Synthesis and structures of Se analogues of the antithyroid drug 6-n-propyl-2-thiouracil and its alkyl derivatives: Formation of dimeric Se-Se compounds and deselenation reactions of charge-transfer adducts of diiodine

Article abstract of DOI:10.1002/chem.200501455

Four selenium analogues of the antithyroid drug 6-n-propyl-2-thiouracil (PTU), of formulae RSeU, (R = methyl (Me) (1), ethyl (Et) (2), n-propyl (nPr) (3), and isopropyl (iPr) 4), have been synthesized. Reaction of 1-4 with diiodine in a 1:1 molar ratio in dichloromethane results in the formation of [(RSeU)I₂] (R = methyl (5), ethyl (6), n-propyl (7) and isopropyl (8)). All compounds have been characterized by elemental analysis, FT-Raman, FT-IR, UV/Vis, ¹H-, ¹³C-, ⁷⁷Se-1D and -2D NMR spectroscopy, and ESI-MS spectrometric techniques. Recrystallization of 4 from dichloromethane afforded (4-CH₂Cl₂). Crystals of [(nPrSeU)I₂] (7), a charge-transfer complex, were obtained from chloroform solutions, while crystallization of 6 and 7 from acetone afforded the diselenides [N-(6-Et-4-pyrimidone)(6-EtSeU)₂] (9·2H ₂O) and [N-(6-nPr-4-pyrimidone)(6-nPrSeU)₂] (10) as oxidation products. Recrystallization of 7 from methanol/ acetonitrile solutions led to deselenation with the formation of 6-n-propyl2-uracil (nPrU) (11). [(nPrSeU)I₂] (7) was found to be a charge-transfer complex with a Se-I bond. These results are discussed in relation to the mechanism of action of antithyroid drugs.

Full text of DOI:10.1002/chem.200501455

DOI: 10.1002/chem.200501455
Synthesis and Structures of Se Analogues of the Antithyroid Drug 6-n-
Propyl-2-thiouracil and Its Alkyl Derivatives: Formation of Dimeric Se–Se
Compounds and Deselenation Reactions of Charge-Transfer Adducts of
Diiodine
[
a]
[a]
[a]
Constantinos D. Antoniadis, Sotiris K. Hadjikakou,* Nick Hadjiliadis,*
[
a]
[b]
[b]
Athanasios Papakyriakou, Martin Baril, and Ian S. Butler
Abstract: Four selenium analogues of
the antithyroid drug 6-n-propyl-2-thio-
uracil (PTU), of formulae RSeU, (R =
methyl (Me) (1), ethyl (Et) (2), n-
propyl (nPr) (3), and isopropyl (iPr) 4),
have been synthesized. Reaction of 1–4
with diiodine in a 1:1 molar ratio in di-
chloromethane results in the formation
NMR spectroscopy, and ESI-MS spec-
trometric techniques. Recrystallization
of 4 from dichloromethane afforded
(4·CH Cl ). Crystals of [(nPrSeU)I ]
(7), a charge-transfer complex, were
obtained from chloroform solutions,
while crystallization of 6 and 7 from
acetone afforded the diselenides [N-(6-
Et-4-pyrimidone)(6-EtSeU) ] (9·2H O)
and [N-(6-nPr-4-pyrimidone)
AHCTREUNG
2
2
A
C
H
T
R
E
U
N
G
(6-
nPrSeU) ] (10) as oxidation products.
2
2
2
2
Recrystallization of 7 from methanol/
acetonitrile solutions led to deselena-
tion with the formation of 6-n-propyl-
2-uracil (nPrU) (11). [(nPrSeU)I ] (7)
2
of [(RSeU)I ] (R = methyl (5), ethyl
was found to be a charge-transfer com-
2
Keywords: bioinorganic chemistry ·
charge-transfer complexes · hetero-
(
6), n-propyl (7) and isopropyl (8)). All
plex with a SeꢀI bond. These results
compounds have been characterized by
elemental analysis, FT-Raman, FT-IR,
are discussed in relation to the mecha-
nism of action of antithyroid drugs.
cyclic
selenoamides
·
iodine
adducts · selenium
1
13
77
UV/Vis, H–, C–, Se–1D and -2D
Introduction
It has been proposed that PTU is more likely to act at the
stage of the de-iodination of T from ID-1enzyme, by react-
4
The first step in the action of the thyroid hormone has been
shown to be monodeiodination of prohormone thyroxine
ing with the intermediate ID-1-SeI, leading to a dead-end
[1,2]
selenenyl sulfide ID-1-Se-S(PTU).
A
H
R
U
It has also been pro-
(
T ) to the biologically active hormone 3,5,3’-triiodothyro-
posed that the selenium analogues of PTU, 6-n-propyl-sele-
nouracil, (PSeU), might be a more potent inhibitor of ID-1
4
[1]
nine (T ). The mechanism of this deiodination reaction
employs a selenocysteine-containing enzyme, iodothyronine
deiodinase-I (ID-1), which is responsible for the removal of
one iodine atom of thyroxine T and its conversion to T .
The drugs most often used in the case of overproduction of
3
[
2a,4a]
than PTU,
and it was estimated to be twice as potent as
[4a]
PTU in inhibiting ID-1activity
on account of the more
[1,2]
[1c,2e,4]
facile formation of a SeꢀSe bond.
Selenium com-
4
3
pounds are also known to be present in the thyroid gland in
the form of selenocysteine in glutathione peroxidase GPx,
an enzyme that degrades intracellular H O , which activates
T (Gravesꢀ disease, hyperthyroidism) are N-methyl-2-mer-
capto-imidazole (MMI) and 6-n-propyl-2-thiouracil (PTU).
3
[3]
2
2
[5]
the thyroid peroxidase (TPO).
Despite the fact that uncharged covalent selenium–iodine
compounds were regarded as nonexistent for a long time,
the crystal structures of selenoether-iodine complexes were
reported in the 1960s. Organic selone and/or selenoamides
are believed to act as donors towards diiodine and certain
iodine compounds as charge-transfer complexes that are
generally more stable than those of the corresponding sulfur
[
a] Dr. C. D. Antoniadis, Assist. Prof. S. K. Hadjikakou,
Prof. N. Hadjiliadis, Dr. A. Papakyriakou
Section of Inorganic and Analytical Chemistry
Department of Chemistry
[6]
[7]
University of Ioannina, 45110 Ioannina (Greece)
Fax : (+30)26510-44831
E-mail: nhadjis@cc.uoi.gr
[
b] M. Baril, Prof. I. S. Butler
[6b,8–12]
compounds.
Although, fully characterized uncharged
Department of Chemistry, McGill University
8
01Sherbrooke, Montreal Quebec H2A 2 K6 (Canada)
covalent selenium–iodine (Se–I) compounds with two-center
6888
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Chem. Eur. J. 2006, 12, 6888 – 6897

FULL PAPER
two-electron bonds are still extremely rare, the conditions
for the formation of Se–I compounds are now well-under-
alkyl-2-selenoamides 1–4 in dichloromethane solutions
(231nm for 1, 232 nm for 2, 231nm for 3, and 233 nm for 4
(e = 35000–40000)) red-shifted in chloroform that can be
[6b,8–12]
stood.
Reactions between selones or selenoamides
!
with diiodine or interhalogens I–X (X = I, Br or Cl) lead to
assigned to p* p transitions.
[11]
the formation of charge-transfer complexes
including:
The visible spectra of the selenoamide–diiodine adducts
in dichloromethane exhibit one distinct absorption band at
495–505 nm (at 501nm for 5 and 6 and at 497 nm for 7 and
i) “spoke structures” or “extended spoke structures” bearing
a linear arrangement of Se-I-X (X = I, Br or Cl) or Se-I-
I···I–I groups, ii) two-coordinate iodine(i) cationic or iodoni-
um salts with selone compounds ([LSe-X-SeL], iii) donor
oxidation products, including dicationic diselenides [LSe–
[14]
8), which is assigned to the “blue-shift” band of I2.
A
shoulder in the range of 285–287 nm (at 286 nm for 5,
285 nm for 6, and at 287 nm for 7 and 8) for these com-
plexes can be assigned, based on literature examples, to a
charge-transfer (CT) band from the HOMO of the donor to
2
+
ꢀ
SeL] ·2I , or neutral diselenides, and iv) T-shaped com-
3
[5a,6b,8–12]
pounds with a linear I-Se-X (X = I, Br or Cl) group.
[
9a,15,16]
Monocationic diselenide species have not yet been observed
for selone–iodine interaction products.
the diiodine LUMO (s *).
According to an assump-
p
[
16]
tion by Laurence et al., CT absorption bands of I –thio-
2
To better understand selenium–I chemistry and possibly
A
H
R
U
G
2
draw conclusions concerning the higher potential activity of
perpendicular arrangement of the I2 moiety towards the
plane of N-C=S, and this hypothesis seems to apply to the
[4a,b]
PSeU over PTU
and their mechanism of action in gener-
al, four alkyl selenouracil derivatives were synthesized. We
report herein reactions of these selone or selenoamides with
I2 to afford charge-transfer adducts and diselenide products.
Diselenides are easily produced upon leaving selenium com-
seleno
thio
A
T
E
N
A
H
E
N
amide with in-plane conformation, where the XꢀC=S····I
torsion angle was close to 08, exhibit a CT band at 295–
305 nm, while those with perpendicular arrangements with
the angle near 908 displayed this band at about 320–
plexes of RSeU with I to stand in acetone.
2
[16]
3
50 nm. Generally, in the case of thioamide–diiodine com-
plexes, perpendicular arrangements are expected when the
[
16]
Results and Discussion
substituents around the thioamide group are bulky,
whereas a planar arrangement is expected when there is a
[16]
General aspects: Compounds 1–4 were synthesized as
NH group cis to the thione group. Therefore, coplanar ar-
rangements are expected for all our complexes because they
all contain a cis-NH group that is able to form a hydrogen
[
4c]
shown in Scheme 1. The crystal structures of compounds
–4 and 4·CH Cl2 were determined by X-ray diffraction.
1
2
These structures together with detailed structures of com-
pounds 7, 9, 10, and 11 are reported separately, and only
the relevant structural features are discussed in this paper.
bond to I . This is confirmed in the case of compound 7
2
[13]
where the I-Se-C-N torsion angle is ꢀ0.458 (see the crystal
structure below). Because complex 7 also shows a CT band
at 287 nm, the CT bands that appear in the region of 285–
2
87 nm for complexes 5–8 should be assigned to a coplanar
arrangement of the N-C=Se group with I . The wavelength
2
values of CT bands for the torsion angles in a perpendicular
arrangement are unknown at present for the selenoamide–I2
complexes because no such crystal structure has been deter-
mined thus far.
Scheme 1. Alkyl selenouracil compounds synthesized. R = methyl (Me,
1
), ethyl (Et, 2), n-propyl (nPr, 3), and isopropyl (iPr, 4).
The absorption bands at 308–315 nm, as well as the bands
at 226–228 nm in the spectra of complexes 5–8, are attribut-
!
ed to intraligand (p* p) transitions because they are also
Reaction of 1–4 with diiodine in a 1:1 molar ratio in di-
present at the same wavelength for the free ligand.
chloromethane solutions results in the formation of
(RSeU)I ] (R = methyl (5), ethyl (6), n-propyl (7) and iso-
1
1
[
H NMR: H NMR spectroscopy provides good indications
2
propyl (8)).
for the formation of one intermediate product 7i on leaving
a acetone or methanol solution of complex 7 [(PSeU)I ] to
2
Spectroscopy:
stand (Scheme 2). This forms a final diselenide 7ii in ace-
tone and nPr-Uracil in methanol.
UV/Vis: The UV/Vis spectra of 6-alkyl-2-selenoamides 1–4
in dichloromethane show one absorption in the region of
Thus, ligand 3 (PSeU) shows one signal at d = 5.84 ppm,
assigned to H5 of selenouracil ring in (CD ) CO. This shifts
3
2
3
3
10–312 nm (311 nm for 1, 310 nm for 2, 312 nm for 3, and
10 nm for 4) with e values in the range of 5000–8000. These
to d = 5.96 ppm in complex 7. One hour later, a new band
appears at d = 6.43 ppm, which can be assigned to H5’,
with H5 coinciding with the starting complex resonance at d
= 5.96 ppm of the intermediate product 7i (Scheme 2). A
black precipitate starts appearing simultaneously in the
values, together with a shift to slightly higher wavelengths of
the lmax on going from dichloromethane to acetone and
chloroform, indicate a p* n transition. A second band at
!
1
231–233 nm is also observed in the UV/Vis spectra of 6-
H NMR tube, which is elemental Se. A second species ap-
Chem. Eur. J. 2006, 12, 6888 – 6897
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6889

N. Hadjiliadis, S. K. Hadjikakou et al.
[
17a]
1
60.7 ppm,
respectively.
1
3
Further C NMR peaks of all
compounds are reported in the
Experimental Section.
7
7
77
Se NMR: The
Se NMR
spectra of compounds MeSeU
(
(
1), EtSeU (2), and nPrSeU
3) in [D ]DMSO each show a
6
single resonance with a chemi-
cal shift at d = 321.8, 322.1,
and 325 ppm, respectively, as-
signed to the unique Se nuclei
of
the
molecules.
The
7
7
Se NMR spectra of com-
plexes
[MeSeU)I2]
(5),
[
[
EtSeU)I2]
(nPrSeU)I ] (7) in (CD ) CO
(6),
and
2
3 2
show resonance signals with
chemical shifts at d = 361.3
(
5), 362 (6), and at 362.4 (low
intensity) and 358.7 ppm
strong) (7), which can be as-
(
7
7
signed to the Se nucleus of
the (RSeU)I complex. For all
2
compounds, the second strong
signal observed near
d
=
3
58.0 ppm is probably attribut-
able to the intermediates 7i
that result when their deuterat-
ed acetone solutions are left to
stand for more than 1h.
Scheme 2.
ESI-MS: The ESI-MS spectra
of compounds 1–4 show peaks
centered at m/z 191 for
1
+
+
pears in the H NMR spectra after leaving for 12 h in the
[MeSeU·H] (1), at m/z 205 for [EtSeU·H] (2), at m/z 219
+
+
same solvent. This species exhibits two resonance at d =
.31and 5.88 ppm assigned to H5 ’ and H5 of a new disele-
for [nPrSeU·H] (3) and at m/z 219 [iPrSeU·H] (4), which
are attributed to their molecular ions.
6
nide species, namely 7ii.
Owing to the cleavage of the CꢀSe bond observed in
The resonance at d = 6.38 ppm, assigned to 7i, disap-
pears completely after about 48 h. At this stage, the relative
intensity of H5’ of 7ii at d = 6.30 ppm with respect to H5
of 7 at d = 5.87 ppm is 0.35. On the other hand, in
methanolic solutions (see crystal structures below), the ESI-
MS spectra (of freshly prepared solutions in 1/1 MeOH/
H O) of complexes 5–8 contain several fragments. Thus
2
fragments observed at m/z 297, 325, 353, and 353 are attrib-
+
(
CD OD) solutions, the H5 signal of ligand 3 is at d =
uted to the cations [C H N O Se] in the case of 5i,
3
10 10
4
2
+
+
5
5
.88 ppm. Two bands appear for complex 7 at d = 6.47 and
.97 ppm assigned to H5’ and H5 of intermediate 7I, which,
[C H N O Se] for 6i and to [C H N O Se] for 7i and
12 14 4 2 14 18 4 2
8i, respectively, which may be formed by the N substitutions
however, end up in compound 11 nPr-Uracil, in which C=Se
is replaced by a C=O bond following hydrolysis of the N3ꢀ
of RSeU by 6-R-4-pyrimidone (Scheme 2).
1
C2’ bond of 7i. Further H NMR peaks of all compounds
Vibrational spectroscopy: Characteristic IR bands of the
are reported in the Experimental Section.
complexes and their compounds are listed in Table 1.
13
13
C NMR: The C NMR spectrum of ligand 3 exhibits the
The vibrational spectra of complexes (RSeU)I show dis-
2
ꢀ
1
following signals: d = 105.2 (C5), 157.6 (C6), 160.9 (C4),
and 176.2 ppm (C2 bonded to Se); the assignments were re-
vealed by an HMBC experiment.
tinct bands at 1547–1557 and 1388–1399 cm , which can be
[
17b]
assigned to ns
A
H
R
U
G
A
H
R
U
G
The cor-
2
responding bands observed for the free compounds 1–4 are
ꢀ
1
ꢀ1
Product 7ii exhibits signals at d = 106.7 (C5), 154.3 (C6),
at 1542–1552 cm and 1378–1399 cm , respectively. These
ꢀ
1
198.2 (C4), and 125.1 ppm (C2). The corresponding signals
bands shift upon coordination ((n (N CSe): 5 cm (5) and
1 5 cm (7)), while d
A
H
R
U
G
s 2
ꢀ
1
for C5’, C6’, C4’, and C2’ appear at 106.7, 157.9 210.1, and
A
H
R
U
G
6890
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6888 – 6897

Dimeric Se–Se Compounds
FULL PAPER
Table 1. Characteristic vibration bands in the IR and Raman spectra of
complexes 5–8 and/or compounds 1–4.
ꢀ
1
ꢀ1
Compound
IR
A
H
R
U
G
]
Raman[cm ]
A
H
R
U
G
n
as
A
C
H
T
R
E
U
N
G
(C=O)
n
s
A
T
E
N
2
d(NCSe)
A
H
R
U
G
1
2
3
4
5
6
7
8
1634
1660
1660
1655
1680
1639
1685
1685
1552
1552
1541
1547
1557
1552
1557
1547
1378
1399
1383
1383
1388
1388
1393
1399
211s, 234vs
216s, 232vs
214s, 232 vs, 264br, 299br
206sh, 234vs
ꢀ
1
Figure 1. ORTEP diagram of compound 1. Selected bond lengths [Š] and
angles [8]: Se(2)ꢀC(2) 1.832(2), O(4)ꢀC(4) 1.233(3), Se(2)-C(2)-N(3)
and 16 cm (8)). The n(CO) bands are observed in the IR
ꢀ
1
spectra of the complexes in the 1639–1685 cm region and
shift to higher wavenumbers compared to the corresponding
bands observed for the free compounds 1–4 (46 (5), 25 (7),
0 cm (8)] upon coordination to I , while in case of 6 the
n(CO) are shifted to lower wavenumbers (21cm ).
1
21.99(16).
ꢀ
1
3
2
ꢀ
1
The characteristic Raman frequencies of the compounds
are also included in Table 1. Diiodine vapor gives a strong
ꢀ
1
ꢀ1
A
C
H
T
R
E
U
N
G
n(I–I) band at 216 cm , which appears at 180 cm in the
A
C
H
T
R
E
U
N
G
[9c,17c]
solid state.
This band shifts to lower wavenumbers
upon coordination to a donor atom, reflecting the reduction
in the IꢀI bond order and the subsequent strengthening of
[
11a,b]
the SeꢀI bond being formed.
The Raman spectra of
ꢀ
1
complexes 5–8, recorded in the 300–50 cm region, show a
strong band at 206–216 cm , very close to that reported for
a diiodine vapor. It is presumably attributable to the par-
ꢀ
1
[9c]
tial loss of iodine from the complexes. It might also be at-
[
11d]
tributable to the stretching of SeꢀSe bonds.
A second,
very strong band in the Raman spectra of complexes record-
ꢀ
1
Figure 2. ORTEP diagram of compound 2. There are three independent
molecules in the asymmetric unit. Selected bond lengths [Š] and angles
ed at 232–234 cm
is assigned to the C-Se-I bending
[11f]
mode.
[
8]: Se(12)ꢀC(12) 1.835(6), Se(22)ꢀC(22) 1.848(6), Se(32)ꢀC(32) 1.828(7),
Recrystallization of powered alkylselenouracils 1–4 from
water gave crystals suitable for an X-ray diffraction study.
To investigate the influence of solvent on the extended
structures formed by the alkylselenouracils, 4 was also re-
crystallized from dichloromethane as the 1:1 adduct
O(14)ꢀC(14) 1.240(8), O(24)ꢀC(24) 1.242(8), O(34)ꢀC(34) 1.227(7);
Se(12)-C(12)-N(13) 121.5(4), Se(22)-C(22)-N(23) 122.8(4), Se(32)-C(32)-
N(33) 121.2(5).
Compound 7 (Figure 6) exhibits the so-called “spoke”
[18]
4
·CH Cl . ORTEP diagrams and selected bond lengths and
structure. There are only a few crystal structures reported
2
2
[11a,d,19]
angles of 1–4 and 4·CH Cl are shown in Figures 1–5, respec-
in the literature that contain the C=SeꢀIꢀI group.
2
2
tively.
The molecular structures of
the alkylselenouracils are un-
[13]
remarkable.
Furthermore,
the molecular structure of 4 is
not affected by recrystallisa-
tion from dichloromethane as
4
·CH Cl . The CꢀSe bond
2
2
lengths in 1–4 and in 4·CH Cl
2
2
vary
from
1.824(2)
to
1
.848(6) Š, indicating a double
[9b]
bond character.
The free
ligands do not undergo
any change upon recrystalliza-
tion in polar (aqueous) sol-
vents.
Figure 3. ORTEP diagram of compound 3. There are two independent molecules in the asymmetric unit. Se-
lected bond lengths [Š] and angles [8]: Se(1) C(1) 1.837(16), Se(21) C(21) 1.835(16), O(5) C(5) 1.23(2),
O(25)ꢀC(25) 1.24(2); Se(1)-C(1)-N(6) 121.7(12), Se(1)-C(1)-N(6) 121.7(12).
ꢀ
ꢀ
ꢀ
Chem. Eur. J. 2006, 12, 6888 – 6897
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6891

N. Hadjiliadis, S. K. Hadjikakou et al.
Figure 6. ORTEP diagram of complex 7. Selected bond lengths [Š] and
angles [8]: I(1)ꢀI(2) 2.8928(10), I(1)ꢀSe 2.7807(11), SeꢀC(2) 1.876(6),
O(4)ꢀC(4) 1.213(8); I(2)-I(1)-Se 176.75(2), I(1)-Se-C(2) 96.9(2).
Figure 4. ORTEP diagram of compound 4. There are three independent
molecules in the asymmetric unit. Selected bond lengths [Š] and angles
[
11d]
methyl-imidazolidin-2-yl)diselenone)
and
(mbis)·2I2
ꢀ
C(12) 1.850(4), Se(22)ꢀC(22) 1.827(5), Se(32)ꢀC(32) 1.835(4),
(mbis
=
1,1’-bis(3-methyl-4-imidazolin-2-selenone)me-
Complex 7 consists of a selenoamide ligand
bonded with a diiodine molecule through selenium, with
[
8]: Se(12)
[20]
O(14)ꢀC(14) 1.230(5), O(24)ꢀC(24) 1.228(7), O(34)ꢀC(34) 1.227(7);
Se(12)-C(12)-N(11) 120.6(3), Se(22)-C(22)-N(21) 123.8(3), Se(32)-C(32)-
N(31) 122.9(3).
thane).
SeꢀI = 2.7807(11) Š, (Figure 6). This bond length is the
longest ever measured and indicates a weak interaction
(
Table 2).
The CꢀSe bond length of 7 (SeꢀC(2) = 1.876(6) Š)
(
Figure 6) is significantly longer than that of the correspond-
ing free ligand nPrSeU (3) (average CꢀSe bond lengths
1
.836(11) Š, Figure 3), owing to its coordination to diiodine,
but it is similar to the CꢀSe bond lengths found for selenoa-
mide–diiodine CT complexes with spoke structures
(
Table 2).
The corresponding IꢀI bond lengths are longer with
values of IꢀI = 2.8928(10) Š in 7 (Figure 6), as compared
[14b,21a]
to the IꢀI distances either in the gas phase (2.677 Š),
Figure 5. ORTEP diagram of compound 4·CH
2
Cl
2
. There are two inde-
[14b,21b]
pendent molecules of 4 in the asymmetric unit, solvated by two dichloro-
methane molecules. Selected bond lengths [Š] and angles [8]: Se(2)ꢀC(2)
or in crystalline diiodine (2.717 Š at 110 K),
as a result
of the Se···I interaction. However, the IꢀI bond length
found in 7 is the shortest such distance measured in diio-
dine–selenoamide complexes (Table 2), consistent with the
previously discussed weak Se···I interaction.
1
1
.829(6), Se(12)ꢀC(12) 1.825(5), O(4)ꢀC(4) 1.232(7), O(14)ꢀC(14)
.233(7); Se(2)-C(2)-N(1) 123.0(4), Se(12)-C(12)-N(11) 123.5(4).
These include (tzSeMe)·I (tzSeMe = N-methylthiazolidine-
The IꢀI bond order of compound 7 is calculated to be
2
[11a]
[21a]
2(3H)-selone,
(btSeMe)·2I (btSeMe = N-methyl-benzo-
0.547, according to Paulingꢀs equation
fied as type B according to Bigoli et al.
and can be classi-
2
[11a]
+
ꢀ
[15a,b]
thiazole-2(3H)-selone,
[(L·I )·(L ) ·2I ](L = bis(N,N’-di-
A
H
R
U
G
2
2
3
Table 2. Bond lengths [Š], bond angles [8], and other structural parameters of known iodine complexes.
[
a]
Compound
[{(nPrSeU)I
SeꢀI [Š]
2.7807
C=Se [Š]
IꢀI bond coord[Š]
2.8927
Bond order[e]
0.547
Se-I-I[8]
X-C-Se-I torsion[8]
ꢀ0.45X = N3
Ref.
[b]
A
C
H
T
R
E
U
N
G
2
}·I
2
] (7)
1.8757
176.75
ꢀ
179.31X = N1
172.16X = N1
[
c]
[11a]
[11a]
[11d]
[19]
A
C
H
T
R
E
U
N
G
(tzSeMe)·I
2
2.726(1)
2.639(1)
2.683(1)
2.776(1)
1.877(8)
1.853(8)
1.8825
2.983(1)
3.071(1)
3.025(1)
0.428
0.337
0.382
177.49(3)
176.66(3)
175.52
ꢀ
12.04X = S1
172.99X = N1
[
2
c]
A
C
H
T
R
E
U
N
G
(btSeMe)·2I
ꢀ
7.26X = S1
72.99X = N6
105.06X = N3
+
3ꢀ [c]
}
A
C
H
T
R
E
U
N
G
{(L·I
2
)·(L
2
) ·2I
ꢀ
[
2
c]
A
C
H
T
R
E
U
N
G
(mbis)·2I
1.879
1.858
2.912(1)
2.995(1)
0.519
0.415
176.86(4)
175.63(4)
ꢀ100.15X = N1
2.716(2)
81.75X = N2
ꢀ
100.32X = N3
8
4.58X = N4
[
a] Calculated in this work. [b] This work. [c] tzSeMe = N-methylthiazolidine-2(3H)-selone, btSeMe = N-methylbenzothiazole-2(3H)-selone, L =
bis(N,N’-dimethylimidazolidin-2-yl)diselenone, mbis = 1,1’-bis(3-methyl-4-imidazolin-2-selenone)methane
6892
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6888 – 6897

Dimeric Se–Se Compounds
FULL PAPER
For selenium “spoke” structure complexes, such as 7,
there is a linear correlation between the SeꢀI and IꢀI dis-
tances [Eq. (1)].
2
dðSeꢀIÞ ¼ ꢀ0:7981 dðIꢀIÞ þ 5:0983 R ¼ 0:9805
ð1Þ
Given that the IꢀI interatomic distance for free diiodine
[14b,21b]
in the solid state is (2.717 Š),
SeꢀI interatomic distance calculated from Equation (1) is
.93 Š. Thus, the value of 2.7807 Š for 7 suggests a relative-
the longest possible
2
ly weak interaction between selenium and iodine.
The I1-Se-C2-N3 or I1-Se-C2-N1 torsion angles for com-
pound 7 are ꢀ0.5(6)8 or ꢀ179.3(5)8, respectively, which con-
firm the coplanar arrangement of IꢀI with respect to the
Figure 7. ORTEP diagram of molecule 11. Selected bond lengths [Š] and
angles [8]: O(2)ꢀC(2) 1.2285(13), O(4)ꢀC(4) 1.2387(15), N(1)ꢀC(2)
[15]
C=Se group as predicted by UV/Vis spectroscopy. Finally,
the values for the Se-I-I angles also imply an almost linear
arrangement, as expected for CT complexes with a “spoke”
structure.
1
.3668(15), N(3)ꢀC(2) 1.3653(14); O(2)-C(2)-N(3) 122.39(11), O(4)-C(4)-
N(3) 119.56(11), O(4)-C(4)-C(5) 125.10(9).
Recrystallization of 7 in MeCN/MeOH (1/1) solutions re-
sults in the formation of compound 11, according to the re-
action shown in Scheme 2.
substituted by a deselenided molecule. Two such moieties
are bonded through a SeꢀSe bond to form the correspond-
ing diselenide. Table 3 compares the structural parameters
of compounds 9 and 10 with other compounds of similar
structure.
The two C=O bond lengths found for 11 are almost equal
(
O(2)ꢀC(2) 1.2285(13) and O(4)ꢀC(4) 1.2387(15) Š, respec-
tively) (Figure 7) and are within the range of the CꢀO
The SeꢀSe bond lengths found in 9 and 10 are 2.428(2)
bonds found for similar compounds, such as 1,3,6-trisubsti-
and 2.4427(6) Š, respectively, and they are in the range of
other diselenoamides (2.34–2.59 Š) (Table 3).
tuted uracils (1,3-Me-6-R-2-U) (C1ꢀO(1) 1.233(3) (R =
Me), 1.224(2) (R = Et), 1.212(3), 1.221(3), 1.220(3) (R =
The CꢀSe bond lengths in 9 and 10 (1.925(4) and
[22a]
nPr), and 1.220(5) 1.226(5) (R = nBu),
Triethylammoni-
1.922(4) Š, respectively (Figure 8 and Figure 9)) are longer
than those of the corresponding free ligands EtSeU (2) and
nPrSeU (3) (average CꢀSe bond lengths 1.837 and 1.8404 Š,
respectively), owing to the dimerization (Table 3). The CꢀSe
um
2,4-dioxo-6-(1,1,2,2,3,3-hexafluoropropyl)-5-benzylsul-
[22b]
fonyl-3H-2,4-dihydropyrimidine
C(4)ꢀO(2) 1.237(2) Š).
(C(2)ꢀO(1) 1.235(3) and
Recrystallization of 6 and 7 from Me CO solutions results
bond lengths found in 9 and 10 are in the range of other
such compounds (1.874–1.952 Š) (Table 3). Compounds 9
and 10 are neutral diselenoamides with two unequal CꢀN
2
in the formation of the diselenide compounds 9 and 10
(
Scheme 2). Each is a selenoamide ligand that has been N-
Table 3. Bond lengths [Š], bond angles [8], and other structural parameters of known diselenoamides.
Compound
SeꢀSe [Š]
2.428(2)
2.4427(6)
2.5188(7)
CꢀSe [Š]
1.925(4)
1.922(4)
1.911(5)
CꢀN [Š]
Se-Se-C [8]
C-Se-Se-C torsion [8]
Ref.
[
a]
9
1.283(6), 1.412(6)
1.296(4), 1.407(4)
1.310(5), 1.312(5)
1.312(6), 1.319(6)
1.308(8), 1.300(9)
1.295(9), 1.311(8)
1.3049, 1.3067
1.3152, 1.2850
1.3101, 1.2953
1.316(8)
1.319(4), 1.360(5)
1.374(4)
1.332(12), 1.365(13)
1.336(15), 1.362(14)
1.329(13), 1.336(12)
1.340(14), 1.331(13)
1.362(7), 1.326(8)
1.349(8), 1.346(8)
88.99(14)
89.44(8)
89.22(12),96.76(13)
ꢀ179.98(18)
180.00(14)
ꢀ84.25(19)
[
a]
1
1
0
6
[
22a]
1
.895(4)
1.917(6)
.916(6)
+
3ꢀ [b]
[11d]
A
C
H
T
R
E
U
N
G
{(L·I
2
)·(L
2
) ·2I
}
2.3715(14)
95.2(2) 95.2(2)
82.4(3)
1
[
22b]
1
7
2.5970
1.9211
1.9400
96.24
89.27
77.63
ꢀ80.49
2.7171
1.9053
[
22c]
22d]
22d]
18
19
20
21
2.3447(11)
2.3568(14)
2.4003(4)
2.409(2)
1.952(6)
1.880(3)
1.874(2)
1.874(10)
93.69(18)
99.45(12)
98.33(8)
95.7(3)
ꢀ180.0(3)
ꢀ64.20(15)
ꢀ50.67(13)
66.5(4)
[
[
[
[
[
22e]
22e]
22e]
1
.874(11)
1.879(9)
.881(10)
1.900(5)
.887(6)
2
2
2
3
2.434(2)
2.416(2)
96.0(3)
98.3(3)
96.07(18)
98.91(17)
67.6(4)
93.1(3)
1
1
[
a] This work. [b] 16 = bis(Se,Se’-bis(N,N’-dimethylimidazolidin-2-ylidene)diselenium) bis(N,N’-dimethylimidazolidine-2 selone) heptakis(7,7,8,8-tetra-
cyanoquinodimethane), L = bis(N,N’-dimethylimidazolidin-2-yl)diselenone, 17 = tris(selenourea) dichloride monohydrate, 18 = N,N,N’,N’-tetraethylth-
iuramdiselenide, 19 = bis(1-methylimidazol-2-yl)diselenide, 20 = bis(2-(4-bromophenyl)-4-(4-nitrophenyl)imidazol-5-yl)diselenide dimethylformamide
solvate, 21 = Se,Se’-bis(1,3-dimethyl-4-imidazolin-2-yl)diselenium dibromide, 22 = Se,Se’-bis(1,3-Dimethyl-4-imidazolin-2-yl)diselenium diiodide, 23 =
perhydro
A
C
H
T
R
E
U
N
G
(1,2-a)(2,1-e)bis(3-methylimidazo)-3,4-diselena-1,6-diazocine triiodide tetraiodide.
A
C
H
T
R
E
U
N
G
Chem. Eur. J. 2006, 12, 6888 – 6897
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6893

N. Hadjiliadis, S. K. Hadjikakou et al.
Conclusions
Scheme 2 summarizes the reactions involved in the forma-
tion of compounds 5–11. While 6-alkyl-2-selenouracil com-
pounds (RSeU) (Scheme 2, 1–4) are stable in various sol-
vents, including water and other polar or nonpolar solvents,
“
spoke”-like CT complexes of formulae [(RSeU)I ] are
2
formed in dichloromethane solutions; however, they are un-
stable in methanol/acetonitrile and/or acetone solutions
(
Scheme 2). [(RSeU)I ] is transformed to 6-alkyl-2-uracil in
2
methanolic/acetonitrile solutions (Scheme 2). Upon recrys-
tallization of the compound in acetone, the diselenides are
formed possibly through the formation of a substituted sele-
1
13
nouracil, as indicated by H and C NMR spectra as well as
ESI-MS spectra. The whole process may be hydrolytic
(
Scheme 2).
The discovery that ID-l contains selenocysteine at its
Figure 8. ORTEP diagram of molecule 9. Selected bond lengths [Š] and
angles [8]: Se(2)ꢀSe(2a) 2.428(2), Se(2)ꢀC(2) 1.925(4), O(4)ꢀC(4)
[1a]
active site raised the possibility that the seleno analogues
of N-methyl-2-mercapto-imidazole (MMI) and 6-n-propyl-2-
thiouracil (PTU) might be better inhibitors of ID-1than
their respective parent compounds because they are expect-
ed to form an enzyme-Se-Se-drug adduct more readily than
1
1
.233(5), N(3)ꢀC(12) 1.420(5), O(14)ꢀC(14) 1.232(3), N(11)ꢀC(12)
.296(4), N(13)ꢀC(12) 1.337(3); Se(2a)-Se(2)-C(2) 88.99(14), C(2)-Se(2)-
[4a]
the corresponding enzyme-Se-S-drug complex. Viser et al.
have shown that 6-n-propyl-2-selenouracil (PSeU) strongly
inhibits enzyme ID-1, being twice as potent as PTU. Howev-
[4b]
er, Taurog et al.
reported an almost equal inhibitory
action of ID-1by both PTU and PSeU and no activity of
the selenoanalogue (MSeI) of MMI (N-methyl-2-seleno-imi-
dazole) and MMI itself. This may be explained by the exis-
[5a]
tence of MSeI as a diselenide, while PSeU is in its selone
form.
[5a,b]
Mugesh et al
reported that the inhibition of lactoper-
oxidase (LPO) by MMI is more facile than that of its seleni-
um analogue MSeI and the mechanism for the inhibition of
LPO by MMI is different from that of MSeI. They also re-
ported that MSeI, similarly to the sulfur analogue MMI,
cannot inhibit ID-1, probably because of its inability to form
[5a]
a stable –Se–Se- bond with the active site of the enzyme.
Figure 9. ORTEP diagram of molecule 10. Selected bond lengths [Š] and
angles [8]: Se(2)ꢀSe(2a) 2.4427(6), Se(2)ꢀC(2) 1.922(4), O(4)ꢀC(4)
However, MSeI has been shown to exhibit high GPx activi-
ty, leading to the assumption that the selenium analogues of
antithyroid drugs may have significant antioxidant activity
1
1
.236(4), N(3)ꢀC(12) 1.436(4), N(11)ꢀC(12) 1.271(4), N(13)ꢀC(12)
.356(4), O(14)ꢀC(14) 1.230(4); Se(2a)-Se(2)-C(2) 89.44(8), C(2)-Se(2)-
[5a,b]
Se(2a)-C(2a) 180.00(14).
in the thyroid gland.
[4b]
Taurog et al.
also compared both antithyroid drugs
PTU and MMI with respect to their ability to inhibit ID-1.
They concluded that the methyl substituent on the N atom
of MMI or MSeI may be involved in the inhibitory action
by preventing the formation of a hydrogen bond between
the H(N) of the drug and the active site of the enzyme. This
is further supported by the observation that N-methyl-6-n-
propyl-2-thiouracil (NMPTU) does not show ID-1inhibitory
activity at all, while 2-mercaptoimidazole (MMI lacking the
N-methyl substituent) has substantial ID-1inhibitory activi-
ty. Therefore, Taurog et al. proposed that the ID-1deiodi-
nase inhibitory mechanism of selenoamides, similar to 6-n-
propyl-2-selenouracil (PSeU), should not only be based on
the greater propensity of PSeU to form the enzyme-Se-Se-
PSeU adduct compared to its sulfur analogue PTU, but also
Se(2)-C(2a) ꢀ179.98(18).
bond lengths (1.283(6), 1.312(6) and 1.296(4), 1.407(4) Š, re-
spectively, as expected for such compounds (Table 3, com-
pound (19): CꢀN 1.319(4), 1.360(5) Š). The bond lengths
become equal in the case of ionic diselenoamides (Table 3).
The measured Se-Se-C bond angles in compounds 9 and
10 are 88.99(14) and 89.44(8)8, respectively, and are inde-
pendent of the molecular formula. The Se-Se-C bond angles
of known deselenides vary between 89 and 998 (Table 3).
The C-Se-Se-C torsion angles in compounds 9 and 10 are ex-
actly 1808 by symmetry, indicating a coplanar arrangement.
This torsion angle varies between 180, 90, and 608 in all
cases (Table 3).
[4b]
6894
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6888 – 6897

Dimeric Se–Se Compounds
FULL PAPER
on the ability of the H(N) atom of PSeU to participate in a
hydrogen bond with the active site of the enzyme.
Our findings show that the complexes of 6-n-propyl-2-se-
lenouracil (PSeU) and all its alkyl derivatives with diiodine
MeSeU (1): C
5
H
6
N
2
OSe; yield: 60%; m.p. >2508C; elemental analysis
calcd (%): C 31.76, H 3.20, N 14.82; found: C 30.93, H 2.92, N 14.81;
MS: m/z: 187; IR (KBr): n˜ = 3554 w, 3483 w, 3416 w, 3088 m, 2930 m,
2
884 m, 1680 s, 1634 vs, 1552 vs, 1419 vs, 1378 m, 1347 s, 1235 m, 1189 s,
ꢀ1
1
148 vs, 1025 w, 958 w, 881 m, 846 s, 805 m, 584 s, 538 m, 508 s cm
;
1
readily convert into [{N-(6-nPr-PM)
Scheme 2, 10) in acetone or to 6-Pr-U (Scheme 2, 11) in
methanol, which are the final products. This may support
A
H
R
U
G
H NMR ([D ]DMSO): d
=
5.93 (s, H5), 2.2 (s, 3H, H7), 1.151–
]DMSO): d = 174.125, 161.213, 153.255,
06.588, 19.334 ppm; Se NMR ([D ]DMSO): d = 321.8 ppm; UV/Vis
(CH Cl ): l (loge) = 311 nm (4.0), 231 nm (4.38).
EtSeU (2): C OSe; yield: 75%; m.p. 219–2248C; elemental analysis
2
6
1
3
(
1.149 ppm (d); C NMR ([D
6
7
7
1
6
[4a]
[4b]
2
2
the previous conclusions made by Visser
and Taurog
6
8 2
H N
for the possible formation of stable –Se–Se- bonds, among
other factors, to explain the ID-1deiodinase activity of PTU
and PSeU. Obviously, more work is required for any defini-
tive conclusion to be made. The relative instability of the –
Se–Se- bond, observed with MSeI, must also be taken in to
calcd (%): C 35.48, H 3.97, N 13.79; found: C 34.95, H 4.24, N 13.59;
MS: m/z: 205; IR (KBr): n˜ = 3037 m, 2894 m, 1660 vs, 1552 vs, 1454 s,
1399 s, 1296 s, 1230 s, 1178 vs, 1071 m, 1004 s, 933 m, 902 s, 835 vs, 749 m,
ꢀ
1
1
733 m, 605 vs, 549 vs, 523 s cm
H5), 2.41–2.35 (q, 2H, H7), 1.89 ppm (s, 3H, H8);
([D ]DMSO): 173.921, 160.962, 158.966, 103.888, 24.922,
8.785 ppm; Se NMR ([D ]DMSO): d = 322 ppm; UV/Vis (CH Cl ): l
loge) = 310 nm (4.33), 232 nm (4.53).
nPrSeU (3): C OSe; yield: 68%; m.p. 189–1908C; MS: m/z 219; el-
emental analysis calcd (%): C 38.72, H 4.64, N 12.90; found: C 38.52, H
6
; H NMR ([D ]DMSO): d = 5.79 (s,
1
3
C NMR
[5a]
6
d
=
account.
7
7
1
(
6
2
2
7
10 2
H N
Experimental Section
4
1
9
1
.32, N 12.52; IR (KBr): n˜ = 3477 w, 3416 w, 3032 s, 2919 s, 1659 vs,
623 vs, 1542 vs, 1440 s, 1383 m, 1332 m, 1281 m, 1240 s, 1163 vs, 1009 m,
53 m, 902 w, 815 s, 789 w, 554 s, 523 s cm ; H NMR ([D
0.87–10.79 (d, NH1, NH3), 5.80 (s, H5), 2.49–2.33 (t, 2H, H7), 1.58–1.46
Materials and instruments: All solvents used were of a reagent grade.
Absolute ethanol, diiodine, and selenourea were obtained from Sigma-
Aldrich. Ethyl acetoacetate, ethyl propionyl acetate, ethyl butyrylacetate,
ethyl isobutyrylacetate, and ethylbenzoylacetate were purchased from
Lancaster Chemicals Co. and were used without further purification. Ele-
mental analyses for C, H, N were carried out with an Exeter Analytical
Inc. CE-440 Elemental Analyser. Elemental analysis for iodine was car-
ried out by means of the Schoniger oxygen flask method that employs
ꢀ
1
1
6
]DMSO): d =
1
(
2
=
1
m, 2H, H8), 0.87–0.83 ppm (t, 3H, H9); H NMR (CDCl
3
): d = 5.99(s),
.51–2.45(m), 1.73–1.64(t), 1.03–0.85 (m) ppm; H NMR ((CD CO): d
5.84 (s, H5), 2.52 (t, 2H, H7), 1.68 (m, 2H, H8), 0.98 ppm (t, 3H, H9);
H NMR (CD OD): 5.88(s), 2.43(m), 1.64(t), 0.98 ppm (m);
]DMSO): d = 173.722, 160.428, 156.931, 104.563, 33.108,
1
3 2
)
3
d =
1
3
C NMR ([D
20.646, 13.254 ppm; C NMR ((CD
6
1
3
[
23]
3
)
2
CO): d = 176.2, 160.9, 157.6, 105.2,
]DMSO): d 325 ppm; UV/Vis
(CH Cl ): n (loge) = 312 nm (4.39), 231 nm (4.46).
Leipert titration.
Melting points were measured in open tubes on a
7
7
3
4.6, 21.7, 13.6 ppm; Se NMR ([D
6
=
GallenkampMF-370 melting point apparatus and are uncorrected. IR
ꢀ
1
2
2
spectra in the 4000–370 cm region were obtained as KBr discs with a
Nicolet Avatar360 FTIR spectrometer. A Perkin-Elmer Lambda5 UV/
Vis spectrophotometer was used to measure the electronic absorption
spectra. Mass spectrometry measurements were performed on a Micro-
mass LCT instrument. NMR spectra were recorded on Bruker Avance
spectrometers operating at proton frequencies of 250.13 and 400.13 MHz
and equipped with 5-mm multinuclear inverse probes with z gradients.
7 10 2
iPrSeU (4): C H N OSe; yield: 45%; m.p. 219–2208C; elemental analysis
calcd (%): C 38.72, H 4.64, N 12.90; found: C 38.18, H 4.59, N 12.03;
MS: m/z: 219; IR (KBr): n˜ = 3140 m, 2914 m, 1655 vs, 1614 s, 1547 vs,
1445 w, 1383 s, 1296 m, 1245 m, 1158 vs, 1076 s, 1004 s, 943 w, 902 m, 825 s,
769 m, 635 m, 549 s cm ; H NMR ([D ]DMSO): d = 5.80 (s, H5), 2.78–
6
2.64 (m, H7), 1.14–1.11 ppm (d, 6H, H8); C NMR ([D ]DMSO): d =
ꢀ
1
1
1
3
6
Samples were prepared in [D
6
]acetone (99.96%) and all experiments
171.649, 158.477, 99.714, 28.069, 18.301 ppm; UV/Vis (CH Cl ): l (loge)
2
2
were performed at 298.0 K. Chemical shifts are given relative to solvent
= 310 nm (3.9), 233 nm (4.47).
1
13
signals at d = 2.05 ppm for H and d=29.8 ppm for C. Proton decou-
2
Synthesis of complexes (RSeU)I (5–8): The appropriate RSeU (1mmol,
A
H
R
U
G
1
3
pling, achieved with the WALT-16 scheme, and C spectra were recorded
0
.187 g of 1, 0.203 g of 2, 0.217 g of 3 or 4) was added to a dichlorome-
1
13
with a 308 flip angle. Gradient-selective 2D H{ C} HMQC and HMBC
A
H
R
U
G
thane solution of iodine in a 1:1 molar ratio under nitrogen and in the
dark at 08C. The mixture was stirred for 24 h, and the orange microcrys-
talline powders formed were filtered off, dried in air, and stored in a
experiments were performed with and without decoupling, respectively.
Synthesis of compounds 1–4: All reactions and manipulations were car-
ried out in dry ethanol, under nitrogen, in the dark using Schlenk techni-
ques. 6-Methyl-2-selenouracil (MeSeU, 1) and 6-n-propyl-2-selenouracil
2
freezer. Crystals of [(nPrSeU)I ] (7) were grown from chloroform solu-
tions. Recrystallization of 6 and 7 from an acetone solution and resulted
in the formation of oxidation products of formula 9 and 10. Selenium
was observed to precipitate from the reaction as a black powder. Crystal-
line 6-n-propyluracil (11) was obtained by recrystallization of 7 from
MeCN/MeOH (1/1), and may have been formed as a result of the pres-
ence of traces of water.
(
nPrSeU, 3) were synthesized according to the method described by
[4a] [4b] [4c]
Visser et al., Taurog et al.,
used for the synthesis of compounds 2 and 4 (Scheme 1). Sodium metal
0.48 g, 0.02 mol) was dissolved in anhydrous ethanol (10 mL) and sele-
nourea (1.72 g, 0.014 mol) and 0.01 mol of the appropriate 8-oxo ester
1.33 g ethyl acetoacetate for 1, 1.44 g ethyl propionylacetate for 2,
and Hu et al. The same method was
(
(
A
H
R
U
G
2 2
(5): L/I = 1/1; yield: 72%; m.p. 163–1658C; elemental analy-
1
.582 g ethyl butyrylacetate for 3, and 1.58 g ethyl isobutyrylacetate for
4
) were added to the clear solution. The mixture was heated under reflux
6
3
1
5
2
.06, I 54.23; MS: m/z: 615, 457, 378, 296, 191; IR (KBr): n˜ = 3217 s,
114 s, 3022 s, 2925 s, 2883 s, 1680 vs, 1639 vs, 1557 vs, 1460 m, 1429 m,
388 s, 1352 s, 1240 m, 1158 s, 1143 s, 1040 m, 948 m, 825 vs, 748 vs, 712 s,
to yield a clear solution in about 10 min. Shortly afterwards, a precipitate
began to form that did not change greatly in appearance after 2 h. After
a total heating time of 6–7 h, the mixture was allowed to stand overnight.
The solvent was removed in vacuo at 40–508 to near dryness and the resi-
due was dissolved in water (10 mL). The product was precipitated by the
ꢀ
1
1
89 vs, 538 s, 502 s cm
.68–2.62 (m), 1.21–1.17 ppm (m); Se NMR ((CD
Cl ): l (loge) =
;
H NMR ((CD
3
)
2
CO): d = 6.39 (s), 5.96 (s),
CO): d = 361.7,
498 nm (3.45),
7
7
3 2
)
3
361.9 ppm (shoulder); UV/Vis (CH
13 nm (4.57), 228 nm (4.32).
(EtSeU)I (6): L/I = 1/1; yield: 53%; m.p. 136–1388C; elemental analy-
sis calcd (%): C 15.77, H 1.76, N 6.13, I 55.55; found: C 15.68, H 1.73, N
5.89, I 55.99; MS: m/z: 575, 501, 421, 407, 325, 155; IR (KBr): n˜
1675 vs, 1634 vs, 1547 vs, 1465 m, 1388 m, 1291 m, 1158 m, 1071 w, 922 w,
2
2
addition of concentrated hydrochloric acid (1.4 cm ) and subsequent acid-
3
ification to pH 4 with glacial acetic acid. The 6-alkyl-seleno-2-uracil was
filtered off, washed, and dried. Recrystallization of the resulting powders
from water gave colorless crystals of compounds 1–4 that were suitable
for X-ray single-crystal analysis, while recrystallization of 4 from di-
chloromethane gave crystals of 4·CH
were stored in the dark under N
in DMSO and hot water.
A
H
R
U
G
2
2
=
[
13]
2
Cl
2
.
Crystals of the compounds
ꢀ
1
1
. They were found to be highly soluble
835 s, 748 s, 692 w, 579 m cm
(s), 2.82–2.77 (q), 2.70–2.65 (q), 1.42–1.35 ppm (m);
3 2
; H NMR ((CD ) CO): d = 6.40 (s), 6.04
2
7
7
Se NMR
Chem. Eur. J. 2006, 12, 6888 – 6897
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6895

N. Hadjiliadis, S. K. Hadjikakou et al.
(
3
(CD
14 nm (4.49), 227 nm (4.26).
(nPrSeU)I (7): L/I = 1/1; yield: 54%; m.p. 190–1938C; elemental anal-
ysis calcd (%): C 17.85, H 2.14, N 5.95, I 53.90; found: C 17.19, H 1.84, N
.40, I 53.70; MS: m/z: 931, 807, 593, 457, 434, 353, 340, 298, 169; IR
KBr): n˜ = 3554 m, 3473 s, 3411 s, 3237 m, 3191 m, 3114 s, 3017 s, 2930 s,
3
)
2
CO): d = 362 ppm; UV/Vis (CH
2
Cl
2
): l (loge) = 498 nm (3.33),
O. Hassel, Acta Chem. Scand. 1965, 19, 2000; f) O. Holmesland, C.
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8] a) W. W. du Mont, Review on Heteroatom Chemistry (Ed.: S. Oae),
MYU, Tokyo, 1988, p. 138; b) P. H. Svensson, L. Kloo, Chem. Rev.
A
C
H
T
R
E
U
N
G
2
2
[
5
(
2
1
5
2
003, 103, 1649–1684.
[
9] a) M. C. Aragoni, M. Arca, F. A. Devillanova, A. Garau, F. Isaia, V.
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858 w, 1685 vs, 1634 vs, 1557 vs, 1475 s, 1393 s, 1332 m, 1271 m, 1230 m,
153 s, 1096 m, 1015 w, 963 w, 912 m, 830 s, 743 s, 702 m, 610 b, 569 s,
ꢀ
1
1
33 m cm
;
H NMR (CDCl
3
): d = 5.87 (s), 2.39 (m), 1.67 (t), 1.03
CO): d = 6.30 (s), 5.86 (s), 2.72 (m), 2.53 (t),
OD): d = 6.47 (s), 5.97 (s), 2.45
CO): d = 362.4 (low),
): l (loge) = 504 nm (2.97), 315 nm
1
(
1
m) ppm; H NMR ((CD
3
1
)
2
.70 (m), 0.98 ppm (m); H NMR (CD
3
7
7
(
m), 1.70 (t), 0.99 ppm (m); Se NMR ((CD
58.7 ppm (high); UV/Vis (CH Cl
4.28), 228 nm (4.10).
(iPrSeU)I (8): L/I = 1/1; yield: 81%; m.p. 148–1508C; elemental analy-
sis calcd (%): C 17.85, H 2.14, N 5.95, I 53.90; found: C 17.46, H 1.79, N
3
)
2
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3
(
2
2
[11] a) F. Cristiani, F. Demartin, F. A. Devillanova, F. Isaia, V. Lippolis,
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C
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E
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N
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1
.87, I 53.04; MS: m/z: 571, 477, 434, 353, 340, 169; IR (KBr): n˜
=
685 vs, 1624 vs, 1557 vs, 1465 s, 1399 w, 1306 w, 1224 s, 1194 s, 1173 s,
ꢀ
1
066 s, 1015 m, 927 m, 897b, 851 m, 830 m, 687 w, 656 m cm ; UV/Vis
(
CH
2
Cl
2
): l (loge) = 500 nm (3.27), 314 nm (4.36), 228 nm (4.32).
Acknowledgements
This work was carried out in partial fulfillment of the requirements for a
Ph.D. thesis of CDA within the graduate program in Bioinorganic Chem-
istry coordinated by Professor N. Hadjiliadis. We thank the Marie Curie
Foundation for funding (CAD) as part of the Marie Curie Host Fellow-
ship HPMT-CT-2001–00376 COSMIC. We acknowledge a NATO grant
to N.H. and I.S.B. We thank Professor M. Schrçder and Drs. A. J. Blake,
C. Wilson, and P. Hubberstey, School of Chemistry, The University of
Nottingham, Nottingham (UK), for the X-ray crystal structure determi-
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Dimeric Se–Se Compounds
FULL PAPER
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Received: November 23, 2005
Revised: March 9, 2006
1
996, 35, 3194.
Published online: June 14, 2006
Chem. Eur. J. 2006, 12, 6888 – 6897
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6897