o-hydroxylmethylphenylchalcogens: Synthesis, intramolecular nonbonded chalcogen...OH interactions, and glutathione peroxidase-like activity

Article abstract of DOI:10.1021/jo051309+

The synthesis and characterization of a series of organochalcogen (Se, Te) compounds derived from benzyl alcohol 13 are described. The synthesis of the key precursor dichalcogenides 15, 22, and 29 was achieved by the ortho-lithiation route. Selenide 18 wa

Full text of DOI:10.1021/jo051309+

o-Hydroxylmethylphenylchalcogens: Synthesis, Intramolecular
Nonbonded Chalcogen‚‚‚OH Interactions, and Glutathione
Peroxidase-like Activity
Santosh K. Tripathi,† Upali Patel,† Dipankar Roy,† Raghavan B. Sunoj,† Harkesh B. Singh,*,†
Gotthelf Wolmersha¨user,‡ and Ray J. Butcher§
Department of Chemistry, Indian Institute of Technology, Bombay, Powai, 400076 Mumbai, India,
Fachbereich Chemie, Universita¨t Kaiserslautern, Postfach 3049, Kaiserslautern 67653, Germany, and
Department of Chemistry, Howard University, Washington D.C. 20059
chhbsia@chem.iitb.ac.in
Received June 27, 2005
The synthesis and characterization of a series of organochalcogen (Se, Te) compounds derived from
benzyl alcohol 13 are described. The synthesis of the key precursor dichalcogenides 15, 22, and 29
was achieved by the ortho-lithiation route. Selenide 18 was obtained by the reaction of the dilithiated
derivative 14 with Se(dtc)2. Oxidation of 15 and 22 with H2O2 afforded the corresponding cyclic
ester derivatives 17 and 24, respectively. Oxidation of selenide 18 with H2O2 affords the spirocyclic
compound 19. The presence of intramolecular interactions in dichalcogenides 15 and 22 has been
proven by single-crystal X-ray studies. The cyclic compounds 17 and 19 have also been characterized
by single-crystal X-ray studies. GPX-like antioxidant activity of selenium compounds has been
evaluated by the coupled bioassay method. Density functional theory calculations at the mPW1PW91
level on ditelluride 22 have identified a fairly strong nonbonding interaction between the hydroxy
oxygen and tellurium atom. The second-order perturbation energy obtained through NBO analysis
conveys the involvement of nO f σ*Te-Te orbital overlap in nonbonding interaction. Post wave
function analysis with the Atoms in Molecules (AIM) method identified distinct bond critical point
in 15 and 22 and also indicated that the nonbonding interaction is predominantly covalent.
Comparison between diselenide 15 and ditelluride 22 using the extent of orbital interaction as
well as the value of electron density at the bond critical points unequivocally established that a
ditelluride could be a better acceptor in nonbonding interaction, when the hydroxy group acts as
the donor.
Introduction
nonbonded interactions has been thoroughly investigated
by single-crystal X-ray diffraction, detailed multinuclear
NMR, and theoretical studies. The coordinating groups
generally include tertiary amine, azo, azomethine, py-
Organochalcogen compounds having intramolecular
E‚‚‚X interactions (where E ) Se, Te; X ) N, O) play a
very important role in the areas of organic synthesis,1
enzyme mimetics,2 ligand chemistry,3 and isolation of
metal organic chemical vapor deposition (MOCVD) pre-
cursors.4 We and others have reported the synthesis and
structural characterization of a variety of intramolecu-
larly coordinated organochalcogens where the coordinat-
ing atoms are N, O, and H.5,6 The nature of these
(1) Reviews: (a) Organoselenium Chemistry: A Practical Approach;
Back, T. G., Ed.; Oxford University Press: New York, 1999. (b) Wirth,
T. Tetrahedron 1999, 55, 1. (c) Wirth, T. Angew. Chem., Int. Ed. 2000,
39, 3740. (d) Organoselenium Chemistry: Modern Development in
Organic Synthesis; Wirth, T., Ed.; Springer-Verlag: Berlin, Germany,
2000. (e) Nishibayashi, Y.; Uemura, S. Top. Curr. Chem. 2000, 208,
201. Also see: (f) Uehlin, L.; Wirth, T. Org. Lett. 2001, 3, 2931. (h)
Back, T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67, 499. (j)
Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli,
L.; Temperini, A. Chem. Eur. J. 2002, 8, 1118. (k) Uehlin, L.; Fragale,
G.; Wirth, T. Chem. Eur. J. 2002, 8, 1125. (l) Tiecco, M.; Testaferri,
L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A.
Angew. Chem., Int. Ed. 2003, 42, 3131. (m) Khokhar, S. S.; Wirth, T.
Angew. Chem., Int. Ed. 2004, 43, 631.
* To whom correspondence should be addressed. Tel: (22) 2576 7190.
Fax: (22) 2572 3480.
† Indian Institute of Technology.
‡ Universita¨t Kaiserslautern.
§ Howard University.
10.1021/jo051309+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2005, 70, 9237-9247
9237

Tripathi et al.
SCHEME 1
ridyl, oxazoline, oxazine, and carbonyl groups. There are
very few studies involving the coordinating hydroxy,
ether, and halogen groups. The notable exception is the
pioneering work of Tomoda and co-workers, where in-
tramolecular Se‚‚‚OH, Se‚‚‚OR, and Se‚‚‚halogen interac-
tions have been systematically investigated mainly by
multinuclear NMR and theoretical studies (1-3).7 How-
ever, there are no reports on structural characterization
of E‚‚‚OH interactions in the solid state.
The organochalcogens with an o-hydroxy function (or
hydroxy group present in close proximity) have attracted
attention due to their relevance (i) in organic synthesis,8
(ii) in biochemistry,9 (iii) as intermediates in the catalytic
cycle of seleninate esters,10 (iv) as precursors for GPx
mimics,10 and (v) as hydroxy-containing mimics have
better solubility in water for conducting the bioassay.11
Wirth and co-workers8 have demonstrated the use of 4
and related diselenides in stereoselective selenenylation
reactions. An intramolecular Se‚‚‚O interaction is neces-
sary for high diastereoselectivity. The diselenides with
a free hydroxy group give the highest diastereoselectivity.
Interestingly, the single-crystal structure of 4b does not
show Se‚‚‚OH interaction. Instead, it shows Se‚‚‚OMe
interaction.
The discovery of selenium as selenocysteine in the
active site of the selenoenzyme glutathione peroxidase
(GPx) has led to a growing interest in the biochemistry
of selenium.12 The selenoenzyme functions as an anti-
oxidant and catalyzes the reduction of harmful peroxides
by glutathione and protects the lipid membranes against
oxidative damage.13 The enzyme’s catalytic site includes
a selenocysteine residue in which the selenium undergoes
a redox cycle involving the selenol (Enz-SeH) as the active
form that reduces hydroperoxides and organic peroxides.
The selenol is oxidized to the selenenic acid (Enz-SeOH),
which reacts with reduced glutathione (GSH) to form the
selenenyl sulfide adduct (Enz-SeSG). A second glu-
tathione then regenerates the active form of the enzyme
by attacking the sulfide to form the oxidized glutathione
(GSSG) (Scheme 1).14
(2) (a) Wilson, S. R.; Zucker, P. A.; Huang, R.-R. C.; Spector, A. J.
Am. Chem. Soc. 1989, 111, 5936. (b) Spector, A.; Wilson, S. R.; Zucker,
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2001, 7, 1365.
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Elem. 1998, 136-138, 219. (j) Hiroi, K.; Suzuki, Y.; Abe, I. Tetrahedron:
Asymmetry 1999, 10, 1173. (k) Ehara, H.; Noguchi, M.; Sayama, S.;
Onami, T. J. Chem. Soc., Perkin Trans. 1 2002, 1429. (l) Braga, A. L.;
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Simple organoselenium compounds have been shown
to mimic the GPx activity in vitro. These include ebselen
(2-phenyl-1,2-benzoisoselenazol-3-(2H)-one 5),15 ebselen
analogues,16 benzoselenazolinones,17 selenamide and re-
lated derivatives,18 diaryl diselenides 6 and 7,2a,f,g,19
various tellurides and ditellurides,2c,5b,20 and the semi-
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2, 205. (b) Iwaoka, M.; Katsuda, T.; Tomoda, S.; Harada, J.; Ogawa,
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2125. (b) Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29, 347. (c)
Selenium in Biology and Human Health; Burk, R. F., Ed.; Springer:
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Patent 0-165-534, 1985.
9238 J. Org. Chem., Vol. 70, No. 23, 2005

o-Hydroxylmethylphenylchalcogens
synthetic enzyme selenosubtilisin.21 The diselenides con-
taining basic amino groups have attracted much atten-
tion as GPx mimics because the Se‚‚‚N intramolecular
nonbonded intractions (i) activate the Se‚‚‚Se bond to-
ward the oxidative cleavage, (ii) stabilize the resulting
selenenic acid intermediate against further oxidation,
and (iii) enhance the nucleophilic attack of the thiol at
the sulfur rather than selenium compared with unsub-
stituted phenylselenyl sulfide. Wirth reported, for the
first time, the glutathione peroxidase-like activity of the
new class of diselenides 4 containing an oxygen atom in
close proximity to the selenium.9 Recently, Back et al.10
reported remarkable activity of a novel cyclic seleninate
ester 8 with a Se-O bond as a GPx mimetic. Ester 8 was
derived from allyl 3-hydroxypropyl selenide. In a more
recent study, the same group22 has found that di(3-
hydroxypropyl) selenide 9 exhibited exceptional GPx-like
activity through intermediate spirodioxaselenanonane
10.
Results and Discussion
The key precursor diselenide 1523 was prepared by the
well-established ortho-lithiation8,24 route (Scheme 2).
Attempted reaction of 15 with thionyl chloride to get bis-
(chloromethylbenzyl) diselende, in our hands, afforded
known 6H,12H-dibenzo[b,f][1,5]diselenocin.25 The syn-
thesis of the allyl selenide 16 was approached by the
reduction of 15 with sodium borohydride followed by
quenching of the in situ generated sodium selenolate with
allyl bromide. Synthesis of the cyclic seleninate ester 17
was accomplished by following the method reported by
Back et al. by reacting 16 with tert-butyl hydroperoxide
(TBHP).10 Compound 17 could be alternatively prepared
directly from 15 by its oxidation with an excess of H2O2.
Compound 18 was obtained by the reaction of the ortho-
lithiated product 14 with selenium(II) diethyldithiocar-
bamate [Se(dtc)2].26 Oxidation of 18 with H2O2 afforded
19 in almost quantitative yield. Selenenyl sulfide 20 was
successfully obtained by the reaction of cyclic seleninate
ester 17 with an excess (3-fold) of pentanethiol and was
purified by preparative chromatography using hexane/
dichloromethane (1:1) to give a pale yellow viscous oil.
Compound 20 disproportionates on keeping in solution
at room temperature to the corresponding diselenide and
disulfide. Similarly, selenenyl sulfide 21 was generated
in situ by the reaction of compound 16 with an excess
(4-fold) of PhSH (Scheme 5). Attempted isolation of 21
led to its disproportionation to the corresponding disel-
enide and disulfide. However, the selenenyl sulfides were
stable enough for characterization in solution by 1H, 13C,
and 77Se NMR spectroscopy. The synthesis of tellurium
compounds is depicted in Schemes 3 and 4. Attempts to
prepare the tellurium analogue of 18 by the reaction of
14 with TeI2 led to isolation of a liquid of indefinite
composition.
In continuation of our work on intramolecularly coor-
dinated organochalcogens with nitrogen donors,5 we re-
cently reported intramolecular Se‚‚‚O (formyl oxygen) in-
teraction and GPx-like activity of diselenides having two
ortho oxygens and a novel selenenate ester 11, 12.5f,h In
this paper, we extend this work and report the synthesis
and first structural characterization of diaryl dichalco-
genides (chalcogen ) Se or Te) having hydroxy groups
in close proximity to the selenium atom, their novel
oxidized derivatives, and GPx-like activities. The reaction
mechanism and the intermediates involved in the GPx
catalytic cycle have been investigated by 77Se NMR
spectroscopic studies. Also, we present herein the first
theoretical investigations on Te‚‚‚OH, Te‚‚‚OR (phenoxy),
and Te‚‚‚Cl intramolecular interactions and compare the
same with the corresponding selenium analogues.
Glutathione Peroxidase-like Activity. GPx-like
activities of the selenium compounds were determined
by the coupled reductase assay.27 In this assay, the GPx
activity was measured by a coupled enzyme system
containing glutathione reductase (0.6 unit), GSH (1 mM),
NADPH (0.1 mM), catalyst (0.025 mM), and TBHP (1.2
(16) (a) Jacquemin, P. V.; Christiaens, L. E.; Renson, M. J.; Evers,
M. J.; Dereu, N. Tetrahrdron Lett. 1992, 33, 3863. (b) Zade, S. S.;
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Chem. 2004, 18, 3857.
(17) Galet, V.; Bernier, J.-L.; Henichart, J.-P.; Lesieur, D.; Abadie,
C.; Rochette, L.; Lindenbaum, A.; Chalas, J.; Renaud de la Faverie, J.
F.; Pfeiffer, B.; Renard, P. J. Med. Chem. 1994, 37, 2903.
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(b) Reich, H. J.; Jaspers, C. P. J. Am. Chem. Soc. 1987, 109, 5549.
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Chem. Soc. 2004, 126, 10556.
(20) (a) You, Y.; Ahsan, K.; Detty, M. R. J. Am. Chem. Soc. 2003,
125, 4918. (d) Engman, L.; Stern, D.; Pelcman, M.; Andersson, C. M.
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(b) Wu, Z.-P.; Hilvert, D. J. Am. Chem. Soc. 1990, 112, 5647.
(22) Back T. G.; Moussa Z. Angew. Chem., Int. Ed. 2004, 43, 1268
(23) Iwaoka, M.; Tomoda, S. Phosphorus, Sulfur Silicon Relat. Elem.
1992, 67, 125.
(24) (a) Rickard, C. E. F.; Roper, W. R.; Tutone, F.; Woodgate, S.
D.; Wright, L. J. J. Organomet. Chem. 2001, 619, 293. (b) Constantinos
S. S.; Ioannis D. K.; Maria, M.; George, A. H.; Constantinos, G. S. J.
Org. Chem. 1996, 64, 5589.
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(26) Foss, O. Inorg. Synth. 1953, 4, 91.
(27) Kumar, S.; Panda, S.; Singh, H. B.; Wolmershau¨ser, G.;
Butcher, R. J. J. Sturuct. Chem., in press.
J. Org. Chem, Vol. 70, No. 23, 2005 9239

Tripathi et al.
SCHEME 2a
a Reagents and conditions: (i) n-BuLi, TEMDA, pentane; (ii) Se/THF; (iii) NaBH4, C3H5Br; (iv) TBHP; (v) H2O2; (vi) Se(dtc)2; (vii)
H2O2/AcOH.
SCHEME 3a
TABLE 1. Glutathione Peroxidase-like Activity of
Selenium Compounds Determined by Coupled Reductase
Assay
entry
catalyst
V0a (µM/min)
1
2
6
3
4
5
7
8
9
none
5
1.17
8.63
5.18
30.02
-
26.5
1.41
14.9
12.07
8
15
16
17
18
19
28
bis(2-formylphenyl)Se2
a Reagents and conditions: (i) n-BuLi, TMEDA, pentane; (ii)
Te/THF; (iii) NaBH4, C3H5Br; (iv) TBHP; (v) H2O2; (vi) SOCl2
a Moles of NADPH utilized per minute.
SCHEME 4a
spirocyclic compound 19 where selenium is in oxidation
state IV was less active than the seleninate ester 17.
GPx-like activities of the tellurium analogues 22, 24,
25, and 28 were also evaluated by coupled reductase
assay. During the assay, an immediate formation of a
precipitate was observed soon after the addition of
benzenethiol to the reaction mixture, and therefore, the
obtained values are not satisfactory.
Mechanism. To understand the mechanism and iden-
tify the intermediates involved in the peroxidase reaction
we next set out to use 77Se NMR spectroscopy since its
chemical shift is very sensitive to the environment.
Moreover, all three major intermediates, i.e., RSeH,
RSeOH, and RSeSPh, are expected to show large differ-
ences in their chemical shift values. The model reactions
were monitored by 77Se NMR for 0-1 h. The signals
generally appeared within 5-15 min and did not change
positions with passage of time.
Reaction of 15 with Benzenethiol and TBHP. The
1:1 molar reaction of 15 (413 ppm) with PhSH did not
show signals corresponding to the expected selenenyl
sulfide 21 and selenol 29, indicating that the initial
reaction was too slow. However, when a second equiva-
lent of PhSH was added, two signals at 199.5 and 413
ppm due to selenol 29 and diselenide 15, respectively,
were observed. There is a downfield shift of ∼54.5 ppm
a Reagents and conditions: (i) n-BuLi, pentane/-78 °C; (ii) Te/
THF/[O].
mM). The reduction of TBHP by GSH was also carried
out using ebselen 5 and seleninate ester 8 for comparison.
The decrease in NADPH concentration was monitored
spectrophotometrically at 340 nm, and the results are
summarized in Table 1. It was found that diselenide 15
and cyclic seleninate ester 17 are more efficient catalysts
in comparison to ebselen 5 and have comparable activity
to that of aliphatic seleninate ester 8. The high activity
of 15 is probably due to intramolecular Se‚‚‚O nonbonding
interaction [Se(2)‚‚‚O(2) ) 3.008 Å] (vide infra). Interest-
ingly, bis(formylphenyl)diselenide28 having a strongly
coordinating carbonyl group showed relatively poor activ-
ity (entry 9) as compared to 15, which has a weakly
coordinating hydroxy group. Surprisingly, allyl selenide
16 did not show any considerable activity even when a
4-fold excess amount of the catalyst was used (entry 4).
Similarly, selenide 18 also showed poor GPx activity. The
(28) Wendel, A. Methods Enzmol. 1981, 77, 325.
9240 J. Org. Chem., Vol. 70, No. 23, 2005

o-Hydroxylmethylphenylchalcogens
SCHEME 5
of 77Se NMR for 29 compared with the chemical shift of
benzeneselenol (145 ppm).29 This downfield shift is due
to strong intramolecular interaction between Se and O
atom.
Reaction of 17 with Benzenethiol and TBHP.
From the time of appearance of the 77Se NMR signals,
the reaction of seleninate ester 17 (1348.81 ppm) with 1
equiv of PhSH was found to be extremely slow. Reaction
of seleninate ester with 2 equiv of PhSH afforded the
expected signal of selenenic acid 30 (1199.92 ppm). The
77Se NMR chemical shift is significantly downfield shifted
compared with that of o-nitrobenzeneselenenic acid (1066
ppm)30 but close to the value reported for the selenenic
acid derived from N,N′-dimethylbenzylamine diselenide
(1173 ppm) and bis(4,4′-dimethyl-2-oxazolinyl)phenyl]
diselenide,2f thus indicating a strong Se‚‚‚O interaction
in 30. When seleninate ester was treated with an excess
of TBHP, the signal due to selenenic acid completely
disappeared and only one signal at 1345.8 ppm was
observed, indicating that all selenenic acid had converted
back to the cyclic seleninate ester. A similar reactivity
has been observed by Back et al.10 in the reaction of the
aliphatic selenenic acid derived from cyclic seleninate
ester 8.
Reaction of seleninate ester with a 4-fold exess of PhSH
afforded the expected selenenyl sulfide 21 (506.58 ppm).
The signal of selenenyl sulfide is upfield shifted by 20.58
ppm from that of PhSeSPh (526.0 ppm).31 Reaction of the
selenenyl sulfide with an excess of TBHP did not im-
mediately give the cyclic ester 17, but we observed a new
signal due to formation of diselenide (428.73 ppm) which
may be due to disproportionation of 21 to 15. This
indicates an alternative mechanism for the oxidation of
21 to 17 via disproportionation of 21 into the correspond-
ing diselenide 15 and PhSH (Scheme 6), followed by
oxidation of 15. The presence of the diselenide signal
suggests that disproportionation of the selenenyl sulfide
is a major pathway in the regeneration of 17 from 21.
We have also synthesized related selenenyl sulfide 20
When an equimolar amount of TBHP was added to the
reaction mixture containing selenol 29, two signals at 414
and 495 ppm were observed due to formation of diselen-
ide 15 and selenenyl sulfide 21, respectively. When 15
was treated with both PhSH and TBHP simultaneously,
two signals were observed at 414 and 495 ppm corre-
sponding to 15 and 21, respectively, and no signal due
to selenenic acid 30 (vide infra) was observed. This is
probably due to its fast conversion to selenenyl sulfide.
Selenenic acid 30 and other more oxidized products were
not detected even after the addition of an excess of TBHP
indicating high stability of the selenenyl sulfide.
In conclusion, the reaction of diselenide 15 with 1 equiv
of TBHP and PhSH leads to the rapid formation of
selenenyl sulfide 21 and diselenide 15, and no selenol or
the oxidized species are detected. However, when the
reaction mixture containing selenenyl sulfide was treated
with PhSH, the signal due to selenenyl sulfide disap-
peared completely and only one signal at 413 ppm due
to diselenide 15 appeared, thus indicating that the
selenenyl sulfide converts to selenol 29 which then is
readily oxidized to diselenide 15 (Scheme 5). To test this
hypothesis, a crossover experiment was performed in
which the reaction mixture containing selenenyl sulfide
21 and diselenide 15 was treated with 4-methoxyben-
zenethiol. After 1 h, the 77Se NMR spectrum of the
reaction mixture showed a signal for the new selenenyl
sulfide 31 (545.1 ppm) together with the original sele-
nenyl sulfide 21 (494.6 ppm) and diselenide 15 (414.6
ppm). The formation of the selenenyl sulfide 31 could be
explained by the nucleophilic attack of 4-methoxybenzene
thiol directly at the selenium atom of selenenyl sulfide
21 with displacement of PhSH. The results of the
crossover experiments are, therefore, consistent with the
postulated reaction of selenenyl sulfide 21 with PhSH to
produce selenol 29 and diphenyl disulfide.
(30) Reich, H. J.; Willis, W. W.; Wollowitz, S. Tetrahedron Lett. 1982,
23, 3319. (b) Goto, K.; Nagahama, M.; Mizushima, T.; Keiichi S.;
Takayuki, K.; Renji, O. Org. Lett. 2001, 3, 3569.
(31) (a) Luthera, N. P.; Dunlap, R B.; Odom, J. D. J. Magn. Reson.
1982, 46, 152. (b) Khoon-Sin, T.; Arnold, A. P.; Rabenstein, D. L. Can.
J. Chem. 1988, 66, 54.
(29) McFarlane, W.; Wood, R. J. J. Chem. Soc. A 1972, 1397.
J. Org. Chem, Vol. 70, No. 23, 2005 9241

Tripathi et al.
FIGURE 1. Molecular structure of 15.
TABLE 2. Comparison of Experimentally Obtained
SCHEME 6
Structural Parameters (Å and deg) with That Computed
at the MPW1PW91/LanL2DZdp, 6-311G** Level for
Compound 15
exptl calcd
exptl
calcd
Se(1)-C(11) 1.934(3) 1.940 C(21)-Se(2)-Se(1) 104.40(9) 104.196
Se(1)-Se(2) 2.322(6) 2.359 C(11)-Se(1)-Se(2) 101.99(9) 102.189
Se(2)-C(21) 1.934(3) 1.942 C(12)-C(11)-Se(1) 116.6(2) 122.547
Se(1)-O(1A) 4.640
Se(2)--O(2) 3.008
4.675 C(22)-C(21)-Se(2) 122.7(2) 121.960
2.916
31, together with the formation of seleninic acid thiol
ester 32 (m/z 327) and selenonic acid thiol ester 33. In
the reaction of seleninate ester with 3 equiv of PhSH we
were not able to detect the peak due to selenenyl sulfide,
which may be due to its fast disproportionation into
diselenide and disulfide. The formation of diphenyl
disulfide (m/z 218), seleninic acid 34 (m/z 227), and
selenonic acid 35 (m/z 241.00) was observed.
(438.23 ppm) for comparison of the chemical shifts. This
value is quite close to that of dibenzyl diselenide 15 (428
ppm).
Mass spectrometric technique was also used for the
characterization of the intermediates.
Reaction of 16 with TBHP. When 16 (280.17 ppm)
was treated with 1 equiv of TBHP, it did not show any
considerable shift in 77Se NMR spectrum. Reaction of 16
with 2 equiv of TBHP afforded a very weak signal at
992.76 ppm probably due to the RSe-O-allyl species,
which readily disappeared upon addition of excess TBHP,
and a new signal appeared at 1345.96 ppm due to cyclic
seleninate ester 17 which clearly shows that 2,3-sigma-
tropic shift has taken place.
Crystal Structure of 15. The ORTEP diagram of
compound 15 is shown in Figure 1. The important bond
distances and bond angles along with the calculated
values (vide infra) are given in Table 2. The most
interesting feature of the structure is the presence of Se‚
‚‚OH intramolecular interaction. In compound 15, the Se‚
‚‚O distance {Se(2)‚‚‚O(2) ) 3.008 Å} is shorter than the
The mass spectrum of a mixture of the seleninate ester
17 with 1 equiv of PhSH showed three characteristic
peaks due to formation of selenenic acid thiolester (31,
m/z ) 309.8) and other more oxidized product such as
seleninic acid thiol ester 32 (m/z 327) and selenonic acid
thiol ester 33 (m/z 345.8). The reaction of seleninate ester
with 2 equiv of PhSH shows the formation of selenenic
acid 30 (m/z 203). The formation of selenenic acid was
also confirmed by the 77Se NMR. A signal was observed
at 1199.92 for the reaction of seleninate ester and 2 equiv
of PhSH, other more oxidized products are also observed
such as diphenyl disulfide (m/z 218) and selenonic acid
thiol ester 33. When we added TBHP to this reaction
mixture we got back cyclic seleninate ester 17 (m/z 202.9)
due to oxidation-dehydration of selenenic acid thiol ester
9242 J. Org. Chem., Vol. 70, No. 23, 2005

o-Hydroxylmethylphenylchalcogens
TABLE 3. Comparison of Experimentally Obtained
Structural Parameters (Å and deg) with That Computed
at the MPW1PW91/LanL2DZdp, 6-311G** Level for
Compound 22
exptl calcd
exptl
calcd
Te(1)-C(1A) 2.135(7) 2.145 C(1B)-Te(2)-Te(1) 102.200 102.049
Te(1)-Te(2) 2.696(7) 2.728 C(1A)-Te(1)-Te(1) 99.660 99.944
Te(2)-C(1B) 2.143(7) 2.141 O(1B)-Te(2)-Te(1) 165.600 169.100
Te(2)‚‚‚O(1B) 3.021
Te(1)‚‚‚O(1A) 4.781
2.843
4.827
TABLE 4. Comparison of Experimentally Obtained
Structural Parameters (Å and deg) with That Computed
at the MPW1PW91/LanL2DZdp, 6-311G** Level for
Compound 25
exptl
calcd
exptl
calcd
Te-C(1)
Te-Te#
Cl-C(7)
2.134(3) 2.137 C(1)-Te-Te#
98.69(9) 99.820
2.71(5) 2.721 C(6)-C(1)-Te 123.4(2) 122.516
1.791(4) 1.810 C(2)-C(1)-Te 116.7(2) 117.692
C(1)-C(2) 1.395(5) 1.395 Cl-C(7)-H(7A) 109.200 105.536
Cl-Te
3.974
3.947 Cl-Te-Te#
126.540 126.718
FIGURE 2. Molecular structure of 17. Selected bond length
(Å) and angles (deg): Se-O(2) 1.630(5); Se-O(1) 1.794(5); Se-
C(1) 1.939(4); O(2)-Se-O(1) 105.1(3); O(2)-Se-C(1) 101.4(2);
O(1)-Se-C(1) 86.5(3); C(7)-O(1)-Se 113.6(4); C(2)-C(1)-Se
127.0(5); C(6)-C(1)-Se 108.0(5).
Crystal Structure of 19. The ORTEP diagram of 19
is given the Supporting Information (Figure S45). The
molecule is isostructural with related 3,3′-spirobi(3-
selenaphthalide)36 and crystallizes in space group C2/c
with the selenium atom located at the inversion center.
The O(1)-Se-O(1)#1 and C(1)-Se-C(1)#1 angles are
174.41(13)° and 101.74(15)°, respectively. The corre-
sponding angles in 10 are 172.99° and 102.95°, respec-
tively. Considering the lone pair on selenium, the geom-
etry around selenium atom is trigonal bipyramidal with
the more electronegative oxygens in the apical positions.
Crystal Structure of 22. The ORTEP diagram of
compound 22 is given in the Supporting Information
(Figure S46). The important bond lengths and bond
angles along with the calculated values are given in Table
3. Ditelluride 22 is isostructural with the diselenide 15
and has crystallized in space group P2(1)/n. Similar to
15, ditelluride 22 also exhibits novel Te‚‚‚OH intramo-
lecular interaction, leading to T-shaped geometry around
Te(2) and V-shaped geometry around Te(1). The Te(2)‚‚
‚O(1B) distance is 3.021 Å, which is shorter than the sum
of their van der Waals radii (3.6 Å). The O(1B)-Te(2)-
Te(1) angle is 165.60° and indicates an almost linear
arrangement for the three atoms. The C(1A)-Te(1)-Te-
(2)-C(1B) dihedral angle is -79.1(3)°. The molecules are
linked by hydrogen bonds [O(1A)-H(1AA)‚‚‚O(1B)#1 and
O(1B)-H(1BA)‚‚‚O(1A) #2].
sum of van der Waals radii (3.40 Å)32 and the O(2)-
Se(2)-Se(1) angle is 166.10°, which indicates a weak
nonbonded Se‚‚‚OH interaction in the solid state. Inter-
estingly, the calculated distance for such an interaction
is 2.915 Å (vide infra). The short Se‚‚‚O distance may also
result due to Se‚‚‚HO intramolecular interaction. How-
ever, in view of the observed intermolecular short H-
bonding contact involving the hydroxy group, the Se‚‚‚
HO interaction can safely be ruled out. The other hydroxy
O‚‚‚Se distance is greater than the sum of the van der
Waals radii [Se(1)‚‚‚O(1) is 4.63 Å]. This leads to a
T-shaped geometry around Se(2) and V-shaped geometry
around Se(1). The C(11)-Se(1)-Se(2)-C(21) dihedral
angle is -78.53(13)°, indicating a “cisoid” conformation
for the diselenide.33 In the crystal the molecules are
linked by hydrogen bonds [O(1)-H(1) ‚‚‚O(2)#1, d(H‚‚‚
A) ) 1.95 Å and O(2)H(2) ‚‚‚O(10#2, d(H‚‚‚A) ) 2.00 Å].
Crystal Structure of 17. The ORTEP diagram of 17
is shown in Figure 2. In 17, the Se-O distance (Se-O(1)
) 1.794(5) Å) is closer to the normal single bond distance
of 1.774 Å found in OCSeO.34 The SedO bond distance
(SedO(2) ) 1.630 Å) is shorter than that found in
dicyclohexyl-trans-3,4-dihydroxy-1-selenolane (1.755 and
1.67 Å) where selenium atom is attached to the sp3 carbon
atom [Csp3-Se(OH)-Csp3 and Csp3-Se(O)-Csp3 respec-
tively] but closer to Se-O (1.648 and 1.646 Å) found in
3,3′-(4-chloroquinolyl)selenolane and phenyl-1-bromo-2-
phenylethylene selenolane where selenium atom is di-
rectly attached to the sp2-hybridized carbon atoms [Csp2-
Se(O)-Csp2].35
Crystal Structure of 25. The ORTEP diagram of 25
is provided in the Supporting Information (Figure S47).
The important bond lengths and bond angles and the
corresponding calculated values are given in Table 4. The
molecule has a 2-fold axis running through the center of
the Te-Te bond, and hence, only half the molecule is
represented as the asymmetric unit. Surprisingly, the
structure does not show any Te‚‚‚Cl intramolecular
(32) Pauling, L. The Nature of Chemical Bond, 3rd ed.; Cornell
University Press: Ithaca, NY, 1960.
(36) (a) Dahlen B. Acta Crystallogr. 1974, B30, 647. (b) Claeson, S.;
Langer, V.; Allenmark, S. Chirality 2000, 12, 71. (c) Kawashima, T.;
Ohno, F.; Okazaki, R. J. Am. Chem. Soc. 1993, 115, 10434. (d) Ohno,
F.; Kawashima, T.; Okazaki, R. Chem. Commun. 1997, 1671. (e) Ohno,
F.; Kawashima, T.; Okazaki, R. Chem. Commun. 2001, 463. (f) Kano,
N.; Daicho, Y.; Nakanishi, N.; Kawashima, T. Org. Lett. 2001, 3, 691
(g) Drabowicz, J.; Luczak, J.; Mikolajczyk, M.; Yamamoto, Y.; Mat-
sukawa, S.; Akiba, K Tetrahedron: Asymmetry 2002, 13, 2079.
(33) Sandman, D. J.; Li, L.; Tripathy, S.; Stark, J. C.; Acampora, L.
A.; Foxman, B. M. Organometallics 1994, 13, 348.
(34) (a) Dahlen, B. Acta Crystallogr. 1973, B29, 595. (b) Dahlen B.;
Lindgren B. Acta Chem. Scand. 1973, 27, 2218.
(35) Dikarev, E. V.; Petrukhina, M. A.; Li, X.; Block, E. Inorg. Chem.
2003, 42, 1966 and references therein.
J. Org. Chem, Vol. 70, No. 23, 2005 9243

Tripathi et al.
TABLE 5. Comparison of Experimentally Obtained
Structural Parameters (Å and deg) with that Computed
at the MPW1PW91/LanL2DZdp, 6-311G** Level for
Compound 28
exptl calcd
exptl
calcd
Te(2)-C(1B) 2.131(5) 2.133 C(1B)-Te(2)-Te(2)# 100.66(13) 100.173
Te(2)-Te(2)# 2.693(8) 2.696 C(2B)-C(1B)-Te(2) 126.6(4) 125.668
O(2B)-C(8B) 1.425(6) 1.412 C(6B)-C(1B)-Te(2) 114.4(3) 114.525
O(2B)-H(2B) 0.840
O(1B)-Te(2) 2.929
0.956
2.936
FIGURE 3. NBO contour diagram representing the nO
σ*Te-Te orbital interaction in 22.
f
interaction. The Te‚‚‚Cl distances are ∼3.97 Å and the
Te#-Te-Cl angles (126°) deviate quite significantly from
180°, confirming the absence of any intramolecular
interaction (vide infra). However, the crystal packing
shows strong intermolecular Te‚‚‚Te interaction (3.952
Å) resulting in a stacking of the molecules one over
another along the b-axis (Supporting Information Figure
S48).
The DFT calculations are found to reproduce the
principal structural features of the model organochalco-
gens quite well. As is evident from earlier sections (Tables
2-5), the computed chalcogen‚‚‚O distances are in good
agreement with those found using X-ray crystallography.
Furthermore, key geometrical features such as Se-Se
and Te-Te bond lengths and C-Se-Se and O-Se-Se
angles, along with other geometric parameters obtained
for compounds 15, 22, 25, and 28 are very much compar-
able with the experimentally determined values.
The nature of the chalcogen‚‚‚O nonbonded interaction
is analyzed using the natural bond orbital (NBO) method.
In ditelluride 22, with benzylic alcohol as the donor, the
stabilizing interaction between tellurium and oxygen
atoms primarily arises due to the nO f σ*Te-Te orbital
interaction. The NBO contour diagram for compound 22,
as given in Figure 3, clearly depicts the involvement of
nonbonding orbital on oxygen atom (nO) and σ* antibond-
ing orbital of the Te-Te unit (σ*Te-Te). The second-order
perturbation energy obtained from NBO analysis conveys
the effectiveness of the orbital interaction.41,42 The esti-
mated value for 22 is found to be 8.75 kcal/mol, high-
lighting the presence of a strong nonbonding interaction
between tellurium and oxygen atoms. Deletion of selected
orbitals from the donor-acceptor pair is another way to
substantiate the importance of nonbonding interaction.43a,b
It is interesting to note that the NBO deletion energy
computed for 22 is also high, indicating a fairly good
nonbonding interaction.43c Further, it was noticed that
the Te-Te bond undergoes only a slight elongation
compared to the corresponding diphenylditelluride, com-
puted at the same level of theory.
Crystal Structure of 28. The ORTEP diagram of
compound 28 is provided in the Supporting Information
(Figure S49). The important bond lengths and bond
angles and the corresponding calculated values are given
in Table 5. Ditelluride 28 also crystallizes in space group
C2/c with the inversion center situated at the center of
the Te-Te bond. Interestingly, in this molecule both the
ether and hydroxy groups are present. The Te(2)‚‚‚O(1B)
distance is 2.929 Å and the O(1B)-Te(2)-Te(2)# angle
is 152.22°. Though the hydroxy oxygen is suitably
disposed, the Te‚‚‚OH distance is 4.612 Å and does not
indicate an interaction. This observation is similar to that
reported by Wirth et al. for 4b where the Se‚‚‚O(methoxy)
was found to be 2.977 Å and the distance from the
hydroxy-O was 4.22 Å. Similar to 22, in 28 also
the molecules are linked by hydrogen bonds [O(2A)-
H(2AB)‚‚‚O(2B)#3 d(H‚‚‚A) ) 1.89 Å and O(2B)-H(2BB)‚
‚‚O(2A) d(H‚‚‚A) ) 1.89 Å] (Figure 8). The presence of
the -CH2-CH2-OH substituent on the aryl ring results
in the formation of an interesting O-H‚‚‚O hydrogen
bonding (shown in Figure S50 of the Supporting Infor-
mation), where four molecules of 28 are brought together
to form a O4H4-squarane.
Density Functional Theory Studies
The magnitudes of nO f σ*Te-Te interaction energy
indicate a significant covalent interaction operating
between tellurium and heteroatom. Estimated covalency
factors ø for chalcogen‚‚‚O interaction in compounds 15
and 22 are found to be 34% and 50%, respectively, at the
mPW1PW91 level of theory.44,45 At the same time, atomic
charges computed with natural population analysis46 on
Electronic structure calculations have been carried out
using the density functional theory method with an
immediate objective of identifying the electronic origin
as well as nature of nonbonding interactions in the
present series of compounds. We have employed the
hybrid density functional method, namely mPW1PW91,
for this study. The mPW1PW91 method has been known
to reproduce structural parameters quite well for tel-
lurium compounds.37 Introduction of electron correlation
is known to be critical for an adequate representation of
the closed-shell interactions.38 Use of extended basis sets
is desirable for achieving better agreement between
experimental and calculated geometries.39,40 Thus, we
have used the mPW1PW91/LanL2DZdp, 6-311G** level
of theory for this study.
(41) The second-order perturbation energy estimates the donor-
acceptor interactions. These interactions lead to a departure from
idealized Lewis structure description by losing occupancy from the
localized Lewis type NBOs into the empty non-Lewis orbitals (delo-
calization). For each donor NBO (i) and the acceptor NBO (j), the
stabilization energy (ES) associated with delocalization is estimated
as ES ) ∆Eij ) qi[F(i,j)2/(ꢀj - ꢀi)] where qi is the donor orbital occupancy,
ꢀi and ꢀj are orbital energies, and F(i,j) is the off-diagonal NBO Fock
matrix elements.
(42) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
899.
(43) (a) Giuffreda, M. G.; Bruschi, M.; Lu¨thi, H. P. Chem. Eur. J.
2004, 10, 5671. (b) Bruschi, M.; Giuffreda, M. G.; Lu¨thi, H. P. Chem.
Eur. J. 2002, 8, 4216. (c) Deletion energy is the loss of stabilization
energy due to the selective removal of the acceptor orbital helping in
nonbonding interaction.
(37) Klapo¨tke, T. M.; Krumm, B.; Mayer, P.; Schwab, I. Angew.
Chem., Int. Ed. 2005, 42, 5843.
(38) Pyykko¨, P. Chem. Rev. 1997, 97, 597.
(39) Minkin, V. I.; Minyaev, R. M. Chem. Rev. 2001, 101, 1247.
(40) Sanz, P.; Ya´nez, O.; Mo´, O. Chem. Eur. J. 2002, 8, 3999.
9244 J. Org. Chem., Vol. 70, No. 23, 2005

o-Hydroxylmethylphenylchalcogens
TABLE 6. Second Order Perturbation Energy and BCP
Properties of 15, 22, and 28
optimized Te‚‚‚O distance (2.843 Å) in 22 is shorter than
the Se‚‚‚O distance (2.915 Å) in the corresponding
selenium analogue 15. This observation is opposite to
what one might anticipate on the basis of the larger size
of the tellurium atom. This apparent anomaly can be
explained by considering the acceptor ability of σ*Te-Te
compared to that of σ*Se-Se orbital. In fact, computed
second-order perturbation energy for ditelluride 22 was
found to be more than double that of the diselenide 15
(Table 6). Another key parameter that corroborates this
observation is the higher value of electron density at the
chalcogen‚‚‚oxygen bond critical point. The nonbonding
interaction in 22 is thus evidently stronger than the
corresponding diselenide 15.
NPA charges
second-order
Properties of
perturbation energya
Te‚‚‚O BCPd
serial
no.
acceptor donor
chalcogen oxygen
b
c
2
Echalcogen‚‚‚O
Edel
r
∇ F
15
22
29
4.04
8.75
2.50
10.42
12.25
7.10
0.23
0.35
0.33
-0.72 0.016 -0.013
-0.72 0.022 -0.014
-0.55
BCP absent
a All energies are calculated at the mPW1PW91//mPW1PW91/
LanL2DZdp ECP, 6-311G** level and are in kcal/mol. b Second-
order perturbation energy of nO f σ*Se(Te)-Se(Te) delocalization.
c σ*Se(Te)-Se(Te) orbital deletion energy. d In atomic units.
chalcogens and oxygen atoms (Table 6) suggest a modest
electrostatic contribution toward the nonbonding interac-
tion.
Experimental Section
Next, we have investigated the properties of electron
density at the Te‚‚‚O bond critical point (bcp) using
Bader’s theory of atoms in molecules (AIM) (Table 6).47
The AIM formalism involves topological analysis of the
properties of electron density (F) between interacting
atoms. Chemical bonding can thus be identified by the
presence of a bond critical point (bcp), where electron
density reaches a minimum along the bond path. Distinct
bond critical points associated with chalcogen‚‚‚O inter-
action are identified in compounds 15 and 22. The values
of F obtained for these compounds are in a similar range
as that of the neutral hydrogen bond (Table 6). The F
values are much smaller than a covalent bond (e.g., FC-C
) 0.24 ea0-3) but larger than those for the practical
boundary of molecules (F ) 0.001 ea0-3). The Laplacian
25
49
Se(dtc)2 and TeI2 were prepared by reported methods.
Lithiation of compounds 13 and 26 was done by the previously
reported procedure with slight modification.24 All of the
reactions were carried out under nitrogen or argon atmo-
sphere.
Synthesis of Di(hydroxybenzyl) Diselenide (15). Benzyl
alcohol 13 (1.4 mL, 13.5 mmol) and TMEDA (3.4 mL, 27.5
mmol) were added to pentane (100 mL), and the mixture was
stirred thoroughly. To that was added n-BuLi (17.5 mL, 28
mmol) at 0 °C. The mixture was refluxed at 50 °C for 14 h.
After that lithiated product 14 settled, the dark brown colored
supernant liquid was removed, and THF (30 mL) was added
to the reaction mixture. Selenium (1 g, 10 mmol) powder was
added at 0 °C, and the reaction mixture was stirred for 6-7
h. The product obtained was worked up in the usual manner,
extracted with methyl tert-butyl ether, dried over anhydrous
sodium sulfate, and filtered, and 100 mg of KOH was added
to that solution. Diselenide 15 was obtained after evaporation
of solvent as a yellow solid (1.5 g, 60%). Recrystallization from
toluene afforded yellow crystals: mp 67-68 °C; IR (KBr) 3306
2
(∇ ) of F denotes the curvature of electron density in the
3D-topological space for two interacting atoms, and it is
known to recover the shell structure of an atom.48
A
2
negative value of ∇ F, as in 15 and 22, indicates a locally
concentrated electron density, characteristic of a covalent
interaction. Thus, both NBO and AIM methods suggest
that in compounds 15 and 28 the intramolecular non-
boding interaction is dominantly covalent in nature.
A particularly interesting observation on the ditelluride
28 relates to the distance between tellurium and phenoxy
oxygen, which is found to be around 2.9 Å (both experi-
mental as well as theoretical). While the Te‚‚‚O distance
is good enough to be considered for the existence of
nonbonding interaction, absence of a bond critical point
(using topological analysis using the AIM theory) as well
as very low second-order perturbation energies (using the
NBO analysis) rule out the possibility of nonbonding
interaction between these two atoms.
(br), 2915, 2846, 1440, 1054, 1022, 739 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.85 (s, 2H), 4.7 (s, 4H), 7.2 (t, J ) 7.19 Hz,
2H); 7.3 (t, J ) 7.23 Hz, 2H), 7.4 (d, J ) 7.23 Hz 2H), 7.7 (d,
J ) 7.23 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 65.4, 128.46,
128.85, 128.98, 130.69, 135.07, 142.18; 77Se NMR (300 MHz,
CDCl3) δ 428; ES MS m/z 368.282 (M+, 30). Anal. Calcd for
C14H14Se2O2: C, 45.16; H 3.76. Found: C, 44.96; H, 3.52.
Allyl (2-Hydoxybenzyl) Selenide (16). Sodium borohy-
dride (0.25 g, 6.72 mmol) was added to an ice-cooled solution
of 15 (0.5 g, 1.34 mmol) in absolute ethanol (25 mL). Once the
addition was complete, the ice bath was removed and the
reaction mixture was stirred at room temperature for 30 min.
Allyl bromide (1.5 mL, 5.36 mmol) was added to the clear
colorless reaction mixture, and stirring was continued over-
night. The reaction mixture was poured into 100 mL of ether,
washed with a saturated solution of NH4Cl and NaCl and with
water. It was dried over sodium sulfate and solvent was
evaporated in a vacuum. The residue was chromatographed
(elution with 10% ethyl acetate-petroleum ether) to afford 16
as a colorless liquid (0.3 g, 50%): IR (neat) 3356, 3058, 2927,
1632, 1439, 1195, 1026, 751 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.4 (d, J ) 7.22 Hz, 2H), 4.7 (s, 2H), 4.9 (m, 2H), 5.9 (m,
1H), 7.2 (t, J ) 7.32 Hz, 1H), 7.1 (t, J ) 7.42 Hz, 1H), 7.28 (d,
J ) 7.32 Hz, 1H), 7.45 (d, J ) 8.54 Hz, 1H); 13C NMR (400
MHz, CDCl3) δ 142.8, 134.33, 134.27, 129.56, 128.53, 128.2,
127.8, 117.2, 65.0, 30.8; 77Se NMR (500 MHz, CDCl3) δ 280.11;
ES-MS m/z 227 (M+, 12), 211 (28), 128 (47), 130 (100); exact
mass calcd for C10H12OSe 227.0713, found 227.0487.
Comparison of Acceptor Abilities of Selenium
and Tellurium. It is interesting to note that the
(44) The covalency factor ø for the intramolecular Te‚‚‚O can be
estimated by the following equation ø ) [(RTe + RO)vdW - dTeO]/[(RTe
+
RO)vdw - (rTe + rO)cov] where R and r are the van der Waals and covalent
radii, respectively, and d is the distance between the two interacting
atoms.
(45) Sadekov, I. D.; Minkin, V. I.; Zakharov, A. V.; Starikov, A. G.;
Borodkin, G. S.; Aldoshin, S. M.; Tkachev, V. V.; Shilov, G. V.; Berry,
F. J. J. Organomet. Chem. 2005, 690, 103.
(46) (a) Natural population analysis (NPA) represents the occupan-
cies of a set of natural atomic orbitals (NAOs) for a given molecule in
an arbitrary atomic orbital basis set. (b) Reed, A. E.; Weinstock, R. B.;
Weinhold, F. J. Chem. Phys. 1985, 83, 735.
(47) Bader, R. F. W. Atoms in Molecules: A Quantum Theory; Oxford
University Press: New York, 1990.
(48) Bader, R. F. W.; Fand D. J. Chem. Theory Comput. 2005, 1,
403.
Benzo-1,2-oxaselenolane Se-Oxide (17). TBHP (1.55 mL
of a 70% aqueous solution, 12.16 mmol) was added to a solution
(49) Brauer, G. Handbook of Preparative Inorganic Chemistry;
Academic Press: New York, 1962; Vol. 1, p 433.
J. Org. Chem, Vol. 70, No. 23, 2005 9245

Tripathi et al.
of allyl (benzyl alcohol) selenide (0.46 g, 2.03 mmol) in 30 mL
of dichloromethane, and the reaction mixture was stirred at
room temperature for 6 h. The mixture was concentrated under
vacuum, and the residue was chromatographed (elution with
10% methanol-ethyl acetate) to afford 17 as white powder
(0.25 g, 61%). Crystallization from dichloromethane/hexane (1:
1) afforded colorless needle shaped crystals: mp 139-140 °C;
from colorless to yellow. We were unable to isolate the product
in pure form but we characterized it in situ: IR (KBr) 3388,
1472, 1018, 741 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78-7.79
(m), 7.76-7.7.46 (m), 7.34-7.20 (m), 4.77 (s, 2H), 3.43 (s, SH),
1.78 (b, OH); 77Se NMR (500 MHz) δ 506.
Di(2-hydroxybenzyl) Ditelluride (22). Benzyl alcohol (1.4
mL, 13.5 mmol) and TMEDA (3.4 mL, 25 mmol) were added
to pentane (100 mL), and the mixture was stirred. To that
mixture was added n-BuLi (18.2 mL, 20 mmol) at 0 °C. The
mixture was refluxed at 50 °C for 14 h. The lithiated product
was precipitated. The supernant solvent pentane was removed,
and THF (30 mL) was added to the reaction mixture. Tel-
lurium powder (1 g) was added at 0 °C and the mixture stirred
for 6-7 h. The product obtained was worked up in the usual
manner , extracted with dichloromethane, dried over anhy-
drous sodium sulfate, and filtered. Dark red 17 was obtained
after evaporation of the filtrate. Recrystallization from dichlo-
romethane afforded red crystals: yield 1.5 g, 50%; mp 65-68
IR (KBr) 3077, 2915, 2858, 1435, 1199, 975, 859, 771, 553 cm-1
;
1H NMR (400 MHz, D2O) δ 5.6 (d, 1H), 6.00 (d, J ) 4.88 Hz,
1H), 7.5 (m, 2H), 7.6 (t, J ) 7.63 Hz, 1H), 7.8 (d, J ) 0.61 Hz,
1H); 13C NMR (400 MHz, CDCl3) δ 78.31, 122.67, 125.97,
129.20, 132.19, 143.52, 147.0; 77Se NMR (500 MHz, CDCl3) δ
1352.49; ES-MS m/z 202.9 (M+, 38), 184 (10), 156.9 (100), 82.9
(62.6). Anal. Calcd for C7H6O2Se: C, 41.83; H, 3.009. Found:
C, 42.02; H, 3.17.
The same product was obtained in 70% yield from the
similar oxidation of bis(benzyl alcohol) diselenide 15 (0.5 g,
1.344 mmol) with H2O2 (0.5 mL of a 30% aqueous solution,
4.4 mmol) in dioxane at 0 °C for 30 min. Compound was
recrystallized from water to furnish a white powder (0.35 g,
70%).
1
°C; IR (KBr) 3342, 1577, 1439,1202, 1040,1008, 755 cm-1; H
NMR (400 MHz, DMSO-d6) δ 4.6 (s, 4H), 5.8 (s, 2H), 7.05 (t, J
) 7.32 Hz, 2H), 7.25 (m, 4H) 7.8 (d, J ) 7.32 Hz, 2H); 13C
NMR (400 MHz, CDCl3) δ 66.2, 109.3, 127.0, 127.3, 128.4,
138.6, 143.9; 125Te NMR (300 MHz, CDCl3) δ 301; ES-MS m/z
470 (M+, 100). Anal. Calcd for C14H14Te2O2: C, 35.820; H,
3.006. Found: C, 35.92; H, 3.13.
Di(2-hydroxybenzyl) Selenide (18). To a suspension of
dilithiated derivative 14 (26 mmol) in THF was added Se(dtc)2
(5.3 g, 13 mmol) at 0 °C under a brisk flow of nitrogen. The
reaction mixture was stirred for 6 h and poured into a beaker
containing 100 mL of a cold saturated solution of sodium
bicarbonate. The resulting organic layer and the dichlo-
romethane extracts from the aqueous layer were combined,
dried over sodium sulfate, and concentrated in a vacuum to
give a dark viscous oil. Crystallization of this compound from
dichloromethane/hexane (1:1) afforded 18 as light yellow
needles (1.5 g, 39%): mp 86-87 °C; IR (KBr) 3325, 1461, 1006,
Tellurininate Ester (24). The ester 24 was obtained in
70% yield by reaction of 22 (0.5 g, 1.344 mmol) with H2O2 (0.5
mL of a 30% aqueous solution, 4.4 mmol) in dioxane (20 mL)
at 0 °C for 30 min. The solvent was evaporated and the crude
product recrystallized from CH2Cl2/methanol to give a white
product (0.35 g, 70%): mp 200 °C dec; IR (KBr) 3055, 2909,
2822, 1439, 1049, 1036, 741, 641 cm-1 1H NMR (400 MHz,
;
749 cm-1 1H NMR (400 MHz, CDCl3) δ 2.00 (s, 2H), 4.8 (s,
;
CDCl3) δ 7.3-7.6 (m, 4H), 5.2 (m, 2H); 13C NMR (400 MHz,
DMSO-d6) δ 66.39, 126.43, 128.06, 129.18, 132.36, 141.3,
142.54; 125Te NMR (500 MHz), δ 922; ES-MS m/z 250 (M+, 40).
Anal. Calcd for C7H6O2Te: C, 33.66; H, 2.42. Found: C, 34.01;
H, 2.81.
4H), 7.2 (t, J ) 7.32 Hz, 2H); 7.28 (m, 4H), 7.5 (d, J ) 7.32
Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 65.3, 128.3, 128.9,
129.2, 130.4, 134.4, 142.1; 77Se NMR (500 MHz, CDCl3) δ
325.39; ES-MS m/z 293.03 (45, M+), 245.01 (25), 136.03 (60),
91.07(100); exact mass calcd for C14H14O2Se 293.00, found
293.03. Anal. Calcd for C14H14O2Se: C, 57.37; H, 4.81. Found:
C, 57.38; H, 4.87.
Synthesis of Di(2-chlorobenzyl) Ditelluride (25). Di-
telluride 22 (2.0 g, 5.4 mmol) and pyridine (1.2 mL, 16 mmol)
were taken in dichloromethane (100 mL). Thionyl chloride (1
mL, 13.5 mmol) was then slowly added to the solution at 0 °C
under nitrogen atmosphere. The mixture was stirred for 4 h
at room temperature, after which an excess amount of 2 N
HCl was added. After the usual extraction with dichlo-
romethane a dark red crude product was obtained. Recrystal-
lization from hexane/CH2Cl2 as eluent) afforded 25 as red
crystals (0.7 g, 25%): mp 50-52 °C; IR (KBr) 2930, 2861,1685,
734, 664 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.7 (s, 4H), 7.1 (t,
J ) 7.69 Hz, 2H), 7.25 (m, 2H), 7.35 (d, J ) 7.69 Hz, 2H) and
8.0 (d, J ) 7.69 Hz, 2H); 125Te NMR (300 MHz, CDCl3) δ; m/z
507.85 (M+, 50). Anal. Calcd for C14H12Te2Cl2: C, 33.21; H,
2.38. Found: C, 33.0; H, 2.52.
1,1′-Spirobi[3H-2,1-benzoxaselenolene] (19). Hydrogen
peroxide [(30%) 0.1 g, (0.33 mL, 2.9 mmol)] was added dropwise
with cooling and stirring to a solution of bis(benzyl alcohol)
selenide 18 (0.5 g, 1.7 mmol) in 20 mL of acetic acid. After the
addition, the temperature of the reaction mixture was allowed
to rise to room temperature. The mixture was stirred for 30
min at room temperature. The solvent was evaporated in vacuo
to 2 mL and kept aside to give colorless crystals of 19 (0.3 g,
60%): mp 169-170 °C; IR (KBr) 3049, 2871, 2814, 1439, 1202,
1038, 1014, 773 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J
) 7.32 Hz, 2H), 7.41 (m, 4H), 7.22 (d, J ) 8.54 Hz, 2H), 5.3 (s,
4H); 13C NMR (400 MHz, CDCl3) δ 143.47, 133.83, 130.90,
127.99, 127.75, 124.07, 70.93; 77Se NMR (400 MHz, CDCl3) δ
816.8; ES-MS m/z 292.8 (M+, 10), 231 (10), 165 (100), 152.05
(33.3), 128.08 (18), 115.04 (20); exact mass calcd for C14H12O2-
Se: 291, found 292.89. Anal. Calcd for C14H12O2Se: C, 57.73;
H, 4.12. Found: C, 57.88; H, 4.32.
Di(2-phenoxyethanol) Ditelluride (28). To 2-phenoxy-
ethanol (2.6 mL, 21 mmol) in hexane/pentane (50 mL) was
added n-BuLi (1.6 M, 28 mL, 45 mmol) dropwise at -78 °C,
and the reaction mixture was allowed to come to room
temperature. The resulting solution was stirred for 24 h at
this temperature. The solvent was removed, and 30 mL of dry
THF was added to the lithiated product. Tellurium powder
(2.7 g, 21 mmol) was added at 0 °C under a brisk flow of
nitrogen, and the solution was stirred for 12 h at room
temperature and then poured into a beaker containing 100
mL of saturated NH4Cl solution. The organic layer and the
dichloromethane extract from the aqueous layer were com-
bined and dried over sodium sulfate, and solvent was evapo-
rated in vacuo to afford 1.0 g of the crude product which was
recrystallized from THF/hexane to give 1 g (20% yield) of
yellow crystalline product: mp 165-166 °C; IR (KBr) 3255 (br),
Selenenyl Sulfide (20). Pentanethiol (100 µL, 80 mM) was
added to a solution of 17 (50 mg, 0.25 mM) in dichloromethane
(5 mL), and the mixture was stirred at room temperature for
10 min. The mixture was chromatographed by preparative
TLC using hexane/dichloromethane (1:1) to afford the product
as pale yellow oil (55 mg, 81%): IR (neat) 3377, 1452, 1023,
750 cm-1 1H NMR (400 MHz, CDCl3) δ 7.89-7.26 (m, 4H),
;
4.82 (s, 2H), 2.81 (t, 2H), 2.00 (b, 1H), 1.6 (m, 2H), 1.25 (m,
2H), 0.85 (t, 3H); 13C NMR (400 MHz, CDCl3) δ 142.0, 132.57,
131.73, 128.75, 128.05, 65.58, 38.29, 30.74, 30.03, 22.40, 14.10;
77Se NMR (500 MHz) δ 438.23.
1
Selenenyl Sulfide (21). Benzenethiol (20 µL, 0.199 mmol)
was added to the solution of oxaselenane 17 (10 mg, 0.049
mmol) in 0.5 mL of CDCl3, and the mixture was shaken for 2
min. The color of the reaction mixture immediately turned
2920, 2870, 1437, 1229, 1056, 750 cm-1; H NMR (400 MHz,
CDCl3) δ 3.78 (t, J ) 5.01 Hz 4H), 4.12 (t, J ) 5.19 Hz, 4H),
4.94 (br, 2H), 6.82 (m, 2H), 6.9 (d, J ) 7.47 Hz, 2H), 7.25 (t, J
) 7.12 Hz, 2H), 7.45 (d, J ) 7.63 Hz, 2H); 13C NMR (400 MHz,
9246 J. Org. Chem., Vol. 70, No. 23, 2005

o-Hydroxylmethylphenylchalcogens
CDCl3) δ 59.67, 70.87, 97.46, 111.39, 122.84, 129.43, 136.73,
158.13; 125Te NMR (300 MHz, DMSO) δ 163; ES-MS m/z 529.95
(M+, 100). Anal. Calcd for C16H18O4Te2: C, 36.294; H, 3.426.
Found: C, 36.23; H, 3.47.
elements.54 All other elements are represented with the
6-311G** basis set. Electron correlations are partly incorpo-
rated by using Adamo and Barone’s mPW1PW91 density
functional, i.e., PW91 correlation combined with 25:75 mixture
of Hartree-Fock and PW91 exchange for better reproduction
of long-range effects.55 Natural bond orbital (NBO) analysis
was performed at the same level of theory to quantify the
extent of electron delocalizations contributing to the nonbond-
ing interaction.42 The nature of nonbonded interactions was
further analyzed by inspecting properties of the bond critical
points between tellurium and heteroatoms within Bader’s
Atoms in Molecule (AIM) framework, using the AIM2000
package.57
X-ray Crystallography. The diffraction measurements for
compounds 15, 22, 25, and 28 were performed on a Bruker
P4 and for 17 and 19 on a Stoe IPDS at room temperature
with graphite-monochromated Mo KR radiation (λ ) 0.7107
Å). 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. The isotropic
thermal parameters of the H atoms were fixed at 1.5 times
(CH3 groups) or 1.2 times U(eq) (Ar-H) of the corresponding
C atom. Some details of the refinement are given in Tables
S4 and S5 of the Supporting Information.
Conclusions
Organo dichalcogenides (15 and 22) having hydroxy
group ortho to selenium/tellurium with weak intramo-
lecular chalcogen‚‚‚OH interactions have been structur-
ally characterized. The structural and theoretical studies
indicate that tellurium is a better acceptor for nO f σ*-
type interactions. Ditelluride 22 could be easily converted
to the corresponding chloro derivative. Surprisingly, the
structure and theoretical studies of 25 establish that
there is no intramolecular Te‚‚‚Cl interaction. Dichalco-
genides 15 and 22 can easily be converted to respective
esters. The seleninate esters 17, diselenide 15, and
spirocyclic 19 exhibit good GPx-like antioxidant activity.
Selenide 18 could be easily be converted to the spirocyclic
compound 19. The spirocyclic compound shows relatively
poor GPx-like activity. Ditelluride 28 having both a
phenoxy and a hydroxy group has been prepared. Though
single-crystal X-ray diffraction studies indicate a short
contact between Te‚‚‚O (phenoxy), the AIM calculations
do not support the presence of such an interaction.
Coupled Reductase Assay. The GPx-like activity of 6, 8,
and 15-19 was measured according to the literature method27
using ebselen 5 as a standard. The reaction was carried out
at 37 °C in 0.7 mL of the solution containing 50 mM potassium
phosphate buffer, pH 7.0, 1 mM diethylenetriaminepentaacetic
acid (DTPA), 1 mM GSH, 0.1 mmol of NADPH, 0.6 unit of
glutathione reductase, 2.5 µM of catalyst, and 0.5 mmol of
H2O2. The activity was followed by the decrease of NADPH
absorption at 340 nm (eqs 1-3). Appropriate controls were
carried out without catalyst and subtracted. The consumption
of NADPH in the absence of test catalysts (control) was 1.734
× 10-5 M NADPH/min. The initial reduction rate and activity
are expressed in M/min of NADPH concentration and µmoles
of NADPH utilized per minute per µmole, respectively.
Acknowledgment. We are grateful to the Depart-
ment of Science and Technology (DST), New Delhi, and
Council of Scientific and Industrial Research (CSIR),
New Delhi, for funding this work. D.R. thanks CSIR
New Delhi for a junior research fellowship. We thank
IIT Bombay computer center for the computing facili-
ties.
Computational Methods
All geometries were optimized using analytical gradient
techniques implemented in the Gaussian98 suite of quantum
chemical program.51 All stationary points were characterized
as minima by evaluating Hessian indices on respective poten-
tial energy surfaces. For the tellurium systems, relativistic
effects are known to be nontrivial, and thus we used a basis
set consisting of quasirelativistic effective core potentials
(ECPs).52 LanL2DZdp ECP was employed for tellurium cen-
ters. This is the Hay-Wadt’s ECP plus valence basis func-
tions53 with extra diffuse and polarization functions for p-block
Supporting Information Available: 77Se and 125Te NMR
spectra, ES-MS, tables of activity data, ORTEP diagrams of
compounds 19, 22, 25, and 28, tables of crystal and refinement
data, DFT-optimized geometries, energies, and figures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(50) (a) Sheldrick, G. M. SHELXS 97, Program for Crystal Structures
Solution; University of Gottingen: Gottingen, Germany, 1990. (b)
Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl.
Crystallogr. 1999, 32, 115. (c) Sheldrick, G. M. SHELXL 97, Program
for Crystal Structures Refinement; University of Gottingen: Gottingen,
Germany, 1997.
JO051309+
(54) Check, C. E.; Faust, T. O.; Bailey, J. M.; Wright, B. J.; Gilbert,
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(55) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664.
(56) NBO 5.0 Program., Glendening, E. D.; Badenhoop, J. K.; Reed,
A. E.; Carpenter, J. E.; Bhomann, J. A.; Morales, C. M.; Weinhold, F.
Theoretical Chemistry Institute, University of Wisconsin, Madison,
2001.
(51) Frisch et al. Gaussian 98, revision A.6; Gaussian, Inc.: Pitts-
burgh, PA, 1998.
(52) Huzinaga, S. Gaussian Basis Sets for Molecular Calculation;
Elsevier: Amsterdam, 1984.
(53) (a) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284. (b)
Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
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J. Org. Chem, Vol. 70, No. 23, 2005 9247