A Convenient Multigram Synthesis of DABSO Using Sodium Sulfite as SO2 Source

Article abstract of DOI:10.1021/acs.oprd.7b00083

A convenient synthesis of DABCO·(SO₂)₂ (abbreviated as DABSO) is reported. Using a two-chamber setup, sulfur dioxide is generated in one chamber and consumed in the other. This closed system overcomes safety issues related to working

Full text of DOI:10.1021/acs.oprd.7b00083

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Communication
A convenient multigram synthesis of
DABSO using sodium sulfite as SO2 source
Seger Van Mileghem, and Wim Michel De Borggraeve
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00083 • Publication Date (Web): 12 Apr 2017
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A convenient multigram synthesis of DABSO using sodium sulfite as
SO2 source
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Seger Van Mileghem and Wim M. De Borggraeve*
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, box 2404, B-3001 Leuven,
Belgium
Supporting Information Placeholder
ABSTRACT: A convenient synthesis of DABCO·(SO2)2 (abbreviated as DABSO) is reported. Using a two-chamber set-up, sulfur
dioxide is generated in one chamber and consumed in the other. This closed system overcomes safety issues related to working with
toxic SO2 gas. Pressure build-up is avoided by gradually generating the gas using sodium sulfite as precursor. Moreover, only near-
stoichiometric amounts of SO2 are required for this protocol. The use of anhydrous solvents is not necessary and every step is per-
formed at room temperature. A scale-up was carried out on a 10 gram scale which, after overnight drying, resulted in a quantitative
yield.
KEYWORDS: DABSO, sulfur dioxide, two-chamber reactor, safety
Introduction
thesis of DABSO is reported where SO2 is generated in a con-
trolled fashion and consumed in a closed system, omitting multi-
ple safety issues of working with this toxic gas.
Sulfur dioxide is a ubiquitous commodity chemical which has
several chemical applications in industrial processes. Until re-
cently, it was not often used in an academic lab setting.1 This can
partly be ascribed to the gaseous state of sulfur dioxide, as well
as its notorious toxicity and smell. Considering the importance
of functional groups such as sulfones and sulfonamides in agro-
chemicals, pharmaceuticals and materials, there is a high interest
in new and enhanced synthesis methods.2 Therefore, the use of
sulfur dioxide in synthetic organic chemistry is reviving. It is be-
lieved that the advancement of convenient and stable SO2 surro-
gates is an important driver in the rejuvenation of organic syn-
thesis research involving SO2.3 The Willis group was the first to
demonstrate the utility of DABCO·(SO2)2 (abbreviated as
DABSO), a bench-stable solid reagent, as a sulfur dioxide equiv-
alent in the synthesis of N-aminosulfonamides, sulfonamides and
sulfamides.4 Since then, numerous synthetic studies using
DABSO as SO2 equivalent have been published.5 Moreover, in
some cases the use of DABSO was more successful than using
SO2 gas, presumably due to catalyst poisoning by the excess sul-
fur dioxide.5a
Since DABSO is a relative expensive chemical, some research
groups synthesize it on site.4b, 6 These procedures include the use
of sulfur dioxide gas, implying safety considerations regarding
the handling and storage of sulfur dioxide pressurized vessels and
using a large excess of the gas. Usually DABSO precipitates out
of solution when formed. The Bischoff group circumvented the
use of SO2 vessels by synthesizing DABSO with the commer-
cially available Karl-Fischer reagent.7 However, since this rea-
gent is a solution of a base (usually pyridine) and an alcohol (usu-
ally methanol) containing 15-20% of SO2, this protocol leads to
more complex mixtures and a low atom economy. Moreover,
DABSO is soluble in methanol, resulting in a less efficient pre-
cipitation. To the best of our knowledge, no protocol for the syn-
Figure 1: Reaction set-up. SO2 is gradually generated in cham-
ber B and is consumed in chamber A to form DABSO.
Results and discussion
Here we report a convenient multigram synthesis of DABSO.
By making use of the elegant two-chamber system (COware) re-
ported by Skrydstrup et al.8 it is possible to generate and consume
sulfur dioxide ex situ. Previous success with these reactors for ex
situ gas generation in our group motivated us to pursue this
route.9 The reaction set-up is depicted in Figure 1 and the results
are summarized in Table 1. Metal sulfite salts are known to re-
lease SO2 when reacting with strong acids.10 Moreover, the use
of sodium sulfite as an SO2 surrogate has been applied in palla-
dium-catalyzed aminosulfonylation.11 Due to its simplicity and
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Table 1: Results of two-chamber synthesis of DABSO.a
cheap nature, this was our SO2 surrogate of choice. Since the re-
lease of SO2 from sodium sulfite and strong acid is fast,10 a grad-
ual release is preferred to avoid generating high pressure in the
reactor. Furthermore, sulfur dioxide is far more soluble in water
and organic solvents than other gases used in synthesis (e.g. CO
and H2).12 Therefore, sodium sulfite is solubilized in water, and
sulfuric acid is slowly added by means of a syringe pump, result-
ing in a gradual release of SO2.
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In a first trial, DABCO (673 mg, 6 mmol) was added in THF
(8 mL) in chamber A while 2.5 equivalents (1.89 g) of sodium
sulfite were added in water in chamber B (Table 1, entry a). Next,
sulfuric acid (960 µL, 3 equivalents) was added dropwise over
10 minutes to chamber B. After 15 minutes, a white precipitate
was observed, indicating DABSO formation. After 2 hours of
stirring at room temperature, filtration and overnight drying,
DABSO was obtained in a yield of 94%. (It should be noted that
the overnight drying was performed either on a Schlenk line or
in a desiccator. When drying under high vacuum (lyophilizer), a
lot of product was evaporated due to volatility!) To make sure no
other impurities were precipitating in chamber A, a blank reac-
tion was performed without the use of sodium sulfite (entry b).
No precipitate was formed in chamber A. Using a lower excess
of both sodium sulfite and sulfuric resulted in a nearly identical
yield (entry c). At this stage, it was desirable to perform this re-
action at a larger scale. Therefore, the flow rate of sulfuric acid
was lowered to 50 µL min-1 to avoid pressure build-up and the
reaction was stirred overnight. A first scale-up resulted in a dis-
appointing yield of 63% (entry d). It was hypothesized that this
result could be attributed to increasing the molarity of DABCO
in THF. After stirring overnight, DABSO was precipitated and
barely any THF was visible. This could have led to a physical
barrier (DABSO matrix) between the remaining DABCO and
SO2. To our delight, when more THF was used, this issue was
resolved and a quantitative yield was obtained (entry e). During
this run the pressure inside the reactor was monitored via a ma-
nometer and it never exceeded 2 bar. This confirms there is a
gradual release and consumption of SO2 gas. Since first signs of
precipitation of DABSO are apparent after about 2 hours of reac-
tion (See Supplementary Video), an attempt to decrease the reac-
tion time was tested (entry f). A disappointing yield of 53 % was
obtained and hence more time is needed to bring the reaction to
completion. As it appears, this procedure is about 2.5 times more
cost efficient than the procedure reported by Bischoff et al. and
about 27 times cheaper than commercially available DABSO.7b
(A price comparison can be found in the Supporting Infor-
mation.)
8
9
VH
vH
VH
SO
2
O
SO
mmol
DABCO (mL)
VTHF
eq
Na2SO3
Yield
2
2
4
4
Entry
t (h)
(%)
94
0
(mL) (µL/min)
(µL)
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a
b
c
d
e
f
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100
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50
960
960
800
2.5
0
2
2
2
6
2.2
92
45
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45
30 25
60 40
60 40
6000 2.2 ON 63
6000 2.2 ON 99
50
50
6000 2.2
3
53
a ON = overnight, V = volume, v = syringe flow rate, eq = equivalents
Experimental section
For 1H-NMR, a Bruker 300 Avance (300 MHz), a Bruker 400
Avance (400 MHz) and a Bruker 600 Avance II+ (600 MHz)
with tetramethylsilane as internal standard with CDCl3 and
DMSO were used. The δ-values are expressed in ppm. For 13C-
NMR, a Bruker 300 Avance (operating at 75 MHz), a Bruker
400 Avance (operating at 100 MHz) and a Bruker 600 Avance
II+ (operating at 150 MHz) with the deuterated solvent as inter-
nal standard was used (CDCl3: 77.2 ppm, triplet; DMSO: 39.52
ppm, quintet). The δ-values are expressed in ppm. Elemental
analysis (CHN) was carried out on a Thermo Scientific Flash
2000 Organic Elemental Analyzer. For melting point, a
Reichert-Jung Thermovar was used. All reagents were used as
purchased without further purification. DABCO (98%) was
purchased from Sigma-Aldrich. THF (>99.9%, spiked with
BHT as inhibitor) was purchased from Honeywell. Sodium sul-
fite was purchased from Sigma-Aldrich. Diethyl ether (>99%,
spiked with BHT as inhibitor) was purchased from ChemLab.
Sulfuric acid (>95%) was purchased from Fisher Scientific.
Procedure for the synthesis of 1,4-diazabicyclo[2.2.2]oc-
tane bis(sulfur dioxide) (DABSO)
A symmetrical two-chamber reactor (inner volume = 400 mL)
is charged with a Teflon-coated oval stirring bar in each cham-
ber. 5.050 g of DABCO (45 mmol) is added in chamber A and
12.480 g of Na2SO3 (99 mmol, 2.2 equivalents) is added in
chamber B. Two screw caps with septa are fitted on the reactor
and air is evacuated and back-filled with nitrogen. This process
is repeated three times. THF (60 mL) is added via a syringe in
chamber A and similarly water (40 mL) is added in chamber B
under a positive pressure by means of a nitrogen balloon. After
10 minutes of stirring at room temperature, the balloon is re-
moved and H2SO4 (6 mL) is gradually added via a syringe pump
(50 µL min-1, added over 2h). The mixtures are stirred overnight
at room temperature. After this, the solution in chamber B is
removed and the suspension in chamber A is transferred to a
100 mL sintered-glass funnel under reduced pressure. The
white solid is washed five times with 50 mL of diethyl ether.
DABSO is known to be hygroscopic and therefore, it is trans-
ferred to a flask and dried in a desiccator under vacuum over-
night to afford the product as a white powder (10.75 g, 99%). It
should be noted that DABSO is usually referred to as a bench-
stable solid in literature, while most groups (including our
Conclusion
We have developed a convenient multigram synthesis of
DABSO. Sulfur dioxide is generated and consumed in a closed
two-chamber system, hereby avoiding a lot of safety issues of
working with the toxic gas. The danger of pressure build-up is
avoided by gradually releasing SO2. No heating or cooling is re-
quired, nor is working with anhydrous solvents. High to quanti-
tative yields are obtained. This protocol is suited for synthesizing
DABSO on a 10 g scale.
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group) store it in a freezer or fridge, which is also recommended 2011, 133 (15), 6061-6071; (b) Friis, S. D.; Taaning, R. H.;
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by commercial suppliers. A video recording of the synthetic
procedure can be found in the Supporting Information. Analyt-
ical properties of DABSO prepared in this way are in agreement
Lindhardt, A. T.; Skrydstrup, T., J. Am. Chem. Soc., 2011, 133
(45), 18114-18117.
9.
Veryser, C.; Van Mileghem, S.; Egle, B.; Gilles, P.;
1
with the literature.7b mp 141-143 °C; H NMR (400 MHz,
De Borggraeve, W. M., React. Chem. Eng., 2016, 1 (2), 142-
146.
CD3OD): δ 3.22 (s); 13C NMR (100 MHz, CD3OD): δ 45.4;
Anal calcd: C 29.99, H 5.03, N 11.66; found C 30.38, H 5.24,
N 11.60.
10.
Emmett, E. J.; Willis, M. C., Asian J. Org. Chem.,
2015, 4 (7), 602-611.
11.
Li, W. F.; Li, H. Q.; Langer, P.; Beller, M.; Wu, X. F.,
Corresponding author
Eur. J. Org. Chem., 2014, 2014 (15), 3101-3103.
9
12.
(a) Li, H.; Jiao, X. L.; Chen, W. R., Phys. Chem. Liq.,
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* E-mail: wim.deborggraeve@kuleuven.be
ORCID
2014, 52 (2), 349-353; (b) van Dam, M. H. H.; Lamine, A. S.;
Roizard, D.; Lochon, P.; Roizard, C., Ind. Eng. Chem. Res.,
1997, 36 (11), 4628-4637; (c) Spedding, D. J.; Brimblecombe,
P., Atmos. Environ., 1974, 8 (10), 1063-1063.
Wim De Borggraeve: 0000-0001-7813-6192
Seger Van Mileghem: 0000-0003-0802-2995
Notes
The authors declare no competing financial interest.
Acknowledgement
We would like to thank KU Leuven for financial support via
project OT/14/067.
Supporting Information Available.
Experimental procedures, characterization data and copies of
spectra and a video of this protocol are available free for charge
via the Internet at http://pubs.acs.org.
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