An efficient and practical method for the selective synthesis of sodium diselenide and diorganyl diselenides through selenium reduction

Article abstract of DOI:10.1016/j.tet.2020.131720

Studies on an efficient and practical method for the selective synthesis of diorganyl diselenides over diorganyl selenides are presented. Considering the discrepancies between reports on organoselenium compounds, we wanted to establish a tolerable synthetic method for diorganyl diselenides and investigate their characteristics. We optimized reaction conditions for sodium diselenide preparation using selenium, NH₂NH₂·H₂O, and NaOH and, by treating the obtained sodium diselenide with various alkyl or aryl halides, achieved the selective synthesis of diorganyl diselenides in modest to good yields (57–88%) with good reproducibility. We further studied the mechanistic implication, the effects of solvent changes, and the stability of diorganyl diselenides.

Full text of DOI:10.1016/j.tet.2020.131720

Journal Pre-proof
An Efficient and Practical Method for the Selective Synthesis of Sodium Diselenide
and Diorganyl Diselenides through Selenium Reduction
Yoo Jin Lim, Na Hye Shin, Chorong Kim, Ye Eun Kim, Hyunsung Cho, Myung-Sook
Park, Sang Hyup Lee
PII:
S0040-4020(20)30940-6
https://doi.org/10.1016/j.tet.2020.131720
TET 131720
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 August 2020
Revised Date: 18 October 2020
Accepted Date: 24 October 2020
Please cite this article as: Lim YJ, Shin NH, Kim C, Kim YE, Cho H, Park M-S, Lee SH, An Efficient and
Practical Method for the Selective Synthesis of Sodium Diselenide and Diorganyl Diselenides through
Selenium Reduction, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131720.
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Graphical Abstract

An Efficient and Practical Method for the Selective Synthesis
of Sodium Diselenide and Diorganyl Diselenides through
Selenium Reduction
Yoo Jin Lim, Na Hye Shin, Chorong Kim, Ye Eun Kim, Hyunsung Cho, Myung-Sook
Park, and Sang Hyup Lee*
College of Pharmacy and Innovative Drug Center, Duksung Women’s University, Seoul
01369, Republic of Korea,
*sanghyup@duksung.ac.kr
*To whom correspondence should be addressed:
Sang Hyup Lee
College of Pharmacy, Duksung Women’s University
33, Samyangro 144-gil, Dobong-gu, Seoul 01369, Republic of Korea
Phone: +82-2-901-8393. Fax: +82-2-901-8393.
Email: sanghyup@duksung.ac.kr
1

Graphical Abstract
2

Abstract
Studies on an efficient and practical method for the selective synthesis of diorganyl
diselenides over diorganyl selenides are presented. Considering the discrepancies
between reports on organoselenium compounds, we wanted to establish a tolerable
synthetic method for diorganyl diselenides and investigate their characteristics. We
optimized reaction conditions for sodium diselenide preparation using selenium,
NH2NH2·H2O, and NaOH and, by treating the obtained sodium diselenide with various
alkyl or aryl halides, achieved the selective synthesis of diorganyl diselenides in modest
to good yields (57–88%) with good reproducibility. We further studied the mechanistic
implication, the effects of solvent changes, and the stability of diorganyl diselenides.
Keywords
Organoselenium, Sodium diselenide, Diorganyl diselenide, Hydrazine, Reduction
3

1. Introduction
Selenium (Se) is an essential trace element and a component of the amino acids,
selenocysteine and selenomethionine, in living organisms; thus, selenium must be
required for some specific in vivo processes despite the presence of sulfur, which is
chemically similar [1]. Selenium is implicated in several important biological processes,
such as, forming diselenide bonds as well as disulfide bonds in protein folding and
regulating oxidative stresses [2,3]. It is also a component of enzymes, including
glutathione peroxidase and thioredoxin reductase, and probably participates in redox
processes [2,4]. Recent efforts have been made to replace oxygen in carbohydrates with
selenium to produce biologically active selenocarbohydrates [5–7]. Selenol (RSeH) is
~1,000 times more acidic than the analogous thiol (RSH). For example, the pKa value of
selenol in selenocysteine is 5.2–5.7, whereas that of thiol in cysteine is 8.3 [8].
Furthermore, hydrogen selenide (H2Se, pKa 3.8) is more acidic than hydrogen sulfide
(H2S, pKa 7.0) and water (pKa 15). However, in terms of reactivity, selenol (or selenolate)
is more nucleophilic than thiol (or thiolate) [9]. The reduction potential of selenium is
lower compared with sulfur, and thus, diselenide bonds are believed to be more stable
than disulfide bonds [8]. These complex properties of selenium compounds are not well
understood from chemical or medicinal perspectives, and this lack of understanding
seems to hamper extensive studies on selenium.
Organoselenium compounds tend to be unstable and difficult to manipulate, and
their syntheses are less than straightforward, which may explain the relative lack of
systematic studies on organoselenium compounds, and their characteristics and stabilities.
4

Thus, despite the previous reports, studies on the development of synthetic methods for
these compounds, their derivatization, and elucidation of chemical characteristics are in
strong demand in the area of organoselenium chemistry.
Among many organoselenium compounds, diorganyl diselenides 1 are of
particular interest because of their involvement in important biological processes [10,11].
We thus focused on the synthetic method of 1. Of the few reaction systems that have
already been applied [11–18], those performed using a diselenide dianion (e.g., sodium
diselenide) and an alkyl halide are most common [14,15,17]. In general, elemental
selenium is reduced to the diselenide dianion by appropriate reducing agents, such as
hydrazine (NH2NH2) [14,17], sodium hydride [18], sodium borohydride [12,15] and
lithium triethylborohydride [19], under the various corresponding conditions. However,
the practical limitation of most of these methods lies in the low and variable yields, side
product formation, reducing agent inconsistencies, and harsh reaction conditions.
Furthermore, poor reproducibility has been noted to cause discrepancies between reports
[11,12,15]. Likewise, in our preparations of diorganyl diselenides by previous procedures
[11,12,17], we also experienced poor reproducibility and instability of some products.
Some gave consistently lower yields than reported and, sometimes we observed
unexpected decomposition of the products that occurred in solutions and even in neat
forms. It seems that diselenide compounds undergo further oxidation, diselenide cleavage,
and polymerization. Not only did we find that it was highly difficult to identify these
transformations quantitatively, but also we could scarcely find previous investigations
and even remarks on these kinds of phenomena. These reasons motivated our interest in
organoselenium chemistry, and our attempts to synthesize organoselenium compounds.
5

We believe a few uncertain peculiar aspects of organoselenium chemistry exist, which
requires further extensive studies.
Based on preliminary studies, we selected hydrazine as the reducing agent. Herein,
we report the efficient and practical syntheses of sodium diselenide and corresponding
diorganyl diselenides 1 and describe the mechanistic implication, the effect of solvent
changes, and the stability of diselenide compounds.
2. Results and discussion
2.1. Optimization of the reaction conditions
In order to perform systematic studies on the synthesis of diorganyl diselenides,
we first sought to investigate the reaction conditions suitable for the formation of sodium
diselenide. According to the prior procedures for synthesizing aromatic diselenides
[11,14], we attempted to establish an efficient and practical method for producing
aliphatic and aromatic diselenides with appropriate modifications. We used selenium,
hydrazine hydrate (NH2NH2·H2O), and sodium hydroxide to prepare sodium diselenide.
However, because there was no practical way of checking the formation of sodium
diselenide in reaction media, the reaction mixtures were further treated with appropriate
electrophiles, such as alkyl or aryl halides. We chose benzyl bromide (BnBr) as a
template alkyl halide to capture sodium diselenide in situ, affording dibenzyl diselenide
(1a), as shown in Scheme 1.
6

.
4Se
4NaOH
2Na2Se2
2BnBr
N2
4H2O
+
+ NH2NH2 H2O +
+
Bn Se Se Bn
2
1a
Scheme 1. Formation of sodium diselenide and dibenzyl diselenide (1a).
One-pot reactions were conducted using Se, NH2NH2·H2O, and NaOH in N,N-
dimethylformamide (DMF) solvent for 2 h. Owing to the importance of the reducing
agent, we tried to optimize the reaction conditions by varying the amount of
NH2NH2·H2O and temperature, and the generated sodium diselenide was directly reacted
with BnBr to yield 1a (Table 1). We also considered the effect of the amount of BnBr and
intended to use it in a sufficient amount. Thus, we employed BnBr in the range of 1.0–2.4
eq and found that 1.2 eq is enough to complete these reactions, unless otherwise noted.
Table 1
Optimization of the reaction conditions for sodium diselenide and dibenzyl diselenide
(1a).a
1a formation
(Reaction with BnBr)
Na2Se2 formation
Product
Remarks
Entry
1a
yieldb
(%)
2a
yieldb
(%)
NH2NH2·H2O
(eq)
Temp
(°C)
Time
(h)
1
2
0.25
0.25
25
50
18
15
40
60
6
6
7

c
3
4
5
6
7
8
0.50
0.50
0.75
0.75
1.0
25
50
25
50
25
50
18
15
20
20
20
20
64
81
86
79
62
48
10
c
c
c
1.0
9
a All reactions were run in 1.0 mmol scale of Se (1.0 eq, [c] = 670 mM) and NaOH (1.0 eq) in
DMF for 2 h for formation of Na2Se2; BnBr (1.2 eq) at 25 °C for formation of 1a.
b Isolated yields.
c Trace amount.
Considering the theoretical 0.25 eq NH2NH2·H2O vs. Se, we conducted reactions
at 0.25–1.0 eq NH2NH2·H2O at temperatures of 25 to 50 °C. As was expected, the
NH2NH2·H2O amounts dramatically affected the reaction, and we obtained the best yield
at 0.75 eq NH2NH2·H2O. In particular, with 1.0 eq NH2NH2·H2O, a substantial amount of
side product was formed (see below). Considering the required stoichiometric amount
(0.25 eq) of the reducing agent, the use of 0.75 eq seemed excessive. Nonetheless, we
expected that the excess amount of reducing agent would be attributed to the insufficient
working of the reducing agent and the presence of oxygen. Thus, we concluded that 0.75
eq of reducing agent would be a practically-relevant amount for diselenide formation at
our reaction scale.
The reaction temperature also influenced the results, albeit inconsistently.
Although the conditions of higher temperature with 0.25 and 0.5 eq NH2NH2·H2O
appeared to provide better results than those at 25 °C, we obtained the best result (86%)
at 25 °C with 0.75 eq NH2NH2·H2O. Notably, as shown in Scheme 2, the selenide 2
(RSeR) could be obtained via the selenide dianion (Se2-) as a side product and, in reality,
selenide 2 was usually detected during the reactions. However, mechanistic information
about this kind of side reaction was scarce in this reaction method. We suggest that the
8

2-
diselenide dianion (Se2 ) is further reduced to the selenide dianion (Se2-), which, in turn,
leads to the formation of the corresponding diorganyl selenide 2. Consequently, the
appropriate amount (0.75 eq) of NH2NH2·H2O as a reducing agent resulted in the
selective formation of diorganyl diselenides 1 without the detectable formation of
diorganyl selenides 2.
We noted that the reaction results fluctuated considerably with the reaction
conditions, such as the addition order of reagents, stirring efficiency, and reaction time.
Reactions carried out with a different order of reagent addition (Se vs. reducing agent)
led to strikingly different yields of diselenides 1, selenides 2, and side products. For
example, when we added Se first and then reducing agent, the yield of dibenzyl
diselenide (1a) was 86% without detectable amount of dibenzyl selenide (2a) (Table 1,
entry 5). However, when we changed the addition order (reducing agent first and then Se),
the yield of 1a decreased (38%) and the yield of 2a increased (34%). The influences of
reaction time seemed to be associated with the facts that the formation of diselenide
dianion can equilibrate with selenide dianion (Scheme 2), and that the diorganyl
diselenide products can also undergo disproportionation. The reasons for these sensitive
fluctuations in the reactions are still inconclusive, and in-depth studies are in progress.
When we varied the amount of NaOH (0.5–2.0 eq), results were not improved.
Ultimately, the optimized reaction condition was 1.0 eq Se, 0.75 eq NH2NH2·H2O, and
1.0 eq NaOH at 25 °C for 2 h (addition order: Se, NaOH, and then NH2NH2·H2O),
followed by treatment with 1.2 eq of BnBr at 25 °C for 20 h. In order to verify the
reproducibility, we performed each reaction five times under the optimized conditions at
the reaction scale of 1, 10, and 50 mmol Se, with robust reproducibility. The optimized
9

condition was used in all reactions with different alkyl and aryl halides, unless otherwise
stated.
2-
Scheme 2. The equilibrium of diselenide dianion (Se2 ) and selenide dianion (Se2-) and
the formation of corresponding products.
When a greater than the optimal amount of NH2NH2·H2O (0.75 eq) was used, side
product formation (e.g., hydrazine-associated compounds) became an issue. As examples,
(poly)alkyl hydrazines 3 and (poly)alkyl diazenes 4 could be formed by reacting alkyl
halides and hydrazine or its partially-oxidized species (e.g., diazene HN=NH), as
depicted in Scheme 3. Thus, the reactions appeared to be complex and generate various
side products (Schemes 2 and 3). To the best of our knowledge, this tendency to produce
such side products has not been previously reported. As evidence of these side reactions,
we observed the formation of side products with molecular weight of 3 or 4 in mass
analysis in the reactions for cyclic diselenides (e.g., 1m and 1n), which derives some
10

support from the previous observation that diazene is formed through oxidation of
hydrazine by selenium [20].
[Ox]
[Ox]
H2N NH2
RX
HN NH
RX
N N
R
R
R
N N
N N
R
R
R
3
R= H, alkyl
4
Scheme 3. The formation of (poly)alkyl hydrazines 3 and (poly)alkyl diazenes 4.
2.2. Synthesis of diorganyl diselenides 1
Under the optimized conditions, we achieved the selective synthesis of diorganyl
diselenides 1 in our attempts to expand the scope of this reaction by employing different
aliphatic and aromatic halides (Table 2). As halides we employed primary, secondary,
and tertiary alkyl bromides (or chlorides), and aromatic bromides (or iodides). When
aromatic bromides did not work, aromatic iodides were employed. First, benzyl bromide
and phenethyl bromide gave good yields (Table 2, entries 1 and 3). n-Hexyl bromide and
n-octyl bromide also gave modest yields (entries 5 and 7). Similarly, aliphatic chlorides
such as benzyl chloride, phenethyl chloride, n-hexyl chloride, and n-octyl chloride
afforded good to modest yields (Entries 2, 4, 6, and 8). As secondary alkyl halides, c-
hexyl bromide and 4-heptyl bromide provided good yields (entries 9 and 10). The
secondary halides provided better results than primary halides, which might be associated
11

with the stability of the generated products during work-up and the isolation processes
(see below). Tertiary halides (e.g., t-BuBr) did not provide an appreciable amount of
product, probably due to steric hindrance. The aromatic bromides (or iodides) generally
gave good to modest yields. Unsubstituted phenyl bromide and phenyl bromides with an
electron-donating substituent (e.g., methyl group) gave poor yields (5–11%, data not
shown) even at high reaction temperature (153 °C). It is believed that the reactions
between sodium diselenide and these aromatic bromides suffered from low yields and
side reactions because of low reactivity and high reaction temperatures (e.g., 153 °C). In
order to improve the results, we investigated the use of sodium iodide as a catalyst or
tetrabutylammonium bromide as a phase-transfer catalyst (PTC), which led to no
appreciable improvement. Therefore, we attempted these reactions using aromatic iodides
instead of aromatic bromides during a prolonged reaction time at 153 °C, which
eventually resulted in much improved yields of 59–69% (entries 11–13). In this condition,
we also tested other aromatic iodides with electron-donating substituent (e.g., methoxy or
4-morpholino group), which led to poor results. Different from phenyl bromides with
electron-donating substituents, phenyl bromides with electron-withdrawing substituents
(e.g., cyano, trifluoromethyl, or nitro group) gave good to modest yields (81–58%) at
100 °C (entries 14–16). According to the differences in the reaction results between the
aromatic halides (with an electron-donating or an electron-withdrawing substituent), we
found these reactions were dependent on the electrophilicity of the aromatic halide,
associated with the effects of substituents on the aromatic ring.
As we were also interested in the synthesis of cyclic diselenide compounds, we
attempted to use α,α'-dibromoxylene and 1,4-dibromo-2,3-dihydroxybutane (entries 17
12

and 18) as halides. Notably, because these are intramolecular reactions, we carried out
these reactions using only 0.6 eq of aromatic halides at very low Se concentrations (30
mM). Consistent with our expectations, these reactions worked efficiently and led to the
generation of cyclic diselenides in good and modest yields (72 and 57%). In the reaction
with α,α'-dibromoxylene, when we increased the amount of NH2NH2·H2O to facilitate
the intramolecular cyclization, we detected the formation of the side products 3m and 4m
(Scheme 3). In particular, in the reaction with 1,4-dibromo-2,3-dihydroxybutane, the
product 1n was so polar that the product was not efficiently extracted with conventional
solvents, such as ethyl acetate (EA) or dichloromethane (DCM), and so, the product was
extracted using a 1:2 mixture of EA and t-BuOH. The slightly lower yield of 1n (57%)
than 1m (72%) was probably because of loss in the extraction process.
Table 2
Synthesis of diorganyl diselenides 1.a
Reaction with RX
Yieldb
(%)
Temp
Entry
RX
(eq)
Time
(h)
RX
Product
(ꢀ)
1
2
3
4
BnBr
1.2
1.2
1.2
1.2
20
20
23
23
25
25
25
25
86
85
77
67
1a
BnCl
PhCH2CH2Br
PhCH2CH2Cl
n-HexBr
1b
5
6
1.2
1.2
3
3
25
25
60
57
1c
13

n-HexCl
n-OctBr
n-OctCl
7
8
1.2
1.2
3
3
25
25
63
62
1d
9
1.2
1.2
1.2
1.2
1.2
6
25
25
87
88
60
59
69
1e
10
4
1f
Se
11c
12c
13c
30
30
40
153
153
153
Se
1g
Se
Se
1h
1i
1.2
1.2
6
7
100
100
70
58
14
15
1j
1k
1.2
4
2
81
72
16
100
1l
Se
Se
17d
0.6e
25
1m
14

18d
0.6e
3
25
57
1n
a All reactions were run in 1.0 mmol scale of Se (1.0 eq, [c] = 670 mM), NaOH (1.0 eq), and
NH2NH2·H2O (0.75 eq) in DMF at 25 °C for 2 h for formation of disodium diselenide.
b Isolated yields.
c Aromatic iodides were used instead of aromatic bromides because aromatic bromides led to
poor yields (5~11%).
d [c] = 30 mM concentration (for Se, high dilution condition).
e Half the amount of alkyl bromides (0.6 eq) was used because of intramolecular cyclization.
2.3. Solvent studies
When we performed the reactions in DMF as the solvent, most of our reactions
generated successful results. However, DMF is a high-bp (153 °C) solvent that is difficult
to remove from low-bp dialkyl diselenides, such as dimethyl diselenide (b.p. 156–158 °C)
[17], diethyl diselenide (b.p. 68–70 °C/9–10 mmHg) [21]. DMF solvent may cause
separation problems in some cases. Thus, we wished to check if these reactions work
under other volatile (low-bp) and nonpolar organic solvents relative to DMF. Previously,
tetrahydrofuran (THF) was employed as a solvent in the reactions of alkali metal and Se
to form selenides and diselenides under the effects of a charge-transfer agent and
ultrasound [16], which is different from our present method. We thus chose acetonitrile
(MeCN), THF, and dimethoxyethane (DME) as volatile and less-polar solvents (than
DMF). Using these solvents, we conducted the reactions with NH2NH2·H2O and BnBr as
a template alkyl halide at 25 to 80 °C (Table 3). We were worried about the poor
solubility of the generated sodium diselenide in these solvents, and correspondingly, poor
results in the reactions with BnBr. In reality, the reaction media for the preparation of
sodium diselenide appeared as dark reddish and heterogeneous suspensions. BnBr
15

addition decreased the suspension-like appearance or heterogeneity. Surprisingly,
reactions using these solvents provided fairly good results (50–78% yields). Such
successful applications of these solvents other than DMF could provide important
advantages during work-up and isolation processes. Nevertheless, the solubility and
heterogeneity issues might still limit broad application, and further studies for
improvements are in progress.
Table 3
Solvent effects.a
1a Formation
Na2Se2 Formation
(Reaction with
BnBr)
Product
Entry
1a
Temp
Solvent
Temp
(°C)
Time
(h)
(°C)
yieldsb (%)
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
THF
25
25
25
50
25
25
25
50
80
80
25
25
20
5
78
76
66
69
72
50
3
3
15
DME
25
a All reactions were run in 1.0 mmol scale of Se (1.0 eq, [c] = 670 mM), NaOH (1.0 eq), and
NH2NH2·H2O (0.75 eq) for 2 h for formation of Na2Se2; BnBr (1.2 eq) for formation of 1a.
b Isolated yields.
2.4. Stability studies
Although some of the organoselenium compounds have long-storage stability,
there are still some compounds of low stability, which have not been extensively
16

investigated so far. Our observations led us to believe that some organoselenium
compounds must have some degree of chemical instability; however, we could hardly
find any systematic studies of these compounds and information on this issue. In reality,
we observed that some of the synthesized diselenide compounds in solid-state or in
sticky-oily conditions underwent a distinct change within a short time. Occasionally, we
observed a metal-like black solid that was believed to be elemental selenium or selenium
oxides after storing the diselenide compounds at room temperature for a week. When
stored at lower temperatures (e.g., below 4 °C), we still observed the formation of the
black solid. As a result, we believed that during the storage of diorganyl diselenides,
some kind of oxidation process, disproportionation, and/or polymerization might be
involved in the observed change. The diselenide part (-Se-Se-, oxidation state: –1) in
diorganyl diselenide seemed to be oxidized to elemental selenium (oxidation state: 0) and
then selenium oxide (oxidation state: >0). Although our efforts to identify the black solid
and the side products were inconclusive, we wished to check the stability of
representative diselenide compounds. We used HPLC to periodically check the
qualitative purity of diselenide compounds for eight weeks, thereby estimating the
stability of diselenide compounds. As indicated by the results (Table 4), we tried to check
the stability of dibenzyl diselenide (1a) in closed and open vials. Surprisingly, the
dibenzyl diselenide in solid-state was found to be reasonably stable for eight weeks in a
closed vial under N2 at room temperature, and no detectable change was observed (purity
>97%). The result in an open vial was not much different from that in a closed vial,
without appreciable change (purity >95%). However, when we checked the 1,2-bis(4'-
(trifluoromethyl)phenyl) diselenide (1k) as an aromatic diselenide with electron-
17

withdrawing groups, it was not as stable at room temperature as dibenzyl diselenide. A
substantial amount of 1k was decomposed in eight weeks (purity 76%). These results
suggest that the stabilities of diselenide compounds are dependent on the alkyl/aryl
groups attached to the selenium atoms.
Table 4
Stability test of dialkyl diselenides.a
Purity (%)
Entry Diselenide
1
Condition
Remarks
0 wks
98
2 wks 4 wks
8 wks
97
closed vial
under N2
98
98
98
97
1a
1a
2
open vial
98
95
76
3
open vial
98
96
94
1k
a All experiments were run in 50 mg scale in 4 mL vials.
3. Conclusions
We report an efficient and practical method for the selective synthesis of sodium
diselenide and corresponding diorganyl diselenides 1 over diorganyl selenides 2. The
optimized condition was established as follows: 1) Se (1.0 eq), NH2NH2·H2O (0.75 eq),
and NaOH (1.0 eq) in DMF for 2 h at 25 °C, followed by, 2) alkyl (or aryl) bromide (or
iodide) for 2–40 h at temperatures between 25 and 153 °C. Diorganyl diselenides 1 were
obtained in 57–88% yields under these conditions. In particular, the use of alkyl dihalides
resulted in the formation of cyclic diselenides, 1m and 1n, in good to modest yields. We
18

also verified the reproducibility of the reactions for 1a, by increasing the reaction scale
from 1 to 10 and 50 mmol Se. The solvent studies showed that other volatile (low-bp)
and nonpolar organic solvents (e.g., MeCN) relative to DMF also worked for these
reactions, which might lead to practical advantages in isolation processes. Stability tests
revealed that some of the diorganyl diselenides are unstable during storage under room
temperature conditions, forming a metal-like black solid. Taken together, the reduction of
Se with NH2NH2·H2O and subsequent reaction with alkyl or aryl halides provided
efficient and selective syntheses of diorganyl diselenides 1, and the solvent effects and
the stability of products were also investigated.
4. Experimental section
4.1. General methods
Reagents were of commercial quality and used without further purification, unless
otherwise stated. Reactions were periodically monitored by thin-layer chromatography
(TLC) carried on 0.25 mm Merck silica gel plates (60F-254) and visualized under UV
light, an ethanolic solution of p-anisaldehyde, and/or iodine. Purifications were
performed by preparative TLC (PTLC) and column chromatography. PTLC separations
were carried out on the same silica gel plates. Column chromatography was performed
using Merck silica gels (230-400 mesh). Melting points (uncorrected) were determined in
open capillary tubes using an Electrothermal IA9100 apparatus. FT-IR spectra were
recorded using a Perkin-Elmer Spectrum GX spectrometer and frequencies (ν) are
19

expressed in reciprocal centimeters (cm-1). 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on a Bruker DRX 300 spectrometer and chemical shifts (δ) are
expressed relative to tetramethylsilane (TMS). Mass spectra were obtained in EI or ESI
ionization modes. HPLC analyses were performed using the following Waters Associate
Units: 515 A pump, 515 B pump, dual λ absorbance 2487 detector, 717 plus autosampler,
and C18 ꢀBondapak (stainless steel) column (3.9 x 300 mm). Reaction products were
analyzed under gradient conditions. Condition 1: from 70% A (aqueous) and 30% B
(MeCN) for 3 min (isocratic) to 10% A and 90% B over 30 min (gradient), and then 10%
A and 90% B for 10 min (isocratic); condition 2: from 95% A and 5% B for 3 min
(isocratic) to 50% A and 50% B over 30 min (gradient), then to 10% A and 90% B over 5
min (gradient), and finally, 10% A and 90% B for 10 min (isocratic). The flow rate was 1
mL/min with eluent monitoring at 254 nm. HPLC solvents were filtered (aqueous
solution with Millipore HVLP, 0.45 mm; MeCN with Millipore HV, 0.45 mm) and
degassed before use.
4.2. General procedure for the synthesis of diorganyl diselenides 1
To a stirred mixture of Se (79 mg, 1.0 mmol, 1.0 eq) and NaOH (40 mg, 1.0 mmol, 1.0 eq)
in DMF (1.5 mL) was added NH2NH2·H2O (36 ꢀL, 0.75 mmol, 0.75 eq) under N2. The
resulting mixture was stirred for 2 h at 25 °C during which it turned a reddish-brown. The
alkyl halide was then added, and stirring was continued for 2–40 h at 25–153 °C until
reaction completion (Table 2). The reaction mixture was then diluted with water (30 mL),
extracted with CH2Cl2 (3 × 30 mL), and washed with brine (30 mL). Combined organic
20

layers were dried (MgSO4) and concentrated in vacuo, forming a sticky residue that was
purified by column chromatography (1:50 → 1:1 EtOAc/hexanes) to yield diorganyl
diselenides 1. Spectral data of all compounds were in accordance with the literature
information.
1,2-Dibenzyl diselenide (1a) [12,16]
Use of benzyl bromide (143 µL, 1.2 mmol, 1.2 eq) and 20 h reaction time at 25 °C in
general procedure afforded the title compound 1a (146 mg, 86%). Mp 88–91 °C (lit. [16]
90–91 °C); Rf 0.45 (1:20 EtOAc/hexanes); HPLC tR 22.94 min (condition 1); IR (KBr)
3027, 2932, 1492, 752 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.33–7.18 (m, 10 H, Ar),
3.83 (s, 4 H, CH2); 13C NMR (300 MHz, CDCl3): δ = 139.18 (Ar), 129.22 (Ar), 128.64
(Ar), 127.30 (Ar), 32.75 (CH2); MS m/z 342 [M]+; HRMS (+ESI) calcd for C14H14Se2
[M]+ 341.9426, found 341.9425. Spectral data are in accordance with literature
information [12,16].
1,2-Bis(2-phenylethyl) diselenide (1b) [12]
Use of phenethyl bromide (163 µL, 1.2 mmol, 1.2 eq) and 23 h reaction time at 25 °C in
general procedure afforded the title compound 1b (142 mg, 77%) as a yellow oil. Bp
223–228 °C; Rf 0.4 (1:20 EtOAc/hexanes); HPLC tR 24.75 min (condition 1); IR (KBr)
3058, 3026, 1601, 1494, 1452, 749, 695 cm-1; 1H NMR (300 MHz CDCl3): δ = 7.33–7.19
(m, 10 H, Ar), 3.16 (t, J = 6.9 Hz, 4 H, SeCH2), 3.05 (t, J = 6.9 Hz, 4 H, PhCH2); 13C
NMR (75 MHz, CDCl3): δ = 140.9 (Ar), 128.7 (Ar), 128.6 (Ar), 126.5 (Ar), 37.7
(SeCH2), 30.9 (PhCH2); MS m/z 370 [M]+; HRMS (+ESI) calcd for C16H18Se2 [M]+
21

369.9739, found 369.9736. Spectral data are in good accordance with literature
information [12].
1,2-Di-n-hexyl diselenide (1c) [17,22]
Use of n-hexyl bromide (168 µL, 1.2 mmol, 1.2 eq) and 3 h reaction time at 25 °C in
general procedure afforded the title compound 1c (98 mg, 60%) as a yellow oil. Bp 168–
174 °C (lit. [17] 130 °C/0.8 mmHg); Rf 0.5 (hexanes); HPLC tR 36.71 min (condition 1);
IR (KBr) 3026, 2935, 2924, 2913, 1601, 1397, 1166, 1125, 1073, 1012, 825, 704, 694
cm-1; 1H NMR (300 MHz, CDCl3): δ = 2.91 (t, J = 7.4 Hz, 4 H, SeCH2), 1.72 (quintet, J
= 7.4 Hz, 4 H, CH2), 1.43–1.22 (m, 12 H, (CH2)3), 0.89 (t, J = 6.8 Hz, 6 H, CH3); 13C
NMR (75 MHz, CDCl3): δ = 31.5 (SeCH2), 31.1 (CH2), 30.4 (CH2), 29.4 (CH2), 22.7
(CH2), 14.2 (CH3); MS m/z 330 [M]+; HRMS (+ESI) calcd for C12H26Se2 [M]+ 330.0365,
found 330.0365. Spectral data are in accordance with literature information [22].
1,2-Di-n-octyl diselenide (1d) [23]
Use of n-octyl bromide (207 µL, 1.2 mmol, 1.2 eq) and 3 h reaction time at 25 °C in
general procedure afforded the title compound 1d (121 mg, 63%) as a yellow oil. Bp
212–216 °C; Rf 0.62 (hexanes); HPLC tR 37.37 min (condition 1); IR (KBr) 2955, 2925,
2853, 1464, 721, 703, 695 cm-1; 1H NMR (300 MHz, CDCl3): δ = 2.91 (t, J = 7.4 Hz, 4 H,
SeCH2), 1.73 (quintet, J = 7.3 Hz, 4 H, CH2), 1.41–1.28 (m, 20 H, (CH2)5), 0.89 (t, J =
6.6 Hz, 6 H, CH3); 13C NMR (75 MHz, CDCl3): δ = 32.0 (SeCH2), 31.2 (CH2), 30.4
(CH2), 29.7 (CH2), 29.4 (CH2), 29.3 (CH2), 22.8 (CH2), 14.3 (CH3); MS m/z 386 [M]+;
22

HRMS (+ESI) calcd for C16H34Se2 [M]+ 386.0991, found 386.0989. Spectral data are in
accordance with literature information [23].
1,2-Di-c-hexyl diselenide (1e) [24]
Use of c-hexyl bromide (148 µL, 1.2 mmol, 1.2 eq) and 8 h reaction time at 25 °C in
general procedure afforded the title compound 1e (141 mg, 87%) as a yellow oil. Bp
181–185 °C; Rf 0.41 (hexanes); HPLC tR 33.97 min (condition 1); IR (KBr) 3028, 2927,
2913, 2850, 1448, 1256, 1179, 705, 695 cm-1; 1H NMR (300 MHz, CDCl3): δ = 3.0
(quintet, J = 5.4 Hz, 2 H, SeCH), 2.15–1.23 (m, 20 H, (CH2)5); 13C NMR (75 MHz,
CDCl3): δ = 43.6 (SeCH), 34.7 (CH2), 27.1 (CH2), 25.8 (CH2); MS m/z 326 [M]+; HRMS
(+ESI) calcd for C12H22Se2 [M]+ 326.0052, found 326.0055. Spectral data are in
accordance with literature information [24].
1,2-Bis(4-heptyl) diselenide (1f) [25]
Use of 4-heptyl bromide (189 µL, 1.2 mmol, 1.2 eq), and 4 h reaction time at 25 °C in
general procedure afforded the title compound 1f (157 mg, 88%) as a yellow oil. Bp 160–
164 °C; Rf 0.65 (hexanes); HPLC tR 21.89 min (condition 1); IR (KBr) 2957, 2934, 2910,
2872, 2235, 1464, 1455, 1378, 1179, 908, 650 cm-1; 1H NMR (300 MHz, CDCl3): δ =
2.94 (quintet, J = 6.7 Hz, 2 H, SeCH), 1.67–1.59 (m, 8 H, CH2), 1.52–1.37 (m, 8 H, CH2),
0.92 (t, J = 7.2 Hz, 12 H, CH3); 13C NMR (75 MHz, CDCl3): δ = 46.6 (SeCH), 38.4
(CH2), 21.1 (CH2), 14.1 (CH3); MS m/z 358 [M]+; HRMS (+ESI) calcd for C14H30Se2
[M]+ 358.0678, found 358.0679. Spectral data are in accordance with literature
information [25].
23

1,2-Diphenyl diselenide (1g) [13,26]
Use of phenyl iodide (134 µL, 1.2 mmol, 1.2 eq) and 30 h reaction time at 153 °C in the
procedure afforded the title compound 1g (94 mg, 60%). Mp 59–62 °C (lit. [26] 62–
63 °C); Rf 0.39 (1:100 EtOAc/hexanes); HPLC tR 22.88 min (condition 1); IR (KBr) 2928,
2903, 2253, 1474, 1384, 907, 651 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.63–7.58 (m, 4
H, Ar), 7.27–7.25 (m, 6 H, Ar); 13C NMR (75 MHz, CDCl3): δ = 133.1 (Ar), 131.6 (Ar),
129.3 (Ar), 127.8 (Ar); MS m/z 314 [M]+; HRMS (+ESI) calcd for C12H10Se2 [M]+
313.9113, found 313.9110. Spectral data are in accordance with literature information
[13].
1,2-Bis(2-methylphenyl) diselenide (1h) [13]
Use of 2-methylphenyl iodide (156 µL, 1.2 mmol, 1.2 eq), and 30 h reaction time at
153 °C in general procedure afforded the title compound 1h (100 mg, 59%). Bp 174–
177 °C; Rf 0.3 (hexanes); HPLC tR 26.18 min (condition 1); IR (KBr) 3056, 3026, 2913,
1589, 1462, 1377, 1029, 745, 695 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 7.5
Hz, 2 H, Ar), 7.22–6.99 (m, 6 H, Ar), 2.42 (s, 6 H, CH3); 13C NMR (75 MHz, CDCl3): δ
= 138.9 (Ar), 132.8 (Ar), 131.0 (Ar), 130.1 (Ar), 128.1 (Ar), 127.0 (Ar), 22.4 (CH3); MS
m/z 342 [M]+; HRMS (+ESI) calcd for C14H14Se2 [M]+ 341.9426, found 341.9427.
Spectral data are in accordance with literature information [13].
1,2-Bis(4-methylphenyl) diselenide (1i) [13,27]
24

Use of 4-methylphenyl iodide (262 mg, 1.2 mmol, 1.2 eq) and 40 h reaction time at
153 °C in general procedure afforded the title compound 1i (117 mg, 69%). Mp 41–42 °C
(lit. [27] 42–43 °C); Bp 188–190 °C; Rf 0.46 (1:100 EtOAc/hexanes); HPLC tR 25.27 min
(condition 1); IR (KBr) 3153, 2950, 2927, 2253, 1453, 1385, 908, 651 cm-1; 1H NMR
(300 MHz, CDCl3): δ = 7.49 (d, J = 8.1 Hz, 4 H, Ar), 7.07 (d, J = 7.9, 4 H, Ar), 2.33 (s, 6
H, CH3); 13C NMR (75 MHz, CDCl3): δ = 138.1 (Ar), 133.5 (Ar), 132.4 (Ar), 130.1 (Ar),
21.3 (CH3); MS m/z 342 [M]+; HRMS (+ESI) calcd for C14H14Se2 [M]+ 341.9426, found
341.9428. Spectral data are in accordance with literature information [13].
1,2-Bis(4-cyanophenyl) diselenide (1j) [28]
Use of 4-cyanophenyl bromide (218 mg, 1.2 mmol, 1.2 eq) and 7 h reaction time at
100 °C in general procedure afforded the title compound 1j (127 mg, 70%). Mp 154–
157 °C (lit. [28] 158 °C); Rf 0.24 (1:5 EtOAc/hexanes); HPLC tR 18.24 min (condition 1);
IR (KBr) 3028, 2932, 2917, 2254, 2230, 1586, 1482, 1452, 907, 705, 651 cm-1; 1H NMR
(300 MHz, CDCl3): δ = 7.67 (d, J = 8.5 Hz, 4 H, Ar), 7.59–7.51 (m, 4 H, Ar); 13C NMR
(75 MHz, CDCl3): δ = 136.8 (Ar), 133.0 (Ar), 132.8 (Ar), 130.6 (Ar), 118.3 (CN); MS
m/z 182 [(1/2)M]+, Repetitive mass analyses strongly showed the peak at the half of
molecular weight.; HRMS (+ESI) calcd for C14H8N2Se2 [M]+ 363.9018, found 363.9017.
Other spectral data are in accordance with literature information [28].
1,2-Bis(4-(trifluoromethyl)phenyl) diselenide (1k) [29]
Use of 4-(trifluoromethyl)phenyl bromide (168 µL, 1.2 mmol, 1.2 eq) and 7 h reaction
time at 100 °C in general procedure afforded the title compound 1k (130 mg, 58%). Mp
25

44–46 °C; Rf 0.44 (hexanes); HPLC tR 38.12 min (condition 1); IR (KBr) 3025, 2923,
1601, 1397, 1324, 1127, 1073, 825, 735, 698 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.69
(d, J = 8.1 Hz, 4 H, Ar), 7.51 (d, J = 8.2, 4 H, Ar); 13C NMR (75 MHz, CDCl3): δ = 133.2
(Ar), 130.8 (Ar), 126.4 (Ar), 126.3 (Ar) 122.2 (CF3); MS m/z 450 [M]+; HRMS (+ESI)
calcd for C14H8F6Se2 [M]+ 449.8861, found 449.8863. Spectral data are in accordance
with literature information [29].
1,2-Bis(4-nitrophenyl) diselenide (1l) [27,30]
Use of 4-nitrophenyl bromide (242 mg, 1.2 mmol, 1.2 eq) and 4 h reaction time at 100 °C
in general procedure afforded the title compound 1l (163 mg, 81%). Mp 168–170 °C (lit.
[30] 175–177 °C); Rf 0.70 (1:2 EtOAc/hexanes); HPLC tR 24.29 min (condition 1); IR
(KBr) 3006, 2360, 2342, 1504, 1473, 1348, 1275, 1261, 851, 750, 682 cm-1; 1H NMR
(300 MHz, CDCl3): δ = 8.17 (d, J = 8.6 Hz, 4 H, Ar), 7.61 (d, J = 8.6 Hz, 4 H, Ar); 13C
NMR (75 MHz, CDCl3): δ = 133.5 (Ar), 130.6 (Ar), 124.8 (Ar), 124.5 (Ar); MS m/z 404
[M]+; HRMS (+ESI) calcd for C12H8N2NaO4Se2 [M+Na]+ 426.8712, found 426.8710.
Other spectral data are in accordance with literature information [27].
1,2-Benzene-3,6-dihydrodiselenin (1m) [31]
Use of α,α'-dibromo-o-xylene (158 mg, 0.6 mmol, 0.6 eq), excess amount of solvent (33
mL of DMF, high dilution) and 2 h reaction time at 25 °C in general procedure afforded
the title compound 1m (94 mg, 72%). Mp 116–125 °C (lit. [31] 115–128 °C); Rf 0.43
(1:2 CH2Cl2/hexanes); HPLC tR 29.62 min (condition 1); IR (KBr) 2925, 2253, 1493,
1452, 907, 695 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.31–7.20 (m, 4 H, Ar), 3.96 (s, 4
26

H, CH2); 13C NMR (75 MHz, CDCl3): δ = 137.2 (Ar), 128.3 (Ar), 127.9 (Ar), 24.4 (CH2);
MS m/z 264 [M]+; HRMS (+ESI) calcd for C8H8Se2 [M]+ 263.8956, found 263.8959.
Spectral data are in accordance with literature information [31].
4,5-Dihydroxy-1,2-diselenane (1n) [32]
Use of 1.4-dibromo-2,3-butanediol (149 mg, 0.6 mmol, 0.6 eq), excess amount of solvent
(33 mL of DMF, high dilution), 3 h reaction time at 25 °C, and then, extraction with a
mixture of diethylether (Et2O) and t-buthanol (1:2) in general procedure afforded the title
compound 1n (70 mg, 57%). Mp 113–117 °C (lit. [32] 116–118 °C); Rf 0.37 (3:1
EtOAc/hexanes); HPLC tR 15.12 min (condition 2); IR (KBr) 3155, 2921, 2253, 1452,
1384, 1265, 907, 651 cm-1; 1H NMR (300 MHz, DMSO-d6): δ = 5.17 (d, J = 3.5 Hz, 2 H,
OH), 3.40–3.32 (m, 4 H, CH2), 3.03 (t, J = 11.04, 2 H, CH); 13C NMR (75 MHz, DMSO-
d6): δ = 73.8 (COH), 31.1 (CH2); MS m/z 248 [M]+; HRMS (+ESI) calcd for C4H8
NaO2Se2 [M+Na]+ 270.8752, found 270.8742. Spectral data are in accordance with
literature information [32].
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgments
27

This work was supported by the National Research Foundation of Korea (NRF)
Grant (2016R1D1A1B03930981, 2018R1D1A1B07048631, and 2019M3E5D5066543),
and by Priority Research Centers Program through NRF (2016R1A6A1A03007648)
funded by the Ministry of Education, Science and Technology (MEST).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
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