Preparation and characterization of bis[4-dimethylamino-2-pyrimidyl] dichalcogenides (S, Se, Te): X-ray crystal structure of bis[4-dimethylamino-2-pyrimidyl] diselenide and its physicochemical behavior in microemulsion media

Article abstract of DOI:10.1016/j.tet.2008.10.069

Novel and synthetically important bis[4-dimethylamino-2-pyrimidyl] dichalcogenides (S, Se, Te) have been prepared and characterized with the help of elemental analysis and various spectroscopic techniques. The methodology employs hydrazine hydrate in dimethylformamide to reduce elemental chalcogen to generate the dichalcogenide anions, E₂^2- (E=S, Se, Te), followed by reaction with 2,4-dichloropyrimidine to afford bis[4-dimethylamino-2-pyrimidyl] dichalcogenides in good yield. It further exploits the additional compositional degree of freedom available in mixed surfactant solution to allow solubilization and stabilization of bis[4-dimethylamino-2-pyrimidyl] diselenide in microemulsion media.

Full text of DOI:10.1016/j.tet.2008.10.069

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Tetrahedron 65 (2009) 247–252
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation and characterization of bis[4-dimethylamino-2-pyrimidyl]
dichalcogenides (S, Se, Te): X-ray crystal structure of bis[4-dimethylamino-2-
pyrimidyl] diselenide and its physicochemical behavior in microemulsion media
,
a
a
b
c
K.K. Bhasin a , Ekta Arora , Khushwinder Kaur , Sung-Kyu Kang , Michael Gobel ,
*
T.M. Klapoetke c, S.K. Mehta a
,
*
a Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India
b Korea Institute of Energy Research, 71-2 Jang-dong, Yuseong-gu, Daejeon, South Korea
c Department of Chemistry and Biochemistry, Ludwig Maximilian University, Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2008
Received in revised form 18 October 2008
Accepted 21 October 2008
Available online 25 October 2008
Novel and synthetically important bis[4-dimethylamino-2-pyrimidyl] dichalcogenides (S, Se, Te) have
been prepared and characterized with the help of elemental analysis and various spectroscopic tech-
niques. The methodology employs hydrazine hydrate in dimethylformamide to reduce elemental
chalcogen to generate the dichalcogenide anions, E22ꢀ (E¼S, Se, Te), followed by reaction with 2,4-di-
chloropyrimidine to afford bis[4-dimethylamino-2-pyrimidyl] dichalcogenides in good yield. It further
exploits the additional compositional degree of freedom available in mixed surfactant solution to allow
solubilization and stabilization of bis[4-dimethylamino-2-pyrimidyl] diselenide in microemulsion media.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Selenium
Tellurium
Pyrimidine
Organochalcogens
Microemulsion
1. Introduction
Microemulsions are dynamic supramolecular aggregates spon-
taneously formed by dissolving surfactant in organic media.10–12
In the last few decades various organochalcogen (alkyl, aryl,
mixed alkylaryl, pyridyl selenium, and tellurium) compounds have
been extensively studied owing to their novel and unparallel
properties.1 These compounds find widespread use as convenient
intermediates or reagents in organic synthesis,2 biochemistry,3
organic superconductors,4 and semi-conducting materials.5 In an
effort to synthesize these compounds various procedures have
been explored.6 Tanji et al.7 employed the reaction of 2-bromo-
pyridine with lithium alkyl tellurolates to obtain alkyl pyridyl tel-
lurides while Bhasin et al.8 have developed and optimized the
conditions for the preparation of stable bis(2-pyridyl) diselenide/
ditelluride by lithiating pyridine using BF3–Et2O complex followed
by insertion of elemental selenium/tellurium and subsequent oxi-
dation. Bis(2-pyridyl) diselenide has also been shown to be a po-
tential immuno-stimulant and inducer of interferon gamma and
other cytokines in human peripheral blood leukocytes.9
These aggregates allow molecules of disparate polarities (i.e., di-
organodiselenides)13 to be brought into contact with each other.
Microemulsions help in solubilization of molecules insoluble in
organic and aqueous solvents and can provide useful reaction
media for organic synthesis. The physiochemical properties of such
systems are often very different from those of naked molecules or
condensed phases and are influenced by confinement effects, in-
homogeneous distribution, orientation order, and interfacial in-
teractions.14,15 Water-in-oil microemulsions exhibit a low electrical
conductivity as the layers of surfactant separate water droplets.
However, when the temperature
q increases beyond the critical
value (i.e., qc) the conductivity increases sharply. This sudden rise in
conductance has been related to increase in the attractive in-
teractions between the droplets that facilitate migration of sur-
factant counter ions along connected paths through the
microemulsion, leading finally to the phenomenon of electric per-
colation.16–19
In pursuance of our work20 on pyridylchalcogen compounds, we
wish to report herein, a convenient and facile method for synthesis
of some newly designed pyrimidyl chalcogen compounds by
employing hydrazine hydrate as a reducing agent for elemental
* Corresponding authors. Tel.: þ91 172 2534407; fax: þ91 172 2545074.
E-mail addresses: kkbhasin@pu.ac.in (K.K. Bhasin), skmehta@pu.ac.in (S.K.
Mehta).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.069

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248
K.K. Bhasin et al. / Tetrahedron 65 (2009) 247–252
chalcogen atom in dimethylformamide. This line of approach ap-
pears to be potentially useful in view of the many known bio-
logically important compounds,21 which contain the pyrimidyl
moiety. Amir et al.22 have provided a broad view of antiinflamatory
activity possessed by compounds having a pyrimidine nucleus. 2,4-
Diaminopyrimidine derivatives, that have been well estabilished as
antiviral agents, now have been modified to antitumor agents.23 5-
Alkyl- or 5-alkylaryl-substituted pyrimidine derivatives are useful
intermediates in the synthesis of antiviral nucleosides. Schinazi
et al.24 reported the synthesis and the biological activity of several
5-(phenylselenenyl)-pyrimidine nucleosides as potential antiviral
agents. More recently,25,26 a variety of newly synthesized 6-phe-
nylselenenyl acyclic pyrimidines was found to have potent anti-
humanimmunodeficiency virus type-1 (HIV-1) activity. Bardos27
group synthesized 5-selenium-substituted derivatives (dis-
elenides) of uracil, 20-deoxyuridine, and 20-deoxyuridylic acid.
Amino- and dimethylamino-substituted dipyrimidyl diselenides
have been reported28 by use of UV irradiation. Curiously, these
compounds have not been studied extensively compared to the
corresponding aromatic and aliphatic derivatives although the
pyrimidyl compounds are anticipated to exhibit interesting prop-
erties due to presence of two electron withdrawing nitrogen in
their skeleton structure. To explore the behavior of studied com-
pounds, an additional study has been carried out by assimillating
bis[4-dimethylamino-2-pyrimidyl] diselenide, C12H16N6Se2, in wa-
ter/AOT/isooctane (ME-I) and water/AOTþLC/isooctane (ME-II)
microemulsion media.
algae.34 Recently, it has been shown that the 6-DMAP (inhibitor of
cyclin dependent kinase [CDK]) is used to study the DNA endor-
eduplication during elongation and differentiation of primary
roots.35 6-DMAP is also used to activate embryos and oocytes that
give rise to cloned rabbits that are produced by nuclear transfer
from adult somatic cells.36
The preparation of 1a–1c involves reduction of chalcogen atom
to dichalcogenide anion by hydrazine hydrate in alkaline medium
followed by relatively fast nucleophilic substitution reaction on C-2
of 2,4-dichloropyrimidine (a position w.r.t. both nitrogen in the
ring). Hydrazine hydrate is preferred over other reducing agents
because of its low cost, easy work up, high yield, and inert reaction
conditions. The chlorine atom on C-4 is also reactive and displays
a slow nucleophilic substitution reaction by N,N-dimethylamino
anion from DMF to give the desired products (Scheme 2).
O
C
CH3
CH3
O
CH3
CH3
OH-
-
N
+
H
N
+
OH
CH3
E
H
H3
N
C
CH3
H3
C
Cl
N
Cl
N
H3
C
N-
N-
N
+
N
N
E
E
H3
C
N
2
2
2
1a-1c
1a: E = S
1b: E = Se
1c: E = Te
2. Results and discussion
The synthetic strategy to prepare disubstituted pyrimidyl chal-
cogen compounds employs 100% hydrazine hydrate in DMF to re-
duce chalcogens to generate dichalcogenide anions E22ꢀ (E¼S, Se,
Te) followed by reaction with 2,4-dichloropyrimidine to give 1a–1c
in good yield (Scheme 1).
Scheme 2. Proposed mechanism for preparation of bis[4-dimethylamino-2-pyrimidyl]
dichalcogenides.
All the compounds prepared during the course of these in-
vestigations are stable to be purified by column chromatography
(silica gel using hexane/ethyl acetate). The compounds are soluble
in conventional organic solvents and have a shelf life of several
months without any sign of decomposition even at room
temperature.
DMF
4 E + N2H4.H2O + 4 NaOH
2 Na2E2 + 5 H2O + N2
Cl
NMe2
N
2.1. Spectroscopic studies
DMF
2-
N
E2
+
N
1H NMR characterization of dichalcogenide compounds shows
an upfield shift of ring protons w.r.t. the protons of 2,4-dichloro-
pyrimidine due to displacement of electronegative chlorine with
chalcogen atom. The aliphatic protons of the methyl carbon of
dimethylamino group resonate at higher field in selenium and
tellurium compounds as compared to sulfur one. The aromatic
E
N
Cl
2
1a-1c
1a: E = S
1b: E = Se
1c: E = Te
Scheme 1. Synthesis of bis[4-dimethylamino-2-pyrimidyl] dichalcogenides.
protons in pyrimidyl ring H-3 and H-4 resonate at high
d value in
The advantage of this methodology is the selective nucleophilic
substitution of chlorine atom at second position of 2,4-dichloro-
pyrimidine by dichalcogenide anion. An interesting observation in
this reaction is the simultaneous substitution of chlorine atom at
fourth position of 2,4-dichloropyrimidine by dimethylamino group
from the solvent dimethylformamide. It is well known that DMF
can act as formylating agent,29 however, in these reactions it acts as
nucleophilic reagent leading to replacement of activated chloro
group by dimethylamino group, –N(CH3)2. The dimethylamino
group being more bulky and less nucleophilic than the dichalco-
genide anion attacks the fourth position of the pyrimidine ring. It is
interesting to note that in addition to drugs like anticholinergic,30
fungicide,31 antipyretic,32 antihistamine,30 and narcotic analgesic,33
the dimethylamino group is also present in important molecules
such as 6-dimethylamino-purine (6-DMAP), a very important
chemical, present in 0.78–0.08 mol % in the DNA composition of
case of diselenide compared to ditelluride that can be clearly
explained on the basis of decreased electronegativity down the
group in chalcogen family. However, the chemical shift is unusually
upfield in case of disulfide (S<Te<Se) that may be attributed to
interelectronic repulsions in this compound. 13C NMR spectroscopic
results reveal that the aromatic carbons fall in the region of 100–
162 ppm. The chemical shift value of the methyl carbon of dime-
thylamino group appear at about 37 ppm in case of diselenide and
ditelluride whereas at 36.6 ppm in disulfide. A comparison of
stretching frequencies, obtained from FTIR results, nE–C (where E¼S,
Se, Te) in pyrimidyl dichalcogenide reveals a regular trend in the
variation of absorption values.
As commonly observed in EIMS, extensive dissociation of C–E
bond (E¼Se, Te) occurred and consequently the base peaks did not
correspond to molecular ion peaks. In case of bis[4-dimethylamino-
2-pyrimidyl] diselenide, the mass spectrum is complicated due to

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K.K. Bhasin et al. / Tetrahedron 65 (2009) 247–252
249
[I>2s(I)] unique reflections, which were used in all calculations.
The final R indices were R1¼0.1027, wR (F2)¼0.1696 (all data).
The two pyrimidine rings have an average C–C bond length of
1.319 Å and C–C–C bond angle of 115.7ꢂ. The Se–Se bond distance of
2.3162(16) Å relates well with the corresponding distances repor-
ted for other diselenides, which ranges from 2.29 to 2.39 Å (Pauling
scale).37 The Se–C bond length [Se1–C1 1.905(7) Å] is also in
agreement with the value of 1.93 Å suggested by Pauling a typical
value of other diselenides.37
2.3. Assimilation of bis[4-dimethylamino-2-pyrimidyl]
diselenide in microemulsion media
Bis[4-dimethylamino-2-pyrimidyl] diselenide, C12H16N6Se2, has
been assimilated in microemulsion (water/AOT/isooctane (ME-I)
and water/AOTþLC/isooctane (ME-II)) and characterized with the
help of conductivity and spectroscopic techniques. The conduc-
tance behavior of ME-I and ME-II has been monitored when tem-
perature is varied under a constant composition. The solubilization
increases from 2.5 to 50 mM for bis[4-dimethylamino-2-pyrimidyl]
diselenide, C12H16N6Se2, in ME-II as compared to 15 mM in ME-I.
The temperature–conductance profiles of bis[4-dimethylamino-2-
pyrimidyl] diselenide, C12H16N6Se2, at different concentrations viz.,
5 and 15 mM for ME-I and 5, 15, 30, and 50 mM for ME-II have been
depicted (Fig. 2). The percolation parameters for ME-I and ME-II are
tabulated in Table 1. The plots have been fitted to Sigmoidal
Boltzmann equation.38
Figure 1. ORTEP diagram showing the conformation for bis[4-dimethylamino-2-pyri-
midyl] diselenide (1).
several isotopes of selenium. The fragment corresponding to 4-N,N-
dimethylamino pyrimidine radical is the most intense and appears
at m/e 122 and is assigned as the base value. The fragment ions
containing selenium show a highly characteristic and definite
pattern of signal intensities depending on the natural abundance of
various isotopes of selenium. Bis[4-dimethylamino-2-pyrimidyl]
ꢁ
ditelluride shows prominent peak corresponding to [C12H16N6Te]þ
(m/e 372) while other low intensity peaks result from
ꢁ
ꢁ
[C10H10N5Te]þ (m/e 328) and [C10H6N5Te]þ (m/e 324).
"
!
#
logsi ꢀ logsf
logsf
ꢀ1
q
2.2. Crystal structure determination of bis[4-dimethylamino-
2-pyrimidyl] diselenide (1)
log
s
¼ logsf 1 þ
f
1 þ expð ꢀ
qcÞ=Dq
g
(1)
To have a better understanding of the structural details, single
crystal X-ray diffraction of (1) was carried out. A perspective view
and atom numbering scheme of (1) is given (Fig. 1). Crystal data for
(1): C12H16N6Se2, M¼402.23; monoclinic; a¼9.2362(11), b¼13.2178(15),
c¼12.7392(16) Å; V¼1555.1(3) Å3; T¼200 K; rcalcd¼1.718 g/cm3;
Z¼4; 3601 reflections measured, R1¼0.0665, wR2¼0.1450 for 1379
where i, f, and c are the initial, final, and percolative stages.
At constant composition, bis[4-dimethylamino-2-pyrimidyl]
diselenide 1b has been found to delay the percolation process. The
delay becomes more pronounced with the increase in concentra-
tion of organodiselenide.
Maitra et al.39 have reported that in the percolative ME, the
droplets retain their closed structure although infinite clusters are
formed due to inter droplet interactions. The mutual contact and
the bridging between the droplets are due to the presence of ad-
ditives either at the interface or in the core of the droplets. The
pyrimidyl derivatives have two active N-sites that anchor the
droplet surface. This results in the straight bridging of the droplets
and the conduit formation is favored. The pyrimidyl derivative is
a rigid non-planer moiety in which one (pyrimidyl–Se–)– unit is
bent leaving the central horizontal plane. It contains electronically
active –(–Se–Se–)– moiety along with two N-sites. The molecule
adheres to the droplet interface but the configuration results in the
eclipsed bridging due to two droplets engulfing the same
4
ME I
5mM
15mM
Without
ME II
5mM
15mM
30mM
50mM
2
Without
Table 1
Percolation threshold temperature for and ME-I and ME-II at different organo-
diselenide concentrations
[Organodiselenide]
[Concn] log si
log sf
qc (K)
(mM)
Differential SBE
0
Without
d
ꢀ0.46ꢃ0.02 3.02ꢃ0.03 308.55
ꢀ0.59ꢃ0.02 3.30ꢃ0.06 309.55
307.73
C12H16N6Se2 (ME-I)
5
15
309.68
313.64
ꢀ0.66ꢃ0.02 3.39ꢃ0.09
313.64
C12H16N6Se2 (ME-II) 2.5
ꢀ0.61ꢃ0.01 2.88ꢃ0.03
ꢀ0.60ꢃ0.02 2.82ꢃ0.03
ꢀ0.60ꢃ0.02 2.93ꢃ0.02
318.13
318.63
319.15
317.88
318.56
319.99
326.17
290
300
310
320
330
340
5
15
50
(K)
ꢀ0.57ꢃ0.01 3.43ꢃ0.05 327.15
Figure 2. Variation of temperature for C12H16N6Se2 for ME-I and ME-II at [AOT]/
[LC]¼0.774:0.01.
log si¼initial conductance, log sf ¼ final conductance.

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250
K.K. Bhasin et al. / Tetrahedron 65 (2009) 247–252
A
B
C
D
5
0
2
2
3
ME-II
Me-I
6
7
4
5
6
7
8
4
6
4
6
8
8
8
9
10
10
10
4000 3800 3600 3400 3200 3000
1820 1800 1780 1760 1740 1720 1700
1080 1070 1060 1050 1040 1030 1020
-1
1320 1300 1280 1260 1240 1220 1200
Wavenumber(cm
)
Figure 3. Comparison of infrared stretching band of ME-I and ME-II at
u
¼30 in the presence of organodiselenide¼10 mM showing different stretching regions. (A) OH, (B) CO,
(C) SOꢀ3 , (D) COC ester linkage.
organodiselenide moiety. However, the introduction of LC in ME-II
leads to the immobilization of hydrophobic and hydrophilic re-
gions, which allows the formation of extended structures that are
organized over multiple length scale40 and this restricts bis[4-
dimethylamino-2-pyrimidyl] diselenide, C12H16N6Se2, only at the
interface.
Se2, indicates a shift toward higher frequency of around 11.3 cmꢀ1
as compared to pure ME-II than ME-I. The peak centered at
1706 cmꢀ1, assigned to CO stretching shows similar trend of shift
toward the higher frequency with the incorporation of organo-
diselenide. The high frequency values observed in ME-II as com-
pared to ME-I further reveal the entrapping of organodiselenide in
the micellar interface and the formation of rigid interface.41 How-
ever, a shift of around 1 cmꢀ1 is observed for C–O–C and SOꢀ3 of AOT.
A representative spectrum for different absorption regions has
been presented (Fig. 3).
2.3.1. Spectroscopic characterization
1H NMR spectra of ME-I and ME-II with and without the dis-
elenide reveal a unique peak due to aromatic region in bis[4-
dimethylamino-2-pyrimidyl] diselenide molecules. An inspection
of data reveals that the peaks due to aromatic protons are retained
in ME-I and ME-II indicating that the organodiselenide moiety is
intact in ME system and is not subjected to any breakdown. Peaks
due to aromatic protons and head group protons are downfield in
ME-I as compared to ME-II. These findings are consistent with the
fact that addition of LC in ME-I involves progressive change in the
electron cloud of the protons of the head group. The organo-
diselenide interaction is mainly localized in the proximity of the
polar head groups of the surfactant. This is revealed by the shifts of
the head group protons in ME-I and ME-II.
UV–vis spectra of the prepared MEs are depicted (Fig. 4) with
peak values at 326.61 nm in ME-I and 321.30 nm in ME-II. The
observed values are due to Se-C4H2N2 chromophore, which in-
volves 4p electrons of Se in conjugation with 6p electrons of the
pyrimidyl ring. This is supported by the interpretation of UV–vis
spectra of related compounds cited in the literature.42 The slight
red shift observed in ME-I as compared to ME-II suggests that the
organodiselenide is more tightly held at the micellar interface in
ME-II and, therefore, indicate that ME-II serves as a better host for
the assimilation of organodiselenide.
A comparison of OH band frequencies of ME-I and ME-II as-
similating bis[4-dimethylamino-2-pyrimidyl] diselenide, C12H16N6
3. Conclusion
The present report constitutes the first successful attempt to
synthesize novel bis[4-dimethylamino-2-pyrimidyl] dichalcoge-
nides (S, Se, Te) by simple synthetic methodology. The synthesis
involve nucleophilic substitution by dimethylamino group from the
solvent dimethylformamide, which otherwise act as a formylating
agent. These compounds are anticipated to have potential appli-
cations in medicinal field. In addition, the interactions of bis[4-
dimethylamino-2-pyrimidyl] diselenide with core water, AOT, and
Lecithin head groups in microemulsion media reveal significant
enhancement of its solubilization capacity.
ME-I
ME-II
2.5
2.0
1.5
1.0
0.5
0.0
4. Experimental section
4.1. Materials and instrumentation
All experiments were carried out in dry oxygen-free nitrogen
atmosphere. Hydrazine hydrate (Qualigens India, purity >99%),
selenium (Hi-media, purity >99%), elemental sulfur (Hi-media,
purity >99%), tellurium (Hi-media, purity >96%), uracil (Hi-media,
purity >95%), sodium bis-(2-ethylhexyl) sulfosuccinate (AOT)
(Fluka, purity >99%), phosphatidylcholine (Lecithin) (LC) (Fluka,
purity w98%), isooctane (E-Merck, purity >99%) were newly pur-
chased and stored in dessicator prior to use.
270
300
330
(nm)
360
390
420
Figure 4. Variation of absorbance versus wavelength for C12H16N6Se2.