[a] The experimental values are given in parentheses. [b] The second lone
ꢀ
pair of electrons on selenium and oxygen atoms (on the Se O bond) has
an occupancy of 1.99.
Figure 5. The molecular structure of 21. Thermal ellipsoids are set at
ꢀ
ꢀ
50% probability. Significant bond lengths [ꢁ] Se O1 1.850(5), Se C1
Molecular Structure of 18
ꢀ
ꢀ
ꢀ
1.852(6), Se···O4 2.538(4), and angles [8] O1 Se C1 86.6(2), O1 Se···O4
157.94(0).
The geometry around the selenium atom is see-saw type
ꢀ
with the O1 Se···O3 bond angle of 151.90(18)8 (Figure 4).
ꢀ
The Se O1 distance (1.795 (4) ꢁ) is closer to the normal
Molecular Structure of 22
single bond distance. The Se=O2 bond distance (1.631(9) ꢁ)
is quite close to that reported for seleninate esters 3a
(1.630 ꢁ)[9a] and 4b (1.608(6) ꢁ).[10b] The Se···O3 distance
(2.747(0) ꢁ) is longer than that observed for 4b
(2.636 ꢁ),[10b] thus indicating a weak Se···O interaction in 18.
The molecular structure of 22 is similar to that of selenenate
ester 10 except for the ortho coordinating group to the sele-
nium (Figure 6). The Se···O3 distance 2.562(2) ꢁ is similar
ꢀ
to that observed in 10. Whereas, the Se O1 distance of
1.836(2) ꢁ is slightly shorter than the average distance of
1.859(2) ꢁ in 10. In the packing diagram of ester 22, there
are intermolecular hydrogen-bonding interactions (O···H
2.572 ꢁ) between the oxygen atom of the nitro group and
the hydrogen atom of the benzene ring of the other mole-
cule. The Se···Se intermolecular distance of 3.603 ꢁ is con-
Figure 4. The molecular structure of 18. Thermal ellipsoids are set at
Figure 6. The molecular structure of 22. Thermal ellipsoids are set at
ꢀ
ꢀ
ꢀ
ꢀ
50% probability. Significant bond lengths [ꢁ] Se O1 1.795(4), Se O2
50% probability. Significant bond lengths [ꢁ] Se O1 1.836(2), Se C1
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1.631(4), Se C1 1.934(5), Se···O3 2.747(5), and angles (8) O1 Se C1
1.867(3), Se···O3 2.562(2), and angles [8] O1 Se C186.97(11), C7 O1 Se
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
86.5(2), O2 Se C1 101.7(2), O1 Se O2 104.7(2), O1 Se···O3 151.9(18).
114.46(19), O1 Se···O3 156.82(9).
Chem. Asian J. 2011, 6, 1431 – 1442
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1435

H. B. Singh et al.
FULL PAPERS
siderably shorter than the sum of the van der Waals distance
of these two atoms (see Figure S91 in the Supporting Infor-
mation).
170.478. The Se1A···O1A and Se1B···O1B distances of
2.429(2) ꢁ and 2.416 ꢁ, respectively, are smaller than that
in selenenate ester 15, 18, 21, and 22, thus suggesting stron-
ger Se···O interactions in 29. The geometry around the
ꢀ ꢀ
oxygen atom is V-shaped with a S1A O Se1B bond angle
of 118.22(9)8. The calculated distances for Se···O distance is
Molecular Structure of 27
Though intramolecular interactions (between Se···O and the
nitro group) have been suggested in 27 based on electron
diffraction studies,[24] its structure by single-crystal X-ray dif-
fraction has not been reported. As expected the geometry
around selenium is T-shaped due to the strong Se···O inter-
action (Figure 7). The Se1···O1A distance of 2.420(12) ꢁ is
shorter than that observed for esters 15, 21, and 22. The
2.352 ꢁ and is close to the experimental value (see below).
Computational Studies
Role of the ortho-Nitro Group in the Intramolecular Ring
Cyclization
ꢀ
Se1 Br1 bond distance of 2.351(7) ꢁ is much smaller than
the reported values for (1R)-2-endo-(N-pyrrolidinyl)methyl-
The arylselenenyl bromide 20 with two ortho coordinating
groups (-NO2 and -CHO) could not be isolated (Scheme 3)
and underwent an intramolecular ring cyclization due to
strain in the aromatic ring. The calculated strain in the aro-
matic ring is found to be 4.288. Thus, compound 20 probably
undergoes hydrolysis to give selenenic acid 23, which after
cyclization affords esters 21 and 22 with average torsion
angles of 0.888 (experimental value=1.728) and 0.988 (ex-
perimental value=0.338), respectively (for the optimized
geometry and coordinates see Table S7 of the Supporting
Information). A similar strain in the aromatic benzene ring
due to the second ortho coordinating group has been ob-
served in dimethyl-5-tert-butylisophthalateselenenyl bromide
with an average torsion angle of 4.188 (experimental=
6.578).[9d]
2-exo-hydroxy-3-endo-camphorylselenenyl
bromide
2.747 ꢁ.[25] The O1A···Se1 Br1 bond angle of 175.24(16)8 is
ꢀ
close to a linear arrangement.
Comparison of CH2 Versus the C=O Group Present in the
Five-Membered Heterocycles
The consequences of introducing the CH2 group (in ester
15) in place of the C=O group (in ester 8) on the electronic
environment of selenium have been probed by computation-
Figure 7. The molecular structure of 27. Thermal ellipsoids are set at
ꢀ
ꢀ
50% probability. Significant bond lengths [ꢁ] C1A Se1 1.894(15), Se1
ꢀ
ꢀ
Br1 2.351(7), Se1···O1A 2.420(12), and angles [8] C1A Se1 Br1
ꢀ
98.30(42), O1A Se1···Br1 175.24(26).
ꢀ
al studies. It is noteworthy that the Se O bond distance in 8
with a carbonyl group is greater than that observed for 15
ꢀ
with a CH2 group (Table 2). Similarly, the Se O bond dis-
tance in 4b is longer than that observed in 18. The NBO
Molecular Structure of 29
The molecular structure of 29 is shown in Figure 8. The ge-
analysis[26] was used to probe the strength of the Se···O inter-
ꢀ
ometry around the selenium is T-shaped with the bond
actions. The data suggest that a shorter Se O bond leads to
a weaker Se···O interaction and hence lowers the second-
ꢀ
ꢀ
angles O Se1A···O1A of 171.26(7)8 and O Se1B···O1B of
order perturbation energy (ESe···O). The second order pertur-
bation energies of 4b (ESe···O =6.78 kcalmolꢀ1) and
8
(ESe···O =20.04 kcalmolꢀ1) are found to be greater compared
to that observed for 18 (ESe···O =5.17 kcalmolꢀ1) and 15
(ESe···O =17.16 kcalmolꢀ1), respectively. The NBO analysis
shows that the introduction of the C=O group in place of
the CH2 group increases the positive charge on the selenium
in ester 8. The high NBO second-order perturbation ener-
gies of compounds 27 and 29 are due to the difference in
nO!s*SeꢀBr (36.01 kcalmolꢀ1) and nO!s*SeꢀO (28.04 kcal
molꢀ1) orbital interactions, respectively.
Figure 8. The molecular structure of 29. Thermal ellipsoids are set at
It is evident that the stronger Se···O interactions are pres-
ꢀ
50% probability. Significant bond lengths [ꢁ] Se1A O 1.8231(18),
ꢀ
ent in the system with more linear O···Se O angles. The
ꢀ
Se1A···O1A 2.429(2), Se1B O 1.8358(17), Se1B···O1B 2.416(3), and
lone pair occupancy in ester 8 on selenium (1.74) and
ꢀ
ꢀ
ꢀ
ꢀ
O
angles [8] Se1B O Se1A 118.22(9), O Se1A···O1A 171.26(7),
ꢀ
Se1B···O1B 170.47(7).
oxygen (1.79) atoms of the Se O bond are found to be
1436
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1431 – 1442

Synthesis of Cyclic Selenenate/Seleninate Esters
smaller compared to esters 15, 21, and 22 (Table 2). Nu-
cleus-independent chemical shifts (NICS) for the five-mem-
bered heterocyclic ring in 8 was found to be ꢀ5.4 ppm, thus
indicating more aromatic character than that in esters 15,
21, and 22 (Table 3).
showed significant GPx-like activities. Compounds 4b, 8,
and 18 exhibited much higher activities than others. Com-
pound 4b showed the highest GPx-like activity in this series
of compounds. The high activity of 4b is not surprising in
view of the fact that the presence of the nitro group in the
ortho position to the selenium enhances the GPx-like activi-
ty of organoselenium compounds.[28] Furthermore, to delin-
eate the effect of the ortho-nitro group on the GPx-like ac-
tivity of 4b, 8, 15, 18, 21-22, the GPx-like activity of 3a
(without the ortho-nitro group) was measured. The GPx-like
activity of 3a was found to be quite low as compared with
4b and 18 under identical conditions. The high GPx-like ac-
tivity of selenenate ester 8, as compared to selenenate ester
15, is probably due to the conjugative effect of the carbonyl
group and the more positive charge on selenium. Similarly,
seleninate esters 4b and 18 containing selenium(IV) were
found to be more active than the precursor selenenate
esters 8 and 15, which contain selenium(II). The high activi-
ties of 4b and 18 are probably due to the presence of a high
positive charge on the selenium atom as well as weak Se···O
interactions (Table 2). Acyclic compound 29 is found to be
the least active in this series.
Table 3. Summary of properties of electron density at the bond critical
point (BCP). AIM calculations were carried out by using the wave func-
tions obtained at the B3LYP/6-31G(d)//B3LYP/6-311+G
values are calculated in the gas phase at the B3LYP/6-31G(d)//B3LYP/6-
311+G(d,p).
ACHTUNGTREN(NUNG d,p). NICS (0)
ACHTUNGTRENNUNG
2
Compounds
1Se···O
5 1Se···O
HSe···O
ACHTUNGETRN(NUNG ea0 )
NICS(0)[d]
ꢀ3 [a]
ꢀ5 [b]
ꢀ4 [c]
(ea0
)
(ea0
)
4b
8
0.023
0.038
0.036
BCP absent
0.037
0.068
0.112
0.108
+0.0005
ꢀ0.0011
ꢀ0.0007
ꢀ1.8
ꢀ5.4
ꢀ3.5
ꢀ3.2
ꢀ4.7
ꢀ4.7
–
15
18
21
22
29
0.112
0.112
0.140
ꢀ0.0008
ꢀ0.0008
ꢀ0.0024
0.037
0.046
[a] The electron density at the BCP. [b] The Laplacian of the electron
density at the BCP. [c] The total energy density at the BCP. [d] NICS (0)
values are calculated at the centre in the five-membered heterocyclic ring
in ppm.
In our previous report,[29] the initial reduction rate of het-
ꢀ
erocycles containing a Se N bond such as 2-(4-bromophen-
The atoms in molecules (AIM)[27a–b] analysis of the se-
lenenate/seleninate esters performed with AIM2000,[27c] con-
firms the presence of bond critical points (BCP) at the
Se···O bond (Table 3). It should be noted that this correla-
tion by AIM theory relates to orbital interaction in NBO
analysis. Thus, both NBO and AIM methods indicate the
presence of weaker intramolecular secondary Se···O interac-
tions in 4b, 8, 15, 21, and 22 as compared with that in 29.
Although, NBO analysis showed a weak Se···O interaction
(ESe···O =5.17 kcalmolꢀ1) for 18; on carrying out AIM analy-
sis BCP could not be located.
yl)-7-nitro-1,2-benzisoselenazol
A
was found to be 472.7ꢁ3.5 mmminꢀ1. Seleninate ester 4b is
almost eight times and two times more active than ebselen
and 2-(4-bromophenyl)-7-nitro-1,2-benzisoselenazolACHTUNGTRENNUNG(2H)-3-
one selenium oxide, respectively, under identical conditions.
These observations further demonstrate that the selenenate/
ꢀ
seleninate esters with a Se O bond are even more effective
catalysts than the more commonly studied selenium-nitro-
gen heterocycles.
To confirm that the catalysts 3a, 4b, and 18 were indeed
behaving as mimetics of GPx, kinetic reactions were fol-
lowed until the completion of the reactions (10000 sec).
Also a number of control experiments have been carried
out. The combinations: 1) catalyst and GSH, 2) catalyst and
H2O2, 3) GSH and H2O2, 4) catalyst, GSH, and H2O2, were
taken in a cuvette (containing 100 mm phosphate buffer
pH 7.5, EDTA, NADPH, and GR EDTA=ethylendiamine-
tetraacetate; NADPH=reduced nicotinamide adenine dinu-
cleotide phosphate) and the decrease in the absorbance of
NADPH was measured. When only GSH and the catalyst
(3a/4b/18) were taken (without H2O2), a significant decrease
in the absorbance of NADPH was observed (see Figure S92
in the Supporting Information). This indicated the reaction
of GSH with the catalysts. When the combination of cata-
lysts (3a/4b/18), GSH, and H2O2 was taken, a very large de-
crease in the absorbance of NADPH was observed
(Figure 9).
Glutathione Peroxidase-Like Activity
The initial rates (n0) for the reduction of H2O2 by reduced
glutathione (GSH) in the absence and presence of catalysts
were determined by the coupled reductase assay from a
linear fit spanning the first 5–10% of the reaction (Table 4).
It was found that compounds 4b, 8, 15, 18, 21–22, and 24
Table 4. Initial rates, n0 (mMminꢀ1) for the reduction of H2O2 by GSH in
the presence of compounds 3a, 4b, 8, 15, 18, 21-22, 24, and 29.
[b]
[b]
Compounds
n0 [mMminꢀ1
]
Compounds
n0 [mMminꢀ1
]
Control[a]
ebselen
3a
4b
8
8ꢁ1
18
21
22
24
29
–
565ꢁ5
342ꢁ1
278ꢁ5
383ꢁ3
126ꢁ5
–
104ꢁ3
467ꢁ3
816ꢁ4
731ꢁ11
265ꢁ5
To find the effect of these side reactions, the control data
(obtained from Figure S92 in the Supporting Information)
were subtracted from the data obtained from Figure 9. The
data obtained after the subtraction is shown in Figure S93
and Tables S29-31 in the Supporting Information. The graph
for the consumption of H2O2 versus time from this data also
15
[a] The control values were obtained from the reduction of H2O2 by
GSH in the absence of GPx samples. [b] Assay conditions: reactions
were carried out with phosphate buffer (100 mm), pH 7.5, with EDTA
(1 mm), GSH (2 mm), NADPH (0.4 mm), GR (1.3 unitmLꢀ1), GPx sam-
ples (80 mm), and H2O2 (1.6 mm).
Chem. Asian J. 2011, 6, 1431 – 1442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1437

H. B. Singh et al.
FULL PAPERS
with an excess of H2O2 did not immediately yield 4b at d=
1348 ppm, but the formation of diselenide 33 (d=526 ppm)
was observed. This may be due to disproportionation of 32
to 33 and Ph2S2. The minor change (17 ppm) in the chemical
shifts of 4b could be due to the presence of water in H2O2,
as the 77Se NMR chemical shifts of organoselenium com-
pounds are generally solvent dependent.
Based on 77Se NMR experiments, a catalytic mechanism
for ester 15 has also been proposed (see Scheme S2 in the
Supporting Information).
Conclusions
In conclusion, the first examples of stable cyclic selenenate/
seleninate esters with an sp3 carbon have been reported by
the aromatic nucleophilic substitution reactions of 2-bromo-
3-nitrobenzylalcohol (13) and 2-bromo-3-nitrobenzyldehyde
(17) with Na2Se2/nBuSeNa. The first synthesis of a stable
lactol selenenate ester 21 is reported and also the second ex-
Figure 9. Time course of NADPH disappearance in the absence and pres-
ence of catalyst by using UV/Vis spectrometry: a) GSH+H2O2 (no cata-
lyst); b) 3a+GSH+H2O2; c) 18+GSH+H2O2; d) 4b+GSH+H2O2. Assay
conditions: reactions were carried out with phosphate buffer (100 mm),
pH 7.5, EDTA (1 mm), GSH (0.25 mm), NADPH (0.4 mm), GR (1.3
unitmLꢀ1), selenium catalysts (10 mm), and H2O2 (0.20 mm).
ample of 3,3’-oxybis(7-nitro-1,2-benzisoselenoleACTHNUTRGNEUG(N 3H)) (22).
From our present results and previous studies,[3e,9b–c] it is
further corroborated that the diselenides with two ortho co-
ordinating groups to the selenium differ remarkably in the
structural features as well as reactivity in comparison to the
diselenides with only one ortho coordinating group to the
selenium. This study further demonstrates the presence of a
carbonyl group in the five-membered ring and an intramo-
lecular secondary Se···O interaction with an ortho-nitro
group enhances the GPx-like activity of seleninate esters 4b
and 18 compared to that of without a carbonyl group and
with unsubstituted seleninate ester 3a. Seleninate esters 4b
and 18 exhibit better GPx-like ativity than their parent se-
lenenate esters 8 and 15, respectively.
shows 4b as the best catalyst in the series (Figure S93, see
the Supporting Information).
Catalytic Mechanism for 4b
To understand the mechanism and identify the intermediates
involved in the catalytic cycle of seleninate ester 4b with
promising GPx-like activity, detailed 77Se NMR spectrosco-
py was carried out (see Scheme S1 in the Supporting Infor-
mation). When 4b (d=1365 ppm) was treated with one
equivalent of PhSH in deuterated dimethyl sulfoxide, the re-
action was found to be very slow. Upon addition of 2 equiv-
alents of PhSH to the solution of 4b, a new 77Se NMR
signal was observed at d=1375 ppm. The signal observed at
1375 ppm can be assigned to thioseleninate 30. The forma-
tion of thioseleninate has been reported by Kice et al.[30]
Experimental Section
General Procedure
2-Bromo-3-nitrobenzoic acid, 2-bromo-3-nitrobenzyl alcohol, and 2-
bromo-3-nitrobenzaldehyde were prepared by the reported procedures.[14]
Selenium powder and 3-nitrophthalic acid were purchased from Sigma
Aldrich. All the reactions were performed under nitrogen or an argon at-
mosphere by modified Schlenk techniques and were occasionally moni-
tored by using TLC. Solvents were purified by standard techniques.[31]
Melting points were recorded on a VEEGO melting point (VMP-1) ap-
paratus and are uncorrected. 1H (399.88 MHz), 1H (299.95 MHz), 13C
(100.56 MHz), and 77Se (57.26 MHz) NMR spectra were recorded on a
Varian NMR-Mercury plus & Bruker AvanceIII 400 MHz spectrometer
and a Varian NMR-Mercury plus 300 MHz for 77Se NMR at the indicated
frequencies. Chemicals shifts (d) are shown with respect to SiMe4 (TMS)
Upon addition of one more equivalent of PhSH to the mix-
ture, the signal of 4b at d=1365 ppm completely disap-
peared and a new signal was observed at 635 ppm as well as
at d=1375 ppm for thioseleninate 30. The 77Se NMR signal
at d=635 ppm is assigned to selenosulfide 32, which is
formed via selenenic acid 31. A 77Se NMR signal for the for-
mation of 31 was not observed. The identification of seleno-
sulfide 32 was further confirmed by adding 4 equivalents of
PhSH into the solution of 4b. Treatment of selenosulfide 32
1
as an internal standard for H and 13C spectroscopy, and Me2Se was used
an external standard for 77Se spectroscopy; s=singlet, d=doublet, t=
triplet, dd=doublet of doublets, dt=doublet of triplets, m=multiplet.
The high resolution mass spectra (HRMS) were recorded at room tem-
perature on a Micro mass Q-TOF (YA 107) mass spectrometer. Elemen-
tal analyses were analyzed on a CHN-CE instrument Flash 1112 series
EA Theroquest elemental analyzer. Infra-red (IR) spectra were recorded
in the range of 4000–450 cmꢀ1 by using KBr for solid samples and neat
for liquid samples between CsI plates on a Perkin–Elmer precisely spec-
1438
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1431 – 1442

Synthesis of Cyclic Selenenate/Seleninate Esters
trum one FT-IR spectrometer. The UV/Vis spectra for GPx-like activity
in solution were recorded on a JASCO, V-570 spectrometer.
133.5, 143.6, 143.9, 145.8 ppm; 77Se NMR (57.26 MHz, [D6]DMSO): d=
1367 ppm; IR (KBr): n˜ =3098, 3021, 2923, 1609, 1565, 1525 (NO2), 1340,
871 (Se=O), 810, 738, 527 cmꢀ1; HRMS (Q-TOF MS ES+): m/z: calcd
for C7H5SeNO4 [M+H]+: 247.9462; found: 247.9462; elemental analysis
calcd (%) for C7H5SeNO4: C 34.17, H 2.05, N 5.69; found: C 34.52, H
1.79, N 5.69.
Synthesis of 7-nitro-1,2-benzisoselenoleACTHNUGRTENUNG(3H) (15): Method A
Compound 13 (3.1 mmol, 0.71 g) in THF (10 mL) was added to a brown
solution of Na2Se2 (6.1 mmol) with constant stirring under a nitrogen at-
mosphere at 08C. The reaction mixture was stirred for 4 h at room tem-
perature and then water (50 mL) was poured into it and again stirred for
10 min. The resulting mixture was extracted with diethyl ether (80 mL).
The combined organic layers were dried over anhydrous Na2SO4. Remov-
al of the solvent and purification of the residue by silica-gel column chro-
matography (elution with 10% ethyl acetate/petroleum ether) afforded
15 as a dark-red solid. Recrystallization from CHCl3/petroleum ether
(1:1) afforded dark red square-shaped crystals. Yield: 0.21 g (30%);
m.p. 138–1408C; 1H NMR (399.88 MHz, CDCl3): d=5.55 (s, 2H; CH2),
Synthesis of 2-(butylselanyl)-3-nitrobenzaldehyde (19)
NaBH4 (5.5 mmol, 0.21 g) was added to a solution of di-n-butyl disele-
nide (3.0 mmol, 0.82 g) in deoxygenated ethanol (20 mL) under a nitro-
gen atmosphere at 08C. The reaction mixture was stirred for 30 min at
room temperature. Then compound 17 (5.5 mmol, 1.2 g) was added to
the in situ prepared nBuSeNa at 08C. The reaction mixture was stirred
for an additional 3 h at room temperature. The excess of the solvent was
removed under vacuum. The residue was dissolved in CHCl3 and washed
with water (20 mL). The organic layers and the CHCl3 extracts from the
aqueous layer were combined and dried over anhydrous Na2SO4. Remov-
al of the solvent and purification of the residue by silica-gel column chro-
matography (elution with 5% ethyl acetate/petroleum ether) afforded 19
as an orange liquid. Yield: 1.1 g (78%). 1H NMR (399.88 MHz, CDCl3):
d=0.86 (t, 3JH,H =7.3 Hz, 3H; CH3), 1.35 (sextet, 3JH,H =8.3 Hz 2H;
CH2), 1.54 (quintet, 3JH,H =5.2 Hz 2H; CH2), 2.84 (t, 3JH,H =7.3 Hz, 2H;
CH2), 7.59 (td, 3,3JH,H =7.9, 0.6 Hz, 1H; ArH), 7.93 (dd, 3,4JH,H =7.9,
1.5 Hz 1H; ArH), 8.08 (dd, 3,4JH,H =7.5, 1.5 Hz 1H), 10.55 ppm (s, 1H;
CHO); 13C NMR (100.6 MHz, CDCl3): d=13.5, 22.7, 32.3, 33.1, 128.0,
128.7, 129.2, 132.1, 139.0, 156.0, 192.3 ppm; 77Se NMR (57.26 MHz,
CDCl3): d=207 ppm; IR (neat): n˜ =3075, 2960, 2932, 2872, 1694, 1586,
1533, 1370, 1232, 908, 809, 739 cmꢀ1; HRMS (Q-TOF MS ES+): m/z:
calcd for C11H13O3NSe [M+H]+: 288.0139; found: 288.0130.
3
7.39 (t, JH,H =7.3 Hz, 1H; ArH), 7.46 (dd, 3,4JH,H =7.3, 1.2 Hz, 1H; ArH),
8.16 ppm (dd, 3,4JH,H =7.9, 0.9 Hz, 1H; ArH); 13C NMR (100.6 MHz,
CDCl3): d=77.7, 122.8, 126.7, 127.8, 141.2, 141.7, 143.4 ppm; 77Se NMR
(57.26 MHz, CDCl3): d=1360 ppm; IR (KBr): n˜ =3088, 2840, 1599, 1571,
1495, 1356, 1272, 981, 734 cmꢀ1; HRMS (Q-TOF MS ES+): m/z: calcd for
C7H5SeNO3 [M+H]+: 231.9513; found: 231.9509; elemental analysis
calcd (%) for C7H5SeNO3: C 36.54, H 2.19, N 6.09; found: C 36.75, H
2.34, N 5.85.
Method B
LiAlH4 (4.3 mmol, 0.16 g) was added to a suspension of selenium powder
(4.3 mmol, 0.29 g) in dry THF (50 mL) at 08C under a nitrogen atmos-
phere. The reaction mixture was stirred for 1.5 h at room temperature to
give a red solution of LiAlHSeH. Compound 13 (4.3 mmol, 1.0 g) was
added to the stirred solution of LiAlHSeH at 08C and further stirred for
2 h at room temperature. A mixture of I2 (4.3 mmol, 1.1 g) and KI
(0.86 mmol, 0.14 g) was dissolved in THF (5 mL) and added dropwise to
the reaction mixture. The mixture was stirred for 3 h at room tempera-
ture. The resulting mixture was passed through a Celite pad and removal
of the solvent gave a dark brown semi-solid. The crude product was chro-
matographed on a silica-gel column (elution with 10% ethyl acetate/pe-
troleum ether) to give 15 (0.62 g, 21%) and 17 (0.70 g, 24%).
Synthesis of 7-nitro-1,2-benzisoselenolACTHNURTGNEU(GN 3H)-3-ol (21)
Bromine (1.8 mmol, 0.28 g, 0.09 mL) in the presence of Et3N (3.5 mmol,
0.35 g, 0.48 mL) was added to a solution of selenide 19 (1.8 mmol, 0.50 g)
in CHCl3 (10 mL) at 08C with continuous stirring under an inert atmos-
phere. After complete addition of bromine, the reaction mixture was
stirred for 2 h at room temperature. Removal of the solvent under re-
duced pressure gave a dark-red solution, which then turned into an
orange precipitate after being kept at room temperature. The precipitate
was filtered-off and the filtrate was purified by silica-gel column chroma-
tography (elution with 10% ethyl acetate/petroleum ether) to give prod-
uct 21 as a dark-orange solid. Recrystallization from toluene gave dark
red crystals. Yield: 0.15 g (35%); m.p. 82–848C; 1H NMR (399.88 MHz,
CDCl3): d=3.24 (d, 3JH,H =5.8 Hz, 1H; OH), 6.84 (d, 3JH,H =6.7 Hz, 1H;
CH), 7.52 (t, 3JH,H =8.0 Hz, 1H; ArH), 7.74 (d, 3JH,H =7.3 Hz, 1H; ArH),
8.32 ppm (d, 3JH,H =8.3 Hz, 1H; ArH); 1H NMR (399.88 MHz, CDCl3,
D2O exchange): d=6.83 (s, 1H; CH), 7.52 (t, 3JH,H =8.0 Hz, 1H; ArH),
7.74 (d, 3JH,H =7.3 Hz, 1H; ArH), 8.32 ppm (d, 3JH,H =8.3 Hz, 1H; ArH);
13C NMR (100.6 MHz, CDCl3): d=103.6, 106.4, 124.7, 128.2, 130.6, 130.7,
140.1 ppm; 77Se NMR (57.26 MHz, CDCl3): d=1342 ppm; IR (KBr): n˜ =
3370, 3086, 2921, 1607, 1576, 1495, 1455, 1419, 1298, 1275, 1042, 956, 943,
802, 733 cmꢀ1; HRMS (Q-TOF MS ES+): m/z: calcd for C7H5NO4Se
[M+H]+: 247.9462; found: 247.9463; elemental analysis: calcd (%) for
C7H5NO4Se: C 34.17, H 2.05, N 5.69; found: C 34.19, H 2.00, N, 5.76.
Synthesis of bis(2-oxa-1-selenaindan-7-yl)diazene (16)
A solution of compound 13 (2.0 mmol, 0.46 g) in THF (10 mL) was
slowly added to a brown solution of Na2Se2 (4.0 mmol, 0.82 g). The reac-
tion mixture was refluxed for 3 h and then allowed to cool to room tem-
perature. The reaction mixture was poured into 10 mL of water and ex-
tracted with tert-butylmethylether (100 mL). The separated organic layers
were combined and dried over anhydrous Na2SO4. Removal of the sol-
vent and purification of the residue by silica-gel column chromatography
(elution with 20% ethyl acetate/petroleum ether) afforded a dark-black
compound 16. Yield: 0.08 g (20%); m.p. >2508C; 1H NMR
(399.88 MHz, CDCl3): d=5.47 (s, 2H; CH2), 7.32 (d, 3JH,H =6.7 Hz, 1H;
ArH), 7.5 (t, 3JH,H =7.6 Hz, 1H; ArH), 8.19 ppm (d, 3JH,H =8.2 Hz, 1H;
ArH); 77Se NMR (57.26 MHz, CDCl3): d=254, 537, 1205, 1223 ppm; ES-
MS (Q-TOF MS ES+): m/z: calcd for C14H10N2O2Se2: 398.9151 [M+H]+;
found: 398.9463; HRMS (Q-TOF MS ES+): m/z: calcd for
C14H10N2O2Se2 [M+H]+: 398.9151; found: 398.9167; elemental analysis:
calcd (%) for C14H10N2O2Se2: C 42.44, H 2.54, N 7.07; found: C 44.02, H
3.32, N 7.25.
Synthesis of 3,3’-oxybis(7-nitro-1,2-benzisoselenoleACTHNUGTRNEUNG(3H)) (22)
The orange precipitate obtained during the synthesis of compound 21
(vide supra) was recrystallized from hot DMSO to give dark-orange
needle-like crystals of 22. Yield: 0.03 g (7%); m.p. 2068C; 1H NMR
(299.95 MHz, [D6]DMSO): d=6.78 (s, 1H; CH), 7.60 (t, 3JH,H =7.7 Hz,
1H; ArH), 7.82 (d, 3JH,H =7.3 Hz, 1H; ArH), 8.35 ppm (d, 3JH,H =8.4 Hz,
1H; ArH); 13C NMR (100.6 MHz, [D6]DMSO): d=103.1, 124.3, 128.5,
131.1, 140.8, 141.0, 141.1 ppm; 77Se NMR (57.26 MHz, [D6]DMSO): d=
1302 ppm; IR (KBr): n˜ =2925, 2853, 1609, 1575, 1509, 1305, 1280, 964,
917, 737 cmꢀ1; HRMS (Q-TOF MS ES+): m/z: calcd for C14H8N2O7Se2
[(MꢀC7H4NO4Se)+H]+: 230.9435; found: 230.9437; elemental analysis:
calcd (%) for C14H8N2O7Se2 : C 35.46, H 1.70, N 5.91; found: C 35.72, H
1.44, N 6.35.
Synthesis of 7-nitro-1,2-benzisoselenoleACTHNUTRGENUG(N 3H) selenium oxide (18)
H2O2 (30%, 1.3 mmol, 0.04 g, 0.15 mL) was added to a chloroform solu-
tion (2 mL) of compound 15 (0.21 mmol, 0.05 g) and the mixture was
stirred for 9 h at room temperature to give a colorless solution. The or-
ganic layers were dried over anhydrous Na2SO4. Removal of the solvent
afforded a viscous oil that was recrystallized from dichloromethane/
hexane to give a light-yellow crystalline solid 18. Yield: 0.05 g (85%);
2
m.p. 190–1928C; 1H NMR (399.88 MHz, [D6]DMSO): d=5.78 (d, JH,H
=
15 Hz, 1H; CH), 5.89 (d, 2JH,H =15 Hz, 1H, CH), 7.93 (t, 3JH,H =7.8 Hz,
1H; ArH), 8.06 (d, 3JH,H =7.3 Hz, 1H; ArH), 8.35 ppm (d, 3JH,H =8.3 Hz,
1H; ArH); 13C NMR (100.6 MHz, [D6]DMSO): d=77.1, 123.6, 130.6,
Chem. Asian J. 2011, 6, 1431 – 1442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1439

H. B. Singh et al.
FULL PAPERS
Synthesis of 2-(butylseleninyl)-3-nitrobenzoic acid (24)
mental analysis: calcd (%) for C7H3NO5Se: C 32.33; H 1.16, N 5.39;
found: C 32.11, H 0.99, N 5.39.
H2O2 (30%, 2.0 mmol, 0.20 mL) was added to a solution of selenide 19
(0.34 mmol, 0.10 g) in CHCl3 (5 mL) at room temperature. The resulting
mixture was stirred for 3 h at room temperature. The resulting yellow
precipitate was filtered off and dried under vacuum to afford the product
(0.10 g, 90%); m.p. 145–1478C; 1H NMR (299.95 MHz, [D6]DMSO): d=
Preparation of 7-nitro-1,2-benzisoselenolACTHNUTRGNEUNG
(2H)-3-one (8)[10a]
Bromine (0.53 mmol, 0.09 g, 0.03 mL) in presence of Et3N (1.1 mmol,
0.11 g, 0.14 mL) was added to a dry chloroform solution (5 mL) of com-
pound 25b (0.53 mmol, 0.17 g) at 08C with continuous stirring under
inert atmosphere. After complete addition of bromine, the reaction mix-
ture was stirred for 2 h at room temperature. Removal of the solvent and
purification of the residue by silica-gel column chromatography (elution
with 4% ethyl acetate/petroleum ether) afforded pure compound 8.
Yield: 0.13 g (95%; see Ref. [10a] 75%); m.p. 1688C; 1H NMR
(399.88 MHz, [d3]CHCl3): d=7.79 (t, 3JH,H =7.9 Hz, 1H, ArH), 8.45 (d,
3JH,H =7.3 Hz, 1H; ArH), 8.61 ppm (d, 3JH,H =7.9 Hz, 1H; ArH);
13C NMR(100.60 MHz, CDCl3): d=125.0, 128.6, 129.3, 136.5, 141.2, 145.7,
168.5 ppm; 77Se NMR (57.26 MHz, CDCl3): d=1364 ppm; IR (KBr): n˜ =
1715, 1607, 1573, 1510, 1425, 1341, 1286, 1057, 920, 735 cmꢀ1; HRMS (Q-
TOF MS ES+): m/z: calcd for C7H3NO4Se [M+H]+: 245.9306; found:
245.9306; elemental analysis: calcd (%) for C7H3NO4Se: C 34.45, H 1.24,
N 5.74; found: C 34.37, H 0.94, N 5.94.
0.89 (t, 3JH,H =7.3 Hz , 3H; CH3), 1.43 (sextet, 3JH,H =7.8 Hz, 2H; CH2),
3
1.75 (m, 2H; CH2), 3.57 (m, 1H; CH), 3.72 (m, 1H; CH), 7.92 (t, JH,H
=
7.8 Hz, 1H; ArH), 8.08 (dd, 3,4JH,H =7.8, 1.5 Hz, 1H; ArH), 8.17 ppm (dd,
3,4JH,H =7.3 Hz, 1H; ArH); 13C NMR (100.6 MHz, [D6]DMSO): d=13.4,
21.5, 26.6, 57.7, 127.0, 128.0, 131.9, 133.9, 138.5, 150.7, 166.3 ppm; IR
(KBr): n˜ =2958, 2934, 2872, 1726, 1583, 1550, 1363, 714 cmꢀ1 77Se NMR
;
(57.26 MHz, [D6]DMSO): d=1375 ppm; HRMS (Q-TOF MS ES+): m/z:
calcd for C11H13NO5Se [M+H]+: 320.0037; found: 320.0034; elemental
analysis: calcd (%) for C11H13NO5Se: C 41.52, H 4.12, N 4.42; found: C
41.29, H 3.89, N 4.67.
Synthesis of methyl(2-bromo-3-nitrobenzoate) (25a)
2-bromo-3-nitrobenzoic acid[14b] (2.0 mmol, 5.0 g) was added to a mixture
of methanol (30 mL) and concentrated sulfuric acid (1 mL) and the reac-
tion mixture was refluxed for 4 h. After refluxing, it was allowed to cool
to room temperature. The solvent was evaporated using a rotary evapo-
rator and the residue was dissolved in water (50 mL). The mixture was
extracted by adding CCl4 (20 mL). The lower organic layer was separated
and washed with a solution of NaHCO3. It was then allowed to stand for
20 min. The separated organic layer was washed with water and dried
over Na2SO4. The excess of solvent was removed by using a rotary evapo-
rator to give a white solid. Yield: 3.0 g (57%); m.p. 82–848C; 1H NMR
(399.88 MHz, CDCl3): d=3.98 (s, 3H; CH3), 7.53 (t, 3JH,H =7.9 Hz, 1H,
ArH), 7.76 (dd, 3,4JH,H =7.9, 1.5 Hz, 1H; ArH), 7.86 ppm (dd, 3,4JH,H =7.9,
1.8 Hz, 2H; ArH); 13C NMR (100.60 MHz, CDCl3): d=53.2, 112.8, 126.7,
128.3, 133.1, 135.9, 152.1, 165.6 ppm; IR (KBr): n˜ =3082, 3016, 2961,
2923, 1738, 1591, 1533, 1423, 1363, 1273, 812 cmꢀ1; HRMS (Q-TOF MS
ES+): m/z: calcd for C8H6NO4Br [M+Na]+: 281.9378; found: 281.9392;
elemental analysis: calcd (%) for C8H6NO4Br: C 36.95, H 2.33, N 5.39;
found: C 36.87, H 2.14, N 5.32.
Computational Methods
All theoretical calculations were executed by using Gaussian 03 suite of
quantum chemical programs.[32] The hybrid Becke 3-Lee–Yang–Parr
(B3LYP) exchange correlation functional was implemented for DFT cal-
culations.[33] The geometry optimizations were carried out at the B3LYP
level of DFT by using the 6–31G(d) basis sets. The total energies of the
optimized geometries were computed based on the inclusion of zero-
point corrections. The 77Se NMR calculations were performed at the
B3LYP/6-311+G (d,p) level on B3LYP/6–31G(d)-level-optimized geome-
tries by using the gauge-including atomic orbital (GIAO) method (refer-
enced with respect to the peak of Me2Se).[34] The quantifications of orbi-
tal interaction were done by natural bond orbital (NBO) analysis at the
B3LYP/6-311+GACTHNUTRGNEUNG
(d,p) level.[26] Nucleus-Independent Chemical Shifts
(NICS)[35] have been carried out at the B3LYP/6-31G(d)//6-311+G
ACHTUNGTRENNUNG(d,p)
level. Atoms in molecules (AIM)[27] calculations have also been used to
confirm the distinct bond critical point.
Synthesis of methyl(2-(butylselanyl)-3-nitrobenzoate) (25b)
Coupled Reductase Assay
Compound 25b was synthesized from di-n-butyl diselenide (1.2 mmol,
0.40 g), deoxygenated ethanol (20 mL), NaBH4 (2.4 mmol, 0.10 g), and
25a (2.4 mmol, 0.62 g) according to the procedure described for the prep-
aration of 19. Removal of the solvent and purification of the residue by
silica-gel column chromatography (elution with 4% ethyl acetate/petrole-
um ether) afforded the product as an orange liquid. Yield: 0.45 g (60%);
The GPx-like activity of organoselenium compounds was determined by
the spectrophotometric method at 340 nm as described by Wilson et al.[1a]
The test mixture contained GSH (2 mm), ethylene diamine tetra acetate
(EDTA 1 mm), glutathione reductase (GR; 1.3 unitmLꢀ1), and b-nicoti-
namide adenine dinucleotide phosphate (NADPH 0.4 mm) in potassium
phosphate buffer (100 mm, pH 7.5). GPx samples (80 mm) were added to
the test mixture at 258C and the reaction was initiated by the addition of
H2O2 (1.6 mm). The initial reduction rates were calculated from the oxi-
dation rate of NADPH at 340 nm. The initial reduction rate was deter-
mined at least 3–4 times and calculated from the first 5–10% of the reac-
tion by using 6.22 mmꢀ1 cmꢀ1 as the extinction coefficient for NADPH.
3
1H NMR (399.88 MHz, CDCl3): d=0.87 (t, JH,H =7.6 Hz, 3H; CH3), 1.36
(sextet, 3JH,H =8.0 Hz, 2H; CH2), 1.56 (quintet, 3JH,H =7.3 Hz, 2H; CH2),
3
3
2.87 (t, JH,H =7.6 Hz, 2H; CH2), 3.96 (s, 3H; CH3), 7.47 (t, JH,H =7.9 Hz,
1H; ArH), 7.77 ppm (m, 2H; ArH); 13C NMR (100.60 MHz, CDCl3): d=
13.5, 22.8, 30.6, 31.9, 52.9, 123.6, 125.7, 128.5, 132.0, 140.0, 155.4,
167.4 ppm; 77Se NMR (57.26 MHz, [d3]CHCl3): d=294 ppm; IR (neat):
n˜ =2957, 2928, 2873, 1727, 1533, 1438, 1351, 1292,1267, 1119, 759,
720 cmꢀ1
;
HRMS (Q-TOF MS ES+): m/z: calcd for C11H13O3NSe
X-ray Crystallographic Analysis
[M+H]+: 318.0245; found: 318.0240.
X-ray crystallographic studies were carried out for compounds 15, 18, 21,
22, 27, and 29 on an Oxford Diffraction Gemini diffractometer using
graphite-monochromatized MoKa radiation (l=0.7107 ꢁ). The diffraction
measurements for compounds 18, 21, 22, and 29 were performed at
200(2) K and for 15 at 293(2) K and for 27 at 123(2) K. The structures
were solved by direct method and refined by a full-matrix least-squares
procedure on F2 for all reflections in SHELXL-97 software.[36] Hydrogen
atoms were localized by geometrical means. A riding model was chosen
for refinement. The isotropic thermal parameters of hydrogen atoms
were fixed at 1.5 times for CH3 groups or 1.2 times U(eq) (Ar-H) of the
corresponding carbon atoms. CCDC 734615 (15), CCDC 734616 (18),
CCDC 734617 (21), CCDC 734618 (22), CCDC 734620 (27), and
CCDC 734619 (29) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif
Preparation of 7-nitro-1,2-benzisoselenolACTHNUTRGENUG(N 2H)-3-one selenium oxide
(4b)[10a]
Ester 4b was synthesized from compound 25b (0.75 mmol, 0.24 g),
CHCl3 (2 mL), and H2O2 (4.5 mmol, 0.15 g, 0.50 mL) according to the
procedure described for the preparation of compound 24. The stirring
was continued for 3 h at the room temperature. The yellow precipitate
obtained was filtered and dried under vacuum to give compound 4b.
Yield: 0.08 g (41%); m.p. 225–2288C; 1H NMR (399.88 MHz,
[D6]DMSO): d=8.15 (t, 3JH,H =7.9 Hz, 1H; ArH), 8.47 (d, 3JH,H =7.6 Hz,
1H; ArH), 8.74 ppm (d, 3JH,H =8.3 Hz, 1H; ArH); 13C NMR
(100.60 MHz, [D6]DMSO): d=128.7, 130.0, 135.3, 135.9, 143.3, 148.7,
168.5 ppm; 77Se NMR (57.26 MHz, [D6]DMSO): d=1365 ppm; IR (KBr):
n˜ =1747, 1607, 1535, 1340, 1263, 1058, 914, 735 cmꢀ1; HRMS (Q-TOF MS
ES+): m/z calcd for C7H3NO5Se [M+H]+: 261.9255; found: 261.9257; ele-
1440
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1431 – 1442

Synthesis of Cyclic Selenenate/Seleninate Esters
Crystal data for 15: C7H5NO3Se, Mr =230.08, monoclinic, space group P1
21/n 1, a=6.7355, b=7.7603, c=14.3221 ꢁ, a=g=908, b=91.5078, V=
748.35(8) ꢁ3, Z=4, T=293(2) K, 1calcd =2.042 Mgmꢀ3, GOF=1.159, R1=
0.0383, wR2=0.0621ACHTUNGTRENNUNG[I>2s(I)]; R1=0.0771, wR2=0.0839 (all data). Of
the 6791 reflections that were collected, 2386 were unique (Rint =0.0303).
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Crystal data for 18: C7H5NO4Se, Mr =246.08, monoclinic, space group P1
21/n 1, a=7.6373(9), b=11.6251(13), c=9.4141(13) ꢁ, a=g=908, b=
112.672(8)8, V=771.24(16) ꢁ3, Z=4, T=200(2) K, 1calcd =2.119 Mgmꢀ3
,
GOF=1.036, R1=0.0700, wR2=0.1369 [I>2s(I)]; R1=0.1421, wR2=
0.1651 (all data). Of the 8974 reflections that were collected, 2469 were
unique (Rint =0.0938).
Crystal data for 21: C7H5NO4Se, Mr =246.08, monoclinic, space group P1
21/c 1, a=11.6864(6), b=4.7444(3), c=14.3761(7) ꢁ, a=g=908, b=
94.012(5)8, V=795.13(8) ꢁ3, Z=4, T=200(2) K, 1calcd =2.056 Mgmꢀ3
,
GOF=1.101, R1=0.0709, wR2=0.1447 [I>2s(I)]; R1=0.1298, wR2=
0.1760 (all data). Of the 5865 reflections that were collected, 2475 were
unique (Rint =0.0731).
[4] V. Galet, J.-L. Bernier, J.-P. Hꢄnichart, D. Lesieur, C. Abadie, L.
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2803.
Crystal data for 22: C14H8N2O7Se2, Mr =474.14, monoclinic, space group
C1 2/c 1, a=14.7959(5), b=4.3821(2), c=23.1293(7) ꢁ, a=g=908, b=
93.354(3)8, V=1497.07(10) ꢁ3, Z=4, T=200(2) K, 1calcd =2.104 Mgmꢀ3
,
GOF=0.966, R1=0.0400, wR2=0.0866 [I>2s(I)]; R1=0.0753, wR2=
0.0993 (all data). Of the 7129 reflections that were collected, 2446 were
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Crystal data for 27: C12H8Br2N2O4Se, Mr =561.94, orthorombic, space
group Pc 21 b, a=4.012(5), b=25.656(5), c=15.259(5) ꢁ, a=b=g=908,
V=1571(2) ꢁ3, Z=4, T=293(2) K, 1calcd =2.376 Mgmꢀ3, GOF=0.953, ,
R1=0.0916, wR2=0.2173 [I>2s(I)]; R1=0.1566, wR2=0.2484 (all
data). Of the 14499 reflections that were collected, 4461 were unique
(Rint =0.2190).
Crystal data for 29: C12H8N2O5Se2, Mr =418.12, monoclinic, space group
P1 c 1, a=3.9939(10), b=12.3641(3), c=13.5940(3) ꢁ, a=g=908, b=
92.924(2)8, V=670.41(3) ꢁ3, Z=2, T=200(2) K, 1calcd =2.071 Mgmꢀ3
,
GOF=0.878, R1=0.0265, wR2=0.0448 [I>2s(I)]; R1=0.0383, wR2=
0.0461 (all data). Of the 9366 reflections that were collected, 4201 were
unique (Rint =0.0279).
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Acknowledgements
This work was supported by the Department of Science and Technology
(DST), New Delhi. We are thankful to the Sophisticated Analytical In-
strument facility (SAIF), Indian Institute of Technology (IIT), Bombay,
for performing 300 MHz NMR spectroscopic analyses for 77Se NMR.
V.P.S wishes to thank the IIT, Bombay for a teaching assistantship.
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[16] For characterization data of 8 see the Experimental Section. The ob-
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1401 ppm; see Ref. [10a]).
[17] The full characterization data of 4b have not been reported in the
literature, except for its crystal structure (see Ref. [10a]). For full
characterization data of 4b see the Experimental Section.
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FULL PAPERS
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