Synthesis and structural characterization of pincer type bicyclic diacyloxy- and diazaselenuranes

Article abstract of DOI:10.1039/c1dt10862j

Synthesis and structural characterization of a new class of pincer type bicyclic diacyloxy- and diazaselenuranes is reported. The reaction of dimethyl 2-bromo-5-tert-butylisophthalate (28) with sodium benzeneselenolate affords the corresponding monoseleni

Full text of DOI:10.1039/c1dt10862j

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PAPER
Synthesis and structural characterization of pincer type bicyclic
diacyloxy- and diazaselenuranes†
K. Selvakumar,a Harkesh B. Singh,*a Nidhi Goel,b Udai P. Singhb and Ray J. Butcherc
Received 8th May 2011, Accepted 28th June 2011
DOI: 10.1039/c1dt10862j
Synthesis and structural characterization of a new class of pincer type bicyclic diacyloxy- and
diazaselenuranes is reported. The reaction of dimethyl 2-bromo-5-tert-butylisophthalate
(28) with sodium benzeneselenolate affords the corresponding monoselenide, dimethyl
5-tert-butyl-2-(phenylselanyl)isophthalate (29). Reduction of 29 with LiAlH4 provides
5-tert-butyl-2-(phenylselanyl)-1,3-phenylene)dimethanol 31. Oxidation of 29 or its hydrolyzed
derivative, 5-tert-butyl-2-(phenylselanyl)isophthalic acid (30), with H2O2 results in the formation of
bicyclic diacyloxyselenurane (25). The reaction of 30 with aniline using the DCC coupling reaction
gives 5-tert-butyl-N1,N3-diphenyl-2-(phenylselanyl)isophthalamide (38). Reaction of 38 with H2O2
leads to the formation of the corresponding bicyclic diazaselenurane (27) via selenoxide intermediate
39. Compounds 25, 27, 29 and 31 were characterized by single crystal X-ray crystallography. The
structural aspects of the pincer type bicyclic chalcogenuranes are investigated using experimental and
computational studies and compared with the related systems.
Introduction
Spiroselenuranes, a class of selenoorganic compounds, have at-
tracted considerable current interest due to their chiral nature.1
Synthesis of spirodiacyloxyselenurane 1 (Chart 1) was first re-
ported by Lesser and Weiss in 1914.2 The structural determination
of compound 1 revealed a pseudo trigonal bipyramidal geometry
around the selenium center in which the two oxygen atoms
occupy axial positions and two carbons and the lone pair
reside in the equatorial plane.3 Such spirocycles are found to
be chiral due to their molecular dissymmetry. Compounds 14
and 35 have been resolved by HPLC using a chiral column
and their absolute configurations were established. Several other
spirodiacyloxyselenuranes,6 spiroselenuranes/telluranes of mixed
type (alkoxy/acyloxy) such as 47 and oxaselenetanes8 (e.g. 5)
containing both 4- and 5-membered rings have also been reported.
Apart from their stereochemistry, the spiroselenuranes were
found to show excellent glutathione peroxidase (GPx)-like activity.
Glutathione peroxidase is a selenoenzyme which decomposes the
Chart 1
harmful hydroperoxides to harmless water/alcohols.9,10 Back et
al., for the first time, studied the GPx-like activity of spirodioxy-
selenurane 611 and tellurane 7.12
aDepartment of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai, 400076, India. E-mail: chhbsia@chem.iitb.ac.in
The related GPx mimics containing Se–O bonds such as selene-
nate and seleninate esters have also been reported.13 Systematic
studies on GPx-like activities of organochalcogens containing
E–O (E = Se or Te) bonds (6–13) reveal the following fea-
tures; (i) aliphatic compounds are more efficient as GPx-mimics
than the corresponding aromatic analogues, (ii) organotellurium
compounds show better GPx-like catalytic activity than the
corresponding selenium compounds, and (iii) spirocycles with an
electron donating substituent attached to the aromatic ring show
bDepartment of Chemistry, Indian Institute of Technology Roorkee, Roorkee,
247667, India
cDepartment of Chemistry, Howard University, Washington, D.C, 20059,
USA
† Electronic supplementary information (ESI) available: 1H, 13C and 77Se
NMR of 25, 27, 29, 30, 31 and 37. Optimized structures and coordinates
of 1, 24, 25a, 44 and 45. Cyclic voltammogram of 25, 27, 29, 30, 31, 37, 38
and 47. X-ray crystallographic data for 25, 27, 29 and 31. CCDC reference
numbers 823627–823630. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1dt10862j
9858 | Dalton Trans., 2011, 40, 9858–9867
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better catalytic properties because of the rate determining step
being the selenoxide formation.14
Results and discussion
Synthesis
Although detailed studies on GPx-like activity of spirodioxyse-
lenuranes have appeared in the recent past, relatively little attention
has been paid to spirodiazaselenuranes. Spirodiazasulfurane 14
and related compounds have long been known in the literature.15
However, the structural characterization of spirodiazaselenu-
rane/tellurane was not attempted until 2007.16 In an attempt to
make the spirodiazaselenurane 15, Back and co-workers obtained
the ionic compounds 16 and 17.16 Compound 16 was found to be a
more potent catalyst in comparison to the ebselen.17 Very recently,
Mugesh and co-workers reported the synthesis and structure of the
first stable spirodiazaselenurane (22)/tellurane (23) (Scheme 1).18
The mechanism for the cyclization of organochalcogen oxides
(20/21) obtained respectively from diorganyl monochalcogenides
(18/19) has been studied in detail. The comparison of GPx-like
activities of spirochalcogenuranes 22/23 showed that the tellurium
analogue acted as a superior catalyst than the corresponding
selenium analogue.
The SNAr reaction of aryl bromide 28 with the in situ generated
sodium benzeneselenolate afforded monoselenide 29 (Scheme 2).
Scheme 2
It was hydrolyzed to give the carboxylic acid derivative 30.
Oxidation of monoselenide 30 with H2O2 resulted in the formation
of bicyclic selenurane 25 in three hours (Scheme 2). However,
reaction of 29 with H2O2 resulted in the formation of 25 after three
days. The time difference observed for the complete conversion
of 29 and 30 to form 25 is extremely large. It implies that the
cyclization reactions take place via different reaction routes for
29 and 30. Mugesh and co-workers reported that the secondary
amide (18) underwent a rapid intramolecular cyclization to afford
the spirodiazaselenurane (22), whilst the tertiary amide (34) un-
derwent slow hydrolytic cyclization to give spirodioxyselenurane
(1) (Scheme 3, eq 1).18 A similar mechanism could be operating in
the cyclization of 29 and 30 (Scheme 3, eq 2 and 3).
Scheme 1
In the recent past we19 and others20 have been involved in
the synthesis of selenoheterocyclic compounds, such as cyclic
selenenate esters and ebselen analogues, using the SNAr reaction
approach. In these reactions, the two electron withdrawing groups
(CHO, COOH, COOMe and COONHR) at the 2,6-position of
the aryl bromide facilitated the easy incorporation of selenium.19
The resultant organoselenium species have been found to undergo
facile intramolecular cyclization under different reaction condi-
tions. The cyclization is due to the aromatic ring strain resulting
from the intramolecular coordination and steric crowding around
the selenium center.21 We envisaged that a new class of pincer
type bicyclic diacyloxy- and diazaselenurane (25 and 27) related
to spirobicylic systems (1–15) could be easily synthesized using the
strategy where two carboxylate or two amide groups forming the
bicycles were present on the same phenyl ring. Synthesis of such
bicyclic compounds (24 and 26) is known in sulfur chemistry.22
However, similar cyclic compounds are not known in the selenium
chemistry. In addition, we probe the nature of O–E–O (E = S, Se
and Te) bonding present in the bicyclic chalcogenuranes 24 and 25
using computational chemistry and IR spectroscopy and compare
them with related systems.
Scheme 3
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The reduction of monoselenide 29 with lithium aluminum
hydride provides compound 31. The reaction of monoselenide
31 with an excess of hydrogen peroxide results in the formation of
a mixture of selenoxide 32 and dialkoxyselenurane 33 (Scheme 2)
(based on 77Se NMR spectroscopy). However, it was difficult to
separate the bicylic selenurane 33 from the mixture. Selenium
compounds with redox-active quinone moieties have attracted
considerable interest due to their potential antioxidant activity and
anticancer activity.23 Therefore, the synthesis of bicyclic selenu-
ranes containing a naphthoquinone moiety has been undertaken.
The reductive cleavage of the Se–Se bond in 35 with sodium
metal in the presence of a catalytic amount of naphthalene
afforded sodium selenolate 36 in situ. Sodium selenolate 36, on
treatment with 2-bromo-1,4-naphthoquinone, gave compound 37
(Scheme 4). However, attempted cyclization of 37 with H2O2
resulted in the formation of an intractable mixture.
Fig.
1
Molecular structure of 29 (drawn at 50% ellipsoid). Sig-
nificant bond lengths (A) and angles (◦): Se(1) ◊ ◊ ◊ O(1) 2.843(2),
Se(1)–C(1) 1.927(5), Se(1)–C(11) 1.917(3), C(11)–Se(1)–C(1) 100.13(8),
C(11)–Se(1) ◊ ◊ ◊ O(1) 155.24(6).
˚
1.927(5), which is almost equal to the bond length of C(11)–Se(1)
˚
(1.917(3) A).
One of the carbonyl oxygens of the ester group is in close
proximity to the selenium. The Se(1) ◊ ◊ ◊ O(1) secondary bonding
˚
distance was found to be 2.843(2) A, which is less than the sum
24
˚
of van der Waals radii of Se and O (3.40 A). This Se ◊ ◊ ◊ O
Scheme 4
bond distance is very close to the Se ◊ ◊ ◊ O bond distance observed
25
˚
for bis(o-formylphenyl) selenide (40) (2.806 A). However, it is
˚
Having achieved the synthesis of selenurane 25, we thought to
extend this procedure for the synthesis of bicyclic diazaselenurane
27 (Scheme 5). The reaction of monoselenide 30 with aniline
using DCC coupling resulted in the formation of monoselenide
38. The monoselenide 38, upon reaction with H2O2, resulted in
the formation of bicyclic diazaselenurane 27, presumably via the
selenoxide intermediate (39).
significantly shorter than that observed for 18 (3.234 A) which has
an amide group as a donor.18 The O(1) ◊ ◊ ◊ Se(1)–C(11) bond angle
was 155.24(6)◦. These features suggest that the presence of the hy-
pervalent interaction between selenium and O(1).26 Interestingly,
the geometrical features around selenium in compound 29 are
quite different from the geometry observed around selenium in 4-
tert-butyl-2,6-di(formyl)phenyl phenyl selenide 41 and compound
31 (vide infra), in which both the oxygen atoms are pointed
away from selenium. It is essentially due to the conformational
constraints present in the 2,6-disubstituted systems which restricts
the rotation of the ester groups along the C–C bond.
Molecular structure of 31. Compound 31 crystallizes in the
monoclinic crystal system (Fig. 2). The molecular geometry
around selenium is V-shaped with a C(1)–Se–C (13) bond angle of
99.64(16)◦. Aromatic rings are found to be mutually perpendicular
with an interplanar angle of 84.24◦. Interestingly, out of the two
hydroxyl groups, none are coordinated to the selenium. A similar
situation was also found in the case of the selenide with two
formyl groups around selenium.19c This may be due to the poor
electron donating property of the OH group and the availability
of rotational degrees of freedom along the (Ar)C–C(CH2) bonds
which could prevent the O ◊ ◊ ◊ Se ◊ ◊ ◊ O repulsive interaction.21 The
compound shows hydrogen bonding interactions between the
hydroxyl groups (Fig. 3).
Scheme 5
X-Ray crystallographic study
Molecular structure of 29. The molecular structure of monose-
lenide 29 is given in Fig. 1. It crystallizes in a monoclinic crystal
system. The geometry around the selenium is V-shaped with a
C(11)–Se(1)–C(1) bond angle of 100.13(8)◦. Both of the ester
carbonyl groups are not in plane with the aromatic ring plane.
The interplanar angle between the aryl ring and the phenyl ring
is 66.41◦. The bond length of the C(1)–Se(1) covalent bond is
Molecular structure of 25. Diacyloxyselenurane 25 crystallizes
in a monoclinic crystal system (Fig. 4). The geometry around
9860 | Dalton Trans., 2011, 40, 9858–9867
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˚
distance between Se(1) and C(5) is 1.869(2) A, whereas the distance
˚
between Se(1) and C(13) is 1.921(2) A. It could be due to the
electron withdrawing nature of the two carboxylate groups which
strengthens the Se(1)–C(5) bond (vide infra).
The O(3)–Se–O(2) angle is 163.86 (7)◦, which is significantly
smaller than that observed for 1 (172.4(3)◦), the monocyclic
selenurane 42 (169.9 (2)◦)28 and spiroselenurane 6 (172.99◦).11
However, it is in close ◦agreement with the corresponding angles
163.4(2)◦ and 165.8(2) , observed for the 1,2-oxaselenetane 58a
and spirocyclic selenurane 43,29 respectively.
Fig. 2 Molecular structure of◦31 (drawn at 50% ellipsoid). Significant
˚
bond lengths (A) and angles ( ): Se–C(1) 1.927(3), Se–C(13) 1.914(4),
C(13)–Se–C(1) 99.64(16).
In an idealized TBP structure, the axial bond angle must be 180◦.
However, this angle is severely affected by the stereoelectronic
environment around the central atom. The lone pair effect is
predominant in divalent and tetravalent group 16 organometallic
and inorganic compounds and causes deviation of the angle
from the ideal 180◦. For instance, 1, 6 and 42 have significantly
smaller axial bond angles than the ideal 180◦. However, the angles
observed in 5 and 43 are even smaller than those observed in
1, 6 and 42. The reason for the smaller axial O–Se–O angle in
compound 5 could be accounted for using the ring size effect.
The fused 5-membered ring and the 4-membared ring at selenium
may lead to the reduced axial O–Se–O angle. Day and Holmes
explained that a larger deviation of the O–Se–O angle from
180◦, observed in 43, may result from repulsion of the lone pair.
Compound 25 is somewhat closer to 1 than the other related
compounds. The significant deviation of the O–Se–O angle in 25 in
comparison to 1 may presumably result from the conformational
constraints in which both the carboxylates are in the pincer
position (vide infra).
Fig. 3 1-D packing diagram of 31 showing hydrogen bonding interaction.
Molecular Structure of 27. Compound 27 crystallizes in mon-
oclinic crystal system with P 1 21/c 1 space group (Fig. 5). The
geometry aroundselenium is pseudo trigonal bipyramidal in which
two Se–N bonds occupy the axial positions and two Se–C bonds
and a lone pair occupy the equatorial plane. The phenyl ring
attached to the N(2) is almost planar with the bicyclic selenurane
ring, with an interplanar angle of 3.45◦ and the phenyl rings
attached to N(1) and Se have interplanar angles of 42.26◦ and
81.40◦, respectively, with respect to the bicylic selenurane ring. The
Fig. 4 Molecular structure of compound 25 (drawn at 50% ellipsoid).
Significant bond lengths (A) and angles (◦): Se(1)–C(5) 1.869(2),
˚
Se(1)–C(13) 1.921(2), Se(1)–O(3) 2.012(2), Se(1)–O(2) 2.016(2),
C(5)–Se(1)–C(13) 103.35(8), C(5)–Se(1)–O(3) 82.20(8), C(13)–Se(1)–O(3)
91.22(7), C(5)–Se(1)–O(2) 81.76(8), C(13)–Se(1)–O(2) 90.72(8),
O(3)–Se(1)–O(2) 163.86(7).
˚
selenium is pseudo trigonal bipyramidal (TBP) in which two
Se–O bonds occupy the axial positions, two Se–C bonds and a lone
pair occupy the equatorial positions. The phenyl ring of 25 bisects
its bicyclic selenurane ring with an interplanar angle of 86.54◦.
distances between Se and N are; Se–N (1), 2.041(1) A and Se–N
˚
(2), 2.122(1) A. These are significantly longer than the length of a
normal covalent Se–N bond (1.87 A) and are slightly shorter than
those (2.180(7) and 2.154(7) A) observed for a divalent selenium
˚
˚
cation (2,6-bis[(dimethylaminomethyl)phenyl] selenenium ion).30
It could be expected that the elongated Se–N bond lengths in
27 are due to the hypervalent bonding interactions in which one
of the nitrogen atoms behaves as a donor and another Se–N s*
orbital acts as an acceptor. The Se–N bond distances are noticeably
different from the Se–N distances observed in compound 22. The
Se–N distances are unsymmetrical in compound 27, whereas these
distances are almost symmetrical in compound 22. This may be
due to the steric interaction between the three phenyl groups. It
˚
The Se–O bond distances are (Se(1)–O(3) 2.012(2) A, Se(1)–O(2)
˚
2.016(2) A) significantly elongated than the usual covalent Se–
O bond limit (1.83 A). These are longer by about a distance of
˚
˚
˚
0.038(2) A and 0.043(2) A than the distances observed for the
axial Se–O bonds in 1. Three polymorphs of 1 with different space
groups (C2/c,3 P21,4 Pca2127) are reported in the literature. In
all the polymorphs of 1, the Se–O distances and O–Se–O angles
are conserved. Another interesting feature of compound 25 is the
presence of asymmetry in C–Se bond lengths. The covalent bond
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◦
˚
Table 1 Bond lengths and bond angles (A and
)
Entry
E–C(5)
E–C(13)
E–O(2)
E–O(3)
O(2)–E–O(3)
24
25a
44
45
1
1.768
1.884
2.060
1.825
1.936
1.824
1.969
2.145
1.825
1.936
1.899
2.024
2.125
1.879
1.996
1.933
2.024
2.125
1.879
1.991
170.30
164.54
154.87
176.51
172.49
minima in the potential energy surface. The calculated E–O bond
length and O–E–O angles are summarized in Table 1. It shows
that the E–C(5) bond lengths in 24, 25a and 44 are significantly
shorter than that of the corresponding E–C(13) bond length. This
feature is experimentally observed in the X-ray crystallographic
structure of 25 (vide supra). However, E–C(5) and E–C(13) bonds
are more symmetrical in spirocyclic sulfurane 45 and selenurane
1. The E–C(13) distances in 24, 25a and are nearly equal to the
E–C(5) and E–C(13) in 45 and 1. In the case of pincer type bicyclic
chalcogenuranes (24, 25a and 44), the difference in bond lengths
between E–C(5) and E–C(13) is larger while going from S (24,
Fig. 5 Molecular structure of compound 27 (drawn at 50% ellipsoid).
◦
˚
Significant bond lengths (A) and angles ( ): Se–C(1) 1.877(2), Se–C(25)
1.947(2), Se–N(1) 2.041(1), Se–N(2) 2.122(1), C(1)–Se–C(25) 103.22(7),
C(1)–Se–N(1) 81.50(6), C(25)–Se–N(1) 91.18(6), C(1)–Se–N(2) 80.44(6),
C(25)–Se–N(2) 90.83(7), N(1)–Se–N(2) 161.81(6).
˚
˚
˚
0.056 A) to Se (25a, 0.085 A) = Te (44, 0.085 A). It reflects that
the Se–C(5) and Te–C(5) bonds in 25a and 44, respectively, are
shorter and stronger than the S–C(5) bond in 24 (vide infra).
To further understand this phenomenon, natural bond orbital
(NBO) second order perturbation analysis31 has been carried on
these systems. The results are summarized in Table 2. It shows
that the negative charge on the O(2) and O(3) atom increases
while going down the group (S (24) < Se (25a) < Te (44)) and
the positive charge on the central chalcogen center increases while
going down the group (S (24) < Se (25a) < Te (44)). In addition,
the donor–acceptor (O- → s* E–O) characteristics decrease
while going down the group. A small amount of donor–acceptor
interaction energy was observed only for sulfur compounds 24 and
45. Other model compounds having Se and Te do not have any
donor–acceptor interaction energy. This is clearly evident from
the O(2)–E–O(3) bond angles which decrease while going down
the group. It indicates the poor overlap of the orbital contributing
to the O(2)–E–O(3) bond in the heavier chalcogens (Se and Te).
It could be viewed that the charge separation in O(2)–E–O(3)
of the hypervalent bond enhances while going down the group.
This is presumably due to more diffuse nature of the valence
is also possible that the intermolecular (C–H ◊ ◊ ◊ O) interaction
between the O atoms of the carbonyl groups with the H atoms
of the adjacent molecules in the crystal lattice may lead to the
unsymmetry in the Se–N bond distance. To validate this, a set of
related molecules have been optimized using density functional
calculations. It has been found that the similar model compounds
have nearly symmetrical Se–N bond lengths in the gas phase
(See ESI†). This partly suggests that the unsymmetry in the Se–
N distance presumably results from the intermolecular packing
forces pre◦sent in the crystal lattice. The N(1)–Se–N(2) angle in 27 is
161.81(6) which is significantly smaller than that observed in 2218
(174.33(9)◦) and it is closer to the angle observed for the divalent
selenium cation (2,6-bis[(dimethylaminomethyl)phenyl] selenium
ion) (161.9(3)◦).30 This further supports the fact that observed dis-
crepancies in the axial bond angles (X–Se–X, X = O or N) between
bicyclic diacycloxy/diamide selenuranes (25/27) and spirobicyclic
diacycloxy/diamide selenuranes (1/22) are essentially due to the
pincer type orientation of the carboxylate/amide groups forming
Se–X bonds in the former (25/27).
Computational studies on the nature of the Se–O bond
To understand the nature of the Se–O bonding in selenurane
25, we have carried out DFT calculations on bicyclic 24, model
chalcogenuranes 25a and 44, and spirobicyclic chalcogenuranes 1
and 45.
Table 2 Natural charges and IR stretching frequencies
a
a
a
Entry qE
qO2
Eb
qO3
Eb
IR nCO(cm-1)
24
1.195 -0.711
1.428 -0.751
3.74
—
-0.716
-0.751
3.01 1722 (CHCl3)c
—
25a
1698 (KBr)d
1701 (CHCl3)d
—
44
46
1.977 -0.842
-0.842
—
—
—
—
—
—
1664 (KBr)e
1686 (CHCl3)h
45
1.199 -0.727
3.96
-0.727
3.95 1729 (Acetonitrile)f
1722 (DMSO)f
1724 (CHCl3)c
1
1.429 -0.752
—
-0.752
—
1695 (KBr)g
The conformation observed in the solid structure of 25, where
the phenyl ring bisects the selenurane ring, has not been found as
minima in the gas phase (25b). The conformation 25a in which the
phenyl ring plane only cuts the axial atoms (O(3), O(2) and Se)
with an interplanar angle of 75.69◦ (See ESI†) has been found as
a q denotes NPA charges on E and O; b Second-order perturbation energy
(kcal mol-1) for the orbital interaction of O- with the s* orbital of opposite
E–O bond; c Reference 32; d This reference, it is for 25; e Reference 33;
f Reference 34; g Reference 12 h This reference
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p-orbital present in heavier chalcogens. Therefore, it partly reveals
that the ionic character in the O–E bond increases while going
down the group. It is further supported by the IR experiments.
The nCO asymmetric stretching vibrations observed in bicyclic
chalogenuranes is follows; 24 > 25 > 46.
action of diaryl monoselenides. In compound 37, the oxidation
at the selenium center occurs at 1.453 V, which is much higher
than those observed for the other monoselenides in the series. It
indicates that oxidation of selenium in 37 would be more difficult.
However, its catalytic activity is nearly doubled in comparison to
the control reaction and other monoselenides. The slightly higher
GPx-like activity of 37 in comparison to the other monoselenides
is presumably due to the quinone moiety.37 It was further
demonstrated from the activity of 1,4-naphthoquinone (47) which
is nearly equal (1.83) to the activity of 37 (2.04). Compound 37
showed two reversible redox couples, one at E1/2 of -0.917 V and
another at a E1/2 of -1.498 V in its cyclic voltammogram. The
corresponding redox couples of 47 are centred at E1/2 of -0.991 V
and -1.548 V, respectively. Therefore, the slightly better peroxide
reduction activity of 37 in comparison to the other monoselenides
could be due to the reversible quinone/hydroquinone (Q/QH2)
redox couple.
Therefore, the shorter E–C(5) bond lengths in 24, 25a and 44
could probably result from the following resonance contribution.
The electron withdrawing carbonyl groups withdraw the electron
density from the chalcogen center via a p-bonding framework.
As is mentioned above, the charge on the central chalcogen
center increases while going down the group. This may lead to
the contraction of the metal valence orbital which in turn could
provide a better orbital overlap between the S/Se/Te and C(5)
carbon atoms. Shortening is appreciable while going from S to Se.
However, no shortening was observed while going from Se to Te
(vide supra). It could be attributed to the energy mismatch of the
2p orbital of carbon and 5p orbital of tellurium, which leads to
the poor 2p–5p orbital overlap.
Conclusions
Synthesis of new bicyclic selenuranes has been achieved using
the SNAr reaction. Intermolecular crystal packing forces cause
asymmetry in the Se–N bond distances in compound 27. The
axial bond angles in the pincer type bicyclic chalcogenuranes
decrease along the group. The computational calculations and
IR studies (nCO stretching frequencies) on such systems indicate
that the increase of the ionic character in O–E bonds while going
from S to Te. The O–E–O angles in the spirobicyclic selenuranes
are slightly higher than the corresponding angle observed in the
pincer type bicyclic chalcogenuranes, which may arise from the
conformational constraints. The slightly better peroxide reduction
activity of 37 in comparison to the related monoselenides may arise
from the catalytic action of the naphthoquinone moiety.
If these canonical structures contribute significantly to the
ground state electronic structures of 24, 25a and 44, the expected
C–E–C angles must increase while going from S to Se and Te. In
contrary, the calculated bond angles (C–E–C) are 109.38◦ (E = S,
24), 100.96◦ (E = Se, 25a), and 101.45◦ (E = Te, 44). It suggests
that the steric requirement of the lone pair plays a predominant
role in defining the ground state electronic structures of the Se and
Te species.35
GPx-like activity
Glutathione peroxidase-like activity of the selenuranes 25, 27,
monoselenides 29, 30, 31 and 37 and ebselen were studied using
the coupled reductase assay method (Table 3). The GPx-like
activities of the monoselenides, except 37, are nearly equal to the
control reaction. Compound 37 and ebselen showed significant
activity under the same assay conditions.36 It is expected that the
oxidation of the selenium center is the first step for the catalytic
Experimental section
General experimental procedures
All organoselenium compounds were synthesized using standard
vacuum-line techniques under a nitrogen or argon atmosphere,
unless mentioned otherwise. Solvents were purified by standard
Table 3 GPx-like activity of monoselenides and selenuranes
d
E
pa/Epc (V)
Initial Rate (V0) (mM min-1)a
Activityb
Epa1 (V)
Epa2
Epc1
c
Entry
Control
Ebselen
25
10.56 0.33
35.69 1.55
12.91 0.09
12.80 0.57
12.54 0.89
13.07 0.49
11.74 0.28
21.49 0.24
1.00
3.39
1.22
1.21
1.19
1.24
1.11
2.04
—
—
—
—
—
—
—
—
—
-0.879
-1.464
-0.950
-1.463
—
—
—
—
—
1.280
1.366
0.977
0.761
0.895
1.453
27
29
30
31
—
37
-0.954
-1.532
-1.033
-1.633
47
19.34 0.61
1.83
—
a Rate of consumption of NADPH per minute; b Relative GPx-like activities of the compounds are expressed with respect to the background reaction
where the catalyst is absent; c Epa1 for selenium centred oxidation; d
pa/Epc for quinone centred oxidation/reduction (Epa2/Epc1).
E
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Table 4 Structure refinement data for 25, 27, 29 and 31
25
27
29
31
Empirical formula
Formula weight
Crystal system
Space group
C18 H16 O4 Se
C30H26N2O2 Se
525.49
C20H22O4 Se
405.34
C18H22O2Se
349.32
375.27
Monoclinic
P 21/c
8.1010(7)
10.8845(9)
17.6635(15)
90
94.607(4)
90
1552.5(2)
4
1.606
2.437
24122
0.0357
0.0875
5896/0/211
1.024
Monoclinic
P 1 21/c 1
10.01795(14)
24.1373(2)
11.14207(15)
90
115.5854(17)
90
2430.03(5)
4
1.436
2.332
11509
0.0317
Monoclinic
P 21/n
11.292(3)
10.3574(19)
15.966(4)
90
93.061(8)
90
1864.7(8)
4
1.444
2.034
17061
0.0284
Monoclinic
P 1 21/n 1
9.4749(4)
20.7654(6)
9.4830(5)
90
119.536(6)
90
1623.31(12)
4
1.429
2.315
19227
0.0584
˚
a (A)
˚
b (A)
˚
c (A)
a (◦)
b (◦)
g (◦)
3
˚
V (A )
Z
rcalcd (M gm-3)
Absorption coefficient (mm-1)
Reflections collected
Final R(F) (I > 2s(I))a
wR(F2) indices (I > 2s(I))
Data/restraints/parameters
Goodness-of-fit on F2
0.0840
5095/0/319
1.014
0.0740
4053/0/231
1.041
0.1337
5417/0/196
1.135
a Definitions: R(Fo) = RꢀFo| - |Fcꢀ/R|Fo| and wR(Fo2) = {R[w(Fo - Fc2)2]/R[w(Fo2)2}
.
2
1/2
procedures and were freshly distilled prior to use. All chemicals
used were of reagent grade and were used as received. 1H
(400.1 MHz), 13C (100.6 MHz) NMR spectra were obtained
on a Varian VXR-400S NMR/Bruker AV-400 spectrometer and
77Se (57.3 MHz) on a Varian VXR-300S NMR spectrometer.
Chemical shifts are cited with respect to TMS (1H, 13C) as the
internal standard and Me2Se (77Se) as an external standard.
Elemental analysis was performed on Carlo Erba model 1106
elemental analyzer. Mass spectral studies were carried on a Q-TOF
micro (YA-105) mass spectrometer with electrospray ionization
mode (MS-ES), Positive mode) analysis. In the case of isotopic
patterns, the m/z value is given for the most intense peak. FT-
IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR
spectrometer with KBr pellets. The single crystal X-ray diffraction
measurements (Table 4) for compounds 25 and 31 were performed
on an Oxford Diffraction Gemini diffraction measurement device
measurements are 50 or 100 mV per second (50 or 100 mV s-1).
The Epa for selenuranes 25 and 27 are obtained after five repetitive
reduction cycle.
GPx-like activity
The reaction was carried out at room temperature (25
1
◦C).
The reaction was carried out in 1.00 mL of phosphate buffer
(100 mM, pH 7.5) containing, 1 mM ethylenediaminetetraacetic
acid (EDTA), 0.23 mM NADPH, and 20 mM catalyst. The initial
reduction rate (5–10% consumption of NADPH) was expressed
as mM of NADPH depleting per minute (mM min-1). After
addition of H2O2, the decrease in NADPH concentration was
monitored at 340 nm (emax = 6.22 ¥ 103 M-1 cm-1) using JASCO
spectrophotometer as a measure of GPx-like activity. Each of the
measurements were carried out in triplicate.
˚
with graphite monochromated MoK\a radiation (l = 0.7107 A).
Syntheses
The single crystal X-ray diffraction measurements for compound
29 were performed on an Oxford Bruker Apex 2 diffraction mea-
surement device with graphite monochromated MoK\a radiation
Synthesis of 29. THF (50 mL) was added to a mixture of
diphenyl diselenide (3.8 g, 12 mmol), freshly cut sodium (0.60 g,
26 mmol) and a catalytic amount of naphthalene in a three
necked, round bottom flask. The reaction mixture was stirred
at 50 ◦C for 6 h. Aryl bromide 28 (8.1 g, 25 mmol) in THF
(20 mL) was then added to the reaction mixture at 0–5 ◦C and
the mixture stirred at room temperature for a further 2 h. The
reaction mixture was poured into water and extracted twice with
CHCl3 (2 ¥ 150 mL). The combined organic layers were evaporated
to get a pale yellow solid. It was recrystallized from a chloroform
and ethyl acetate mixture (3 : 1). Yield: 5.7 g (58%). m.p.: 132–
134 C. H NMR (CDCl3): d 7.73 (2H, s, Ar–H) 7.37(2H, m,
Ph–H), 7.22 (3H, m, Ph–H), 3.69 (6H, s, –OCH3), 1.33 (9H, s,
C(CH3)3). 13C NMR (CDCl3): d 168.1 (C O), 150.7, 136.9, 132.9,
132.6, 129.5, 129.0, 129.1, 127.3 (Ar and Ph–C), 52.3 (OCH3),
34.8 (C(CH3)3), 31.0 (C(CH3)3). 77Se NMR (CDCl3): d 418; FT-
IR (KBr, cm-1): 2952, 1733 (COO), 1716 (COO), 1436, 1289,
1249, 1217, 1203, 1180, 1007, 778, 692. ES-HRMS: m/z calcd
for C20H22O4Se: 406.07. Found: 424.10 [M+O+2H]+ (50%), 407.08
˚
(l = 0.7107 A). The single crystal X-ray diffraction measurements
for compound 27 were performed on Xcalibur, Ruby, Gemini
diffraction measurement device with graphite monochromated
˚
CuK\a radiation (l = 1.5418 A). The structures were solved
by direct methods (program SHELXS-97) and full-matrix least
squares refinement on F2 (program SHELXL-97).38 Aryl bromide
28 was synthesized by a reported synthetic procedure.39
Cyclic voltammetry experiments
◦
1
Cyclic voltammetry experiments were carried out on CH Instru-
ments 600A electrochemical analyzer. The solvent acetonitrile
was purified by standard techniques. Tetrabutyl ammonium
perchlorate (0.1 M) was used as an electrolyte. The analyte con-
centration was 0.001 M. A platinum microelectrode, an Ag+/Ag
electrode, and platinum wire were used as working, reference and
counter electrodes, respectively. The scan rates for each of the
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[M+H]+ (100%), 375.05 [M-OMe]+ (90%), 329.03 [M-Ph]+ (25%).
Anal. Calcd for C20H22O4Se: C 59.26, H 5.47. Found: C 58.52, H
5.54.
room temperature for an additional 20 min. It was then poured
into water and extracted with CHCl3 (2 ¥ 30 mL). The combined
organic layers were dried over sodium sulfate and evaporated to
get a yellowish orange solid. The solid obtained was recrystallized
from a petroleum ether– ethyl acetate (3 : 1) mixture. Yield: 0.26 g
Synthesis of 30. Monoselenide 29 (1.2 g, 3.0 mmol) was
dissolved in THF (15 mL) under a nitrogen atmosphere. To this, an
aqueous solution (15 mL) of sodium hydroxide (0.48 g, 12 mmol)
was added dropwise. The resultant solution was stirred at room
temperature for 18 h. The reaction mixture was neutralized with
concentrated hydrochloric acid, added drop-by-drop until it gave a
Congo red to the pH paper. The precipitate obtained was dissolved
in ethyl acetate (150 mL). The organic layer was washed twice
with water, then with brine, and dried over sodium sulfate. The
volume of the dried organic layer was reduced to about 15 mL by
rotary evaporator, which resulted in the formation of a pale yellow
precipitate. The precipitate obtained was filtered with a Buckner
funnel and washed with an ethyl acetate–petroleum ether (1 : 2)
mixture. It was ◦recrystallized from ethyl acetate. Yield: 1.0 g (88%).
1
(24%). H NMR (CDCl3): d 8.12 (1H, d, J = 6.8 Hz, Quinone-
H), 8.03 (1H, d, J = 6.8 Hz, Quinone-H), 7.85 (2H, s, Ar–H),
7.23 (m, 2H, Quinone-H), 6.37 (1H, s, Quinone-H), 3.84 (6H,
s, OCH3), 1.40 (9H, s, C(CH3)3). 13C NMR (CDCl3): d 182.9
(C O, Quinone), 181.7 (C O, Quinone) 167.6 (COO), 155.6,
154.4, 140.3, 134.2, 133.9, 133.3, 132.3, 131.5, 129.1, 126.8, 126.6,
118.2, 109.9 (Ar–C + Quinone-C), 52.6 (OCH3), 35.1 (C(CH3)3),
30.9 (C(CH3)3). 77Se NMR (CDCl3): d 386. FT-IR (KBr, cm-1):
2953, 1733 (COO), 1665, 1651, 1589, 1568, 1434, 1334, 1295,
1251, 1215, 1100, 1176, 990, 778, 695, 594. ES-MS: m/z Calcd for
C24H22O6Se: 486. Found: 509 [M+Na]+(5%), 487 [M+H]+(34%),
455 [M-OMe]+ (100%). ES-HRMS: m/z calcd for C24H22O6Se:
486.06. Found: 487.07 [M+H]+ (100%), 455.04 [M-OMe]+ (65%).
Anal. Calcd for C24H22O6Se: C 59.39, H, 4.57. Found: C 58.91, H
4.62.
1
m.p.: 250–252 C. H NMR (DMSO-d6): d 7.67 (2H, s, Ar–H),
7.22 (5H, m, Ph–H), 1.30 (9H, s, C(CH3)3); 13C NMR (DMSO-
d6): d 168.8 (C O), 151.0, 139.3, 132.6, 131.9, 129.2, 127.7, 127.6,
127.0, 124.7 (Ar and Ph–C), 34.6 (C(CH3)3), 30.8 (C(CH3)3). 77Se
NMR (DMSO-d6): d 413. FT-IR (KBr, cm-1): 3070, 2966, 2549,
1710 (COO), 1438, 1423, 1297, 1255, 1226, 1201, 903, 739, 689. ES-
MS: m/z calcd for C18H18O4Se: 378. Found: 401 [M+Na]+ (4%),
361 [M-OH]+ (80%), 301 [M-Ph]+ (100%). ES-HRMS: m/z calcd
for C18H18O4Se: 378.04. Found: 396.07 [M+O+2H]+ (35%), 379.05
[M+H]+ (50%), 361.03 [M-OH]+ (100%), 300.99 [M-Ph]+ (80%).
Anal. Calcd for C18H18O4Se: C 57.30, H 4.81. Found: 57.81, H
5.40.
Synthesis of 38. Dry THF (15 mL) was added to a mixture
of monoselenide 30 (0.98 g, 2.6 mmol) and HOBT (0.72 g,
5.3 mmol). Aniline was then added to the reaction mixture and
it was kept under ice cold conditions for 10 min. To the above
was added a solution of dicyclohexyl carbodiimide (DCC) (1.1 g,
5.3 mmol) in THF (10 mL). The ice bath was removed after the
addition and the reaction mixture was stirred at room temperature
for 6 h. The precipitated dicyclohexyl urea (DCU) formed was
filtered through a sintered funnel and concentrated on a rotary
evaporator to give a semi-solid which was dissolved in CHCl3
(50 mL) and washed with 5% aq NaOH followed by 1 N HCl
finally with brine. The organic layer dried over sodium sulfate
was evaporated and recrystallized from ethyl acetate to give the
desired compound. It was recrystallized from a petroleum ether–
ethyl acetate (1 : 3) mixture. Yield: 0.57 g (42%). 1H NMR (CDCl3):
d 7.77–7.09 (19 H, m, Ar and Ph–H), 1.36 (9H, s). 77Se NMR
(CDCl3): d 358. FT-IR (KBr, cm-1), 3395 (N–H), 2965, 1675
(CONH), 1658, 1597, 1520, 1438, 1316, 755, 691, 512. ES-MS: m/z
Calcd for C30H28N2O2Se: 528. Found: 529 [M+H]+(13%), 436 [M-
PhNH]+(100%). ES-HRMS: m/z calcd for C30H28N2O2Se: 528.13.
Found: 529.14 [M+H]+ (100%), 436.08 [M-PhNH]+(90%).
Synthesis of 31. Lithium aluminum hydride (0.15 g, 4.0 mmol)
was placed in a three necked round bottomed flask and kept under
nitrogen. To this, a solution of monoselenide 29 (0.82 g, 2.0 mmol)
in dry THF (30 mL) was added dropwise over a period of 20 min
in ice cold conditions. The reaction mixture was stirred at room
temperature for 3 h. The unreacted lithium aluminum hydride
was quenched with water (dropwise addition) under nitrogen. The
reaction mixture was poured in water, acidified with 1 mL of
dilute HCl, then extracted with ethyl acetate. The organic layer
was washed with water and dried over sodium sulfate. It was
evaporated to get a pale yellow solid which was recrystallized from
a chloroform–◦ethyl acetate mixture (3 : 1). Yield: 0.26 g (37%).
m.p.: 140–142 C. 1H NMR (CDCl3): d 7.53 (2H, s, Ar–H), 7.20–
7.09 (5H, m, Ph–H), 4.79 (4H, s, CH2), 2.20 (2H, s (br), OH), 1.36
(9H, s, C(CH3)3). 13C NMR (DMSO-d6): d 151.9, 145.5, 132.5,
129.5, 128.7, 126.1, 122.8, 121.1 (Ar and Ph–C), 63.6 (CH2), 34.7
(C(CH3)3), 31.2 (C(CH3)3). 77Se NMR (CDCl3): d 250. FT-IR
(KBr, cm-1): 3352 (OH), 2965, 2950, 1577, 1477, 1437, 1225, 1060,
1013, 889, 734, 690, 666. ES-HRMS: m/z calcd for C18H22O2Se:
350.08. Found: 368.11 [M+O+2H]+ (25%), 351.09 [M+H]+ (2%),
333.08 [M-OH]+ (60%), 315.06 [M-OH-H2O]+ (100%). Anal. Calcd
for C18H22O2Se: C 61.89, H 6.35. Found: C 61.83, H 5.68.
Synthesis of 25. An excess of hydrogen peroxide was added
to a methanolic solution (10 mL) of monoselenide 30 (0.11,
0.03 mmol) in a round bottomed flask. The slow evaporation of
methanol allowed the precipitation of the product after 3 h. The
reaction mixture was concentrated to 2–3 mL. The precipitate
obtained was filtered using a Buckner funnel and washed twice
with water to give diacyloxy selenurane 25. It was recrystallized
from a mixture of methanol and chloroform (1 : 2). Yield: 0.08 g
(71%). m.p.: 263–265 ◦C. 1H NMR (CDCl3): d 8.45 (2H, s,
Ar–H), 7.26 (1H, m, Ph–H) 7.51 (4H, m, Ph–H), 1.47 (9H, s,
C(CH3)3). 13C NMR (CDCl3): d 167.2 (CO), 162.7, 138.5, 133.3,
130.7, 130.3, 130.1, 127.6 (Ar and Ph–C), 36.5 (C(CH3)3), 31.5
(C(CH3)3). 77Se NMR (CDCl3): d 742. ES-MS: m/z calcd for
C18H16O4Se: 376. Found: 377 [M+H]+(100%). ES-HRMS: m/z
calcd for C18H16O4Se: 376.02. Found: 377.03 [M+H]+ (100%). FT-
IR (KBr, cm-1) 2965, 1698 (COO), 1477, 1445, 1309, 1241, 1131,
Synthesis of 37. THF (25 mL) was added to a mixture of
diselenide 35 (0.66 g, 1.0 mmol), naphthalene (catalytic amount)
and sodium metal (0.05 g, 2.2 mmol), in a three necked round
bottomed flask. The reaction mixture was stirred at room tem-
perature for 8 h. To this was added 2-bromo-1,4-naphthoquinone
(0.53 g, 2.2 mmol) in three portions. The reaction was stirred at
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1115, 919, 754, 731, 585; Anal calcd for C18H16O4Se: C 57.61, H
4.30. Found: C 57.02, H 4.10.
(b) R. Brigelius-Flohe´, Free Radical Biol. Med., 1999, 27, 951–965; (c) P.
Mauri, L. Bennazi, L. Flohe´, M. Maiorino, P. G. Pietta, S. Pilawa, A.
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Synthesis of 27. 0.100 mL of 30% H2O2 was added to the
stirred solution of monoselenide 38 (0.12 g, 0.2 mmol) in 15 mL
of methanol. The reaction mixture was stirred for 3 h at room
temperature. The solvent was evaporated on a rotary evaporator
and the residue was recrystallized from ethyl acetate to give a
colorless solid. It was dissolved in CHCl3 (2.5 mL) in a 3 mL
sample vial and kept at room temperature for one week. The pale
yellow crystals obtained were washed with◦ether and dried under
vacuum. Yield 0.04 g (38%); m.p.: 259–261 C. 1HNMR (CDCl3):
d 8.50 (2H, s, Ar-H), 7.42–6.89 (15H, m, Ph–H), 1.53 (9H, s,
C(CH3)3). 13C NMR (CDCl3): d 162.8 (CO), 161.3, 139.9, 138.0,
134.8, 132.2, 130.2, 129.3, 127.7, 125.8, 125.7, 125.5, 125.2 (Ar and
Ph–C), 36.4 (C(CH3)3), 31.5 (C(CH3)3). FT-IR (KBr, cm-1): 1653
(CON), 1631, 1614, 1592, 1488, 1359, 869, 738, 690, 473. ES-MS:
m/z Calcd for C30H26N2O2Se: 526. Found: 527 [M+H]+(100%).
ES-HRMS: m/z calcd for C30H26N2O2Se: 526.12. Found: 527.12
[M+H]+ (100%). Anal. Calcd for C30H26N2O2Se: C 68.57, H 4.99,
N 5.33. Found: C 67.81, H 4.61, N 4.56.
10 For reviews on GPx mimetics, See: (a) G. Mugesh and H. B. Singh,
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14 D. J. Press, E. A. Mercier, D. Kuzma and T. G. Back, J. Org. Chem.,
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Computational details
All calculations were performed using the Gaussian03 suite of
quantum chemical programs.40 The full geometry optimizations
were performed on suitably designed model systems 1, 24, 25a, 44
and 45 at the B3LYP/6-31g(d) level of theory and all geometries
were characterized by the frequency calculations. For tellurium
compound 44 LANL2DZ effective core potential (ECP) was
used.13c The Natural Bond Orbital (NBO)41 analysis for all the
systems was performed at B3LYP/6–311g+(d, p) level of theory
and for tellurium compound 44 LANL2DZ effective core potential
(ECP) was used.
18 B. K. Sarma, D. Manna, M. Minoura and G. Mugesh, J. Am. Chem.
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Singh and G. Wolmersha¨user, Eur. J. Org. Chem., 2004, 3857–3864;
(c) S. S. Zade, S. Panda, H. B. Singh, R. B. Sunoj and R. J. Butcher, J.
Org. Chem., 2005, 70, 3693–3704.
20 C. Lambert and L. E. Christiaens, Tetrahedron, 1991, 47, 9053–9060.
21 K. Selvakumar, H. B. Singh and R. J. Butcher, Chem.–Eur. J., 2010, 16,
10576–10591.
22 W. Walter, B. Krische and J. Voss, J. Chem. Research (S)., 1978, 332–
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23 V. Jamier, L. A. Ba and C. Jacob, Chem.–Eur. J., 2010, 16, 10920–10928
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24 A. Bondi, J. Phys. Chem., 1964, 68, 441–451.
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Acknowledgements
HBS gratefully acknowledges the Department of Science and
Technology, New Delhi, for the Ramanna Fellowship. KS is
thankful to CSIR, New Delhi, for SRF and SAIF, IITB, for
spectral data collection.
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