Aromatic ring strain in arylselenenyl bromides: Role in facile synthesis of selenenate esters via intramolecular cyclization

Article abstract of DOI:10.1002/chem.201000394

The synthesis and reactivity of 2,6-disubstituted arylselenium compounds derived from 2-bromo-5-tertbutylisophthalic acid (43) are described. The syntheses of bis(5-tert-butylisophthalic acid dimethyl ester)diselenide (46) and bis(5-tert-butylisophthalic

Full text of DOI:10.1002/chem.201000394

DOI: 10.1002/chem.201000394
Aromatic Ring Strain in Arylselenenyl Bromides: Role in Facile Synthesis of
Selenenate Esters via Intramolecular Cyclization
K. Selvakumar,[a] Harkesh B. Singh,*[a] and Ray J. Butcher[b]
Abstract: The synthesis and reactivity
of 2,6-disubstituted arylselenium com-
pounds derived from 2-bromo-5-tert-
butylisophthalic acid (43) are de-
scribed. The syntheses of bis(5-tert-bu-
tylisophthalic acid dimethyl ester)disel-
served in the single-crystal X-ray struc-
tures of compounds 46, 47 and 53 is
compared and contrasted. The corre-
sponding selenenyl bromides 54 and
55, derived from the reaction of disele-
nides 46 and 47 with bromine, are
quite stable in the solid state. However,
they undergo hydrolysis and subse-
quent intramolecular cyclization upon
heating or after having been kept in so-
lution over a period of time to give the
corresponding selenenate esters 56 and
57. The X-ray crystallographic study
and density functional theory calcula-
tions on 54 at the B3LYP/6-31G(d)
level of theory indicate a significant
distortion in planarity of the aromatic
ring. Glutathione peroxidase-like activ-
ities of diselenides 46 and 47 and their
selenenate esters 56 and 57 have been
studied both by thiophenol and bioas-
say methods. The very low glutathione
peroxidase-like activity of the disele-
nides (46 and 47) and their selenenate
esters (56 and 57) in the thiophenol
assay is attributed to the presence of
the relatively strong Se···O intramolec-
ular interaction in the selenenyl sulfide
intermediates. The interaction retards
the catalytic activity through both thiol
exchange and an intramolecular cycli-
zation reaction.
ACHTUNGTRENNUNGenide (46) and bis(5-tert-butylisophthal-
ic acid diisopropyl ester)diselenide (47)
have been achieved by the reaction of
the corresponding ester precursors with
disodium diselenide. Reduction of
disel
hydride affords 2,2’-bis(5-tert-butylben-
zene-1,3-dimethanol)diselenide (53).
ACHTUNGTRENNUNGenide 46 with lithium aluminum
Diselenides 46 and 47 exhibit intramo-
lecular Se···O interaction. Compound
53 does not show any intramolecular
Se···O interaction. The anomalous
Se···O nonbonded coordination ob-
Keywords: cyclization · glutathione
peroxidase · ring strain · selenium
Introduction
Glutathione peroxidase (GPx) is a selenoenzyme, which
protects the cell membranes and other intracellular compo-
nents from deleterious effects of organic hydroperoxides
and hydrogen peroxide.[1] It catalyzes the reductive cleavage
ꢀ
of the O O bond in peroxides by using glutathione (GSH)
as the reducing agent (Scheme 1). The peroxides oxidize sel-
[a] K. Selvakumar, Prof. Dr. H. B. Singh
Department of Chemistry
Scheme 1. Catalytic cycle of glutathione peroxidase.
Indian Institute of Technology Bombay
Mumbai 400076 (India)
Fax : (+22)2576-7152
E-mail: chhbsia@chem.iitb.ac.in
AHCTUNGTREGeNNNU nol (ESeH) of the active site to the corresponding selenen-
ic acid (ESeOH). The selenenic acid undergoes a rapid nu-
cleophilic substitution reaction with GSH to produce the
corresponding selenenyl sulfide (ESe-SG) intermediate. The
nucleophilic attack of a second molecule of GSH at sulfur in
ESe-SG, considered to be the rate determining step, regen-
erates the catalytically active selenol.
[b] 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/chem.201000394.
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FULL PAPER
The role of selenium in catalytic reductive cleavage of
peroxides has been extensively studied using small organo-
selenium compounds. Examples of small-molecule GPx
mimics include selenocysteine model (1) and related pep-
thiol exchange reaction at selenenenyl sulfide has continued
to be a challenge in designing glutathione peroxidase
mimics.
Recently, there has been considerable attention on the de-
velopment of 2,6-disubstituted aryl based systems as gluta-
thione peroxidase mimics. Wirth reported the GPx-like ac-
tivity of diselenide 30, which does not show any enhance-
ment in catalytic activity relative to 15 and 16, and has only
one coordinating group.[8a] Diselenide 31 showed quite high
GPx-like activity in comparison to compound 8.[16] However,
the reason for its exceptional catalytic activity was not clear.
Very recently Babhak et al. reported a few 2,6-disubstituted
diaryl diselenides 32–34, as efficient glutathione peroxidase
mimics.[17] These compounds displayed better glutathione
peroxide activity than diselenide 8. It has been reported that
the OMe group in the 6-position of aryl ring (32–34) reduces
strength of the Se···N interaction at the selenenyl sulfide
stage of the catalytic cycle. The weak interaction prevents
the thiol exchange reaction at the selenium center and pro-
motes nucleophilic attack of thiol at sulfur.
More recently, it has been found that some other diorgan-
yl diselenides with two ortho donors around selenium
showed striking contrast in the reactivity and GPx-like activ-
ity in comparison to the analogous compounds with one
ortho donor group. For example, attempted synthesis of the
diselenides containing two amide groups either through
ortho-lithiation[18] or by the disodium diselenide method[19]
always led to the formation of ebselen analogues 35–39. The
ebselen analogues 35[20] and 37[19] showed significantly great-
er glutathione peroxidase activity than ebselen 4. Com-
pound 35 was found to be approximately nine times more
active. It has been noted that the interaction of the nitro
group with selenium in compound 35 enhances its catalytic
activity relative to ebselen mainly through electronic ef-
fects.[20] However, theoretical calculations on the catalytic
activity of 35 suggested that the enhanced catalytic activity
may arise from steric effects rather than any electronic
effect.[21] Mugesh and co-workers[22] showed that the at-
tides/selenocystein derivatives,[2] camphor-derived selenen-
ACHTUNGTRENNUNG
amide (2),[3] benzisoselenazine (3),[4] ebselen (4)[5] and its an-
alogues (5–7),[6] diselenides with secondary intramolecular
Se···Z (Z=N[7] or O[8]) interactions (8–17), cyclic seleninate
esters (18–20),[9] azaselenonium chloride (21) and hydroxide
(22),[10] spirodioxyselenuranes (23–28),[11] and seleninic acid
anhydride (29).[12] GPx-like activity of the artificial enzyme
selenosubtilisin has also been reported.[13] Selenosubtilisin
accepts aromatic thiol (3-carboxy-4-nitrobenzenethiol) as a
cofactor for the reduction of peroxides, owing to the lack of
a GSH binding site. The requirement of thiol-binding micro-
environments for high GP-like molecules has been studied
to a certain extent by well known bioorganic enzyme
models, cyclodextrins with a ditelluride linkage[14] and den-
drimers with a diselenide core.[15]
Diorganyl diselenides having weak intramolecular Se···Z
interactions are considered to be important class of GPx
mimics. Intramolecular Se···Z interaction in diorganyl disele-
nides fine tunes the catalytic property of selenium in various
intermediates; selenol, selenenic acid, and selenenyl sulfide
by altering the electrophilic character of the selenium
center. It has been shown that a strong Se···Z intramolecular
interaction at the selenenyl sulfide stage is detrimental to
catalysis, as it leads to the thiol exchange reaction.[5e] The
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10577

H. B. Singh et al.
tempted preparation of disele-
nides with two ortho oxazoline
groups resulted in the isolation
of ebselen analogue 40 through
intramolecular cyclization. The
ebselen analogue 40 was found
to show anti-thyroid action by
inhibiting the lactoperoxidase
activity. Interestingly, the analo-
gous diselenides with one ortho
oxazoline ring[23] or one benz-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
diselenide 31 resulted in the
isolation of an intramolecularly
stabilized, low-valent, cyclic sel-
ACHTUNGTRENNUNG
enenate ester 41.[16,25] This is
the first selenenate ester to
show excellent glutathione per-
oxidase activity.[16] Again, the
reasons for the instability of 42
were not understood, whether
it is owed to the lack of non-
bonded Se···O interactions or to
the steric congestion around the
selenium center.
Scheme 2. Synthetic route for diselenides 46 and 47, and hydrolysis of 46 at reflux: a) SOCl2, reflux, 6 h;
b) iPrOH, Et3N, ice-cold, 1 h; c) Na2Se2, THF, reflux, 32 h; d) MeOH, H2SO4, reflux, 18 h; e) Na2Se2, THF, RT,
24 h; f) concentrated HCl; g) N-hydroxysuccinimide, DCC, THF, RT, 6 h.
The main objective of this
work is to unravel the instabili-
ty of 2,6-disubstituted arylselACTHNUGTRNEUNGenenyl bromide 42 by synthe-
Table 1. 77Se NMR chemical shifts.
sizing related derivatives with an ester as the ortho coordi-
nating group, and study their stability and reactivity by
using experimental and computational methods. In addition,
we attempt to explain the contrasting glutathione peroxides-
like activities of 2,6-disubstituted diaryl diselenides and sel-
Compound
77Se NMR, d [ppm]
Solvent
46
47
48
49
50
53
54
55
56
57
59
72
519
517
211
548
1360
346
944
941
1399
1390
1382
547
CDCl3
CDCl3
CDCl3
[D6]acetone
[D6]acetone
CD3OD
CDCl3
CDCl3
CDCl3
ACHTUNGTRENNUNGenenate esters based on the results obtained from kinetics,
77Se NMR experiments and computational studies.
Results
CDCl3
[D6]DMSO
CDCl3
Syntheses: The precursor 2-bromo-5-tert-butyl-isophthalic
acid dimethyl ester 44 was prepared from 43 by following a
reported method.[26] Isopropyl ester 45 was synthesized by
the standard synthetic procedure. (Scheme 2). The reaction
of compound 43 with thionyl chloride led to the formation
of the corresponding acid chloride, which was allowed to
react in situ with a triethylamine solution of isopropyl alco-
hol to give compound 45. Reaction of aryl bromides 44 and
45 with in situ generated Na2Se2 afforded diselenides 46 and
47, respectively. In this reaction, the presence of two ester
groups ortho to bromine activates the aromatic ring towards
addition elimination reaction.[19,25]
in comparison to the diselenide 31 (d=376 ppm) having two
non-coordinating ortho formyl groups.[16,25] The significant
downfield shift in the 77Se NMR spectra is indicative of a
moderately strong intramolecular Se···O coordination in di-
AHCTUNGTREGsNNNU elenides 46 and 47. It was further confirmed by using single
crystal X-ray crystallography (vide infra). The yield of 46
(23%) is quite low at room temperature in comparison with
31 (40%),[25] which was also synthesized at room tempera-
ture. To improve the yield of 46, when the reactants were re-
fluxed in THF, surprisingly, the yield of 46 reduced fur-
ther.[27] During usual workup, the yellowish appearance of
the aqueous layer indicated the presence of some selenium
The chemical shifts (Table 1) observed for the 77Se NMR
spectroscopy study on diselenides 46 and 47 are d=519 and
517 ppm, respectively, and are significantly downfield shifted
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Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
products. Therefore, the organic and aqueous layers were
analyzed separately. The oily liquid obtained from the or-
ganic layer was chromatographed using petroleum ether
(60–808C) and ethyl acetate. The catalytic amount of naph-
thalene used during in situ preparation Na2Se2 was removed
by petroleum ether. Afterwards the polarity of the eluent
was raised using ethyl acetate (0–10%). The first fraction
obtained was highly malodorous in nature, probably Me2Se2,
and could not be characterized. The second fraction was
monoselenide 48 and the third was unreacted 44. The fourth
fraction was the desired diselenide 46.
The aqueous layer upon neutralization with concentrated
HCl followed by usual workup gave a yellow solid. The
77Se NMR spectrum of the crude mixture showed the pres-
ence of diselenide 49 (d=548 ppm) and selenenate ester 50
(d=1360 ppm) along with other signals for the partially hy-
drolyzed compounds. Attempted purification of selenenate
ester 50 by fractional crystallization was unsuccessful pre-
sumably due to the presence of the polar carboxyl functions.
Then, the crude mixture was esterified with N-hydroxysuc-
Scheme 3. Reaction of diselenides 46 and 47 with oxidizing and reducing
agents: a) Na, THF, naphthalene, 6 h; b) MeI, 08C, 45 min; c) LiAlH4,
ACHTUNGTRENNUNGcinimide using DCC coupling. The solid obtained was
passed through a short silica-gel column using petroleum
ether and ethyl acetate (5%) as an eluent to afford the de-
sired cyclic selenenate ester 52 (yield 2%). Compound 51
could not be isolated from the column. Compound 52
showed two well separated doublets in the aromatic region
of 1H NMR spectrum with a coupling constant of 2.4 Hz
which was similar to the related selenenate esters (vide
infra).
The above observations indicated that diselenide 46 un-
derwent facile hydrolysis of the methoxy ester group at
reflux. Careful analysis of aqueous layer of the reaction mix-
tures revealed that both methyl and isopropyl esters under-
go hydrolysis under the reflux condition, but the hydrolysis
was more severe in the case of the former. The severe hy-
drolysis of methyl ester is probably owed to the SN2 nucleo-
philic attack of Na2Se2 on the primary carbon of the methyl
group.[27]
RT 6 h; d) air, 15 min; e) Br2, CHCl3; 08C, RT, 3 h; f) H2O; g) H2O2,
Methanol, RT, 16 h.
,
Our major interest is focused on the oxidative bromina-
tion of diselenides 46, 47, and 53. The bromination of disele-
nides 46 and 47 resulted in the formation of novel selenenyl
bromides 54 and 55, respectively. In contrast to compound
42, compounds 54 and 55 were found to be noticeably stable
in the solid state. They can be isolated and stored in closed
vessels for a long period of time. Also, hydrolysis was not
evident during spectral characterizations, such as recording
1H, 13C, and 77Se NMR spectra. However, they slowly con-
vert to their corresponding selenenate esters in solution
(open air) over a period of time. For example, compound
54, when kept in chloroform/petroleum ether mixture (3:1)
for crystal growth, afforded approximately 1:1 ratio of dark
orange crystals of 54 along with off white colored amor-
phous solid of selenenate ester 56 in one week. The selenen-
yl bromide 54 crystals were separated from the selenenate
ester 56 by hand picking. Both compounds 54 and 55 were
found to be unstable towards heating and chromatography,
during which these result in the formation of corresponding
selenenate esters 56 and 57 respectively. Compound 54 un-
derwent rapid cyclization reaction in the presence of trieth-
Although the mechanism for the formation of monosele-
nides 48 is not understood, it could be synthesized by direct
ꢀ
methods. The reductive cleavage of the Se Se bond in 46
with metallic sodium in the presence of a catalytic amount
of naphthalene followed by the addition of methyl iodide af-
forded unsymmetrical monoselenide 48 (Scheme 3). Its
77Se NMR spectrum showed a peak at d=211 ppm. It is
slightly upfield shifted with respect to the chemical shift
(d=238 ppm)
reported[25]
for
4-tert-butyl-2,6-di-
ACHUTGTNRNEUGyN lACTHNGUTRENaUNG mine to afford 56. The ES-MS of compound 54 shows
A
three m/z peaks 409.3, 329.1, and 315.1 of our interest corre-
sponding to [M+H]+, [MꢀBr]+, and [56+H]+, respectively.
Similarly, the mass spectrum of compound 55 shows two
prominent m/z peaks, one at 385.1 and another peak at
343.0. The m/z peak at 385.1 for [MꢀBr]+ and the peak at
343.0 corresponds to the cyclic selenenate ester [57
H]+. It proves that selenenyl bromides 54 and 55 have mod-
erate stability and undergo rapid cyclization under quite
mild conditions. The 77Se NMR chemical shifts for the com-
pounds 54 and 55 are d=944 and 941 ppm respectively.
tramolecular Se···O interaction. This is, presumably, owed to
the weak electron accepting nature of Se C(Me) s* orbital.
ꢀ
This indicates the lack of intramolecular Se···O interaction
in 48. The reduction of 46 with LiAlH4 followed by air oxi-
dation afforded diselenide 53. Its 77Se NMR spectrum
showed a peak at d=346 ppm, which is very similar to that
of diselenide 31 (d=376 ppm).[25] This suggests the absence
of any intramolecular Se···O interaction in 53. It was further
corroborated by X-ray structure analysis (vide infra).
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10579

H. B. Singh et al.
These 77Se NMR chemical shifts are significantly different in
magnitudes compared with related selenenyl bromides 60
(d=1030 ppm)[28] and 61 (d=
1042 ppm).[29] It signifies weak-
ening of the Se···O intramolecu-
lar coordination in 54 and 55
relative to 60 and 61. It was fur-
ther supported by natural bond
orbital (NBO) analysis (vide
infra).
A plausible mechanism for the formation of selenenate
esters involves hydrolysis of selenenyl bromides 54 and 55
to the corresponding selenenic acids 62 and 63, respectively.
In general selenenic acids are quite unstable.[30] Hence, sele-
nenic acids 62 and 63 undergo intramolecular cyclization to
form the corresponding selenenate esters (56 and 57) via tet-
Figure 1. Molecular structure of compound 46 (50% ellipsoid), Selected
ꢀ
ꢀ
bond lengths [ꢁ] and bond angles [8]: Se1 C1A 1.931(3), Se1 Se2
ꢀ
2.319(6), Se2 C1B 1.934(3), Se1···O1A 2.760, Se2···O1B 2. 747, C1A-
Se1-Se2 104.21(9), C1B-Se2-Se1 104.00(9), O1A-Se1-Se2 167.29(7), O1B-
Se2-Se1 167.37(7), C1A-Se1-Se2-C1B 95.35(13).
rahedral
intermediates
64
and
65,
respectively
(Scheme 4).[31] The intermediates proposed for this mecha-
nism are supported by computational studies (vide infra).[32]
lengths relate well to the corresponding distances reported
for 66 (2.65, 2.71 ꢁ). The oxygen atoms of ester are coordi-
nated in a unique fashion in which one of the selenium in-
ꢀ
teracts with the carbonyl oxygen (C=O···Se Se) of its side
arm. The second selenium is participating in secondary
ꢀ
bonding interaction (CH3O···Se Se) with methoxy ester,
which is disordered over two conformations 0.796(6)/
0.204(6). In the major component the secondary interaction
is with the methACTHNUTRGNEUNGoxy oxygen and in the minor component is
with the carbonyl oxygen. This is the first example of a dio-
Scheme 4. Proposed mechanism for the cyclization of 54 and 55.
ꢀ
rganyl diselenide with both C=O···Se Se···OCH3 interac-
tions present in the same molecule. Related macrocycle 66
The bromination of diselenide 53 does not result in the
formation of the corresponding selenenyl bromide
(Scheme 3), rather it gave back the starting material. This
result is probably owed to the instability of the resultant sel-
ꢀ
with one ortho ester has only C=O···Se Se···O=C interac-
tion.[33] In the structure of 66 the carbonyl groups and aro-
matic rings are in the same plane. In contrast to compound
66, the structure of 46 shows none of the carbonyl groups to
be in plane of the aromatic ring (vide infra).
ACHTUNGTRENNUNGenenyl bromide, which undergoes hydrolysis to form sele-
nenic acid, which then disproportionates to give back disele-
nide 53. Seleninate ester 59, in which selenium is in the +4
oxidation state (SeIV), was synthesized by oxidation of disel-
ACHTUNGTRENNUNGenide 46 with excess H2O2.
X-ray crystallography: The molecular structures of disele-
nides 46, 47, and 53, selenenyl bromide 54 and selenenate
esters 56 were established by single crystal X-ray crystallo-
graphic study. The important structural features are de-
scribed below.
Molecular structure of diselenide 46: The molecular struc-
ture of 46 is shown in Figure 1. The coordination geometry
around the selenium atoms is distorted T-shaped with each
selenium atom bonded to another selenium atom, a carbon
and intramolecularly coordinated to an oxygen atom. It has
a transoid geometry (C1A-Se1-Se2-C1B, 95.35(13)8) along
Molecular structure of diselenide 47: The molecular structure
(Figure 2) of compound 47 is quite similar to that of com-
pound 46. The geometry around the selenium atoms is dis-
ꢀ
torted T-shaped. The geometry along Se Se bond axis is
transoid (C1A-Se1-Se2-C1B, 108.47(8)8). It also has a simi-
ꢀ
ꢀ
the Se Se bond axis. The most distinct feature of the struc-
ture is the presence of intramolecular Se···O interactions in
a diselenide having two ortho coordinating groups.
lar C=O···Se Se···OiPr interaction. The selenium–oxygen
nonbonded distances are 3.00 ꢁ (Se1···O1A) and 2.76 ꢁ
(Se2···O4B). It is important to note that the change of the
substituent from methyl to isopropyl lengthens the C=
The selenium–oxygen nonbonded distances are 2.760 ꢁ
(Se1···O1A) and 2.747 ꢁ (Se2···O1B). The Se···O bond
ꢀ
ꢀ
O···Se Se bond length with a negligible change in RO···Se
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Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
ample of conformational polymorphism. In both cases the
geometry around the selenium atoms is V-shaped.
The interesting feature of the structure of the diselenide
53 is the absence of any intramolecular Se···O interactions.
In both polymorphs, out of the four oxygen atoms, none is
in contact with the selenium atoms. However, compound 17
with mono ortho coordinating group has been found to
show a very weak contact (3.008 ꢁ) between selenium and
oxygen.[8b] Interestingly, the polymorph with the transoid
ꢀ
conformation has C H···Se (2.775 ꢁ) interaction between
the one of the hydrogen atom of the methylene group and
the selenium atom.[34] It is similar to the C H···Se interac-
ꢀ
tion found in related compound diselenocin (2.92 ꢁ).[35]
Figure 2. Molecular structure of compound 47 (50% ellipsoid), Selected
ꢀ
ꢀ
bond lengths [ꢁ] and bond angles [8]: Se1 C1A 1.9319(19), Se1 Se2
Molecular structure of 54: The molecular structure of sele-
nenyl bromide 54 is given in Figure 4. This is the first struc-
turally characterized selenenyl bromide to have two hetero-
ꢀ
2.325(3), Se2 C1B 1.9446(18), O1A···Se1 3.000, O4B···Se2 2.758, C1A-
Se1-Se2-C1B 100.47(8), C1A-Se1-Se2 101.85(6), C1B-Se2-Se1 100.94(6),
O1A-Se1-Se2 146.96, O4B-Se2-Se1 165.78, C1A-Se1-Se2-C1B 108.47(8).
Se bond length. Similarly, the substituent change decreases
ꢀ
the C=O···Se Se (146.968) bond angle dramatically with a
ꢀ
small change in Se Se···OR (165.788) bond angle. It indi-
cates that in compound 47 alkoxy group is found to be a
better donor than the carbonyl donor. It has been further
supported by computational studies (vide infra).
Molecular structure of diselenide 53: The molecular struc-
ture of compound 53 is shown in Figure 3. Asymmetric unit
contains two independent molecules and a molecule of
Figure 4. Molecular structure of 54 (50% ellipsoid), Selected bond
ꢀ
ꢀ
lengths [ꢁ] and angles [8]: Se C1 1.924(3), Se Br 2.3712(9), Se···O1
2.419(3), O1···Se-Br 166.31(7), Br-Se-C(1) 99.75(11), C1-Se-O1 77.38(12),
C6-C1-C2-C3 10.1(5), C1-C2-C3-C4 ꢀ0.5(5), C2-C3-C4-C5 ꢀ7.3(5), C3-
C4-C5-C6 5.6(5), C4-C5-C6-C1 4.1(5), C5-C6-C1-C2 ꢀ11.8(5).
AHCTUNGTREGaNNUN tom donors ortho to selenium. The geometry around Se is
T-shaped with selenium bonded to a carbon, oxygen and
bromine. The Se···O bond length is 2.420 (2) ꢁ. This dis-
tance is longer than the Se···O bond length (2.305(19) ꢁ re-
ported for the ortho-substituted benzene derivative, 2-for-
mylphenylselenenyl bromide (60).[36] This significantly
higher Se···O distance may be owed to the weak donating
property of the ester donor. The most interesting feature of
the structure is the puckering of the aromatic ring. This is
clearly seen from the torsion angles observed for the aryl
Figure 3. Molecular structure of compound 53 (50% ellipsoid, hydrogen
atoms and methanol removed for clarity), Selected bond lengths [ꢁ] and
ꢀ
ꢀ
ꢀ
bond angles [8]: Se1A C1A 1.924(2), Se1A Se1B 2.3392(3), Se1B C1B
ꢀ
ꢀ
1.9268(19), Se2 C1C 1.928(2), Se2 Se2 2.3379(5), C1A-Se1A-Se1B
101.03(6), C1B-Se1B-Se1A 103.10(6), C1C-Se2-Se2i 100.12(6), C1A-
Se1A-Se1B-C1B 77.90, C1C-Se2-Se2i-C1-Ci ꢀ103.29(9).
ꢀ
ꢀ
ꢀ
carbon atoms C1 C2 (10.1(5)8), C2 C3 (ꢀ0.5(5)8), C3 C4
ꢀ
ꢀ
ꢀ
methanol as a solvate. Out of the two molecules, one has a
cisoid geometry (C1A-Se1A-Se1B-C1B, 77.90(8)) and the
(ꢀ7.3(5)8), C4 C5 (5.6(5)8), C5 C6 (4.1(5)8), C6 C1
(ꢀ11.8(5)8). There is no puckering observed in the aryl ring
of 60. These observations are further corroborated by com-
putational studies. (vide infra).
other has
a
transoid geometry (C1C-Se2-Se2-C1C
ꢀ
ꢀ103.29(8)) around the Se Se axis. This difference in con-
ꢀ
formational angle may probably be due the O H···O hydro-
gen bonding in the crystal structure. The existence of the
two slightly different structures may be considered as an ex-
Molecular structure of 56: The molecular structure of sel-
AHCTUNGTREGeNNUN nenate ester 56 is shown in Figure 5. This is only the
Chem. Eur. J. 2010, 16, 10576 – 10591
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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10581

H. B. Singh et al.
ꢀ
more favorable if R is tert-butyl group and C=O···Se Se is
more favorable when the substituent is hydrogen.
Structural anomaly among 2,6-disubstituted diaryl disele-
nides: At this juncture, it is relevant to generalize the struc-
tural features of diorganyl diselenides as having one ortho
donor function versus two ortho donor functions. Intramo-
lecular coordination is invariably present in low valent dio-
rganyl diselenides with one ortho donor atom (N or O).
However, remarkable structural differences have been
found among diselenides with two ortho donors around sele-
nium depending upon the donor function. Low valent dio-
rganyl diselenides with two ortho formyl or two primary al-
cohol groups do not have Se···O intramolecular coordina-
tion. Whereas, the diselenides with two carboxyl or ester
functions have Se···O intramolecular coordination in which
selenium is in contact with one of the oxygen of the carbon-
yl group or alkoxy group. Also, the examination of X-ray
Figure 5. Molecular structure of 56 (50% ellipsoid), Selected bond
ꢀ
ꢀ
lengths [ꢁ] and bond angles [8]: Se C1 1.853(2), Se O1 1.871(2), Se···O4
2.472(2), O1-Se-O4-C12 0.0, O1-Se-C1-C2 0.0, C1-Se-O1-C7 0.0, O4-Se-
O1-C7 0.0, C1-Se-O4-C12 0.0, Se-C1-C2-C7 0.0(2), C6-C5-C4-C3 0.(03),
C3-C2-C1-C6 0.0(3).
second example of a cyclic selenenate ester
Table 2. Conformational analysis of model unsymmetrical diselenides.[a]
to have been characterized by X-ray crys-
tallography. The Se···O nonbonded distance
(2.472 ꢁ) is in good agreement with the
value of 2.465 ꢁ reported for the cyclic sel-
ACHTUNGTRENNUNGenenate ester 41, the latter has a formyl
group as the coordinating group.[16] This in-
teraction leads to the formation of a fused
tricyclic system with significant planarity.
The planarity of the molecule is quite ap-
parent from the torsion angle observed for
the atoms defining the tricyclic ring system.
Interestingly, the combination of CH···O
and Se···Se interactions lead to the forma-
tion of a linear 1D chain. The Se···Se non-
covalent bond length is 3.612(8) ꢁ. It is
well within the sum of van der Waals radii
of selenium atoms (3.8 ꢁ).[37a]
ꢀ
ꢀ
Entry
O···Se [ꢁ]
Se Se [ꢁ]
O···Se Se [8]
DE [kcalmolꢀ1
]
49a
49b
46a
46b
67a
67b
47a
47b
68a
68b
2.684
2.867
2.653
2.768
2.647
2.769
2.655
2.740
2.698
2.903
2.344
2.332
2.345
2.333
2.345
2.333
2.344
2.332
2.342
2.329
160.90
155.72
163.32
161.50
162.99
159.64
162.15
160.69
156.46
148.50
1.78
1.40
0.94
0.58
ꢀ0.74
[a] All the structures were optimized by using DFT-B3LYP/6-31G(d).
Discussion
The role of alkoxy group in preference of the donor atom:
To understand the effect of alkoxy groups on nonbonded
Se···O interaction, a detailed computational study was car-
ried out by varying the substituents from H to tert-butyl in
the alkoxy group of the diselenides (vide supra). The results
are summarized in Table 2. To simplify this problem, we
crystal structures of diselenides (31, 46, and 47) and compu-
tational structure[38] of selenenyl bromide 42a reveals that
the carbonyl groups have different orientations with respect
to C1 carbon to which the selenium is attached.[39] These ori-
entations appear to be dependent on electronegativity of
ꢀ
the trans substituent X (O···Se X, X=Br, SeAr) group and
ꢀ
sliced the molecules through the Se Se bond to get two con-
the ortho substituent (CHO, COOMe, CH2OH).
formations a and b in which one half of the diselenide was
substituted with a SeMe group and the 4-tert-butyl group
was replaced with H. Interestingly, the calculated ground-
state-energy difference between conformation a and b de-
creases on going from H to tert-butyl group. The reversal of
the sign for tert-butyl substituent clearly indicates that the
inductive electron-donating effect of the alkyl groups in-
creases the electron density around oxygen on going from H
In general, nonbonded interaction becomes repulsive
when more than one heteroatom is placed around neutral
low-valent selenium center.[40] It becomes attractive when
selenium has a positive charge or the trans substituent at-
tached to the selenium is more electronegative. For example
the unusual selenium cation with two pendant nitrogen arms
has an attractive interaction (N···Se+···N).[40] Hence, the ab-
sence of intramolecular coordination in 53 is owed to the
low valent selenium with weak electron accepting the trans
ꢀ
to tert-butyl group. Therefore, the RO···Se Se interaction is
10582
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Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
ꢀ
bond (Se Se) and weak donor property of the hydroxyl
(anti, anti) in which selenium is in contact with hydrogen
atoms of the formyl group by without disturbing the conju-
gation of the aromatic ring with carbonyl groups.
ꢀ
function. The rotational degree of freedom around the Ar
CH2 bond is another factor which contributes to the ground
state electronic structure of 53 in which all oxygen atoms
pointed away from low-valent selenium atoms to avoid the
repulsive O···Se···O.
It is also clear that the repulsive Se···O intramolecular in-
teraction in 31 becomes attractive in compound 42a. It is
owed to the relatively higher electronegativity of bromine in
42a compared to selenium, which makes selenium more
electrophilic. Also, selenium in compound 31 has a +1 oxi-
dation state (SeI), whereas selenium in compound 42a has a
+2 oxidation state (SeII). This oxidation process brings one
of the formyl oxygen closer to selenium.
ꢀ
The examination of torsion angles (C(CO) C(Ar) in car-
boxyl or ester containing diselenides (46 and 47) reveals
that it varies from 22.82 to 1368. This suggests that the con-
tributing structure II allows the rotation of carbonyl func-
ꢀ
tion along the C(CO) C(Ar) bond. This contributes to the
observation of both syn, anti and anti, anti orientations of
carbonyl groups in the same molecule (46 and 47). The out
of plane orientation of the carbonyl group from the benzene
plane indicates that the p-electron conjugation between the
carbonyl group and the aromatic ring is not effective and
leads to a energetically unfavorable situation. The presence
of a Se···O interaction indicates that the small loss in reso-
nance stabilization energy is compensated by the nonbonded
Se···O interaction energy. Therefore, the presence of intra-
molecular coordination in these compounds is owed to two
reasons: 1) carboxyl or ester groups are more electron with-
drawing (mesomeric effect) than formyl groups that may
withdraw some electron density from selenium, which, in
turn, draws the oxygen closer to selenium; 2) These disele-
nides are in forced conditions in which selenium has to be in
contact with either alkoxy oxygen or carbonyl oxygen in any
situation without disturbing the resonance delocalization in
a dramatic way (Ar ? C=O). However, we do not know
which one has the major contribution for this interaction.
The presence or absence of Se···O intramolecular interac-
tion in compounds having carboxyl or formyl groups can be
explained by considering resonance forms I, Ia, and II. The
contributing structure I (formyl) or Ia (esters) allows the de-
localization of aromatic p electrons with p electrons of the
carbonyl group and the contributing structure II allows the
effective delocalization of the lone pair electrons of alkoxy
group into carbonyl group p electrons. All the contributing
Effect of the mono ortho-verses di-ortho coordination on
the ring strain in arylselenenyl halides: To understand the
effect of intramolecular interaction and the additional sub-
stituent at the 6-position on the distortion of the benzene
ring (vide supra), we carried out a detailed quantum me-
chanical calculations on mono ortho-and di-ortho-substitut-
ed arylselenium compounds. The results are summarized in
Table 3. The calculated structures of compounds 60 and 61
with one ortho coordinating have perfectly planar aromatic
rings with the average torsion angle of 08. The introduction
of an additional COOMe group in 61 (i.e., compound 54a)
at the second ortho position significantly increases the aver-
age torsion angle of the aromatic ring from 0.0 to 4.188. No-
forms, IACHTUNGTRENNUNG(formyl), Ia, and II (esters) may create significant
partial negative charge on carbonyl oxygen. By taking this
resonance into account one would expect that the disele-
nides with two formyl groups and ester groups to have
Se···O intramolecular interaction. However, the interaction
is only observed in the latter case and not in the former.
Compounds with ortho formyl groups will have only I as
the contributing form. Therefore, it should be stressed here
that the effective conjugation is possible in resonance struc-
ture I only when a, bꢁ1808 (anti, anti) , a, bꢁ08 (syn, syn)
or aꢁ0, bꢁ1808 (syn, anti). The observation of anti, anti (a,
bꢁ1808) conformation for 31 and syn, anti conformation for
42a (a=3.638, b=169.168 indicates that these groups are in
effective delocalization with aromatic ring.[39] Hence, the ab-
sence of intramolecular Se···O interaction in 31 is owed to
the following reasons: 1) Se is in a low-valent oxidation
state, 2) weak electron-accepting property of the trans bond
ꢀ
tably, the O···Se Br bond angle reduces from 177.78 to
166.128. This is owed to the second ortho substituent, which
reduces effective orbital overlap required for the strong
nonbonded Se···O interaction and concomitantly introduces
a strain in the aromatic ring. A related example is hexafer-
rocenyl benzene, which has an average torsion angle of
13.998 in the benzene ring, owing to the repulsive interac-
tion (steric effect) between the adjacent ferrocenyl rings.[41]
ꢀ
(Se Se), 3) the linearity required by the Se···O intramolecu-
lar coordination is hampered by the second ortho formyl
group, and iv) the availability of alternate conformation
Chem. Eur. J. 2010, 16, 10576 – 10591
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10583

H. B. Singh et al.
Table 3. Calculated structural parameters for molecules.[a]
ꢀ
ꢀ
Entry Se···O [ꢁ] Se X [ꢁ] Average torsion
O···Se X
bond angle [8]
angle [8][b]
exptl
calcd
42a
46c
46a
54a
60
61
69
70
2.357
2.738
2.653
2.408
2.314
2.365
2.320
2.380
2.418
2.346
2.345
2.400
2.422
2.408
1.812
2.271
–
4.47
1.48
2.99
4.18
0.00
0.00
3.14
4.43
166.23
155.65
163.32
166.12
178.01
177.78
170.97
165.90
0.65[c]
–
6.57[d]
–
–
–
–
[a] All the structure were optimized using DFT-B3LYP/6-31G(d) level of
theory. [b] The average torsion angle in aryl ring is the average of six tor-
sion angle observed in the aryl ring (sum of six torsion angles divided by
six). [c] Average torsion angle observed in the aromatic ring of 46 which
has 4-tert-butyl group. [d] Average torsion angle observed in the aromatic
ring of 54 which has 4-tert-butyl group.
Scheme 5. Possible reaction pathways for the cyclization of 54a.
Table 4. Relative electronic DACHTUNGTRNEUNG
(E+ZPE)[a] energies of the intermediates
for the cyclization of 54a to 56a.
Entry
D
G
Average
torsion angle [8]
[b]
[kcalmolꢀ1
It is also evident that the distortion becomes even more
severe if the group trans to the donor substituent is strongly
electronegative and causes stronger hypervalent interaction
between selenium and the heteroatom. For example, the dis-
tortion is minimum when X is SeAr (46c 1.488) or SeMe
(46a, 3.08). This observation indicates that both steric
crowding and strong intramolecular coordination introduce
strain in the aromatic ring.
54a+H2O
54aRC
54aINT-I
62a···HBr[a]
62a
0
4.18
4.24
1.00
3.40
3.02
5.02
0.85
0.82
0.10
0.00
ꢀ4.98
ꢀ4.98
9.14
–
11.34
14.35
–
71
64a···HBr[a]
64a
56a···MeOH[a] +HBr
56a
3.81
–
[a] Hydrogen-bonded complexes. [b] E+ZPE=electronic energy+zero
point vibrational energy.
Experimental and computational study on the intramolecu-
lar cyclization of selenenyl bromide 54: The formation of 56
from 54 was studied by using the model compound 54a.
This conversion can occur through three possible reaction
paths (Paths I, II and III) involving the model reaction com-
plex 54aRC (Scheme 5). Attempts to get the appropriate
transition states for the reaction Paths I and III by means of
computational methods were not successful. The relative en-
ergies obtained for the intermediates proposed in the cycli-
zation Paths I and III are given in Table 4.[32]
Path I involves nucleophilic attack of water molecule at
selenium center. The reaction at low valent selenium center
is generally known as an addition-elimination reaction[42]
and involves the following major steps: 1) breaking of C=
O···Se bond in 54a and concomitant formation of the hyper-
coordinate intermediate (54aINT-I), owing to the interac-
tion between selenenyl bromide 54a and H2O, 2) elimina-
tion of HBr from the hypercoordinate intermediate 54aINT-
I to form selenenic acid 62a (Scheme 5), and 3) intramolec-
ular cyclization of 62a to form cyclic selenenate ester 56a
via the intermediate 64a.
complex (54aRC) involves the breaking of the Se···O1
(2.865 ꢁ) interaction between the oxygen of carbonyl group
and selenium and the formation of Se···O5 (3.032 ꢁ) bond
between oxygen of water molecule and selenium. An impor-
tant feature of this transformation is the reduction in aver-
age torsion angle of the benzene ring from 4.18 to 1.008
while going from 54a to intermediate 54aINT-I. The hyper-
valent intermediate 54aINT-I undergoes elimination reac-
tion to form the selenenic acid 62a. The average torsion
angle in aromatic ring of selenenic acid 62a was found to be
3.028. Hence, the selenenic acid 62a undergoes further cycli-
zation to form a tetrahedral intermediate 64a, which has
little strain (average torsion angle, 0.828) in its aromatic
ring. The complete release of strain (average torsion angle,
0.08) was observed only in the product 56a. Therefore, the
aromatic ring strain is the major driving force for this cycli-
zation. Although an addition-elimination reaction is pro-
posed, the observation of [54ꢀBr]+ and [55ꢀBr]+ in ES-MS
spectral study (vide supra) suggests that it could be an elimi-
nation-addition reaction as well.
The nonbonded interaction between selenium and oxygen
of ester group in 54aRC is 2.421 ꢁ (Se···O1). The formation
of hypercoordinate intermediate 54aINT-I from the reaction
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Chem. Eur. J. 2010, 16, 10576 – 10591

Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
Table 5. NBO analysis on the optimized geometries 42a, 54a, 60, and 61
(B3LYP/6-31G(d)) were performed at B3LYP/6-311+GACTHNUTRGNE(UNG d, p) level of
theory.
The formation of the heterocycle 56a is also possible
through alternate reaction paths Paths II and III involve the
nucleophilic attack of a water molecule at the electrophilic
carbonyl-carbon (Scheme 5). Reaction Paths II and III are
essentially similar. Reaction Path II is concerted, whereas
Path III is stepwise. Hence, Path II should be distinguishable
from Path I and III by the reaction of 54 with H2S. The reac-
tion of selenenyl bromide 54 with H2S afforded thioselenen-
ate ester 72 as the major product (Scheme 6). Compound 72
[a]
[b]
[b]
Entry
ESe···O [kcalmolꢀ1
]
qSe
qO
42a
54a
60
25.04
19.97
30.26
24.91
0.51883
0.49103
0.53504
0.48809
ꢀ0.53762
ꢀ0.60328
ꢀ0.54610
ꢀ0.60924
61
[a] Orbital interaction energy obtained from NBO analysis. [b] qSe and qO
denotes the NPA charges on Se and O respectively.
the additional substituent in 6-position reduces the strength
of the Se···O intramolecular interaction. It has been report-
ed[31,44] that the rate of nucleophilic displacement at seleni-
um center in ortho-nitro coordinated arylselenenyl halides
decreases (>106-fold) with respect to the corresponding un-
coordinated arylselenenyl halides, owing to the presence of
the ortho donor in the apical position of the pseudo-trigonal
bipyramid. It supports our experimental and computational
findings that the extent of hydrolysis of intramolecularly sta-
bilized arylselenenyl bromides depends upon the relative
strength of Se···O intramolecular coordination. Although in-
tramolecular coordination affords moderate stability to the
2,-6-disubstituted arylselenenyl bromides, it is less than suffi-
cient to compensate for the aromatic ring strain.
Scheme 6. Reaction of H2S with selenenyl bromide 54.
was characterized by using elemental analysis, NMR spec-
troscopy (1H, 13C, 77Se) and IR spectroscopy. Compound 72
has a resonance peak at d=547 ppm in the 77Se NMR spec-
trum, which implies that sulfur is attached to selenium. The
stretching frequency of the intramolecularly coordinated
ꢀ
carbonyl group (C=O···Se S) of 72 was observed at
Glutathione peroxidase activity of diselenides and selenen-
ate esters: The glutathione peroxidase like activities of the
diselenides and selenenate esters were studied both by ben-
zenethiol[7b] and classical coupled reductase assay methods[7a]
(Table 6). The initial reaction rate for the reduction of H2O2
in the benzene thiol assay is much lower for selenenate
esters 56 and 57 in comparison to 31, which has formyl
group as the donor group.[16] Comparison (Table 6) of gluta-
thione peroxidase-like activity of diselenides indicates that
diselenides 46, 47 (ꢁ20 times), and diselenide 53 (6.5 times)
are less active than diselenide 31.
n˜1654 cmꢀ1. The corresponding stretching frequency
(n˜1642 cmꢀ1 (C=O···Se O)) is significantly blue shifted in
compound 56. This significant increase in stretching frequen-
cy of the intramolecularly coordinated carbonyl (C=O···Se
S) group in compound 72, with respect to the same in com-
pound 56, is attributed to the weak electron-accepting prop-
erties of the Se S bond in the former case. As Path II in-
volves a concerted mechanism, product 73 would result with
a Se O linkage, whereas the observed product is 72, which
has a Se S linkage. Therefore, Path II is less likely than
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Paths I and III.
Path III involves the reaction of water with the carbonyl
carbon of the reaction complex to form intermediate 71,
which undergoes subsequent cyclization reaction to form the
tetrahedral intermediate 64a. Intermediate 71 (Path III) has
relatively more strain (5.058) and is higher in energy
(11.34 kcalmolꢀ1) than the intermediate 62a (9.14 kcal
molꢀ1). Therefore, conversion of 54aRC to 64a via this in-
termediate is less likely.
Having established reaction Path I as the most probable
reaction path, the effect of additional ortho substituent on
the strength of Se···O intramolecular interaction and its sig-
nificance in hydrolysis reaction of selenenyl bromides (42a,
54a, 60, and 61) was studied by natural bond orbital (NBO)
analysis.[43] The stabilization energies ESe···O obtained for or-
bital nO!s*SeꢀBr intramolecular interaction are listed in the
Table 5. It is interesting to note that, the nO!s*SeꢀBr orbital
interaction energies observed for Se···O interaction in mono
ortho substituted organylselenenyl bromides are approxi-
mately 5 kcalmolꢀ1 higher than that of the corresponding
2,6-disubstituted organylselenenyl bromides. It indicates that
Mechanistic studies on cyclic selenenate ester 56: The factors
for the low glutathione peroxidase-like activity of disele-
Table 6. The initial rate for the reduction of H2O2 by organoselenium
compounds at 25ꢂ18C.
Compound
[a]
[c]
Initial rate, V0 [mmminꢀ1
]
Initial rate, V0 [mmminꢀ1
]
control
ebselen
31
46
47
53
56
57
2.33ꢂ0.05
2.78ꢂ0.09[b]
64.15ꢂ2.26
3.86ꢂ0.16
3.38ꢂ0.28
9.78ꢂ0.18
1.88ꢂ0.16
1.86ꢂ0.02
4.80ꢂ0.32
14.97ꢂ0.29
20.66ꢂ0.55
19.29ꢂ0.74
–
38.80ꢂ0.67
8.76ꢂ0.14
9.11ꢂ0.24
[a] The initial rates were calculated by following the product (PhSSPh)
formation at l=305 nm using UV method. The reactions were carried
out in methanol, with H2O2 (5.8 mm), PhSH (1 mm), catalyst (0.01 mm).
[b] 0.05 mm ebselen was used. [c] The initial rates were calculated by fol-
lowing the depletion of NADPH concentration at l=340 nm using UV
method. The reactions were carried in 100 mm phosphate buffer, pH 7.48,
with EDTA (1 mm), glutathione reductase (1 unit), NADPH (0.23 mm),
GSH (0.1 mm), catalysts (0.020 mm), H2O2 (0.26 mm).
Chem. Eur. J. 2010, 16, 10576 – 10591
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10585

H. B. Singh et al.
nides 46 and 47, selenenate esters 56 and 57, both thiophe-
nol and bioassay, were delineated from 77Se NMR spectro-
scopic studies.
Reaction of selenenate ester 56 with hydrogen peroxide: Re-
action of selenenate ester 56 with one equivalent of hydro-
gen peroxide leads to the formation of cyclic seleninate
ester 59 (d=1334 ppm), which returns to the selenenate 56
upon addition of two equivalents of thiophenol. Therefore,
residual catalytic activity observed for selenenate esters 56
and 57 in the coupled reductase assay is essentially owed to
the shuttling of selenium between SeII and SeIV oxidation
states. Based on experimental studies we propose the cata-
lytic mechanism in Scheme 7. The low catalytic activity of
the diselenides 46 and 47 is attributed to, as stated above for
the selenenate esters 56 and 57, the presence of strong intra-
molecular coordination at the selenenyl sulfide stage.
Reaction of selenenate ester with thiophenol: The reaction of
selenenate ester 56 towards PhSH was studied by using
77Se NMR spectroscopy. The reaction of 56 with two equiva-
lents of PhSH leads to rapid formation of selenenyl sulfide
74. Its signal was observed at d=624.0 ppm in 77Se NMR
spectrum. It is downfield shifted in comparison to the relat-
ed derivative 2-(N-cyclohexyl,N-methyl benzyl amine)selen-
yl phenylsulfane (d=574 ppm).[7b] This significant downfield
shift is owed to the presence of strong Se···O intramolecular
interaction in selenenyl sulfide
74. It was found to be very
stable in solution and did not
disproportionate to the corre-
sponding diselenide or undergo
intramolecular cyclization to
form 56. Mugesh and co-work-
ers have showed that the low
catalytic efficiency of ebselen is
owed to the presence of
a
strong Se···O intramolecular in-
teraction at selenenyl sulfide
stage, which leads to the thiol
exchange reaction.[5e] Similarly,
these selenenate esters may un-
dergo a thiol exchange reaction,
which hampers the catalytic
conversion of thiol to disulfide.
Scheme 7. Mechanism for the catalytic reduction of H2O2 by selenenate ester 56 using PhSH as GSH alterna-
tive.
Reaction of selenenyl sulfide 74
with hydrogen peroxide: The
sel
enenyl
sulfide
obtained
above was treated with 1 equiv-
alent of H2O2. It produced selenenate ester 56 (d=
1402 ppm) and seleninate ester 59 (d=1334 ppm). It indi-
cates that in presence of peroxide, selenenyl sulfide 74 un-
dergoes intramolecular cyclization. Notable distortion (aver-
age torsion angle=3.458) was observed in the aromatic ring
of 74a (optimized structure).[45] Hence, the aromatic ring
strain in 74 may probably lead to the peroxide-promoted
Mechanistic studies on diselenide 53: Reaction of 53 with
one equivalent of hydrogen peroxide does not produce any
signal for selenenic acid 76 (Scheme 8). This is presumably
owed to the reduced stability of selenenic acid, which could
not be detected in the 77Se NMR spectrum.[30,47] Also, it does
not undergo intramolecular cyclization when reacting with
H2O2, presumably owing to the lack of Se···O (CH2OH) in-
tramolecular coordination in 76. Addition of two equiva-
lents of PhSH to 53 does not produce any selenenyl sulfide
77. However, addition of four equivalents of H2O2 to a mix-
ture containing compound 53 and 4 equivalents of PhSH
leads to the immediate appearance of a peak at d=440 ppm
in 77Se NMR spectrum corresponding to selenenyl sulfide
77.
ꢀ
cleavage of the Se S bond via the intermediate selenoxy
sulfide 75, which leads to intramolecular cyclization to form
56 again. The competing decomposition of selenenyl sulfide
in presence of peroxides has been also observed for an ali-
phatic selenenyl sulfide[9a] and ebselen.[46] The selenenic acid
62 and selenoxysulfide 75 inter-
mediates proposed during oxi-
dation of the selenenyl sulfide
were not observed, owing to
the rapid intramolecular cycli-
zation reaction. This cyclization
reaction also contributes to the
deactivation of the catalytic
process.
The significant upfield shift in 77Se NMR with respect to
74 shows selenenyl sulfide 77 does not have any Se···O intra-
molecular interaction. Therefore, first step is the oxidation
of diselenide 53 to selenenic acid 76, which reacts very rap-
idly with PhSH to form selenenyl sulfide intermediate 77.
The 77Se NMR signal intensity corresponding to diselenide
53 was relatively high with respect to the signal intensity
10586
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10576 – 10591

Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
lar interaction operates in sele-
nenic acid obtained from 31
which prevents over-oxidation
of selenium center. The lack of
Se···O interaction at the sele-
nenyl sulfide stage prevents
thiol exchange reaction thus en-
hances the catalytic activity of
31. This study proves that
formyl group is an optimal
donor in 2,6-disubstituted diaryl
diselenides, which fine tunes
the selenium center depending
upon the
X (X=OH, SPh)
group in GPx catalytic cycle.
Compound 31 displayed good
GPx-like activity by allowing
conformational changes in cata-
lytic intermediates.
Scheme 8. Catalytic mechanism for 53.
corresponding to 77 and implicates the instability of sele-
nenic acid and selenenyl sulfide which convert back to the
diselenide by means of a disproportionation reaction.[47]
Therefore, in the thiophenol assay, compound 53 is less
active than 31. It may be because of a lack of intramolecular
Se···O coordination in selenenic acid (76) that the dispropor-
tionation reaction is so rapid. Conversely, diselenide 53 is
about two times more active than diselenide 31 in our bioas-
say, due to the higher solubility of the former in the buffer.
Indeed, among these compounds diselenide 31 with two
ortho formyl groups is the most active catalyst in the thio-
phenol assay. Its high catalytic activity can be rationalized
on the basis of computational studies. Optimization of sele-
nenyl sulfide and selenenic acid corresponding to the model
diselenide 31a (Scheme 9) have been carried out at B3LYP/
Conclusion
Isolation of the first examples of diorganyl diselenides 46
ꢀ
and 47 with unique C=O···Se Se···OR intramolecular inter-
actions demonstrates the role of nonbonded interactions in
overcoming resonance destabilization. Diselenides 31 and 53
do not have any intramolecular coordination. These remark-
able structural differences found in 2,6-disubstituted low
valent diorganyl diselenides lead to the following conclu-
sions: 1) juxtaposed chalcogens (O···Se···O) repel each
other, 2) conformational constraints or choices define the
ground state electronic structures, 3) Se···O interaction be-
comes attractive if the ortho group is more electron with-
drawing. The presence of Se···O intramolecular coordination
in selenenyl bromides 42, 54, and 55 is essentially owed to
the higher electronegativity of the bromine. However, the
linearity required for the Se···O intramolecular interaction
causes significant strain in the aromatic ring owing to the
presence of additional ortho substituent. This study clearly
demonstrates that the Se···O intramolecular stabilizing inter-
action in 2,6-disubstituted arylselenenyl bromide system is
less than sufficient to compensate the aromatic ring strain.
The distortion in the planarity of the aromatic rings of 54
and 55 leads to facile intramolecular cyclization to give cor-
responding selenenate esters (56 and 57). Thus, 2,6-disubsti-
tuted arylselenium compounds could be used for the synthe-
sis of stable selenium (II) heterocycles. The selenenate
esters derived from diselenide 46 and 47 do not show any
significant GPx activity in thiophenol assay owing to the
thiol exchange reaction and peroxide mediated intramolecu-
lar cyclization at selenenyl sulfide stage. This study further
demonstrates that the presence of ester groups in 2,6-posi-
tions does not facilitate the GP-like activity of organoseleni-
um compounds. Compound 31 displayed good GPx-like ac-
tivity by allowing conformational changes in catalytic inter-
mediates.
Scheme 9. Lowest energy conformers of selenenyl sulfide 78b and sele-
nenic acid 79a intermediates derived from diselenide 31a.
6-31G(d) level of theory. It shows that selenenyl sulfide 78b
derived from 31a having no Se···O interaction (anti, anti)
conformation is 0.87 kcalmolꢀ1 is more stable than confor-
mation having Se···O intramolecular interaction (syn, anti)
78a; However, opposite trend is observed for selenenic acid
derived from 31a. Intramolecularly stabilized (syn, anti) con-
formation of selenenic acid 79a is 5.95 kcalmolꢀ1 more
stable than the conformer 79b, which does not have Se···O
interaction (anti, anti).[45] It suggests that Se···O intramolecu-
Chem. Eur. J. 2010, 16, 10576 – 10591
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10587

H. B. Singh et al.
129.6, 128.4, 126.2, 52.7, 34.9, 31.1, 10.8 ppm; 77Se NMR (CDCl3): d=
211.3 ppm; IR (KBr): n˜ =2952.0, 1722.0, 1435.2, 1246.2, 1000.7,
781.5 cmꢀ1; ES-MS: m/z: calcd for C15H20O4Se: 344.05; found: 345.0
[M+H]+ (10%), 312.9 [MꢀOMe]+ (100%); elemental analysis (%)
calcd for C15H20O4Se: C 52.48, H 5.87; found: C 52.68: H, 5.87.
Experimental Section
All organoselenium compounds were synthesized under nitrogen or
argon atmosphere by using standard vacuum-line techniques. Solvents
were purified by standard procedures and were freshly distilled prior to
use. 1H (400 MHz), 13C (100.56 MHz) NMR spectra were obtained by
using a Varian VS400 NMR spectrometer and 77Se (57.26 MHz) by using
a Varian 300 NMR spectrometer. Chemical shifts are cited with respect
to TMS (1H, 13C) as the internal standard and Me2Se (77Se) as the exter-
nal standard. Mass spectral (MS) studies were completed by using a Q-
TOF Micro mass spectrometer with electrospray ionization mode analy-
sis. In the case of isotopic patterns, the value is given for the most intense
peak. FT-IR spectra were recorded by using a Perkin–Elmer Spectrum
One FT-IR spectrometer with KBr pellets or liquid film. The kinetic ex-
periments and UV-visible spectrum measurements were completed by
using a JASCO V-570 spectrophotometer.
Synthesis of compound 53: To lithium aluminum hydride (0.090 g,
2.4 mmol) placed in a three necked round bottomed flask, was added a
freshly dried THF (10 mL). The solution was brought to 0–108C and
added a THF solution (10 mL) of diselenide 46 (0.300 g, 0.5 mmol) drop-
wise. After addition of the diselenide, the ice bath was removed and the
reaction mixture stirred at room temperature for 6 h. The excess lithium
aluminum hydride was quenched with dropwise addition of water under
a nitrogen atmosphere. The reaction mixture was poured into water, al-
lowed to stand over in an open atmosphere for air oxidation (15 min).
The mixture was acidified with glacial acetic acid (1 mL) and extracted
with ethyl acetate to give a orange solid. Yield: 0.094 g (35.0%); m.p.
206–2088C; 1H NMR ([D6]DMSO): d=7.41 (s, 4H), 5.10(t, J=5.6 Hz,
4H), 4.35(d, J=5.2 Hz, 8H), 1.30 ppm (s, 18H); 13C NMR ([D6]DMSO):
d=152.4, 145.6, 123.8, 122.8, 63.6, 34.7, 31.3 ppm. 77Se NMR (CD3OD):
d=346.2 ppm; IR (KBr): n˜ =3275.3, 2955.0, 1592.4, 1462.8, 1222.6,
1143.7, 1066.0, 1013.9, 877.3, 679.12 cmꢀ1; elemental analysis (%) calcd
for C24H34O4Se2: C 52.95; H 6.29; found: 53.16, H 6.35.
Synthesis of diselenide 46: Selenium powder (0.353 g, 4.5 mmol), freshly
cut sodium (0.104 g, 4.5 mmol) and a catalytic amount of naphthalene
were loaded in a three-necked round-bottomed flask equipped with a
reflux condenser. To this dry THF (40 mL) was added under a nitrogen
atmosphere. The reaction mixture was heated to reflux for 6 h to give
disodium diselenide. To the above, 2-bromo-5-tert-butyl-isopthalic acid
dimethyl ester 44 (0.658 g, 2 mmol) was added at 0–58C under a brisk
flow of nitrogen. The reaction mixture was stirred at the room tempera-
ture for additional 24 h. Then it was slowly poured into water (200 mL).
The aqueous layer was extracted twice with chloroform (2ꢂ50 mL). The
organic layers were combined, dried with sodium sulfate and evaporated
to give an orange oil. The compound was purified by column chromatog-
raphy using silica gel (60–120) as the stationary phase and petroleum
ether (60–808C)/ethyl acetate (1:0.1) as the eluent. The yellow solution
obtained was evaporated to afford a yellow colored solid. Yield: 0.153 g
(23.3%); m.p. 132–1348C; 1H NMR (CDCl3): d=7.71 (s, 4H), 3.84 (s,
12H), 1.30 ppm (s, 18H); 13C NMR (CDCl3): d=168.3, 151.1, 136.7,
130.7, 129.7, 52.8, 34.9, 31.1 ppm; 77Se NMR (CDCl3): d=519.4 ppm; IR
Synthesis of compound 54: Bromine (0.162 g, 1.0 mmol) in CHCl3
(15 mL) was added to
a stirred solution of diselenide 46 (0.658 g,
1.0 mmol) in CHCl3 (10 mL) at 08C. After the addition of bromine, the
reaction mixture was stirred for additional 3 h at room temperature. The
reaction mixture was then poured into water, extracted with chloroform
and dried over magnesium sulfate. The dried organic layer was evaporat-
ed to give a brown solid. Recrystallization from dichloromethane/petrole-
um ether (3:1) gave reddish-brown needles of selenenyl bromide. Yield:
0.16 g (19.6%); m.p. 130–1338C; 1H NMR (CDCl3): d=7.94 (s, 2H),
4.01ACHTNUGRTNEUNG
(s, 6H), 1.35 ppm (s, 9H); 13C NMR (CDCl3): d=168.7, 150.8, 136.4,
132.9, 131.4, 53.6, 34.9, 31.2 ppm; 77Se NMR (CDCl3): d=943.8 ppm; IR
(KBr): n˜ =2953.0, 1720.4, 1645.3, 1446.5, 1271.51, 999.11, 777.23,
621.8 cmꢀ1; ES-MS: m/z: calcd for C14H17BrO4Se: 408.15; found: 409.27
[M+H]+ (10%), 329.14 [MꢀBr]+ (98%), 315.13 [56<M+>H]+
(100%); elemental analysis (%) calcd for C14H17BrO4Se: C 41.20, H
4.20; found: C 41.41, H 3.93.
(KBr): n˜ =2955.0, 1724.0, 1436.2, 1285.3, 1252.1, 1211.9, 995.8, 769.7 cmꢀ1
;
ES-MS: m/z: calcd for C28H34O8Se2: 658.06; found: 680.87 [M+Na]+,
328.95 [M/2]+ (100%); elemental analysis (%) calcd for C28H34O8 Se2: C
51.23, H 5.22; found: C 51.66, H 5.32.
Synthesis of compound 55: To a stirred solution of diselenide 47 (0.415 g,
0.54 mmol) in chloroform (15 mL) was added a chloroform solution
(10 mL) of bromine (0.098 g, 0.6 mmol) at 08C. After the addition of bro-
mine, the reaction mixture was stirred at room temperature for 3 h. The
dark-brown solution obtained was filtered through solid sodium bicar-
bonate and evaporated to afford a dark-brown oil. The oil obtained was
mixed with 2–3 mL of pentane and kept in a freezer at ꢀ228C to give a
dark-brown solid after 6 days. Yield: 0.245 g (48.9%); m.p. 87–898C;
1H NMR (CDCl3): d=7.89 (s, 2H), 5.29 (Sept, J=6.4 Hz , 2H), 1.43 (d,
J=6.8 Hz, 12H), 1.36 ppm (s, 9H); 13C NMR (CDCl3): d=167.9, 150.7,
136.5, 133.7, 130.9, 71.1, 34.8, 31.2, 21.9 ppm; 77Se NMR (CDCl3): d=
941.1 ppm; ES-MS: m/z: calcd for C18H25BrO4Se 464.01; found: 385.1
Synthesis of diselenide 47: Disodium diselenide was synthesized by a sim-
ilar procedure as adopted for 46 using selenium powder (1.035 g,
13.0 mmol), freshly cut sodium (0.30 g, 13.0 mmol), catalytic amount of
naphthalene and THF (40 mL). After the addition of 2-bromo-5-tert-
butyl-isopthalic acid diisopropyl ester 45 (4.9 g, 13.0 mmol), the reaction
mixture was refluxed for additional 32 h. The compound was purified by
column chromatography using silica gel (60–120) as stationary phase and
petroleum ether (60–808C)/ethyl acetate (2.5:0.1) as a mobile phase. The
oil obtained after column chromatography was dissolved in pentane and
kept in the freezer (ꢀ228C) for one week to give a yellow solid. Yield
1.37 g (27.4%); m.p. 88–908C; 1H NMR (CDCl3): d=7.65 (s, 4H), 5.12
(Sep, J=6.4 Hz, 4H), 1.32(d, J=6.4 Hz, 24H), 1.30 ppm (s, 18H);
13C NMR (CDCl3) d=167.4, 151.1, 137.9, 129.8, 129.1, 69.7, 34.8, 31.1,
22.0 ppm; 77Se NMR (CDCl3): d=517.1 ppm; IR (KBr): n˜ =2977.8,
1715.8, 1279.5, 1101.4, 931.3 cmꢀ1; ES-MS: m/z: calcd for C36H50O8Se2:
770.18; found: 382.86 [M/2]+ (100%), 342.86 [57+H]+; elemental analy-
sis (%) calcd for C36H50O8Se2: C 56.25, H 6.56; found: C 56.21, H 6.35.
[MꢀBr]
+A +A
CHUTGTNREN(NUG 100%), 343.04 [57+H] CHTUNTGREN(NUGN 70%); IR (KBr): n˜ =2971.1, 1716.9,
1641.8, 1265.6, 1192.2, 959.4, 831.0 cmꢀ1; elemental analysis (%) calcd for
C18H25BrO4Se: C 46.57, H 5.43; found: C 47.01, H 5.29.
Synthesis of compound 56: Selenenyl bromide 54 was generated in situ
as described above using diselenide 46 (0.150 g, 0.23 mmol), bromine
(0.037 g, 0.23 mmol) and CHCl3 (10 mL). To the above was added a mix-
ture of triethylamine (0.07 mL) in 2 mL methanol/water (1/0.1). The reac-
tion mixture stirred for 20 min, poured in water and extracted with
CHCl3 (10 mL). It was dried over sodium sulfate and evaporated get a
pale yellow solid. It was recrystallized from petroleum ether/ethyl acetate
(1:0.5) mixture. Yield: 0.075 g (52%); m.p. 167–1698C; 1H NMR
(CDCl3): d=8.33 (d, J=2.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H) 4.14 (s,
3H), 1.43 ppm (s, 9H); 13C (CDCl3) d=170.6, 169.6, 152.9, 148.8 131.9,
130.8, 122.9, 122.5, 54.6, 35.4, 31.6 ppm; 77Se NMR (CDCl3): d=
1398.6 ppm; IR (KBr): n˜ =2961.8, 1721.8, 1642.4, 1439.0, 1367.9, 1350.7,
Synthesis of monoselenide 48: Diselenide 46 (0.738 g, 1.1 mmol), metallic
sodium (0.052 g, 2.2 mol) and catalytic amount of naphthalene were
taken in three-necked flask. To this was added freshly distilled THF
(15 mL). The reaction mixture was stirred for 6 h at the room tempera-
ture. The reaction mixture was brought to 08C and methyl iodide
(0.145 mL, 2.2 mmol) was added. The stirring was further continued at
the room temperature for 45 min. After this, THF in the reaction mixture
was evaporated to get a dark brown oil, which was purified by column
chromatography using silica gel (60–120) as stationary phase and petrole-
um ether/ethyl acetate (5.0:0.1) as an eluent. The colorless oil obtained
was recrystallized from pentane to give a colorless solid. Yield: 0.468 g
(61.0%); m.p. 52–548C; 1H NMR (CDCl3) d=7.67 (s, 2H), 3.95 (s, 6H),
2.25 (s, 3H), 1.33 ppm (s, 9H). 13C NMR (CDCl3) d=168.9, 151.1, 138.4,
1265.0, 1101.7, 882.5, 782.6, 587.3 cmꢀ1
+A
C13H14O4Se: 314.01; found: 315 [M+H] (100%); elemental analysis (%)
calcd for C13H14O4Se: C 49.85, H, 4.51; found: C 50.16, H 4.47.
; ES-MS: m/z: calcd for
CTHUNGTRENNUNG
10588
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10576 – 10591

Arylselenenyl Bromides and Selenenate Ester Cyclization
FULL PAPER
Synthesis of compound 57: To a stirred solution of diselenide 47 (0.715 g,
0.93 mmol) in chloroform (15 mL) was added a chloroform solution
(10 mL) of bromine (0.162 g, 1 mmol) at 08C. After the addition of bro-
mine, the reaction mixture was stirred at room temperature for 3 h. The
dark brown solution obtained was evaporated to give a dark brown oil.
The oil obtained was loaded on a silica gel column (60–120), eluted with
petroleum ether and ethyl acetate to give a colorless solid. The solid ob-
tained was recrystallized from pentane to give the pure selenenate ester.
Yield: 0.325 g (51.3%); m.p. 146–1488C; 1H NMR (CDCl3): d=8.33 (d,
J=1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 5.39 (sept, J=6.4 Hz, 1H), 1.49
(d, J=5.6 Hz, 6H) 1.44 ppm (s, 9H); 13C (CDCl3) d=170.8, 168.9, 152.8,
148.8 131.7, 130.5, 123.1, 123.0, 35.4, 31.7, 22.1 ppm; 77Se NMR (CDCl3):
d=1389.5 ppm; IR (KBr): n˜ =2970.6, 1719.7, 1627.4, 1447.4, 1378.0,
1267.0 1100.0; 897.1, 584.9 cmꢀ1; ES-MS: m/z: calcd for C15H18O4Se:
342.02; found: 343.26 [M+H]+ (100%); elemental analysis (%) calcd for
C15H18O4Se: 52.79, H 5.32; found: C 53.07, H 5.41.
Table 7. Crystal data and structure refinement for 46, 47, and 53.[51]
46
47
53
empirical formula
formula weight
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
a [8]
b [8]
C28H34O8Se2 C36H50O8Se2 C24.67H36O4.67Se2
656.47
768.68
565.12
triclinic
P1
monoclinic monoclinic
¯
P121/n1
C12/c1
9.884(2)
10.6314(10) 11.8571(3)
15.5911(15) 27.5474(6)
104.253(8)
96.610(13)
105.634(13) 90
11.8507(2)
18.5668(6)
24.0059(8)
17.4505(7)
90.00
92.446(4)
90.00
90
101.780(2)
g [8]
V [ꢁ3]
1500.0(4)
2
3789.29(14) 7770.8(5)
Z
4
12
1calcd [Mgmꢀ3
]
1.454
2.510
1.347
1.998
1.449
2.884
absorption coefficient
[mmꢀ1
]
Synthesis of compound 59: To a methanolic solution (20 mL) of disele-
nide 46 (0.361 g, 0.55 mmol), was added an excess of H2O2 (0.17 g,
5.0 mmol) at room temperature. The reaction mixture stirred for 16 h
and then evaporated to get a colorless solid. The crude solid was recrys-
tallized from a methanol/water (2:0.1) mixture and was dried over CaCl2.
reflections collected
22096
36028
0.0313
0.0558
33596
0.0471
0.0863
final R(F) [I>2s(I)][a]
wR(F2) indices [I>2s(I)]
data/restraints/parameters
goodness-of-fit on F2
0.0395
0.1004
9037/0/358
1.131
12571/0/429 15345/0/440
0.966 0.778
1
Yield: 0.132 g (36.5%); m.p. 145–1478C; H NMR (CD3OD): d=8.46 (d,
2
2
J=1.8 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 4.13 (s, 3H), 1.45 ppm (s, 9H);
13C NMR (CDCl3) d=170.4, 168.5, 160.8, 152.1, 133.4, 131.8, 129.01,
128.5, 54.9, 36.9, 31.4 ppm; 77Se NMR ([D6]DMSO) d=1382.0 ppm; IR-
[a] Definitions: R(Fo)=jjFo jꢀjFc jj/jFo j and wR
[w
(Fc2)2]}1/2
G
ACHTUNGTRENUNG
N
.
Table 8. Crystal data and structure refinement for 54, and 56.[51]
ACHTUNGTRENNUNG
54
56
CTHUNGTRENNUNG
empirical formula
formula weight
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
a [8]
b [8]
C14H17BrO4Se
408.15
C13H12O4Se
311.19
monoclinic
I 1 2/m 1
15.7520(5)
6.9494(3)
11.8137(5)
90
102.770
90
1261.22(9)
4
1.639
2.980
5850
0.0275
0.0675
2172/0/108
1.098
C13H14O5Se: C 47.43, H 4.29; found: C 46.41, H 3.84.
Synthesis of compound 72: Bromine (0.08 g, 0.5 mmol) in CHCl3 (15 mL)
was added to a stirred solution of diselenide 46 (0.33 g, 0.5 mmol) in
CHCl3 (10 mL) at 08C. After the addition of bromine, the reaction mix-
ture was stirred for additional 3 h at room temperature. To the above,
H2S gas was bubbled for 2 h to get a pale yellow solution. It was filtered,
washed twice with water and dried over Na2SO4. The dried organic layer
was evaporated to get a pale yellow solid. Yield: 0.250 g (76.0%); m.p.
158–1598C; 1H NMR (CDCl3): d=8.40(d, J=2.4 Hz, 1H), 8.19 (d, J=
2.0 Hz, 1H), 4.09 (s, 3H), 1.42 ppm (s, 9H); 13C NMR (CDCl3): d=195.5,
168.2, 151.1, 144.8, 133.5, 132.6, 130.6, 126.2, 53.5, 35.1, 31.4 ppm;
77Se NMR (CDCl3) d=547.1 ppm; IR (KBr): n˜ =2957.6, 2866.5, 1676.9,
1654.2, 1559.3, 1465.6, 1438.4, 1425.6, 1363.1, 1328.7, 1257.9, 1194.4,
1165.4, 1002.4, 824.6, 783.2, 762.9, 572.7, 483.8 cmꢀ1; elemental analysis
(%) calcd for C13H14O3SSe: C 47.42, H 4.29, S 9.74; found: C 47.32, H
4.28, S 9.67.
triclinic
¯
P1
7.7259(9)
9.775(2)
10.755(3)
75.98(2)
83.355(15)
83.813(14)
780.0(3)
2
1.738
4.977
9755
0.0415
g [8]
V [ꢁ3]
Z
1calcd [Mgmꢀ3
]
absorption coefficient [mmꢀ1
reflections collected
]
final R(F) [I>2s(I)][a]
wR(F2) indices [I>2s(I)]
data/restraints/parameters
goodness-of-fit on F2
0.0703
4709/0/226
1.126
Computational methods: All calculations were performed by using the
Gaussian 03 suite of quantum chemical programs.[48] Full geometry opti-
mizations were performed on suitably designed model systems at the
B3LYP/6–31G(d) level of theory. For the unsymmetrical model disele-
nides (Table 2), the initial coordinates were generated from the crystal
structures (46 or 47). All stable conformers were characterized by the fre-
quency calculations. The relative energies were computed based on the
bottom-of-the-well energies without inclusion of zero-point corrections
unless mentioned otherwise. The natural bond orbital (NBO) analysis[49]
for compounds 42a, 54a, 60 and 61 was carried at the B3LYP/6–311+G-
2
2
[a] Definitions: R(Fo)=jjFo jꢀjFc jj/jFo j and wR
[w
(Fc2)2}]1/2
(Fo )={S[w
N
A
.
Acknowledgements
H.B.S. is grateful to the Department of Science and Technology, New
Delhi, for generous funding. K.S. is thankful to CSIR, New Delhi, for
SRF and SAIF, IITB, for spectral analysis.
ACHTUNGTRENNUNG(d, p) level of theory.
X-ray crystallography: The single-crystal X-ray diffraction measurements
for compounds 46, 47, 53, 54, and 56 were performed by using an Oxford
Diffraction Gemini diffraction measurement device with graphite mono-
chromated MoKa radiation (l=0.7107 ꢁ). The structures were solved by
direct methods and full-matrix least squares refinement on F2 (program
SHELXL-97).[50] Hydrogen atoms were localized by geometrical means.
A riding model was chosen for refinement. For 46, the methoxy ester
group was disordered over two equivalent conformations. The two con-
formations were restrained to be similar and their occupancies refined.
The occupancy factors confined to values of 0.796(6) and 0.204(6). The
crystallographic data 46, 47, 53, 54, and 56 are given in Tables 7 and 8.
[1] a) L. Flohe, W. A. Gunzler, H. H. Schock, FEBS Lett. 1973, 32, 132–
134; b) J. T. Rotruck, A. L. Pope, H. E. Ganther, A. B. Swanson,
D. G. Hafeman, W. G. Hoekstra, Science 1973, 179, 588–590; c) A.
Wendel, Methods Enzymol. 1981, 77, 325–333; d) O. Epp, R. Laden-
stein, A. Wendel, Eur. J. Biochem. 1983, 133, 51–69; e) A. L.
Tappel, Curr. Top. Cell. Regul. 1984, 24, 87–97; f) H. E. Ganther,
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Published online: July 20, 2010
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10591