The role of methoxy substituents in regulating the activity of selenides that serve as spirodioxyselenurane precursors and glutathione peroxidase mimetics

Article abstract of DOI:10.1139/cjc-2015-0329

A series of o-(hydroxymethyl)phenyl selenides containing single or multiple methoxy substituents was synthesized, and the rate at which each compound catalyzed the oxidation of benzyl thiol to its disulfide with excess hydrogen peroxide was measured. This

Full text of DOI:10.1139/cjc-2015-0329

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The Role of Methoxy Substituents in Regulating the Activity of Selenides that Serve as
Spirodioxyselenurane Precursors and Glutathione Peroxidase Mimetics
David J. Press and Thomas G. Back*
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta,
Canada T2N 1N4
Correspondence to:
Eꢀmail: tgback@ucalgary.ca
Tel.: 1ꢀ403ꢀ220ꢀ6256

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Abstract
A series of oꢀ(hydroxymethyl)phenyl selenides containing single or multiple methoxy
substituents was synthesized and the rate at which each compound catalyzed the oxidation of
benzyl thiol to its disulfide with excess hydrogen peroxide was measured. This assay provided
the means for comparing the relative abilities of the selenides to mimic the antioxidant
selenoenzyme glutathione peroxidase. The mechanism for catalytic activity involves oxidation of
the selenides to their corresponding selenoxides with hydrogen peroxide, cyclization to
spirodioxyselenuranes, followed by reduction with two equivalents of thiol to regenerate the
original selenide with concomitant disulfide formation. A single pꢀmethoxy group on each aryl
moiety afforded the highest catalytic activity, while methoxy groups in the meta position had
little effect compared to the unsubstituted selenide and oꢀmethoxy groups suppressed activity.
The installation of multiple methoxy groups on each aryl moiety provided no improvement.
These results can be rationalized on the basis of dominating mesomeric and steric effects of the
p- and oꢀsubstituents, respectively.
Key Words:
Glutathione peroxidase, organoselenium compounds, antioxidants, selenides

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Graphic abstract

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Introduction
Glutathione peroxidase
1,2
(GPx) consists of a family of isozymes, several of which
contain selenium atoms present as selenol moieties of selenocysteine residues. The redox
properties of selenium endow GPx with powerful antioxidant properties that enable it to destroy
harmful peroxides in vivo by catalyzing their reduction with the stoichiometric tripeptide thiol
glutathione. Hydrogen peroxide and lipid peroxides are produced during the course of normal
aerobic metabolism and are harmful to cells and tissues because of their strong oxidizing abilities
and their propensity to generate other reactive oxygen species (ROS) such as the superoxide
radical anion and the hydroxyl radical. Thus, GPx protects living organisms against oxidative
stress by suppressing the formation of ROS.3 Oxidative stress has in turn been implicated in a
variety of disease states and degenerative disorders, including inflammation, mutagenesis and
cancer, neurological damage and dementia, cardiovascular disease and possibly the aging
process.4 ROS produced by neutrophils during ischemic reperfusion of heart attack and stroke
patients is of special concern, as the high levels of oxidative stress they induce can overwhelm
the protective effects of GPx, resulting in serious cardiovascular and neurological injury.5
Epp, Ladenstein and Wendel6 were the first to determine the structure of bovine
erythrocyte GPx, which consists of a tetrameric structure wherein each of the four subunits
contains a selenocysteine moiety. The catalytic cycle of GPx was first proposed by Ganther and
Kraus7 and is shown in Scheme 1. The selenol moiety of each selenocysteine unit (EnzSeH)
functions as a strong reducing agent that converts a peroxide molecule into water or a lipidꢀ
derived alcohol, and is itself reduced to the corresponding selenenic acid (EnzSeOH). Stepꢀwise
reaction of the latter with two molecules of glutathione (GSH) then regenerates the original
selenol via the intermediacy of the selenenyl sulfide (EnzSeSG), while glutathione is oxidized to

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its disulfide (GSSG). The disulfide is in turn recycled to GSH by glutathione reductaseꢀmediated
reduction with NADPH.
Considering the deleterious effects of peroxides and the limitations of GPx to afford
adequate protection under certain physiological conditions associated with exceptionally
elevated levels of oxidative stress, there has been significant interest in the design, synthesis and
bioassay of novel smallꢀmolecule mimetics4a,8 of GPx that could afford additional protection to
such patients. Indeed, ebselen9,10 and ALT 20745a,11 (Figure 1) have undergone clinical trials as
therapies for various disorders related to oxidative stress.
Scheme 1. Catalytic cycle of GPx.
Figure 1. Structures of ALT 2074 and ebselen

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Two classes of compounds that were first investigated as potential GPx mimetics by our
group include the aliphatic and aromatic cyclic seleninate esters 112 and 2,12c,13 as well as the
corresponding spirodioxyselenuranes 314 and 4.12c,13a Later studies of these types of compounds
by Singh et al.15 and by Bayse and Ortwine16 have also been reported. Certain members of both
classes of compounds display >10ꢀfold greater catalytic activity than that of ebselen.12b,13a,14
However, the seleninate esters suffer from a competing deactivation pathway which generates
selenenyl sulfides that remain relatively inert toward further oxidation or thiolysis.12,13b
Moreover, we recently observed that the seleninate esters are capable of catalyzing the further
oxidation of disulfides produced from sacrificial thiols to the corresponding thiolsulfinates, a
process that could unintentionally damage other native disulfideꢀcontaining peptides and
proteins.17 On the other hand, the spirodioxyselenuranes display a more robust catalytic cycle
(Scheme 2) that does not appear to suffer from similar lateꢀstage side reactions. The catalyst in
Scheme 2 can be introduced via either the oxidized selenurane form 4, or the corresponding
reduced selenide analogue 5, as both are stable and isolable compounds. The catalytic cycle,
when starting from selenide 5, involves oxidation to the corresponding selenoxide 6,
immediately followed by spontaneous cyclization to the selenurane 4. Substitution at selenium
with the thiol generates the postulated intermediate 7, followed by reductive elimination with a
second molecule of thiol to regenerate the selenide catalyst. The choice of benzyl thiol instead of
glutathione was made for our in vitro assay of catalytic activity because it has both a
chromophore for HPLC analysis and a distinct methylene signal to facilitate NMR
investigations.

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Figure 2. Structures of representative cyclic seleninate esters 1 and 2, and spirodioxyselenuranes
3 and 4.
Scheme 2. Catalytic cycle of spirodioxyselenuranes 2.
In our earlier investigations, we observed that the aliphatic catalysts 1 and 3 displayed
especially high catalytic activities compared with most of the aromatic analogues that were
studied.12c However, the expected greater metabolic stability and lower toxicity of the aromatic
derivatives8c,18 prompted us to focus attention on the latter compounds. Furthermore, the
unsubstituted selenurane 4a displayed poorer catalytic activity than its derivatives containing

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electronꢀdonating groups para to the selenium atom (4b, 4f), while electronꢀwithdrawing groups
(4c-4e) further diminished its activity.13a The Hammett plot for compounds 4aꢀ4e produced a
reaction constant σ = ꢀ3.1, consistent with a rateꢀdetermining step in which the transition state is
associated with an increase in positive charge that can be stabilized by electronꢀdonating
substituents. This in turn suggests that the oxidation of 5 to 6, i.e. Se(II) to Se(IV), is rateꢀ
limiting in Scheme 2. The corresponding reaction constant for a similar series of substituted
cyclic seleninate esters 2 was determined to be σ = ꢀ0.45, indicating a significantly lower
sensitivity to substituent effects than in the selenurane series.13a This proved to be an additional
advantage for the use of the selenuranes, as they were more amenable to tuning of their catalytic
activity through judicious choice of substituents. Finally, in a recent study of derivatives of
cyclic seleninate esters 2 containing single or multiple electronꢀdonating methoxy substituents at
various positions, we noted that a single pꢀmethoxy group improved activity due to mesomeric
effects, while a mꢀmethoxy group had little effect upon activity and an oꢀmethoxy substituent
suppressed activity, presumably because of steric hindrance of the selenium center. The
introduction of a second or third methoxy group had little further effect upon catalytic activity.19
In view of the undesired complexities associated with cyclic seleninate esters, compared
to spirodioxyselenuranes as GPx mimetics, we turned our attention to a similar series of monoꢀ,
diꢀ and trimethoxy analogues of selenuranes 4 and selenides 5.
Results and Discussion
Since oxidation of the selenium atom had been previously shown to comprise the rateꢀ
determining step in the catalytic cycle shown in Scheme 2,13a it was expected that electronꢀ
donating oꢀ or pꢀmethoxy groups would enhance catalytic activity through mesomeric effects. In

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contrast, metaꢀsubstituted methoxy groups cannot interact with the selenium atom through
resonance and were expected to have a less pronounced effect on catalytic activity. In the case of
oꢀmethoxy substituents, steric effects could retard reaction rates and oppose the expected
mesomeric effect. Moreover, substituents that coordinate to selenium in various redox processes
can also strongly affect reaction rates.20 In related work, Mugesh and coworkers21 reported that
pꢀmethoxy groups had little effect on the activity of diaryl diselenides, while oꢀmethoxy
substituents improved catalytic activity by suppressing unproductive thiol exchange reactions at
selenium that competed with desired thiol attack at sulfur in postulated selenenyl sulfide
intermediates.
Although the selenides and corresponding selenuranes are interconvertible, as shown in
Scheme 2, and either can be introduced into an assay for catalytic activity, the selenides were
chosen for this purpose instead of the corresponding spirodioxyselenuranes, as the use of the
latter can result in abnormally high initial reaction rates due to their very rapid consumption by
thiolysis, followed by the slower, rateꢀdetermining oxidation of the resulting selenides back to
the selenuranes. Furthermore, the concentration of thiols (mainly glutathione) in tissues and
cells of living organisms is generally higher than that of peroxides and so the introduction of the
catalyst in its oxidized selenurane form would in any case likely result in its rapid reduction to
the selenide in vivo.
In view of these considerations, it was of interest to prepare, assay and compare the
compounds shown in Figure 3 in order to delineate the effects of various methoxy substituents
upon the catalytic activity of the present selenide/selenurane system and to compare the
properties of these compounds with those of the corresponding cyclic seleninate series.

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The desired novel oꢀhydroxymethyl selenides 8ꢀ12 shown in Figure 3 were synthesized
as indicated in Scheme 3. The selenides 5a and 5b were prepared as described previously12c,13a
and were included for comparison.
Figure 3. Structures of methoxyꢀsubstituted diaryl selenides.
HO
OH
MeO
Se
OMe
OH
OMe
MeO
Se
OMe
Se
HO
HO
MeO
OH
5b
8
9
HO
MeO
Se
OH
Se
OMe
MeO
OMe
MeO
MeO
OMe
OMe
11
HO
OH
10
HO
MeO
Se
OMe
MeO
MeO
OMe
OMe
12
OH
The preparation of the desired selenides 8 and 9 from the corresponding diselenides 13
and 14, respectively, is shown in Scheme 3. The diselenides had in turn been prepared previously
as intermediates for the synthesis of cyclic seleninate esters,19 while selenide 11 was isolated as a
byproduct of its diselenide analogue.19
In contrast to selenide 5a and its pꢀmonosubstituted derivatives 5bꢀ5f,13a the methoxyꢀ
substituted selenides 8ꢀ10 and 12 proved difficult to prepare in pure form. In general, the crude
products contained the corresponding diselenides and other unidentified byproducts. In order to

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obtain 8ꢀ10 and 12 in the high state of purity required for measurement of their catalytic activity,
they were typically oxidized to the more easily purified spirodioxyselenuranes, followed by
reduction back to their corresponding selenides with benzyl thiol and further purification by
chromatography and/or recrystallization. Thus, while crude yields were moderate, the final yields
of analytically pure products were low. Among various methods that were attempted for the
synthesis of these selenides, the most successful are shown in Scheme 3. Selenides 8 and 9 were
obtained by reduction of diselenides 13 and 14, respectively, with sodium borohydride, followed
by treatment of the resulting selenolates with the diazonium salts derived from diazotization of
the corresponding 2ꢀaminobenzyl alcohols. On the other hand, the m,pꢀdimethoxy selenide 10
and the trimethoxy derivative 12 were best obtained by the treatment of iodides 15 and 16 with
selenourea in the presence of Cu(II)O nanoparticles.22
Scheme 3. Synthesis of selenides 8ꢀ10 and 12.
R
R
Se
2
1. NaBH4
R'
Se
R'
2
OH
R
OH
Cl
N2
R'
2.
8 R= H; R' = OMe 33%
9 R= OMe; R' = H 38%
13 R= H; R' = OMe
14 R= OMe; R' = H
OH
Se
R
Se
2
R
H2N
NH2
MeO
MeO
MeO
MeO
I
CuO, KOH
OH
OH
15 R = H
16 R= OMe
10 R = H 25%
12 R= OMe 18%
The catalytic activities of compounds 5a, 5b and 8ꢀ12 were then measured in our
previously described assay,12,13,23 in which benzyl thiol was oxidized with a small excess of

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hydrogen peroxide in the presence of 10 mol % of the catalyst. The formation of dibenzyl
disulfide was monitored by HPLC and the resulting t1/2 values, representing the time required for
the conversion of 50% of the thiol to its disulfide, are shown in Table 1. Kinetic plots of disulfide
formation vs. time for selenide catalysts 5a, 5b and 8ꢀ12 are provided in Figures 4ꢀ10.
Table 1. Catalytic activity of methoxyꢀsubstituted selenides and cyclic seleninate esters
catalyst
10 mol %
2 BnSH + H2O2
BnSSBn + H2O
CH2Cl2 - MeOH (95:5)
18 oC
Se
2
MeO
catalyst =
OH
entry catalyst
MeO substituent(s)a
t1/2 (h)b,c
20 (53)
5.5 (38)
17 (50)
21 (70)
6.3 (49)
17 (55)
15 (45)
1
2
3
4
5
6
7
none
p
5a
5b
8
m
o
9
m,p
o,p
o,m,p
10
11
12
aOrtho and para refer to positions relative to the Se substituent; meta refers to the position that is
b
meta to the Se substituent and para to the hydroxymethyl group. Values in parentheses are the
t1/2 values for the corresponding similarly substituted cyclic seleninate esters,19 and are included
for comparison. All t1/2 values are the average of 2ꢀ5 runs. cA control reaction in the absence of a
catalyst afforded a t1/2 value of >170 h.

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Figure 4. Kinetic plot for selenide 5a.
100
80
60
40
20
0
y = 0.0375x + 1.9593
R² = 0.9946
0
500
1000
1500
2000
Time (min.)
Figure 5. Kinetic plot for selenide 5b.
100
80
60
40
20
0
y = 0.149x + 1.0747
R² = 0.9984
0
100
200
300
400
Time (minutes)

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Figure 6. Kinetic plot for selenide 8.
100
80
60
40
20
0
y = 0.0448x + 0.6036
R² = 0.9992
0
500
1000
1500
2000
Time (minutes)
Figure 7. Kinetic plot for selenide 9.
100
80
60
40
20
0
y = 2E-05x2 + 0.0139x + 0.686
R² = 0.9967
0
500
1000
Time (minutes)
1500
2000

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Figure 8. Kinetic plot for selenide 10.
100
80
60
40
20
0
y = 0.1255x + 2.0864
R² = 0.9985
0
100
200
300
400
500
600
Time (minutes)
Figure 9. Kinetic plot for selenide 11.
HO
MeO
100
MeO
Se
OMe
80
60
40
20
0
OMe
OH
y = 0.0468x - 0.6578
R² = 0.9981
0
500
1000
1500
2000
Time (minutes)

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Figure 10. Kinetic plot for selenide 12.
100
80
60
40
20
0
y = 3E-05x2 + 0.0284x + 0.2963
R² = 0.9993
0
500
1000
1500
2000
Time (minutes)
The presence of a pꢀmethoxy group in each of the aryl moieties in 5b increased the
catalytic activity almost fourꢀfold relative to the unsubstituted compound 5a (entries 1 and 2).
Single methoxy groups in the meta or ortho positions had little effect, with the former providing
a slightly enhanced rate and the latter a very slightly suppressed one (entries 3 and 4) compared
to 5a. Inclusion of an additional methoxy substituent into the meta positions of the
monomethoxy derivative 5b to give 10 decreased its activity slightly (entry 5), while the
additional ortho substituent in 11 strongly suppressed it (entry 6). The trimethoxyaryl derivative
12 (entry 7) was also nearly three times less active than the pꢀmethoxy derivative 5b. These
results indicate that the presence of an o-methoxy substituent is slightly (entry 4 vs. 1) or
considerably (entry 6 vs. 2, entry 7 vs. 5) detrimental to catalytic activity, while mꢀmethoxy
groups can be either activating (entry 3 vs. 1, entry 7 vs. 6) or deactivating (entry 5 vs. 2)

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Furthermore, a comparison of the present selenides 5b and 8ꢀ12 with the analogous cyclic
seleninate esters reported previously19 reveals that the selenides are all considerably more active,
with shorter t1/2, than their similarly substituted seleninate counterparts.
It is also noteworthy that oꢀmethoxyꢀsubstituted compounds 9 and 12 (but not 11)
displayed nonlinear kinetic behaviour, characterized by a slower reaction rate in the early stages
of the reaction. While the reason for this behaviour is uncertain, we note that all of the present
catalysts, including 9 and 12, persist in their selenide form throughout the reaction, as long as
unreacted thiol is present. Thus, the significant accumulation of an unexpected and more active
catalytic species that could accelerate the reaction in its later stages does not appear to be
responsible for the nonlinear kinetics of these two catalysts (for HPLC analyses of 9 and 12, see
the Supporting Information). Furthermore, the persistence of the catalysts in their reduced
selenide form is consistent with the oxidation of selenium as the rateꢀdetermining step, followed
by a considerably more rapid thiolysis of the resulting spirodioxyselenurane. It is interesting to
note that the anomalous behaviour of 9 and 12 contrasts with the abnormally fast initial reaction
rates observed when similar catalysts are introduced in their oxidized spirodioxyselenurane
form.13a The accelerated rates of the latter can be attributed to the rapid thiolysis of the catalyst
(Scheme 2) to produce the disulfide in the early stages of the reaction, followed by the slower
reoxidation of the reduced selenide catalyst.
In conclusion, the most effective substitution pattern in the selenide/selenurane series of
catalysts is a single pꢀmethoxy substituent (on each aryl moiety), while single ortho and meta
methoxy groups had relatively little effect on activity. There is little or no advantage to the
incorporation of additional mꢀmethoxy groups to the pꢀsubstituted compound 5b and the addition
of an oꢀmethoxy group to 5b or 10 resulted in significant loss of activity. This suggests that

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detrimental steric effects outweigh performanceꢀenhancing mesomeric or coordination effects in
the case of the oꢀmethoxy substituents in the present series of compounds, as well as in the cyclic
seleninate esters. Finally, the hydroxymethyl selenides in Table 1 proved in each case superior
catalysts to the corresponding cyclic seleninate esters under the conditions of this assay.
Experimental Section
General Experimental.
Diselenides 13ꢀ16 and selenide 11 were prepared as described previously.19 2ꢀAminoꢀ4ꢀ
methoxybenzyl alcohol and 2ꢀaminoꢀ3ꢀmethoxybenzyl alcohol are known compounds24 that
were prepared by the reduction of the corresponding carboxylic acids with lithium aluminum
hydride. Iodo alcohols 15 and 16 were obtained by the method of Lete and coworkers.25
1H NMR spectra were recorded at 400 MHz, while 13C and 77Se NMR spectra were
obtained at 101 and 76 MHz, respectively. Chemical shifts of 77Se NMR spectra were measured
with diphenyl diselenide in CDCl3 (463.0 ppm)26 as the standard, relative to dimethyl selenide
(0.0 ppm). High resolution mass spectra were obtained using a time of flight (TOF) analyzer
with electron impact (EI) ionization or a quadrupole TOF analyzer with electrospray ionization
(ESI).
The HPLCꢀbased in vitro assay was carried out in the following manner. Catalytic
activity was measured by adding the catalyst (0.031 mmol; 10 mol % relative to benzyl thiol) to
a mixture of 33% hydrogen peroxide (0.035 M) and benzyl thiol (0.031 M) in 10.0 mL of
dichloromethaneꢀmethanol (95:5) while maintaining the temperature at 18 ºC. The reactions
were monitored by HPLC analysis, using a UV detector at 254 nm and a reversed phase column
(Novapak C18; 3.9 x 150 mm). The eluant was acetonitrileꢀwater (90:10) at a flow rate of 0.9

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mL/min. Naphthalene (0.0080 M) was employed as an internal standard. Benzyl thiol was
redistilled and hydrogen peroxide was titrated27 prior to use. The assay is sensitive to acidic and
other contaminants. Each replicate assay was performed in a clean new vial.28
Preparation of 2,2'-selenobis(4-methoxybenzyl alcohol) (8).
2ꢀAminoꢀ4ꢀmethoxybenzyl alcohol (492 mg, 3.22 mmol) was suspended in 12 mL of
water, cooled to 0 °C and treated with 1.8 mL of concentrated HCl, followed by the dropwise
addition of NaNO2 (260 mg, 3.77 mmol) in 1.8 mL of water. In a separate round bottom flask,
the diselenide 13 (460 mg, 1.06 mmol) was dissolved in 34 mL of THF:water (1:1), cooled to 0
°C and treated with NaBH4 (283 mg, 7.48 mmol). The pH of the diazonium salt solution was
then adjusted to ~5.5 with saturated aqueous sodium acetate. This mixture was subsequently
transferred in a dropwise manner to the clear selenolate solution. The reaction mixture was
warmed to room temperature, left for 2 h and quenched with 15 mL of saturated aqueous NH4Cl
solution. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4) and
concentrated. The resulting oil was purified by flash chromatography (hexanesꢀethyl acetate, 1:1)
to afford 301 mg of a mixture of desired selenide and the diselenide starting material. In order to
separate them, the mixture and 29% hydrogen peroxide (0.51 mL) were dissolved in 10 mL of
dichloromethane and left for 12 h. The resulting mixture of the corresponding
spirodioxyselenurane and cyclic seleninate ester was concentrated under reduced pressure and
separated by flash chromatography (ethyl acetateꢀmethanol, 9:1). The selenurane was reduced to
the desired selenide by treating it with 2 equivalents of benzyl thiol in 5 mL of dichloromethane
for 1 h. Concentration of the mixture and purification by chromatography (ethyl acetateꢀhexanes,
1:1) afforded 123 mg (33%) of selenide 8 as a white solid, mp 115ꢀ116 °C; IR (film) 3319, 2919,
1590, 1471, 1224, 1038 cmꢀ1; 1H NMR (400 MHz; CDCl3) δ 7.35 (d, J = 8.4 Hz, 2 H), 6.89 (d, J

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20
= 2.8 Hz, 2 H), 6.82 (dd, J = 8.4, 2.8 Hz, 2 H), 4.68 (s, 4 H), 3.71 (s, 6 H), 2.11 (br s, 2 H); 13C
77
NMR (101 MHz; CDCl3) δ 159.7, 134.5, 131.8, 130.4, 120.1, 113.6, 65.0, 55.5; Se NMR (76
MHz; CDCl3) δ 335.8; mass spectrum, m/z (EI, relative intensity) 354 (10, M+), 199 (20), 135
80
(82), 121 (68), 108 (75), 77 (100); exact mass calcd. for C16H18O4 Se: 354.0370; found:
354.0357. Anal. calcd. for C16H18O4Se: C, 54.40; H, 5.14; found: C, 54.38; H, 5.49.
Preparation of 2,2'-selenobis(5-methoxybenzyl alcohol) (9).
Selenide 9 was prepared similarly to 8 from 2ꢀaminoꢀ3ꢀmethoxybenzyl alcohol and
diselenide 14 in 38% yield; white solid, mp 182ꢀ183 °C; IR (film) 3214, 2929, 1557, 1462, 1267,
1000 cmꢀ1; 1H NMR (400 MHz; DMSOꢀd6) δ 7.25 (t, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H),
13
6.82 (d, J = 8.0 Hz, 2 H), 5.13 (t, J = 5.6 Hz, 2 H), 4.54 (d, J = 5.2 Hz, 4 H), 3.56 (s, 6 H); C
77
NMR (101 MHz; DMSOꢀd6) δ 158.6, 146.2, 128.5, 119.1, 118.0, 109.9, 62.9, 55.8; Se NMR
(76 MHz; DMSOꢀd6) δ 144.2; mass spectrum, m/z (EI, relative intensity) 354 (50, M+) 200 (65),
80
121 (100), 77 (60); exact mass calcd. for C16H18O4 Se: 354.0370; found: 354.0371. Anal. calcd.
for C16H18O4Se: C, 54.40; H, 5.14; found: C, 54.20; H, 5.18.
Preparation of 2,2'-selenobis(4,5-dimethoxybenzyl alcohol) (10).
Selenide 10 was prepared according to a modification of the general procedure of Reddy,
Kumar and Rao22 for the synthesis of symmetrical aryl selenides. 2ꢀIodoꢀ4,5ꢀdimethoxybenzyl
alcohol (1.09 g, 3.70 mmol) and selenourea (151 mg, 1.23 mmol) were dissolved in 5 mL of
DMSO. Commercially available nanopowder (<50 nm particle size) copper(II) oxide (59 mg,
0.74 mmol) was added and the mixture was degassed with a stream of argon for 20 min.
Potassium hydroxide (138 mg, 2.46 mmol) was added and the mixture was heated at 85 °C for
18 h. The mixture was poured onto 15 mL of water, extracted with ethyl acetate, washed with
brine, dried (MgSO4) and concentrated under reduced pressure. The product was subjected to

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21
flash chromatography (ethyl acetateꢀhexanes, 1:1) to afford a mixture of the desired selenide 10
and the corresponding diselenide, which were separated as in the case of selenide 8 and
diselenide 13. The crude selenide was purified by chromatography (ethyl acetateꢀhexanes, 1:1) to
afford 128 mg (25%) of selenide 10 as a white solid, mp 112ꢀ113 °C; IR (film) 3533, 3419,
1
2924, 1500, 1252, 1195, 1148 cmꢀ1; H NMR (400 MHz; CDCl3) δ 6.96 (s, 2 H), 6.83 (s, 2 H),
4.64 (s, 4 H), 3.83 (s, 6 H), 3.68 (s, 6 H), 2.67 (br s, 2 H); 13C NMR (101 MHz; CDCl3) δ 149.2,
77
148.8, 135.1, 120.9, 117.3, 112.1, 64.9, 56.1, 56.0; Se NMR (76 MHz; CDCl3) δ 310.8; mass
spectrum, m/z (EI, relative intensity) 414 (38, M+), 316 (32), 151 (100) 138 (46); exact mass
80
calcd. for C18H22O6 Se: 414.0582; found: 414.0583. Anal. calcd. for C18H22O6Se: C, 52.31; H,
5.36; found: C, 52.38; H, 5.51.
Preparation of 2,2'-selenobis(3,4,5-trimethoxybenzyl alcohol) (12).
Selenide 12 was prepared similarly to 10 from 2ꢀiodoꢀ3,4,5ꢀtrimethoxybenzyl and
selenourea. in 18% yield as a colourless oil; IR (neat) 3457, 2929, 2848, 1581, 1481, 1314, 1152,
1105, 1010 cmꢀ1; 1H NMR (400 MHz; CDCl3) δ 6.85 (s, 2 H), 4.87 (br s, 4 H), 3.88 (s, 6 H), 3.77
13
(s, 6 H), 3.46 (s, 6 H), 3.36 (s, 2 H); C NMR (101 MHz; CDCl3) δ 154.3, 154.2, 142.1, 139.4,
77
116.4, 108.9, 66.4, 60.9 (x 2), 56.2; Se NMR (76 MHz; CDCl3) δ 156.0; mass spectrum, m/z
(EI, relative intensity) 474 (40, M+), 276 (18), 198 (36), 181 (100), 168 (38); exact mass calcd.
80
for C20H26O8 Se: 474.0793; found: 474.0792.
Acknowledgment
We thank the Natural Sciences and Engineering Research Council of Canada (NSERC)
for financial support. DJP thanks NSERC and Alberta Innovates – Health Solutions for
postgraduate scholarships.

Page 22 of 26
22
Supporting Information
Copies of NMR spectra of selenides 8, 9, 10 and 12, as well as HPLC analyses of
reactions conducted with catalysts 9 and 12 are available in the Supporting Information.
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