2-Phenoxyethanol derived diselenide and related compounds; Synthesis of a seven-membered seleninate ester

Article abstract of DOI:10.1039/c0ob00038h

Syntheses of several diorganodiselenides and, in particular, a seven-membered cyclic seleninate ester derived from 2-phenoxyethanol are described. The seleninate ester was obtained from allyl (2-(2-hydroxyethoxy) phenyl) selenide through a series of oxidation and [2,3] sigmatropic rearrangement steps. The ester exhibits good GPx-like activity in the coupled reductase assay.

Full text of DOI:10.1039/c0ob00038h

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PAPER
2-Phenoxyethanol derived diselenide and related compounds; synthesis of a
seven-membered seleninate ester†
Santosh K. Tripathi,a Sagar Sharma,a Harkesh B. Singh*a and Ray J. Butcherb
Received 23rd April 2010, Accepted 16th September 2010
DOI: 10.1039/c0ob00038h
Syntheses of several diorganodiselenides and, in particular, a seven-membered cyclic seleninate ester
derived from 2-phenoxyethanol are described. The seleninate ester was obtained from allyl
(2-(2-hydroxyethoxy)phenyl) selenide through a series of oxidation and [2,3] sigmatropic rearrangement
steps. The ester exhibits good GPx-like activity in the coupled reductase assay.
Mugesh and Bhabak have shown that the N-phenyl group
Introduction
present in ebselen is important for its antioxidant activity.7
The growing interest in the biochemistry of selenium has been
Recently, several other classes of organoselenium compounds
mainly driven by the discovery of selenocysteine in a number
which exhibit GPx-like antioxidant activity have been reported
of enzymes which include glutathione peroxidase,1 iodothyronine
deiodinase,2 and thioredoxin reductase.3 Glutathione peroxidase
(GPx) is a well known mammalian selenoenzyme that functions
as an antioxidant and is responsible for the destruction of harmful
peroxides in various living organisms. This selenoprotein, bearing
selenol (Enz-SeH) at the active site, catalyzes the reduction of
harmful peroxides in the presence of cofactor glutathione (GSH)
and thereby protects the lipid membranes as well as biologically
important molecules against oxidative stress (Scheme 1). After the
discovery of ebselen (1) as a GPx mimic,4 several organoselenium
derivatives5 including ebselen derivatives6 have been reported in
literature for their antioxidant activity.
in the literature. These include diselenides 2,8a 3,8c and selenide
4,8b cyclic seleninate esters 5,9a 6,9b 7,9c,9d spirodioxyselenuranes
8,8c,9c 99c,9d selenenate ester 10,10 azaselenonium chloride 11,11
seleninic acid anhydride 12,12 having either Se ◊ ◊ ◊ O intramolecular
interaction or Se–O linkage.
Scheme 1 Catalytic cycle of GPx.
aDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai
400076, India. E-mail: chhbsia@chem.iitb.ac.in; Fax: +91 022 2572 3480;
Tel: +91 022 2576 7190
Weak intramolecular interaction (Se ◊ ◊ ◊ N/O) plays an im-
portant role in stabilizing organoselenium compounds13 and
modulating the GPx-like activity of enzyme mimetics.14 Our
group has been involved in the synthesis of organochalcogens
having hydroxyl or ether groups in the vicinity of Se which
can be involved in Se ◊ ◊ ◊ O intramolecular interaction.8c,10,15 The
importance of systems containing hydroxyl group or multiple ether
bDepartment of Chemistry, Howard University, Washington D. C 20059,
USA
† Electronic supplementary information (ESI) available: 1H, 13C, 77Se
NMR spectra, ES-MS, HRMS and all computational data. CCDC
reference numbers 739448 and 739449. For ESI and crystallographic data
in CIF or other electronic format see 10.1039/c0ob00038h
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groups stems from the need for higher water solubility of the
suitable antioxidants in the bio-system. We earlier demonstrated
that diselenide 3, having five-membered Se ◊ ◊ ◊ O intramolecular
interaction and its five-membered seleninate ester 7 showed ex-
cellent GPx-like activity in the coupled reductase assay. However,
the corresponding monoselenide of 3 and its spirodioxyselenurane
8 showed relatively poor catalytic activity.8c Back and coworkers
also reported similar observations for 7 as well as 89c and very
good GPx-like activity of di(3-hydroxypropyl) selenide 4.8b In
continuation of our work on the synthesis of organochalcogens
containing oxygen as donor atom, we now report the synthesis
and GPx-like activity of a novel seven-membered seleninate ester
17. Although seleninate esters where selenium(IV) is incorporated
in a five-membered ring (5), six-membered ring (6), and eight-
membered ring (13)16 are known, to our knowledge, a seleninate
ester in which selenium(IV) is part of a seven-membered ring has
not been reported in the literature.
selenium and subsequent air oxidation gave a yellow solid, which
was recrystallized from dichloromethane to give yellow needles of
15 (Scheme 2). It is worth mentioning that air oxidation of the
intermediate selenolate ion 14a to its diselenide 15 always led to
significant extrusion of elemental red selenium during the work-
up. The difficulty faced in isolation of the diselenide was overcome
by a faster work-up at 0 ◦C. Attempts to prepare seleninate
ester 17 by the direct oxidation of diselenide 15 with tert-butyl
hydroperoxide yielded the product in poor yield. To improve the
yield, 17 was synthesised by the oxidation of allyl selenide 16 which
could be easily derived from 15. The synthesis of allyl derivative 16
was accomplished by the reduction of diselenide 15 with sodium
borohydride followed by addition of allyl bromide.
The conversion of allyl (2-(2-hydroxyethoxy)phenyl) selenide
16 to ester 17 with tert-butyl hydroperoxide involves a series of
oxidation and [2,3] sigmatropic rearrangement steps as proposed
by Back and coworkers for similar allyl selenides.9a The ester was
purified by column chromatography followed by recrystallization.
Repeated attempts to crystallize 17 did not yield good quality
crystals. Interestingly, 17 always gets associated with one molecule
of water which was evident from its FT-IR spectrum that
showed a sharp peak for the OH group at 3376 cm-1. Elemental
analysis of 17 was consistent with one molecule of water of
crystallization. Selenenyl sulfide 18 was generated in situ by the
Results and discussion
Syntheses
Diorganodiselenide 15 was synthesized from 2-phenoxyethanol 14
by the ortho-lithiation route.17 The reaction of 2-phenoxyethanol
with 2 equivalents of n-BuLi at -78 ◦C followed by the addition of
Scheme 2 Reagents and conditions: (i) (a) n-BuLi, TMEDA, Pentane/-78 to 25 ◦C, 24 h, (b) Se/THF, 8 h; (ii) [O2], 17%; (iii) (a) NaBH4, C2H5OH, 1 h
(b) C3H5Br, 6 h, 60%; (iv) TBHP, CH2Cl2, 6 h, 41%; (v) TBHP, CH2Cl2, 5 h, 20%; (vi) PhSH, 5 min, CH2Cl2; (vii) NaH/THF, CH3I, 61%; (viii) n-BuLi,
Pentane/-78 to 25 ◦C, 24 h; (ix) Se/THF, 8 h and then [O2], 28%; (x) CH3OCH2Cl, Et3N/0 to 25 ◦C, 24 h, HCl, 54%; (xi) n-BuLi, Pentane/-78 to 25 ◦C,
24 h; (xii) Se/THF, 8 h and then [O2], 45%; (xiii) CH3OCH2Cl, Et3N/0 to 25 ◦C, 8 h, HCl, 42%.
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Table 1 Comparison of experimentally obtained structural parameters
reaction of compound 17 with an excess of PhSH. Its formation
involves (i) the nucleophilic substitution at selenium by thiol,
(ii) addition of thiol across Se O bond, followed by reductive
elimination of disulfide to give selenenic acid. Selenenic acid
upon reaction with thiol affords selenenyl sulfide.9b Attempted
isolation of 18 led to its disproportionation to the corresponding
diselenide and disulfide. However, the selenenyl sulfide was stable
enough for characterization in solution by ES-MS and 77Se NMR
spectroscopy.
The diselenides 20 and 22 with multiple ether groups were
synthesized by ortho-lithiation of 19 and 21 respectively, fol-
lowed by selenium insertion and then oxidative workup. Dis-
elenide 23 with a plausible Se ◊ ◊ ◊ O interaction in a five-
membered ring was obtained as a viscous yellow oil by
the reaction of bis((2-hydroxymethyl)phenyl) diselenide 3 with
chloro(methoxy)methane in triethylamine.
The 77Se NMR signal for diselenide 15 was observed at 323 ppm
which is 105 ppm upfield as compared to diselenide 3 which
exhibits a strong Se ◊ ◊ ◊ O interaction.8c The large difference in the
chemical shift may be due to weak Se ◊ ◊ ◊ O interaction in 15. It is
well established that weak intramolecular (Se ◊ ◊ ◊ O/N) interaction
leads to a significant downfield shift in the 77Se NMR chemical
shift.5d The 77Se NMR signal of seleninate ester 17 was observed
at 1204 ppm which is close to the 77Se chemical shift (1215 ppm)
reported for the six-membered seleninate ester 6.9b However, this
value of 1204 ppm for 17 in 77Se-NMR shows an upfield shift
of 150 ppm when compared with the five-membered seleninate
ester 7, for which the peak appears at 1353 ppm. Selenenyl sulfide
18 showed an expected chemical shift at 473 ppm due to higher
positive charge on selenium as compared to diselenide 15 (See
Table S1 in ESI†).
˚
(A and deg) with those computed at B3LYP/6-31G(d) level for 15
Expt
Calcd
Expt
calcd
Se–C1
Se–Se#
Se–O1
Se–O2
1.930(3)
2.3099(6)
2.843
1.940
2.326
2.856
4.644
C1–Se–Se#
O1–Se–Se#
103.03(9)
157.42
101.25
155.54
4.648
Table 2 Comparison of experimentally obtained structural parameters
˚
(A and deg) with those computed at B3LYP/6 - 31G(d) level for 22
Expt
Calcd
Expt
Calcd
Se1–C1
Se2–C11
Se1–Se2
Se1–O1
Se2–O4
1.929(7)
1.930(7)
2.3060(11)
2.817
1.931
1.931
2.372
2.849
2.847
C1–Se1–Se2
C11–Se2–Se1
O1–Se1–Se2
O4–Se2–Se1
102.6(2)
101.9(2)
157.62
100.62
100.60
156.50
156.52
153.15
2.838
bent geometry around the selenium atom. The C1–Se–Se#–C1#
dihedral angle is -94.01◦, indicating a “transoid” conformation
˚
for the diselenide. In 15 the Se ◊ ◊ ◊ O1 distance is 2.843 A, which is
18
˚
less than sum of the van der Waals radii (3.42 A). However,
˚
Se ◊ ◊ ◊ O2 distance is 4.648 A which excludes the possibility of
any weak seven-membered intramolecular Se ◊ ◊ ◊ O interaction.
The computed intramolecular Se ◊ ◊ ◊ O distances for 15 obtained
from geometry optimization are in good agreement with the
experimental values.
The hydroxyl group in diselenide 15 is involved in intermolecular
O–H ◊ ◊ ◊ O hydrogen bonding with the H◦◊ ◊ ◊ O distance and
˚
O–H ◊ ◊ ◊ O angle being 1.926 A and 162.7 respectively. This
hydrogen bonding is responsible for the formation of cavities
encompassing four molecules of diselenide that extends to give
a three dimensional network (See Fig S38 in ESI†).
X-ray crystallographic study
Molecular structure of 15. The ORTEP diagram of 15 is
shown in Fig. 1. The important bond distances and bond
angles along with the calculated values (vide infra) are given in
Table 1. Compound 15 crystallizes in I41/a space group with a
Molecular structure of 22. The molecular structure of 22 is
shown in Fig. 2. The important bond distances and bond angles
along with the calculated values (vide infra) are given in Table 2.
Fig. 2 Molecular structure of 22 at 50% ellipsoidal probability.
The C1–Se1–Se2–C11 dihedral angle is -78.36◦, indicating
“cisoid” conformation for the diselenide. In 22, the Se1 ◊ ◊ ◊ O1 and
˚
˚
Se2 ◊ ◊ ◊ O4 distances are 2.817 A and 2.838 A. However, Se1 ◊ ◊ ◊ O2
˚
and Se1 ◊ ◊ ◊ O3 distances are 4.575 and 5.401 A respectively, which
Fig. 1 Molecular structure of 15 at 50% ellipsoidal probability.
are higher than their sum of van der Waals radii.
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Table 3 Initial reduction rate (Vo) of glutathione peroxidase-like activity
In the absence of crystal structure of 17 due to difficulty
in crystallisation, geometry optimization of 17 was performed
in order to gain an idea about the structural features of the
seleninate ester. The optimized geometry of the ester revealed
that the geometry around selenium is pyramidal, with the Se–
of selenium compounds by coupled-reductase assay at 27 ◦
C
Entry
catalyst
Vo (mM min-1)
1
2
3
4
5
6
7
8
9
None
1
4.3 0.4
106.4 3.8
180.1 8.3
451.5 5.6
206.6 3.6
421.5 6.0
113.6 3.4
123.3 2.8
134.6 3.3
˚
O3 bond distance being 1.649 A (Fig. 3). This is close to the
3
1.630 A reported for the five-membered ester (7).8c The computed
˚
7
77Se NMR chemical shift for 17 is 1203 ppm and is in excellent
agreement with the experimental value of 1204 ppm (See Table S1
in ESI†).
15
17
20
22
23
GPx-like activity of the seleninate ester 17 and its catalytic cycle
The GPx-like antioxidant activities of the organoselenium com-
pounds were determined by the coupled reductase assay (Table 3).
It was found that the antioxidant activity of the ester 17 is at a par
with the five membered seleninate ester (7) but much higher than
diselenide 15 and other ether-containing diselenides. Interestingly,
both 15 and 3 have similar GPx-like activity in the coupled-
reductase assay. In comparison to the well known GPx mimic
ebselen, slightly higher values of initial rates were observed for
the diselenides 20 and 23. To rule out the possibility that the
reaction rate becomes considerably slower after the initial stages
of the catalytic cycle or becomes zero, the assay was followed
spectrophotometrically for a longer time (10000 s) for seleninate
ester 17 at 10 mM concentration. It was observed that the amount
of H2O2 taken (200 mM) was almost completely consumed in
3000 s. (See Fig S53 and Fig S54 in ESI.†).
Fig. 3 Optimized geometry of 17.
The antioxidant activity of five-membered seleninate esters 5
and 7 is well studied and their catalytic mechanism involves the
formation of selenenic acid and thioseleninate as intermediates.8b,9b
To understand the detailed mechanism for the GPx-like activity
of the seleninate ester 17, we used 77Se NMR spectroscopy to
identify the possible intermediates. The reactions were followed
by observing 77Se NMR signals for 0–10 min after the addition of
reactants. The signals, generally, appeared within a minute and did
not change positions with the passage of time. The reaction of 17
with one equivalent of PhSH immediately afforded the selenenyl
sulfide 18 whose 77Se NMR signal appeared at 473 ppm along with
the signal of 17. This indicates that the initial reaction of 17 with
thiol is very fast. When one more equivalent of PhSH was added
to this reaction mixture, the signal due to the seleninate ester
17 disappeared completely and the signal for 18 got intensified.
The signal due to selenenic acid 24 was not be observed in the
77Se-NMR spectrum which may be due to the fast conversion
of 17 to 18. When this reaction mixture was treated with two
equivalents of tert-butyl hydroperoxide, the peak due to seleninate
ester 17 reappeared. On further addition of an excess of tert-butyl
hydroperoxide (4 equivalents), the peaks due to seleninate ester
17, selenenyl sulfide 18 along with diselenide 15 were observed.
The formation of diselenide 15 indicated the disproportionation
of selenenyl sulfide 18 in the presence of excess of tert-butyl
hydroperoxide. This may also be an alternate pathway in the
regeneration of 17 from 18 (Scheme 3). However, independent
reaction of 15 with TBHP suggests that the direct formation of
the seleninate ester from the diselenide is a rather slow process
(vide supra). The slow reaction of diselenide 15 with tert-butyl
Intramolecular Se ◊ ◊ ◊ O interaction in the synthesised diselenides
Se ◊ ◊ ◊ O interaction in the synthesized diselenides has been quan-
tified using density functional theory in Gaussian03.19 The second
order perturbation energies (at B3LYP/6-311+g** level) obtained
from NBO analyses20 for Se ◊ ◊ ◊ O (phenoxy/hydroxy/alkoxy)
interaction in all the compounds (except 3 and 23) were found to
be of the order of 2 kcal mol-1. Diselenides 3 and 23 have orbital
interaction energy values of 4.56 and 3.88 kcal mol-1 respectively
(See Table S1 in ESI†). AIM analysis21 showed the absence of
bond critical points in all the compounds with plausible four-
membered Se ◊ ◊ ◊ O rings.‡ The analysis substantiated our earlier
observation on the absence of a weak intramolecular interaction in
four-membered Te ◊ ◊ ◊ O system.8c However, there exists a distinct
bond critical point (bcp) for 3 and 23 involving a five-membered
Se ◊ ◊ ◊ O ring with electron density (r) value of 0.018 a.u. for 3 and
0.021a.u for 23 (See Figure S46 in ESI†).
‡ It is important to note that the short contacts observed for Se–O
interaction in plausible four-membered ring are a characteristic feature for
1,2-disubsituted phenyl systems. We carried out geometry optimization of
a series of 1,2-disubstituted phenyl systems and found that the distance
between the two atoms present in the ortho position is less than the sum
of their van der Waals radii in all the cases. Therefore, the short distance
between any atom X (X = C, N, O, F, P, S, Cl, Se, Br) and O in 1,2-position
in the phenyl ring may be due to the geometrical position. Therefore, the
short distance between Se and O in crystal structures of 15 and 22 does
not necessarily imply Se–O intramolecular interaction. See Table S19 in
ESI for comparision.†
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was allowed to warm up to the room temperature and stirred
for 24 h. Pentane was removed from the reaction mixture with
a syringe and 30 mL of dry tetrahydrofuran was added to the
lithiated product. To this, selenium (1.7 g, 21.5 mmol) powder was
added at 0 ◦C under a brisk flow of nitrogen and the solution
was stirred for 8 h at room temperature. The reaction mixture
was poured into the beaker containing 100 mL of 5% sodium
bicarbonate solution at 0 ◦C. The organic layer and the ether
extracts from the aqueous layer were combined and dried over
sodium sulfate. Solvent was evaporated in vacuo to afford 1.2 g of
the crude product which was recrystallized from tetrahydrofuran–
hexane (0.81 g, 17% yield) m.p. 163–165 ◦C; IR (KBr) 3267, 2925,
1
1458, 1439, 1234, 749 cm-1; H NMR (400 MHz, DMSO-d6) d
7.39 (dd, J = 7.6, 1.5 Hz, 2H), 7.22 (m, 2H), 7.00 (dd, J = 8.2,
0.9 Hz, 2H), 6.90 (td, J = 7.6, 0.9 Hz, 2H), 4.95 (t, J = 5.2 Hz,
2H), 4.11 (t, J = 4.9 Hz, 4H), 3.77 (q, J = 5.2 Hz, 4H); 13C NMR
(400 MHz, DMSO-d6) d 155.9, 129.4, 128.6, 122.1, 117.7, 112.2,
70.7, 59.6; 77Se NMR (300 MHz, DMSO-d6) d 323; ES-MS, m/z
(relative intensity) 456.9 (28, [M + Na]+); exact mass calcd for
C16H18O4Se2Na (M + Na+) 456.9433, found 456.9456.
Scheme 3 GPx catalytic cycle of seleninate ester 17.
Allyl (2-(2-hydroxyethoxy)phenyl) selenide (16). Sodium boro-
hydride (0.13 g, 3.44 mmol) was added portionwise to an ice-cold
suspension of diselenide 15 (0.3 g, 0.69 mmol) in 25 mL of absolute
ethanol. After completion of addition, the ice bath was removed
and the mixture was stirred at room temperature for 1 h. Allyl
bromide (0.3 mL, 3.47 mmol) was added to the colorless reaction
mixture and stirring was continued for additional 6 h. The reaction
mixture was poured into the 100 mL ether, washed with a saturated
solution of NH4Cl, NaCl and with water. The organic layer was
dried over sodium sulfate and evaporated in vacuo. The residue
was chromatographed (elution with 10% ethyl acetate–petroleum
ether) to afford a colorless liquid (0.21 g, 60% yield). IR (neat)
3412, 2930, 1578, 1474, 1242, 1059, 1035, 750 cm-1; 1H NMR (400
MHz, CDCl3) d 7.37 (dd, J = 7.6, 1.5 Hz, 1H), 7.19–7.24 (m, 1H),
6.93 (td, J = 7.6, 1.2 Hz, 1H), 6.87 (dd, J = 8.3, 1.2 Hz, 1H), 5.90–
5.98 (m, 1H), 4.97–5.12 (m, 2H), 4.15–4.17 (m, 2H), 3.94 (q, J =
4.0 Hz, 2H), 3.55 (dt, J = 7.6, 1.3 Hz, 2H), 2.51 (t, J = 6.1 Hz, 1H);
13C NMR (400 MHz, CDCl3) d 157.2, 134.3, 132.2, 128.3, 122.3,
120.6, 117.4, 113.0, 71.1, 61.4, 28.4; 77Se NMR (300 MHz, CDCl3)
d 255; ES-MS, m/z (relative intensity) 258.9 (100, M+); exact mass
calcd for C11H15O2Se (MH+) 259.0237, found 259.0226.
hydroperoxide to form the seleninate ester 17 is responsible for the
lower antioxidant activity of the diselenide 15 as compared to that
of the seleninate ester 17.
Conclusions
In conclusion, we have synthesized a series of diorganodiselenides
with alkoxy group ortho to selenium. Diselenide 15 gave access
to novel seven-membered seleninate ester 17, which showed good
GPx-like antioxidant activity. X-ray structures exclude the pos-
sibility of plausible seven-membered or nine-membered Se ◊ ◊ ◊ O
interaction in the synthesised compounds.
Experimental
General methods
Compounds 38c and 1922 were prepared by reported methods. All
reactions were carried out under nitrogen or argon atmosphere
using standard vacuum-line techniques. Solvents were purified by
standard procedures and were freshly distilled prior to use. Melting
1
points were recorded in capillary tubes. H (399.88 MHz), 13C
Seleninate ester (17). To a solution of allyl selenide 16 (0.15 g,
0.58 mmol) in 20 mL dichloromethane was added tert-butyl hy-
droperoxide (0.43 mL of a 70% aqueous solution, 3.36 mmol) and
this was stirred at room temperature for 6 h. The reaction mixture
was concentrated in vacuo and the residue was chromatographed
(elution with 10% methanol–ethyl acetate) to yield 17 as a white
powder. It was then recrystallized from 1 : 1 dichloromethane–
petroleum ether mixture. (0.06 g, 41% yield). m.p 83–85 ◦C. IR
(KBr) 3376, 2925, 1584, 1471, 1453, 1279, 1072, 1048, 789, 685
(100.56 MHz) and 77Se (57.26 MHz) NMR spectra were recorded
on a Varian 400 MHz and 300 MHz spectrometers at room
temperature. Chemical shifts cited were referenced to TMS (1H,
13C) as internal and Me2Se (77Se) as external standard. IR spectra
were recorded on a Perkin-Elmer Spectrum One FT-IR spec-
trophotometer with KBr pellets or liquid film. Elemental analyses
were performed on a Thermo Quest FLASH 1112 series (CHNS)
elemental analyzer. The Electro-spray mass spectra (ES-MS) were
performed in a Q-Tof micro (YA-105) mass spectrometer. Column
chromatography was performed with silica gel (60–120 mesh).
1
cm-1; H NMR (400 MHz, DMSO-d6) d 7.81 (d, J = 7.7 Hz,
1H), 7.50–7.56 (m, 1H), 7.16–7.23 (m, 2H), 4.13 (t, J = 4.6 Hz,
2H), 3.70 (t, J = 4.9 Hz, 2H); 13C NMR (400 MHz, DMSO-d6) d
156.9, 136.6, 133.4, 124.9, 121.0, 113.3, 70.8, 59.3; 77Se NMR (300
MHz, DMSO-d6) d 1204; ES-MS, m/z (relative intensity) 232.9
(100, M+), exact mass calcd for C8H8O3Se (M+) 232.9717, found
232.9727.
Synthesis of bis[2-(2-hydroxyethoxy)phenyl] diselenide (15). To
a solution of 2-phenoxyethanol (3.0 g, 21.7 mmol) in pentane
(50 mL), taken in a three-necked (250 mL) flask fitted with rubber
septum and a nitrogen inlet, was added dropwise n-BuLi (30 mL,
48 mmol) at -78 ◦C over a period of 10 min. The reaction mixture
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Selenenyl sulfide (18). Thiophenol (0.04 mL) was added to
a solution of seleninate ester 17 (0.021 g, 0.08 mmol) in 2 mL
dichloromethane and stirred for 5 min. The colorless solution
changed immediately to light yellow color. Solvent was removed
in vacuo to get a light yellow residue which could not be purified
and was characterised as such. IR, (neat), 3422, 2926, 2876, 1572,
1056, 748.cm-1; 77Se NMR (300 MHz, CDCl3) d 473; ES-MS, m/z
(relative intensity); 326.9 (60, M+), 348.9 (20, [M + Na]+)
24 h. A white lithiated product precipitated which was allowed
to settle down. The supernatant solvent was removed from the
mixture by cannula and freshly dried tetrahydrofuran (20 mL) was
◦
added. The reaction mixture was cooled to 0 C and Se powder
(0.36 g, 4.6 mmol) was added under a brisk flow of nitrogen. It was
further stirred for 8 h. Oxygen was bubbled through the solution
for 10 min, and the resulting mixture was poured into a beaker
containing cold aqueous NaHCO3 solution. The oily product was
extracted with diethyl ether and then washed with water. The
organic phase was separated, dried over Na2SO4, and filtered.
The compound was purified by chromatography (elution with 20%
ethyl acetate–petroleum ether) to yield 22 as a viscous yellow liquid
(0.53 g, 45% yield). Recrystallization from dichloromethane–
Bis(2-(2-methoxyethoxy)phenyl) diselenide (20). To a solution
of (2-methoxyethoxy)benzene 19 (0.98 g, 6.44 mmol) in pentane
(25 mL) was added dropwise a 1.6 M solution of n-BuLi in
◦
hexane (4.1 mL, 6.6 mmol) at -78 C. The reaction mixture was
allowed to warm up slowly to the room temperature and stirred
for additional 24 h. The white lithiated product obtained was
allowed to settle down and the supernatant solvent was removed
from this mixture by cannula. The reaction mixture was cooled
to 0 ◦C and tetrahydrofuran (20 mL) was added, followed by
addition of Se powder (0.51 g, 6.44 mmol) under a brisk flow
of nitrogen gas. The stirring was continued for additional 8 h.
After this, oxygen was bubbled through the solution for 10 min,
and the resulting mixture was poured into a beaker containing
cold aqueous NaHCO3 solution. The oily product was extracted
with ethyl acetate and then washed with water. The organic phase
was separated, dried over Na2SO4, and filtered. The compound
was purified by chromatography (elution with 5% ethyl acetate–
petroleum ether) to give 20 as a viscous yellow liquid (0.41 g, 28%
yield). IR (neat) 2927, 1575, 1469, 1237, 1125, 749 cm-1; 1H NMR
(400 MHz, CDCl3) d 7.53 (dd, J = 7.9, 1.5 Hz, 2H), 7.18 (td, J =
7.6, 1.5 Hz, 2H), 6.82–6.89 (m, 4H), 4.22 (t, J = 4.8 Hz, 4H), 3.81
(t, J = 4.5 Hz, 4H), 3.50 (s, 6H); 13C NMR (400 MHz, CDCl3) d
156.2, 130.6, 128.1, 122.5, 119.4, 111.8, 71.1, 68.9, 59.7; 77Se NMR
(300 MHz, CDCl3) d 327; ES-MS, m/z (relative intensity) 461.8
(100, M+); exact mass calcd for C18H22O4Se2 (M+) 461.9849, found
461.9837.
◦
hexane mixture yielded yellow crystals: mp 50–51 C; IR (KBr)
2926, 2879, 1572, 1026, 746 cm-1; 1H NMR (400 MHz, CDCl3) d
7.52 (dd, J = 8.0, 1.5 Hz, 2H), 7.16–7.20 (m, 2H), 6.87 (td, J = 7.3,
1.2 Hz, 2H), 6.82 (dd, J = 7.9, 0.9 Hz, 2H), 4.78 (s, 4H), 4.25 (t,
J = 4.5 Hz, 4H), 3.95 (t, J = 4.9 Hz, 4H), 3.43 (s, 6H); 13C NMR
(400 MHz, CDCl3) d 156.1, 130.5, 128.1, 122.4, 119.2, 111.5, 96.9,
68.5, 66.0, 55.5; 77Se NMR (300 MHz, CDCl3) d 328; ES-MS,
(m/z, relative intensity), 544.9 (100, [M + Na]+); exact mass calcd
for C20H26O6Se2Na (M + Na+) 544.9945, found 544.9946.
Bis((methoxymethoxy)benzylether) diselenide (23). Bis((2-
hydroxymethyl)phenyl) diselenide 3 (1.00 g, 2.68 mmol) was
dissolved in 20 mL of triethyl amine, cooled to 0 ◦C and an
excess of chloro(methoxy)methane (5 mL) was slowly added. The
mixture was allowed to warm up slowly to the room temperature
and stirred for 8 h. The reaction was quenched with 5% aqueous
ammonia solution, stirred for 15 min and carefully acidified
with 2 N HCl. After extraction with diethyl ether, the solvent
was removed in vacuo and the remaining yellow oil purified by
chromatography (elution with 10% ethyl acetate–petroleum ether)
to afford a yellow oil (0.52 g, 42% yield). IR (neat) 2926, 2879,
1
1572, 1026, 746 cm-1; H NMR (400 MHz, CDCl3) d 7.73 (dd,
J = 7.3, 1.2 Hz, 2H), 7.34 (dd, J = 7.3, 1.5 Hz, 2H) 7.18–7.24
(m, 4H), 4.70 (s, 4H), 4.68 (s, 4H), 3.42 (s, 6H); 13C NMR (400
MHz, CDCl3) d 138.3, 133.4, 131.7, 129.1, 128.9, 127.9, 96.0, 69.6,
55.9; 77Se NMR (300 MHz, CDCl3) d 426; ES-MS, m/z (relative
intensity), 338.9 (45, [M - (C2H5O2)2]+, 400.9 (12, [M - C2H5O2]+).
(2-(Methoxymethoxy)ethoxy)benzene (21). To a solution of
2-phenoxyethanol (3.00 g, 21.7 mmol) in triethylamine (20 ml)
at 0 ◦C, was added dropwise chloro(methoxy)methane (10 mL,
132 mmol) for a period of 45 min. The reaction mixture was
allowed to warm up slowly to the room temperature and stirred
for 24 h. The reaction was quenched with 5% aqueous ammonia
solution, stirred for 15 min and carefully acidified with 1 M HCl.
It was then extracted with diethyl ether, the solvent was removed
in vacuo and the residue purified by column chromatography
(elution with 10% ethyl acetate–petroleum ether) to afford 21 as
a colorless liquid (2.12 g, 54% yield). IR (neat), 2934, 1601, 1498,
1248, 1042, 756 cm-1; 1H NMR (400 MHz, CDCl3), d 7.27 (t, J =
8.0 Hz, 2H), 6.92–6.97 (m, 3H), 4.72 (s, 2H), 4.14 (t, J = 4.9 Hz,
2H), 3.90 (t, J = 4.6 Hz, 2H), 3.40 (s, 3H); 13C NMR (400 MHz,
CDCl3) d 158.8, 129.5, 120.9, 114.7, 96.6, 67.2, 66.1, 55.3; ES-MS,
m/z (relative intensity), 205.0 (100, [M + Na]+), 183.1 (42, [M +
1]+),151.1 (22, [M - OCH3]+); exact mass calcd for C10H14O3 (M +
Na+) 205.0841, found 205.0835.
X-ray crystallography
The diffraction measurements for compounds 15 and 22 were
˚
performed at room temperature (Mo-Ka radiation, l = 0.7107 A)
on Oxford Diffraction Gemini and STOE IPDS Diffractometer
respectively. The structure solutions were achieved by using direct
methods as implemented in SHELXS-97.23a The structures were
refined by full least-squares methods using SHELXL-97.23b
Computational details
All geometries were optimized using analytical gradient tech-
niques implemented in the Gaussian03 suite of quantum chemical
program.19 Geometries were fully optimized at the B3LYP level
of theory with use of the 6-31G(d) basis sets. All stationary
points were characterized as minima by evaluating Hessian indices
on respective potential energy surfaces. The NMR calculations
were performed at the B3LYP/6-311+G(d,p) level on B3LYP/6-
31G(d) level optimized geometries by the GIAO method. Orbital
1,2-Bis(2-(2-(methoxymethoxy)ethoxy)phenyl) diselenide (22).
To a solution of compound 21 (0.83 g, 4.56 mmol) in pentane
(25 mL) was added dropwise 1.6 M hexane solution of n-BuLi
◦
(3 mL, 4.8 mmol) at -78 C. The reaction mixture was warmed
up slowly to the room temperature and stirred for an additional
586 | Org. Biomol. Chem., 2011, 9, 581–587
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interactions were analyzed by the natural bond orbital (NBO)
method at the B3LYP/6-311+G(d,p) level, and charges were
calculated by natural population analysis (NPA). The nature of
weak intramolecular Se ◊ ◊ ◊ O interactions was further analyzed
by inspecting properties of the bond critical points between
selenium and heteroatoms within Bader’s Atoms in Molecule
(AIM) framework, using the AIM2000 package24 at the B3LYP/6-
311+G(d,p) level.
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Coupled Reductase Assay
The GPx-like activity of 15, 17, 20, 22 and 23 were measured
spectrophotometrically according to the literature method5a using
ebsele◦n 1 as the standard. The catalytic reaction was carried out
at 27 C in 1 mL of the solution containing 100 mM potassium
phosphate buffer, pH 7.5, 1 mM EDTA, 2 mM GSH, 0.4 mM
of NADPH, 1.6 unit of glutathione reductase, 80 mM of catalyst
and 1.6 mM of H2O2. The activity was followed by the decrease of
NADPH absorption at 340 nm (eqn 1–3). Each initial rate for all
the compounds was measured at least four times and calculated
from the first 5–10% of the reaction by using 6.22 ¥ 103 M-1cm-1
as the molar extinction coefficient for NADPH.
9 (a) T. G. Back and Z. Moussa, J. Am. Chem. Soc., 2002, 124, 12104;
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43, 4513.
11 D. Kuzma, M. Parvez and T. G. Back, Org. Biomol. Chem., 2007, 5,
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7066.
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GSH
(1)
(2)
(3)
2GSH +H2O2 ⎯P⎯ero⎯xida⎯se→GSSG +2H2O
GSH
GSSG +NADPH +H+ ⎯⎯⎯⎯→2GSH +NADP+
reductase
NADPH + H2O2 + H+ ⎯⎯→NADP+ + 2H2O
15 S. S. Zade, S. Panda, H. B. Singh, R. B. Sunoj and R. J. Butcher, J. Org.
Chem., 2005, 70, 3693.
Acknowledgements
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We are grateful to the Department of Science and Technology
(DST), New Delhi for funding. S.S. is thankful to UGC, New
Delhi for SRF.
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