Reactions of nitroxides, part 7: Synthesis of novel nitroxide selenoureas

Article abstract of DOI:10.1002/hc.20454

The reactions of 4-isoselenocyanato-2,2,6,6-tetramethylpiperidine-l-oxyl with selected amines and lower alcohols give the corresponding novel selenoureas and selenocarbamates, all bearing the nitroxyl moiety. Some of the synthesized selenoureas and seleno

Full text of DOI:10.1002/hc.20454

Heteroatom Chemistry
Volume 19, Number 6, 2008
Reactions of Nitroxides, Part 7:
Synthesis of Novel Nitroxide Selenoureas
Jerzy Zakrzewski and Maria Krawczyk
Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland
Received 2 October 2007; revised 18 January 2008
inflammatory and antioxidant agents. Recently, se-
ABSTRACT: The reactions of 4-isoselenocyanato-
2,2,6,6-tetramethylpiperidine-1-oxyl with selected
amines and lower alcohols give the corresponding
novel selenoureas and selenocarbamates, all bear-
ing the nitroxyl moiety. Some of the synthesized
selenoureas and selenocarbamates show moderate-
lenoureas have been recognized as effective super-
oxide radical scavengers [3]. Role and importance of
selenium in living organisms have been recently re-
viewed [4]. Relationship between selenium and can-
cer was described [5]. Heterocyclic compounds con-
taining selenium atom may restrain some cancer cell
growth [6].
ꢀ
C
to-good activity against pathogenic fungi.
2008
Wiley Periodicals, Inc. Heteroatom Chem 19:549–
556, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20454
The basic method of the synthesis of sele-
noureas involves two steps. Direct selenation of
either alkyl or aryl isocyanides with metallic se-
lenium in a suitable solvent leads to the corre-
sponding isoselenocyanates [7–21]. Their reaction
with primary and secondary amines affords sele-
noureas [7,10,21–26]. Isoselenocynate may also be
generated in situ from aryl nitrile oxide and a
selenoamide, and, without purification, converted
into a selenourea derivative [27]. Carbodiimides
[3,28], or dichloromethylenedimethyliminium chlo-
ride (synthesized via N,N-dimethylselenocarbamoyl
chloride) [29] are converted into selenoureas us-
ing a new selenating reagent (LiAlHSeH) obtained
by treating lithium aluminum hydride with sele-
nium [30,31]. There are also some specific meth-
ods of selenourea synthesis. A reaction of secondary
amines, triethyl orthoformate, and elemental sele-
nium [32] or a reaction of chloroform or sodium
trichloroacetate with a secondary amine, sodium
hydride, and elemental selenium [33,34] affords
selenoureas.
INTRODUCTION
Selenium plays an important role in living organ-
isms. Its overexposure results in numerous dis-
eases (from depression to some types of cancer).
On the other hand, selenium is an important trace
element (a human organism contains about 6 mg
of selenium). Traces of selenium are important
in oxygen metabolism. Selenium-containing com-
pounds (the most popular is ebselen (2-phenyl-1,2-
benzisoselenazol-3(2H)-one [1,2])) are considered
to be inhibitors of free radicals, as well as anti-
Following parts have published earlier: Part 4 (Heteroatom
Chem 2006, 17(5), 393–401), Part 5 (Org Prep Proc Int 2003, 35(4),
387–390), and Part 6 (Org Lett 2004, 6(5), 695–697).
Correspondence to: Jerzy Zakrzewski; e-mail: zakrzewski@
ipo.waw.pl.
Contract grant sponsor: Polish State Committee for Scientific
Research.
There are only a few examples of nitroxyl rad-
icals containing selenium known [35,36]. Here, as
a continuation of our previous studies on urea and
thiourea nitroxides [37], we report the synthesis of
novel selenoureas bearing the nitroxyl moiety.
Contract grant number: 429/E-142/S/2006.
2008 Wiley Periodicals, Inc.
c
ꢀ
549

550 Zakrzewski and Krawczyk
RESULTS AND DISCUSSION
to selenoureas 5a–h and selenocarbamates 6a,b, re-
spectively (Scheme 1 and Table 1). When the starting
radical 1 was applied as an amine, the biradical se-
lenourea derivative 5h was obtained.
To investigate the possibility of direct selenation
of 2,2,6,6-piperidine derivatives, a selenating reagent
2,4-diphenyl-1,3-diselena-2,4-diphosphetane-2,4-
diselenide (9), ([PhP(Se)(μ-Se)]2) was synthesized
and used. The reagent is able to selenate amides
and formamides by substitution of the oxygen atom
[40,41]. The condensation of dichlorphenylphos-
phine (7) with magnesium in THF [42–46]
yields pentaphenylpentaphospholane [(PhP)5, (8)]
4-Amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(1)
was
converted
into
4-formylamino-2,2,6,6-
tetramethylpiperidine-1-oxyl (2) by treatment with
excess of ethyl formate [38]. The dehydration of 2
with gaseous phosgene [38] or diphosgene leads to
4-isocyano-2,2,6,6-tetramethylpiperidine-1-oxyl (3),
which was selenated with metallic selenium to give
4-isoselenocyanato-2,2,6,6-tetramethylpiperidine-1-
oxyl (4) [39].
The reaction of 4 with a series of amines and
lower alcohols such as methanol or ethanol leads
SCHEME 1 (i) HCOOEt [38] (ii) COCl2 [38] or ClCOOCCl3 (diphosgene) (iii) Se, CHCl3 [39] (iv) (5a–h) HX, benzene (6a,b)
HX/NaX.
TABLE 1 Synthesized Selenoureas (5a–h), and Selenocarbamates 6a,b
X
Compound
Purification Methoda
Yield (%)
mp(◦C) (dec)
Rf(BM9)
N(CH3)2
5a
5b
5c
5d
5e
Cryst.(B)
Cryst.(B)
Cryst.(B)
Cryst.(B)
C (BM9)
35.7
49.2
42.2
47.8
37.2
164.5–167.5
171–175
144–152
187–190
119–123
0.18
0.2
0.28
0.38
0.33
N(C2H5)
N(n-C H27)
N(i-C 2H7) 2
2
2
N(n-C4H9)2
N
O
5f
Cryst.(B)
54.3
177.5–179
0.13
N
5g
Cryst.(B)
19.1
168
0.18
•
HN
N
O
5h
C (BM9)
63.4
159
0.09
OCH3
OC2H5
6a
6b
C (BM9)
C (BE9)
40.0
86.5
Oil
108–116.5
0.36
0.44b
aCryst.(B): crystallization (benzene), C: column chromatography; BM9 = benzene:methanol 9:1; BE9 = benzene:ethanol 9:1; BA95 = ben-
zene:ethyl acetate 95:5.
bBE9.
Heteroatom Chemistry DOI 10.1002/hc

Reactions of Nitroxides, Part 7: Synthesis of Novel Nitroxide Selenoureas 551
(62% yield). Surprisingly, contrary to [42], when
topathogenic fungi at the concentration of 200
ppm. Selenoureas 5a–c, e–h and selenocabamate
6b showed moderate-to-good activity against Botry-
tis cinerea (most of these compounds inhibited
>90% growth of the fungi), and moderate activ-
ity against Fusarium culmorum. Ebselen (2-phenyl-
1,2-benzisoselenazol-3(2H)-one) and fenuron (N-
phenyl-Nꢁ,Nꢁ-dimethylurea) were used as reference
compounds (Table 3). The fungicidal activity of the
synthesized selenoureas is significantly better than
the fungicidal activity of ureas and thioureas bearing
a nitroxyl moiety, which has been tested previously
[37].
diethyl ether instead of THF had been used as a
solvent, no product 8 was obtained. The parent peak
(m/z 540) in mass spectrum of 8 clearly indicates
the five-membered ring [42,45,47]. The reaction of
(PhP)5 with metallic selenium affords compound 9
(89% yield) [48–50].
2,2,6,6-Tetramethylpiperidin-1-oxyl (TEMPO),
2,2,6,6-tetramethylpiperidinol-4-oxyl-1
(TEMPO-
4-OL), 2,2,6,6-tetramethylpiperidinone-4-oxyl-1
(TEMPO-4-ONE), 2,2,6,6-tetramethylpiperidinone-
4 (TAA), and 1-formyl-2,2,6,6-tetramethylpiperidine
(10) were treated with 9. The attempted selena-
tion of TEMPO resulted in decomposition of the
radical, whereas the selenation of TEMPO-4-OL,
TEMPO-4-ONE, and TAA yielded products con-
taining selenium (UV irradiation of TLC spots).
Unfortunately, attempts to isolate detected products
were unsuccessful. The products decompose during
column chromatography with formation of red
selenium.
CONCLUSIONS
Nitroxide selenoureas 5a–h, and selenocarbamates
6a,b—new nitroxyl radicals containing selenium
atom—were synthesized. Some of them show
moderate-to-good activity against pathogenic fungi.
Selenation of 1-formyl-2,2,6,6-tetramethyl-
piperidine 10 with 9 gave 1-selenoformyl-2,2,6,6-
tetramethylpiperidine 11 in 83% yield (Scheme 2).
Selenation of 10 with Se/P gives 11 in only 17%
yield.
EXPERIMENTAL
General
4-Amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(1)
Structures of the synthesized selenoureas 5a–h
and selenocarbamates 6a,b were confirmed by EI
MS, IR (Table 2), and for 11 additionally by 1H,
13C NMR spectra.
The molecular ions in the EI mass spectra of the
synthesized selenoureas 5 are abundant only for 5a
and 5g. The base peaks belong to m/z 124 (except
for 5d (97%) and 5g (26%)). The peak m/z 124 is
attributed to C9H16, which is formed via elimination
of the substituent at C(4) and a hydrogen atom at
C(3) of the substituted TEMPO (m/z 154) followed
by the NO loss [51,52].
Pesticidal activity of the synthesized selenoureas
5a–h and selenocarbamates 6a,b was tested using
preliminary screening tests. The derivatives 5a–h
and 6a,b were tested for acaricidal, herbicidal, in-
secticidal, and fungicidal activity. No activity was
found for weeds, insects, and mites. The prelimi-
nary studies indicated that most of the compounds
showed potential fungicidal activity against phy-
[53], 4-formylamino-2,2,6,6-tetramethylpiperidine-
1-oxyl (2) [38], 4-isocyano-2,2,6,6-tetramethyl-
piperidine-1-oxyl (3) (using gaseous phosgene
as
tetramethylpiperidine-1-oxyl
formyl-2,2,6,6-tetramethylpiperidine
were synthesized as described previously.
protocol for synthesis of 4-isocyano-2,2,6,6-
a
reagent) [38], 4-isoselenocyanato-2,2,6,6-
[39], and 1-
(10) [37]
4
A
a
tetramethylpiperidine-1-oxyl (3) using diphosgene
as a reagent is presented below. 2,4-Diphenyl-1,3-
diselena-2,4-diphosphetane-2,4-diselenide (9) was
obtained following the method described in [49,50].
Yield: 61.7%, mp 202–204◦C (192–204◦C [48]); MS
(EI, 70 eV, m/z, int. [%]): 536 (M+, 1), 534 (1), 456
(7), 454 (8), 452 (6), 268 (96), 266 (86), 188 (19),
157 (11), 111 (99), 109 (45), 107 (100), 77 (30), 51
(33). IR (ν, cm−1, KBr): 3432, 1621, 1437, 1119, 911,
744, 720, 689, 514. Other reagents are commercially
available and were used as received without further
purification. All experiments were performed in a
multinecked round-bottomed flask equipped with
a magnetic bar, a thermometer, a reflux condenser
protected against humidity, and a dropping funnel.
The formation of products was monitored by means
of TLC. TLC control and column chromatography
were carried out on a silica gel Merck Alurolle 5562,
Alufolien 5554, and Merck 1.09385.1000 (0.040–
0.063 mm, 230–400 mesh), respectively. For the
abbreviations for mobile phases used throughout
SCHEME 2 (i) 9, toluene, r.t., 18 h, 83%.
Heteroatom Chemistry DOI 10.1002/hc

552 Zakrzewski and Krawczyk
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Heteroatom Chemistry DOI 10.1002/hc

Reactions of Nitroxides, Part 7: Synthesis of Novel Nitroxide Selenoureas 553
TABLE 3 The Effect of Selenoureas 5a–h and Selenocarbamates 6a,b on Mycelial Growth of Phytopathogenic Fungi (In Vitro
test, 200 ppm)
% of Growth Reductiona
Compound No.
Botrytis cinerea
Fusarium culmorum
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
Ebselen
Fenuron
Control
3
2
3
0
3
2
3
3
0
3
1
0
0
2
2
2
0
2
2
Not tested
2
0
2
0
0
0
aScore index:
0 = 0%–20% growth reduction–no effect.
1 = 20.1%–50% growth reduction–weak activity.
2 = 50.1%–90% growth reduction–moderate activity.
3 = 90.1%–100% growth reduction–good activity.
the text, see Table 1’s footnote a. HRMS and MS
(EI, 70 eV, m/z, int. (%)) data were recorded using
an AMD 604 mass spectrometer. HRMS (ESI) (for
5e,5h,6b) were recorded using a Mariner appara-
tus. IR (ν, cm−1, KBr) data were recorded using a
FT/IR Jasco 420 spectrophotometer. 1H NMR (δ
(ppm), J (Hz), CDCl3, TMS) and 13C NMR (δ (ppm),
CDCl3, TMS) (for nonradical compound 11) data
were recorded using a Varian UNITYplus 200 (200
MHz for 1H) apparatus. EPR data (for 3 and 4)
were obtained with a Bruker ESP 300E (X band)
spectrometer. Conditions of fungicidal bioassay in
vitro are identical with those described previously
in [37].
concentrated under the reduced pressure, and the
solid, red residue (4.4 g) was subjected to column
chromatography (BM95) to give 2.1233 g (78.2%) of
3, mp 142–144◦C (hexane) [38]; (133–134◦C [54,55],
143.5–144.5◦C [56]); MS (70 eV, m/z, int. (%)): 181
(31, M+), 167 (18), 166 (11), 151 (10), 140 (8), 136
(10), 126 (9), 124 (24), 109 (35), 94 (100), 81 (36),
69 (40), 68 (74), 67 (67), 57 (23), 56 (38), 55 (52), 53
(33), 41 (98), 39 (40); IR (KBr, ν, cm−1): 2143; EPR
(aN [G]): 15.49 (toluene), 15.77 (dichloromethane),
15.83 (DMSO); g = 2.0060.
4-Isoselenocyanato-2,2,6,6-
tetramethylpiperidine-1-oxyl (4)
According to [39], metallic selenium and 3 (about
2:1 mol:mol) and chloroform (about 1.5 mL/1 mmol
of 3) were stirred at a gentle reflux for 70 h. Un-
reacted selenium was filtered off, then the filtrate
was evaporated. Crude product was subjected to col-
umn chromatography (BM95) to give 4 (38%, mp
4-Isocyano-2,2,6,6-tetramethylpiperidine-1-oxyl
(3) (using Diphosgene [ClCOOCCl3] as a
Reagent)
To a magnetically stirred solution of 2 (2.985 g,
15 mmol), triethylamine (3.825 g, 38 mmol, ∼5.3
mL), and methylene chloride (15 mL) was cooled
in an ice bath, diphosgene (1.5 mL = 500 μL + 4 ×
250 μL) was added dropwise with a syringe at the
temperature below 10◦C. The formation of 3 was
156–158◦C, R 0.75 /BM9/); HRMS Found: 261.0514,
f
Calcd: 261.0506 for C10H17N2O80Se, M+ (EI); MS (70
eV, m/z, int. (%)): 264 (1), 263 (6), 262 (7), 261 (35,
M), 260 (3), 259 (17), 258 (6), 257 (6), 247 (7), 175
(14), 174 (11), 173 (8), 172 (7), 160 (13), 154 (42), 140
(19), 124 (26), 109 (24), 98 (15), 95 (18), 94 (29), 83
(10), 82 (11), 81 (20), 74 (9), 69 (100), 68 (17), 67 (25),
56 (24), 55 (41), 53 (15.5), 43 (13), 42 (12), 41 (75),
39 (21); IR (KBr, ν, cm−1:) 2161; EPR (aN [G]): 15.46
(toluene), 15.73 (dichloromethane), 15.80 (DMSO);
(g): 2.0061 (toluene), 2.0060 (dichloromethane),
2.0059 (DMSO).
monitored using TLC (BM9, R of 3 ∼0.6 to 0.7). The
f
reaction mixture was transferred into a pear-shaped
flask, and methylene chloride was evaporated un-
der the reduced pressure. Benzene (30 mL) was
then added. The resulting suspension was vigorously
stirred, then the precipitate of triethyl hydrochlo-
ride was filtered off. The precipitate was thoroughly
washed twice with benzene. The benzene filtrate was
Heteroatom Chemistry DOI 10.1002/hc

554 Zakrzewski and Krawczyk
nitroxide selenocarbamates 6a,b are presented in
Tables 1 and 2, respectively.
Selenoureas 5a–h: General Procedure
The appropriate amine was added at 10–15◦C
to 4-isoselenocyanate-2,2,6,6-tetramethylpiperidin-
1-oxyl (4) (0.26 g, 1 mmol) and anhydrous benzene
(about 4 mL). In the case of 5b–g, appropriate liq-
uid amine (1.15 mmol) was added with a syringe. In
the case of 5a, the excess of chilled dimethylamine
dissolved in a small amount of benzene was added
in one portion from a dropping funnel. In the case
of 5h, 4-amine-2,2,6,6-tetramethylpiperidine-1-oxyl
1 (1 mmol) was added dropwise as a solution in
a small amount of benzene. The reaction mixture
was partially concentrated. The pink, fine crystalline
precipitate (5a–d,f,g) was collected, washed with a
small portion of chilled benzene or hexane, and air
dried. In the case of selenoureas 5e and 5h, the
benzene solution is evaporated to dryness under re-
duced pressure. The residues were subjected to col-
umn chromatography (mobile phase BM9) to give
5e and 5h as solidifying oils. Melting points, TLC
properties, and spectral data (HRMS, MS, IR) of the
synthesized nitroxide thioureas 5a–h are presented
in Tables 1 and 2, respectively.
Pentaphenylpentaphospholane (8)
According to [43, 44] with some modifications,
dichlorphenylphosphine 7 (2.5 g, 1.9 mL, 0.014 mol)
in tetrahydrofuran (5 mL) was thoroughly added
dropwise to anhydrous tetrahydrofuran (20 mL) and
thoroughly dried magnesium turnings (0.3414 g,
0.014 mol) at temperature not exceeding 30◦C (ice-
water bath). After all magnesium had been dissolved
(about 2 h), the reaction mixture was stirred for 3 h.
Tetrahydrofuran was evaporated off. Water (about
10–20 mL) was added to the residue. The mixture
was extracted with methylene chloride (about 10–
20 mL). The organic solution was dried with anhy-
drous magnesium sulfate. The solvent was evapo-
rated to give an oil (1.43 g), which was triturated
with pentane and was allowed to crystallize in a re-
frigerator below 0◦C. After approximately 1 month,
dark red precipitate was filtered off and dried un-
der reduced pressure (1.2816 g). The precipitate was
thoroughly washed on a filter with a small amount
of methanol to give fine, off-white crystalline precip-
itate of pentaphenylpentaphospholane (8) (accord-
ing to [43,44] with some modifications): (0.9297 g,
61.7%); mp 150–151.5◦C (148–152◦C [42], 148–152◦C
[57], 149–150◦C [44], 149–150◦C [45], 149–152◦C [58]
151–153◦C [43]). MS (EI, 70 eV, m/z, int. (%)): 540
[57] (66, M+), 370 (16), 355 (58), 324 (26), 293 (13),
262 (100), 185 (53), 183 (70). IR (ν, cm−1, KBr): 3048,
1580, 1480, 1431, 1183, 1067, 1024, 998, 741, 693.
Selenocarbamates 6a,b: General Procedure
The solution of sodium alkoxide (1 mmol/1 mL)
was prepared by dissolving elemental natrium
(0.23 g, 0.01 g atom) in the appropriate an-
hydrous alcohol and diluting the resulting solu-
tion with the same alcohol up to the 10 mL
volume. The starting 4-isoselenocyanate-2,2,6,6-
tetramethylpiperidin-1-oxyl (4) (0.260 g, 1 mmol)
was dissolved in the appropriate anhydrous alcohol
(methanol, ethanol, 6 mL). The alcohol solution of
the appropriate sodium alkoxide (1.2 mL, 1.2 mmol)
was added to the suspension of 4 with a pipette or
a syringe in three approximately equal portions at
20◦C. The reaction mixture was stirred for 10 min at
ambient temperature. The appropriate alcohol was
evaporated under reduced pressure. Diethyl ether
(about 10 mL) was added to the residue. The white
precipitate was dissolved and then formed again.
The precipitate was filtered off and washed with di-
ethyl ether. The filtrate was dried over anhydrous
magnesium sulfate overnight. Drying agent was fil-
tered off, then ether was evaporated under reduced
pressure. The crude selenocarbamates 6a or carba-
mates 6b were subjected to column chromatogra-
phy (mobile phase benzene:appropriate alcohol 9:1,
i.e. BM9 and BE9, respectively) to give selenocar-
bamates 6a,b. Melting points, TLC properties, and
spectral data (HRMS, MS, IR) of the synthesized
1-Selenoformyl-2,2,6,6-Tetramethylpiperidine
(11) (Selenation with 9)
1-Formyl-2,2,6,6-tetramethylpiperidine (10) (0.169
g, 1 mmol), [PhP(Se)(μ-Se)]2 (9) (0.1325 g, 0.25
mmol), and toluene (about 1 mL) were stirred at
ambient temperature for 18 h. The progress of the
reaction was monitored by means of TLC (BM9).
Compound 9 was dissolved, and yellow color of the
toluene solution appeared. Some amount of the col-
loidal selenium was present in the reaction mix-
ture. The reaction mixture was directly subjected
to column chromatography (mobile phase BA95) to
give the yellow-green zone of the 1-selenoformyl-
2,2,6,6-tetramethylpiperidine (11): 0.1932 g, 83.3%,
mp 113–115◦C, R = 0.6 (BM9).
f
1-Selenoformyl-2,2,6,6-tetramethylpiperidine
(11) (Selenation with Se/P)
Red phosphorus (0.124 g,
4 mmol), metallic
selenium (0.790 g, 10 mmol), 1-formyl-2,2,6,
Heteroatom Chemistry DOI 10.1002/hc

Reactions of Nitroxides, Part 7: Synthesis of Novel Nitroxide Selenoureas 555
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6-tetramethylpiperidine (10) (0.169 g, 1 mmol), and
xylene (about 3 mL) were stirred at reflux for 5 h.
The progress of the reaction was monitored by
means of TLC (BM9). Reaction mixture was filtered
through Cellite and washed with benzene until col-
orless filtrate was obtained. Benzene was evapo-
rated. The residue was subjected to column chro-
matography (mobile phase BA95) to give the in-
tensely colored yellow zone of the 1-selenoformyl-
2,2,6,6-tetramethylpiperidine (11): 0.0392 g, 16.9%,
mp 110–114◦C, Rf = 0.57 (BM9); HRMS Found:
233.0675, Calcd: 233.0683 for C10H19NSe, M+(EI);
MS (EI, 70 eV, m/z, int. (%)): 233 (49, M+), 231
(24), 152 (14), 109 (17), 69 (100), 55 (17), 41 (32);
IR (ν, cm−1, KBr): 3436, 2970, 2937, 1424, 1353,
1
1159, 1125, 990; H NMR (200 MHz, CDCl3): 1.45
1
(s, 6H), 1.7–1.9 (m, 6H), 1.98 (s, 6H), 11.28 (s, H,
CHSe); 13C NMR (50 MHz, CDCl3): 15.15 (CH2 26.81
(CH3), 31.93 (CH3), 37.87 (CH2), 40.76 (CH2), 189.80
(CHSe).
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ACKNOWLEDGMENTS
[28] Koketsu, M.; Takakura, N.; Ishihara, H. Synth Com-
mun 2002, 32(19), 3075–3079.
[29] Koketsu, M.; Fukuta, Y.; Ishihara, H. J Org Chem
2002, 67(3), 1008–1011.
[30] Koketsu, M.; Ishihara, H. (Gifu University), Selenat-
ing Reagent. U.S. Patent 7 033 564, 2004.
[31] Ishihara, H.; Koketsu, M.; Fukuta, Y.; Nada, F. J Am
Chem Soc 2001, 123(34), 8408–8409.
We are indebted to Prof. Jacek Mlꢀochowski and
Dr Halina Wo´jtowicz (Department of Organic Chem-
istry, Wroclꢀaw Technical University, Faculty of
Chemistry) for a gift of ebselen.
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