Aspects of intramolecularly coordinated organochalcogen derivatives

Article abstract of DOI:10.1080/10426500801898119

Recent progress in the area of intramolecularly coordinated organochalcogens, in particular, organoselenium derivatives, is reviewed. Intramolecular coordination facilitates isolation of (a) stable organoselenenyl iodides, (b) chiral diselenides, (c) organotriselenides, d) cleavage of TeC bond, e) metal-free synthesis of chalcogenaaza macrocycles, and f) isolation of cyclic selenenate esters. The synthesis of organoselenium compounds incorporating two ortho-coordinating groups is also discussed.

Full text of DOI:10.1080/10426500801898119

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Aspects of Intramolecularly
Coordinated Organochalcogen
Derivatives
Sagar Sharma a , K. Selvakumar a , Vijay Pal Singh a ,
Sanjio S. Zade a & Harkesh B. Singh a
a Department of Chemistry , Indian Institute of
Technology Bombay , Powai, Mumbai, India
Published online: 29 Oct 2008.
To cite this article: Sagar Sharma , K. Selvakumar , Vijay Pal Singh , Sanjio S. Zade
& Harkesh B. Singh (2008) Aspects of Intramolecularly Coordinated Organochalcogen
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:4, 827-839,
DOI: 10.1080/10426500801898119
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Phosphorus, Sulfur, and Silicon, 183:827–839, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801898119
Aspects of Intramolecularly Coordinated
Organochalcogen Derivatives
Sagar Sharma, K. Selvakumar, Vijay Pal Singh,
Sanjio S. Zade, and Harkesh B. Singh
Department of Chemistry, Indian Institute of Technology Bombay,
Powai, Mumbai, India
Recent progress in the area of intramolecularly coordinated organochalcogens, in
particular, organoselenium derivatives, is reviewed. Intramolecular coordination
facilitates isolation of (a) stable organoselenenyl iodides, (b) chiral diselenides, (c)
organotriselenides, d) cleavage of Te C bond, e) metal-free synthesis of chalco-
genaaza macrocycles, and f) isolation of cyclic selenenate esters. The synthesis of
organoselenium compounds incorporating two ortho- coordinating groups is also
discussed.
. . .
Keywords Ebselen; Glutathione peroxidase; Intramolecular Se N coordination;
Organoselenium; Seleninate ester
INTRODUCTION
The chemistry of organoselenium derivatives, having intramolecular
. . .
nonbonded E D interactions 1 (where E is chalcogen and D is donor)
has attracted current interest. Intramolecular coordination facilitates;
(a) isolation of novel hypervalent, stable organoselenium compounds via
intramolecular interaction of selenium with a nearby heteroatom (N, O,
S etc.),1 (b) chiral reagents for asymmetric synthesis,2 (c) ligands for the
isolation of monomeric MOCVD precursors,3 (d) ligands for achiral and
chiral catalysis,4 and (e) glutathione peroxidase mimics.5,6
ACTIVATION OF Te C BOND
Our group is having a long-standing interest in different aspects of the
chemistry of organochalcogen compounds 2–96–11 including, nonbonded
chalcogen-heteroatom interactions (Figure 1). In continuation to this,
we discuss here some recent results from our laboratory.
We are grateful to Department of Science and Technology, (DST) for financial support.
Address correspondence to Harkesh B. Singh, Department of Chemistry, In-
dian Institute of Technology Bombay, Powai, Mumbai-400076, India. E-mail: chhb-
sia@chem.iitb.ac.in
827

828
S. Sharma et al.
FIGURE 1
The key step in Fujiwara-Heck cross-coupling reaction between or-
ganic tellurides and alkenes was proposed to be the migration of an
organic moiety from Te to Pd (transmetalation) in organic telluride-
PdCl2 complexes to afford the organopalladium species.12 McWhin-
nie and co-workers have established the lability of organic groups
from tellurium on reaction with metal compounds.13 In this regard,
the reactions of R2Se (10) and R2Te (12) (where R = 2-(4,4-dimethyl-
2-oxazolinyl)phenyl)) with HgCl2 and Pd(COD)Cl2 were attempted
(Scheme 1). The reaction of selenoether 10 with HgCl2 afforded the
expected complex R2Se.HgCl2 (11), which is stable in solution. In con-
trast, the analogous tellurium complex R2Te.HgCl2 undergoes slow dis-
mutation in chlorinated solvents to give the fragments RTeCl (13) and
RHgCl (14). Mechanistically, this cleavage can be explained through
electrophilic substitution by mercury at the ipso carbon of one aro-
matic ring. It leads to the formation of the σ-intermediate, which re-
sults in polarization of the Te-C bond (Te+-C−). Rearomaticization in
the presence of chloride ion generates 13 and 14 with completion of
the aryl migration. The Te→N intramolecular nonbonding interactions
may be the additional factor facilitating the polarization of the Te C
bond.14 Similarly the reaction of tridentate tellurides 15 and 18 with
Pd(COD)Cl2 led to facile cleavage of the Te C bond and isolation of the
resulting organopalladium 17,20 and organotellurium products 16,19
respectively (Scheme 2).15

Intramolecularly Coordinated Organochalcogen Derivatives
829
SCHEME 1
Isolation of Triselenide
The organoselenium compounds with coordinating nitrogen in close
proximity of chalcogen in the form of oxazoline ring have been thor-
oughly studied by our group.7 To study the chelate ring size effect,
we have studied another substrate oxazine,9 having coordinating
nitrogen as a part of six membered heterocycle. The synthesis of
diselenide 5 was attempted by the ortho-lithiation method. How-
ever, oxidative work-up of lithium arylselenolate afforded triselenide
21 as the major product (Scheme 3). Interestingly, in the previous
reports, similar reactions using ligands, 2-phenyl-2-oxazoline, 4,4-
dimethyl-2-phenyl-2-oxazoline, (R)-4-ethyl-4-hydro-2-phenyloxazoline,
where nitrogen as a member of five-membered oxazoline ring,
have afforded corresponding diselenides. Generally, bulky lig-
ands such as dithiophenetriptycyl,16 tris(trimethylsilyl)methyl17 and
2,6-di[2,6-di(2,6-dimethylphenyl)tolyl]-4-tert-butylphenyl18 have been
used to isolate stable triselenides or tetraselenides. In this

830
S. Sharma et al.
SCHEME 2
SCHEME 3
. . .
case, triselenide 21 has been stabilized by intramolecular Se
N
coordination.
Isolation of Mercury Tellurolate
To gain insight on the stability of organochalcogens having both
intermolecular coordinating and sterically demanding groups,

Intramolecularly Coordinated Organochalcogen Derivatives
831
SCHEME 4
2-[1-(3,5-dimethylphenyl)-2-naphthyl]-4,5-dihydro-4,4-dimethyl-1,3-
oxazole was chosen as a precursor. The synthesis of corresponding
diselenide 9 was accomplished by ortho-lithiation, selenium insertion
into the C-Li bond, followed by oxidative work-up (Scheme 4).8 The
most interesting feature of the structure of diselenide 9 is the existence
. . .
. . .
of both Se N and Se O interactions between selenium atoms and
nitrogen/oxygen in the same molecule. Generally, for the structure
. . .
of selenium compounds incorporating 2-phenyloxazoline, only Se
N
. . .
interactions were observed. The unusual intramolecular Se O in-
teraction in the structure of diselenide 9 has been explained based
on the different orientation of oxazoline ring due to steric crowding.
One of the oxazoline rings is twisted in such a way that nitrogen of
the ring pointed away and oxygen towards the selenium atom. The
. . .
˚
. . .
˚
Se N [2.976(8) A] and Se O [2.9815 A] distances are comparable to
the reported examples. In contrast, the ditelluride analogue showed
. . .
˚
only one type of (Te(1) N(1), 2.718(3) A) intramolecular interaction.
The mercury selenolate 23 and tellurolate 24 complexes were pre-
pared by oxidative addition of corresponding dichalcogenides with
mercury metal in methanol.19 These show high stability towards
light, moisture, and air. Especially, no decomposition was observed
for the mercury tellurolate 24, when the solid was kept in contact
with air or in solution. Thus, synthesis of a novel air stable and
monomeric mercury tellurolate using a ligand having both sterically
more demanding and intramolecular coordinating features has been
achieved.

832
S. Sharma et al.
Template-Free Macrocycle Synthesis
Mixed selenium and nitrogen donor macrocycles are attractive syn-
thetic targets for several reasons. These ligands contain hard and soft
binding sites in close proximity within the same macrocyclic cavity, and,
therefore, can coordinate both hard and soft guest ions, or molecules.
Selenium in a macrocycle is useful for structural investigation using
77Se NMR spectroscopy. In addition, selenium has a greater σ-donating
ability than N, O, and S, which may influence complexation proper-
ties. Finally, incorporation of selenium, which is a larger atom, into
macrocyclic ligands should change the size of the cage cavity thus lead-
ing to interesting coordination behavior. The macrocyclic ligands were
prepared from the precursor bis(o−formylphenyl) selenide, 25, which
itself was synthesized from o−bromotoluene.20 Several 22-, 24-, and
28-membered macrocyclic Schiff base type ligands 26–33 were isolated
in high yield (Scheme 5).21,22 The intramolecular nonbonded interac-
tion plays an important role in the template-free syntheses of Schiff
. . .
base selenaaza macrocycles. Macrocycle 26 showed two Se N non-
˚
˚
bonded interactions with the distances of 2.723 A and 2.729 A which
˚
are slightly shorter than that observed in 30 (2.773 A) where only one
interaction is present. These interactions lead to the interesting reac-
tivity of the macrocycles toward complexation with different metal ions.
Reaction of 26 with Pd(COD)Cl2, unexpectedly, resulted into complex
SCHEME 5

Intramolecularly Coordinated Organochalcogen Derivatives
833
SCHEME 6
34 where one arm of the macrocycle hydrolyzed into two formyl groups.
. . .
Crystal structure of complex 34 showed weak nonbonded Se O inter-
˚
actions (2.855 A). Extending the series, we have reported new selenaaza
29 macrocycle and its reduced form 33 by replacing ethylenediamine
by cyclohexylenediamine.23 The resulting macrocycle has shown non-
bonded interaction comparable to that observed for 26. The macrocycle
has shown usual reactivity toward the metal ion Ni(II) and Co(II).
Isolation of Stable Selenenate Ester
Selenenic acid is a highly reactive species formed during the catalytic
cycle of glutathione peroxidase (GPx).5 Selenenate esters can be con-
sidered as a protected form of the selenenic acid. We have synthesized
and structurally characterized cyclic selenenate ester 37 stabilized by
. . .
Se O interaction. The reaction of diselenide 36 with halogenating re-
gent (SO2Cl2/Br2/I2) followed by quenching with water has unexpect-
edly afforded the novel selenenate ester 37 (Scheme 6).24 Diselenide 36
was synthesized by the treatment of the precursor bromo compound 35
. . .
˚
˚
with disodium diselenide. The Se O distances (2.604 A and 2.465 A)
are considerably shorter than sum of their van der Waals radii.
This is a nice example of the application of nonbonded interactions
to isolate the rather unstable organoselenium compounds. It is interest-
ing to note that there is no intramolecular interaction between any of
the oxygen atoms and the selenium atoms in 36. The structure shows
that all four oxygen atoms of the formyl groups point away from the
selenium centers.24 The novel cyclic selenenate ester 37 and its precur-
sor diselenide 36 exhibit almost 7- and 6-fold enhancement in the GPx
like antioxidant activity as compared to Wilson’s catalyst [bis2-(N, N-
dimethylbenzylamine) diselenide],25 respectively.
The mechanistic pathway has been discussed for the catalytic cycle
of selenenate ester based on 77Se NMR studies and the previous report
by Back et al.26 Four closely related 77Se NMR signals were obtained
when two equivalents of H2O2 were added to a solution of selenenate
ester 37. These signals can be assigned to the cyclic seleninate 38.
Addition of two equivalents of PhSH resulted in one additional signal
corresponding to selenenate 37. The addition of two more equivalents of

834
S. Sharma et al.
PhSH resulted in only the signal corresponding to selenenate 37 being
observed (Scheme 7).
Se
O
OHC
O
2
H2O2
H2O
H2O
37
O
Se
O
SeOH
CHO
OHC
OHC
O
2
38
PhSH
40
SPh
O
Se
PhSSPh
OHC
CHO
PhSH
H2O
39
SCHEME 7
The formation of selenenate ester 37 can be explained by ring opening
by the thiol, followed by breakdown of the hemiacetal to form thiose-
leninate 39. These results corroborated the observations made by Back
et al. that compounds containing Se· · ·O bonds can be equally effective
. . .
catalysts as the commonly studied Se N derivatives.
SCHEME 8

Intramolecularly Coordinated Organochalcogen Derivatives
835
SCHEME 9
We have recently extended the study of GPx-like activity to dise-
lenides with two ortho esters group atoms. Diselenide 41 was synthe-
sized by using Na2Se2 as the selenenating agent (Scheme 8).27
The diselenide upon hydrolysis with NaOH in H2O/THF medium
gave the hydrolyzed diselenide 42, which was used to prepare new cyclic
selenenate esters 44, 45 (Scheme 9).27
SCHEME 10
Novel selenenate ester 48, which is stabilized by a ortho-
coordinating nitro group could be synthesized by treating

836
S. Sharma et al.
3-nitro-2-bromobenzylalcohol28 46 with Na2Se2 at room tempera-
ture. Interestingly, the treatment of 3-nitro-2-bromobenzylalcohol with
Na2Se2 at reflux temperature gives an azoselenenate ester 47 instead
of nitroselenenate ester 48 (Scheme 10).29
Se· · ·OH Interaction
. . .
Although Se O interactions are weaker than the corresponding
. . .
. . .
Se N interactions, the compounds containing Se O interactions do
play a significant role in imparting enhanced GPx-like antioxidant
properties. Tomoda and co-workers synthesized a series of organose-
. . .
lenium compounds 49 (Figure 2) having intramolecular Se O interac-
tion and studied the strength of this interaction by NMR and full NBO
analysis.30 Wirth reported diselenides 50 containing an oxygen atom
in close proximity to the selenium atoms and found significant GPx-
like catalytic activity.31 Back et al. and Singh and co-workers have also
reported high to moderate catalytic activity for five membered seleni-
nate ester 51, spirodioxaselenanonane 52 and the corresponding benzo
analogues 53, 54.32,6
The remarkable activity of the five membered esters and their
benzo analogues 51-54 in coupled reductase GPx assay, prompted us
to synthesize the first seven membered cyclic seleninate ester. The
cyclic seven membered seleninate ester 57 was synthesized from the
diselenide of 2-phenoxyethanol (Scheme 11). The synthesis of bis(2-
phenoxyethanol) diselenide 55 was carried out by ortho-lithiation route,
followed by the insertion of selenium and oxidation.33
FIGURE 2 Please provide caption for Figure 2>

Intramolecularly Coordinated Organochalcogen Derivatives
837
SCHEME 11
Ebselen Analogues as GPx Mimics
Synthesis of ebselen and its anologues has attracted considerable in-
terest due to their promising GPx-like activities and their therapeutic
values.34 Kersting and DeLion35 isolated intramolecularly coordinated
ebselen 58 (Figure 3).
Compounds 59, 60 showed much better GPx activity than ebselen.36
The significant enhancement in the initial reduction rate for t-
. . .
BuOOH was essentially due to the Se O intramolecular interaction.
An attempted synthesis of intramolecularly coordinated organ-
odiselenides by the reaction of N,N-dialkyl/diphenyl-2-bromo-5-tert-
butylisophthalamide with Li2E2 (E S, Se, Te), interestingly, afforded
ebselen derivatives.
This prompted us to explore the synthesis and GPx activity of
intramolecularly stabilized ebselen analogues with amino acids and
peptide chains. We have recently synthesized and characterized a few
FIGURE 3

838
S. Sharma et al.
ebselen analogues 62 which have intramolecularly coordinating amino
acids by active ester method (Scheme 12).27
SCHEME 12
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