A Scalable Process for the Synthesis of 1,2-Dialkyldiselanes and 1-Alkaneselenols

Article abstract of DOI:10.1021/acs.oprd.9b00380

A four-step telescoped process for the synthesis of 1-alkaneselenols entails (1) the rapid formation of potassium selenocyanate from potassium cyanide and selenium in methanol, (2) the nucleophilic substitution of bromoalkanes or alkyl tosylates with potassium selenocyanate, (3) the mild base-catalyzed conversion of the resultant 1-alkaneselenocyanates to 1,2-dialkyldiselanes (the Krief reaction), and (4) the reduction of the resultant 1,2-dialkyldiselanes with hypophosphorous acid to give the desired 1-alkaneselenols. The process has been used to produce 1-octaneselenol on a 10.4 mol scale. Nine examples of the process are described.

Full text of DOI:10.1021/acs.oprd.9b00380

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Communication
A Scalable Process for the Synthesis of 1,2-
Dialkyldiselanes and 1-Alkaneselenols
John Paul Cooksey, Philip J. Kocienski, and A. John Blacker
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00380 • Publication Date (Web): 24 Oct 2019
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A Scalable Process for the Synthesis of 1,2-Dialkyldiselanes and 1-
Alkaneselenols
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John P. Cooksey,† Philip J. Kocieński,† A. John Blacker†‡*
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Institute of Process Research and Development: † School of Chemistry, University of
Leeds, Leeds; ‡ School of Chemical and Process Engineering, University of Leeds, LS2
9JT, UK. *corresponding author: j.blacker@leeds.ac.uk
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TOC Graphic
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H3PO2
alkylbromide
KCN
Se
K2CO3
[alkyl-Se]2
alkyl-SeH
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batch
MeOH
i-PrOH
9 examples
59-94%
9 examples
87-98%
0.1 to 10.4 mole scale
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ABSTRACT
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A 4-step telescoped process for the synthesis of 1-alkaneselenols entails: (1) the rapid
formation of potassium selenocyanate from potassium cyanide and selenium in methanol,
(2) the nucleophilic substitution of bromoalkanes or alkyl tosylates with potassium
selenocyanate, (3) the mild base-catalyzed conversion of the resultant 1-alkaneseleno
cyanates to 1,2-dialkyldiselanes (the Krief reaction) and (4) the reduction of the resultant
1,2-dialkyldiselanes with hypophosphorous acid to give the desired 1-alkaneselenols. The
process has been used to produce 1-octaneselenol on a 10.4 mole scale. Nine examples of
the process are described.
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KEYWORDS
alkylselenol; dialkyldiselenol; 1-octylselenol; potassium selenocyanate; reduced odour.
INTRODUCTION
Alkaneselenols are of interest in the electronic material sector as metal selenide
nanoparticles for quantum dots and surface modifiers.1-2 We recently required a process for
the synthesis of high purity 1-alkaneselenols on a kilogram scale. The overarching factors
governing route selection were the need to contend with the notorious stench of lower
molecular weight organoselenium compounds and the facile aerial oxidation of the target
selenol compounds to their corresponding diselanes.3 Both challenges could be addressed
in principle by selecting reactions amenable to fast and easy workup. Of the many methods
currently available for the synthesis of 1-alkaneselenols and their precursors,4-11 we
selected the route illustrated in Scheme 1, as exemplified by the synthesis of 1-
octaneselenol (4a).
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Br
1a
KSeCN (1.1 equiv)
MeOH, 1 h
93% (100 mmol scale)
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SeCN
2a
K2CO3 (1.0 equiv)
MeOH, 2 h
97% (150 mmol scale)
Se
2
3a
H3PO2 (1.5 equiv)
i-PrOH, 17 h
94% (105 mmol scale)
SeH
4a
Scheme 1. The stepwise synthesis of 1-octaneselenol.
The key advantages of the component reactions are: (1) The efficient installation of the
selenium atom using highly nucleophilic potassium selenocyanate,12,13 (2) the easy
isolation and purification of the 1,2-dioctyldiselane (3a) generated in the penultimate step
and (3) the safe and efficient reduction of 1,2-dioctyldiselane (3a) using cheap
hypophosphorous acid.
RESULTS AND DISCUSSION
The route to 1-octaneselenol (4a) depicted in Scheme 1 began with the addition of 1-
bromooctane (1.0 equiv.) to a suspension of potassium selenocyanate (1.1 equiv., 1.0–1.5
M) in methanol. The mixture was heated at reflux for 1 h, the resultant suspension poured
into ice–water and the product extracted into hexanes. The extract was washed with water,
dried and concentrated in vacuo at 0 °C to give a malodorous yellow oil that was purified
via short-path distillation. The principle contributors to the stench were volatile compounds
that distilled at a bath temperature of ≤60 °C/1.0 mmHg into a liquid nitrogen cooled flask.
When no further forerun distilled, the temperature was raised and the residual oil was
collected to give 1-octaneselenocyanate (2a) in 93% yield as a pale yellow oil,14 which
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displayed a characteristic chemical shift at C = 101.7 (SeCN) and a CN stretch in the
infrared spectrum at 2150 cm–1.
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During the course of these studies we noted the gradual formation of up to 10% of an
orange-coloured, non-polar product, which was identified as 1,2-dioctyldiselane (3a).
Since the formation of 3a could be minimized by limiting the reaction time to 1 h and using
1.0 equiv. of potassium selenocyanate (rather than 1.1 equiv.) we reasoned that it was
formed via a base-catalysed decomposition of the 1-octaneselenocyanate in the protic
solvent. Krief and co-workers15 had reported the scope, limitations and important
mechanistic details of the reaction of organic selenocyanates with base and they found that
it is particularly efficient for the synthesis of 1,2-dialkyldiselanes and that potassium
carbonate is an especially mild reagent for that purpose, as shown in Scheme 2.
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K2CO3 (1.0 equiv)
EtOH–H2O (9:1)
Se
SeCN
2
75 °C, 3 h
80–85%
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Scheme 2. The conversion of 1-butaneselenocyanate to 1,2-dibutyldiselane via the Krief
reaction.
In accordance with Krief's observations, we added potassium carbonate (1.0 equiv.) to a
1.0 M solution of 1-octylselenocyanate (2a) in methanol. After 2 h at reflux a quantitative
conversion to the 1,2-dioctyldiselane 3a occurred in an 97% isolated yield after
distillation.16
The final step of the sequence entailed the reduction of 1,2-dioctyldiselane (3a) to 1-
octaneselenol (4a). Many reagents are known to achieve this transformation including
sodium borohydride in ethanol,17 sodium in liquid ammonia,18 and zinc under acidic
conditions.19 On the basis of its low cost, safety and ease of workup, we selected
hypophosphorous acid for development.20 A 1.0 M solution of diselane 3a and
hypophosphorous acid was heated at reflux in 2-propanol for 17 h during which time the
orange colour discharged giving a colourless solution. Removal of the solvent followed by
a standard extractive workup gave 1-octaneselenol in 94% yield after distillation.21
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Process improvements and scale-up
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The chemistry depicted in Scheme 1 underwent three further refinements (Scheme 3).
Firstly, potassium selenocyanate is commercially available but expensive. A commonly
cited method for preparing it involves heating a mixture of potassium cyanide and selenium
metal to a melt which is then cooled and processed.22 We found that addition of potassium
cyanide to a suspension of selenium in methanol leads to a mild exothermic reaction that
is complete in 30–60 minutes giving a pale grey, turbid reaction mixture containing the
potassium selenocyanate, which can be used without isolation or purification.23 In the
second refinement the succeeding two steps were telescoped; i.e., the 1-bromooctane was
added to the solution of potassium selenocyanate (1.1 equiv.) and after 2 h at reflux
potassium carbonate (1.0 equiv.) was added and stirring at reflux continued for a further 2
h. Thus, the first three steps of the sequence leading to 1,2-dioctyldiselane are conducted
in methanol without the isolation of any intermediates. The overall yield of 1-octaneselenol
for the 4-step telescoped route, summarized in Scheme 3, (86%) is virtually identical to the
3-step route (Scheme 1) beginning with commercial potassium selenocyanate involving
purified intermediates 2a and 3a.
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Se (1.1 equiv) + KCN (1.2 equiv)
Step 1 MeOH, 20–35°C, 1 h
[KSeCN]
1a
n-OctBr ( , 1.0 equiv)
Step 2
MeOH, 2 h
150 mmol scale
SeCN
2a
K2CO3 (1.0 equiv)
MeOH, 2 h
Step 3
92% (3 steps)
Se
2
3a
bp 150–155°C/0.03 mm Hg
H3PO2 (1.5 equiv)
i-PrOH, 17 h
Step 4
94% (105 mmol scale)
SeH
4a
bp 81–85°C/20 mm Hg
Scheme 3. The telescoped process for the synthesis of 1,2-dioctyldiselane.
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The synthesis of 1-octaneselenol (4a) was performed on a 10.4 mole scale using a 25 L
batch reactor equipped with a bleach scrubber. This large-scale process benefited from 4
minor changes to the telescoped route depicted in Scheme 3. Firstly, the suspension of
selenium in methanol was cooled to 15 °C before the addition of potassium cyanide (Step
1). The ensuing exothermic reaction raised the internal temperature to 25 °C. Secondly, in
Step 3, the potassium carbonate was replaced with potassium hydroxide (1.0 equiv.) with
consequent improvement in the ease of stirring. Thirdly, after removal of the volatile
impurities from step 3 at 120 °C/0.15 mmHg, the residual 1,2-dioctyldiselane 3a was used
in the next step without distillation. Finally, the reduction of crude 3a was accomplished
with 3.0 equiv. of hypophosphorous acid in refluxing 2-propanol to reduce the reaction
time to 9 h giving 1-octaneselenol (4a) in an 84% overall yield after distillation.
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In order to explore the generality of the telescoped process we synthesized a further eight
diselanes 3b-3i (Scheme 4) on a 23.2–100 mmol scale in 59–94% yield after purification
by distillation or crystallization (see Supplementary Information). Reduction of the purified
diselanes 3b–3i to the corresponding alkaneselenols 4b-4i with hypophosphorous acid in
refluxing 2-propanol was then accomplished on a 1.8–24.4 mmol scale in 91–98% yield.
The data show that the functional groups that are compatible with potassium carbonate in
refluxing methanol and hypophosphorous acid (pKa 1.2) in refluxing 2-propanol include
imides, methyl esters, terminal alkenes, sulfones and alcohols.
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1. KSeCN (1.1 equiv)
MeOH, 1 h
H3PO2 (1.5 equiv)
R Se
R X
R SeH
2
i-PrOH, 17 h
2. K2CO3 (1.0 equiv)
2 h
3b–i
1b–g i
4b–i
, (X = Br)
(X = OTs)
1h
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SeH
OH
Se
Se
2
SeH
2
OH
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3b
4b
(91%, 23 mmol scale)
bp 35–36 °C/1.2 mmHg
(94%, 100 mmol scale)
3f
(62%, 30 mmol scale)
4f
(87%, 5.0 mmol scale)
bp 100–105 °C/0.05 mmHg
mp 49–50 °C (MTBE–hexane)
bp 160 °C (bath)/0.8 mmHg
Se
SeH
SeH
Se
2
2
CO2Me
CO2Me
3g
4c
4g
(89%, 1.8 mmol scale)
bp 190 °C (bath)/0.8 mmHg
(71%, 75 mmol scale)
(91%, 4.3 mmol scale)
bp 240 °C (bath)/0.5 mmHg
3c
(92%, 23 mmol scale)
mp 45–47 °C (MeOH)
bp 240 °C (bath)/0.5 mmHg
SeH
Se
Se
SeH
2
2
SO2Tol
SO2Tol
3h
(93%, 59 mmol scale)
4d
(98%, 5.0 mmol scale)
bp 150 °C (bath)/0.7 mmHg
3d
4h
(89%, 100 mmol scale)
(97%, 24.4 mmol scale)
mp 60–61 °C (2-PrOH)
mp 90–93 °C (2-PrOH)
mp 28–30 °C (2-PrOH)
O
O
Se
SeH
2
Se
SeH
2
N
O
N
O
4e
(98%, 2.0 mmol scale)
mp 36–39 °C (acetone)
3i
3e
(80%, 93 mmol scale)
(59%, 50 mmol scale)
4i
(91%, 5.0 mmol scale)
mp 50–54 °C (2-PrOH)
mp 80–83 °C (EtOAc–hexane)
mp 64–66 °C (acetone)
Scheme 4. The scope of the process for the synthesis of 1-alkaneselenols and 1,2-
dialkyldiselanes.
CONCLUSION
In conclusion, we have developed a four-step telescoped process for the synthesis of 1-
alkaneselenols that delivers milli- to multi-mole quantities of product with no diminution
in the overall yield. Thus, 1-octaneselenol was prepared in an 86% overall yield on a 150
millimole scale and 84% overall yield on a 10.4 mole scale. The first three steps are
conducted in one pot in methanol, with the corresponding rate advantage of high
concentration (1.0–1.5 M). After removal of the volatile malodorous by-products in Step
3, the residual 1,2-dialkyldiselanes are purified via distillation prior to reduction with
hypophosphorous acid in refluxing 2-propanol (Step 4) or they can be reduced directly to
the corresponding selenol without distillation. In either case, the yield and purity of the
product is the same. The rapid in-situ synthesis of potassium selenocyanate (Step 1) in
methanol and its high solubility is especially advantageous.
EXPERIMENTAL
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Preparation of potassium selenocyanate (KSeCN). To a magnetically stirred suspension of
selenium powder (100 mesh, 7.9 g (100 mmol), 1.0 equiv.) in methanol (100 mL) was
added at room temperature potassium cyanide (6.5 g, 100 mmol, 1.0 equiv.) in a single
portion. Within a few minutes a mild exothermic reaction ensued raising the internal
temperature to 35 °C. As the reaction proceeded, the selenium dissolved leaving a turbid,
light grey reaction mixture. After stirring at ambient temperature for 1 h, the reaction
mixture was filtered through a 1 cm pad of celite and then concentrated in-vacuo to give
an off-white solid. The crude potassium selenocyanate was slurried in hot 2-propanol and
then allowed to cool to room temperature. The resultant 2-propanol solvate of potassium
selenocyanate was collected by filtration and washed with 2-propanol. The labile solvate
lost 2-propanol upon storage at 1.0 mm Hg for 16 h at room temperature to give potassium
selenocyanate (13.5 g, 93.6 mmol, 94%) as a white solid.
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A. Synthesis of 1-octaneselenol with isolation and purification of 2a and 3a (Scheme 1).
1. Synthesis of octane-1-selenocyanate (2a). 1-Bromooctane (100 mmol, 1.0 equiv.) was
added as a single portion to a magnetically stirred solution of potassium selenocyanate
(15.84 g, 110 mmol, 1.1 equiv.) in methanol (75 mL) at room temperature. The reaction
mixture was stirred at reflux for 1 h during which time a white precipitate of potassium
bromide formed. After cooling to room temperature, the reaction mixture was poured into
ice–water (300 mL) and the pale yellow oil extracted into hexanes (2*300 mL). The
combined organic extracts (STENCH) were dried (Na2SO4) and concentrated in-vacuo at
ca. 10 °C. The residual yellow oil was purified by short-path distillation. In order to remove
the malodorous volatiles, the distillation apparatus was initially fitted with a liquid nitrogen
cooled collector and a vacuum (ca 20 mmHg) applied. The pot temperature was increased
to ca. 60 °C whereupon a pale yellow distillate (ca 4.0 mL) was collected. After 10 min the
vacuum was increased to ca. 1.0 mm Hg in order to remove any remaining volatiles. After
fitting a fresh collector, the pot temperature was gradually increased and the octane-1-
selenocyanate (2a, 20.3 g, 93 mmol, 93%) isolated as a pale yellow oil. bp 97–98 °C/1.0
mm Hg. 1H NMR (500 MHz, CDCl3): δ = 3.05 (2H, t, J = 7.4, C1H2), 1.90 (2H, quint, J =
7.4, C2H2), 1.48–1.38 (2H, m, CH2), 1.38–1.22 (8H, m, 4 ´ CH2), 0.88 (3H, t, J = 7.0,
C8H3). 13C NMR (75 MHz, CDCl3): δ = 101.7 (SeCN), 31.8 (CH2), 30.9 (CH2), 29.8
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(C1H2; JSe–C = 50.1), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 22.7 (CH2), 14.2 (C8H3). IR
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(thin film): n = 2150 m (CN) cm–1. See the supporting information for the detection and
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disposal of cyanide.
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2. Synthesis of 1,2-dioctyldiselane (3a). A mixture of octane-1-selenocyanate (2a, 32.7 g,
150 mmol) and K2CO3 (20.7 g, 150 mmol, 1.0 equiv.) in MeOH (150 mL) was heated at
reflux for 2 h. After cooling to room temperature, the mixture was poured into H2O (450
mL). The orange oil that separates was extracted into hexanes (2*225 mL). The aqueous
phase containing potassium cyanide was saved for waste treatment as described in the
supporting information. The combined organic extracts were washed with H2O (100 mL),
dried (Na2SO4) and concentrated in-vacuo. The residual orange oil was purified by short
path distillation to give 1,2-dioctyldiselane (3a, 72.75 mmol, 97%) as an orange oil. bp
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150–155 °C/0.03 mm Hg; lit.22 bp 197–205 °C/3 mm Hg. H NMR (500 MHz, CDCl3): δ
= 2.91 (4H, app t, J = 7.3, C1H2), 1.72 (4H, app quint, J = 7.4, C2H2), 1.42–1.34 (4H, m,
2 ´ CH2), 1.34–1.22 (16H, m, 8 ´ CH2), 0.88 (6H, t, J = 6.9 Hz, C8H3). 13C NMR (125
MHz, CDCl3): δ = 32.0 (2C, CH2), 30.8 (2C, CH2), 30.1 (2C, CH2), 29.3 (2C, CH2), 29.3
.
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(2C, CH2), 24.1 (2C, CH2; JSe–C = 60.7), 22.8 (2C, CH2), 14.2 (2C, CH3) LRMS (EI+
mode): m/z = 386 [M+, 100%], 272 (95%), 176 (80%). HRMS (EI+ mode): m/z = 386.0989
1
[M+, 100%]; calculated for C16H34Se2 [M+]: m/z = 386.0991. H NMR data (400 MHz) for
dioctyldiselane has been reported.23 See the Supporting Information for the detection and
disposal of cyanide.
3. Synthesis of 1-octaneselenol (4a). A suspension of 1,2-dioctyldiselane (3a, 40.4 g, 105
mmol, 1.0 equiv.) in 2-propanol (100 mL) was heated under reflux until dissolution
occurred. Hypophosphorous acid (50% w/v aqueous solution; 20.8 g, 17.3 mL, 157.5
mmol, 1.5 equiv.) was added. Heating at reflux was continued for 17 h whereupon the
reaction mixture was allowed to cool to room temperature. H2O (315 mL) and hexanes
(315 mL) were added and the layers separated. The aqueous layer was extracted with
hexanes (100 mL) and the combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. The residual oil was purified by short path distillation to give 1-
octaneselenol (4a, 38.0 g, 197 mmol, 94%) as a colourless oil. bp 81–85 °C/20 mm Hg;
1
lit.24 bp 117–120 °C/42 mm Hg. H NMR (500 MHz, CDCl3): δ = 2.58 (2H, q, J = 7.1,
C1H2), 1.69 (2H, quint, J = 7.5, C2H2), 1.40–1.33 (2H, m, CH2), 1.33–1.22 (8H, m, 4 ´
CH2), 0.88 (3H, t, J = 7.0, C8H2), –0.69 (1H, t, J = 6.8, SeH). 13C NMR (75 MHz, CDCl3):
δ = 34.1 (CH2), 31.9 (CH2), 29.6 (CH2), 29.2 (CH2), 29.0 (CH2), 22.7 (CH2), 17.7 (CH2;
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1JSe–C = 47.4), 14.1 (CH3). IR (thin film): n = 2321 w (SeH) cm–1. LRMS (EI+ mode): m/z
= 194 [M+, 100%]. HRMS (EI+ mode): m/z = 194.0580 [M+, 100%]; calculated for
C8H18Se [M+]: m/z = 194.0574.
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B. One-pot telescoped synthesis of 1,2-dioctyldiselane (3a).
A black suspension of selenium (100 mesh, 13.03 g, 165 mmol, 1.1 equiv.) and potassium
cyanide (11.72 g, 180 mmol, 1.2 equiv.) in methanol (100 mL) was stirred at ambient
temperature for 1 h forming a pale grey turbid reaction mixture containing potassium
selenocyanate. 1-Bromooctane (29.0 g, 150 mmol, 1.0 equiv.) was added to the reaction
mixture in one portion and the resulting grey suspension heated under reflux for 1 h forming
a yellow/brown suspension. Anhydrous potassium carbonate (20.7 g, 150 mmol, 1.0
equiv.) was then added to the reaction mixture in one portion and the resulting yellow
suspension heated under reflux for 2 h. The reaction mixture was poured into ice–water
(300 mL) and the mixture extracted with hexanes (2*100 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated in-vacuo to give the crude title
compound that was purified by short-path distillation. A yellow malodorous forerun (ca. 3
g) was collected in a liquid nitrogen cooled receiver at a pot temperature of 60 °C (1.0 mm
Hg). After changing the receiver, the 1,2-dioctyldiselane 3a (26.52 g, 69.0 mmol, 92%)
distilled at 150–155 °C/0.03 mmHg. KOH (8.4 g, 150 mmol, 1.0 equiv.) dissolved in H2O
(ca. 10 mL) can be added to the crude 1-octaneselenocyanate instead of anhydrous K2CO3.
SUPPORTING INFORMATION
General information and materials including cyanide waste management, experimental
procedures and characterization data (including 1H and 13C NMR spectra) for 8-tosyloctyl
4-methylbenzenesulfonate (1h), 1-octaneselenocyanate (2a), 1,2-dialkyldiselanes 3a–3i
and 1-alkaneselenols 4a–4i can be found in the supporting information.
AUTHOR INFORMATION
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Tanya Marinko-Covell for recording mass spectrometric data and the
European Regional Development Fund and Yorkshire Forward (Grant number 903993) for
financial support.
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