Ethenesulfonyl Fluoride (ESF): An On-Water Procedure for the Kilogram-Scale Preparation

Article abstract of DOI:10.1021/acs.joc.6b01423

A two-step, on-water procedure for the synthesis of ethenesulfonyl fluoride (ESF) is described. 2-Chloroethanesulfonyl fluoride is made via a neat reaction with an aqueous, nearly saturated potassium bifluoride solution from readily available 2-chloroetha

Full text of DOI:10.1021/acs.joc.6b01423

Subscriber access provided by United Arab Emirates University | Libraries Deanship
Note
Ethenesulfonyl Fluoride (ESF): An On-Water
Procedure for the Kilogram-Scale Preparation.
Qinheng Zheng, Jiajia Dong, and K. Barry Sharpless
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01423 • Publication Date (Web): 20 Oct 2016
Downloaded from http://pubs.acs.org on October 22, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Ethenesulfonyl Fluoride (ESF): An On-Water Procedure for the Kilogram-Scale
Preparation.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Qinheng Zheng, Jiajia Dong,† and K. Barry Sharpless*
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States
Abstract: A two-step, on-water procedure for the synthesis of ethenesulfonyl fluoride (ESF)
is described. 2-Chloroethanesulfonyl fluoride is made via a neat reaction with an aqueous,
near saturated potassium bifluoride solution from readily available 2-chloroethanesulfonyl
chloride. The subsequent dehydrochlorination of 2-chloroethanesulfonyl fluoride proceeds
neatly with magnesium oxide as the base in an aqueous suspension to give ESF. This recipe
enables the preparation of ESF in 98% yield on kilogram scale.
Ethenesulfonyl fluoride (ESF, 1) consists of a vinyl moiety directly linked to a sulfonyl fluoride
group (CH2=CH–SO2F). First reported in 1953,1 this compound has been successfully applied
to several productive fields, including: dyestuffs,2 functional materials (ion exchange
membrane,3 photoresist material,4 etc.), lubricating oil additives,5 and medicinal chemistry.6
The most noteworthy feature is that ESF ranks tops in the reactivity hierarchy of known
Michael acceptors, from which most of the aforementioned applications stemmed.7 The
extraordinary Michael reactivity of ESF was demonstrated in depth by John Hyatt and co-
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 9
1
2
3
4
5
6
7
8
9
workers in a masterful 1979 full paper,8 where nearly 100 examples at 1/20 mol or larger
scale are presented. In our ongoing pursuit of the best small and connective modules for
click chemistry,9 ESF appears to be the perfect one. At present, the uses of ESF in a wider
range of applications are limited by its high price.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Earlier routes to ESF include: (1) aqueous potassium fluoride mediated chloride-fluoride
exchange from ethenesulfonyl chloride;1 (2) chloride-fluoride exchange from 2-
chloroethanesulfonyl chloride followed by a base-mediated dehydrochlorination.10 In 1979
Hyatt et al. summarized previous syntheses and reported a two-step synthesis on a 1.7 mole
scale (54% overall yield).8 From our experience with “on-water” reactivity, we saw
opportunities for further improvements. In 2012, we discovered that interfacial-treatment
with saturated aqueous K(FHF) solution (pH around 3.0) was remarkably effective for the
synthesis of sulfonyl fluorides from the corresponding sulfonyl chlorides.7a Given here are
complete details of our bifluoride improved process for RSO2Cl → RSO2F, as applied in the
conversion of 2-chloroethanesulfonyl chloride (2) to ESF on a kilogram scale.
As shown in Scheme 1, the readily available 2 is converted to ESF in two simple steps:
First, 2-chloroethanesulfonyl fluoride (3) is made via the sulfonyl chloride-fluoride exchange
using saturated K(FHF) solution; Second, MgO mediated elimination (dehydrochlorination) of
3 in aqueous medium affords 1.
Scheme 1. Kilogram-scale preparation of ethenesulfonyl fluoride
2
ACS Paragon Plus Environment

Page 3 of 9
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A 10-L Nalgene® polypropylene carboy11 was equipped with a Teflon®-coated octagonal
stir bar (14 mm × 74 mm). This reaction vessel was charged with water (4400 mL), to which
potassium bifluoride [K(FHF), 1.70 kg, 21.8 mol] was added in one portion. With a magnetic
stirring (600 rpm), K(FHF) started to dissolve into water, and a rapid endotherm was
observed (internal temperature reached ~ 8 ºC). A near saturated K(FHF) solution formed
after 1 h,12 when the solution approached room temperature (~ 22 ºC). At this point, 2 (960
mL, 1.50 kg, 95% purity, 8.73 mol) was added in one portion to the K(FHF) solution. The
biphasic mixture was stirred vigorously (480 rpm) to form an emulsion and with continued
stirring the emulsion was maintained for 2 h at room temperature, or rather, autogenous
1
temperature,13 when H NMR or GC-MS indicated the completion of the reaction. The
stationary mixture separates into two phases. The upper phase is an aqueous solution of
salts,14 and the lower phase is virtually pure 2-chloroethanesulfonyl fluoride. With the aid of
a funnel, the biphasic mixture was poured into a 6-L separatory funnel. The lower phase (ca.
750 mL) was drained into a 1000-mL glass Erlenmeyer flask, dried over anhydrous MgSO4
(10 g), and filtered, giving 3 (1.10 kg, 7.51 mol). Three 1000-mL portions of methylene
chloride were used to wash the reaction vessel and the MgSO4 used to dry neat 3, and to
extract the upper aqueous phase. The combined organic phase was washed by 2 L brine,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 9
1
2
3
4
5
6
7
8
9
dried over 100 g anhydrous MgSO4, and filtered through a 600-mL sintered glass Buchner
funnel. The filtrate was concentrated by rotary evaporation (18 ºC, 0.05 bar) to afford
additional 0.17 kg 3. In total, 3 (1.27 kg, 8.67 mol, 99.3%) was obtained as a slightly yellow
liquid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A 4-L glass Erlenmeyer flask was equipped with a Teflon®-coated octagonal stir bar (14
mm × 74 mm) and was supported by a beaker chain clamp. The flask was charged with
water (1000 mL) and 3 (1.27 kg, 8.67 mol). Under magnetic stirring (600 rpm), an emulsion
was formed. After adding 1.0 kg crushed ice, the mixture cooled to ~ 10 ºC. Magnesium
oxide (MgO, 174 g, 4.35 mol) was added portion-wise over 15 min to the stirred emulsion
creating a white “slurry”,15 which was then allowed to warm to room temperature. The
reaction was judged complete by 1H NMR after 3 h. The insoluble MgO is consumed in the
reaction creating soluble MgCl2, hence, the white “slurry” eventually turns to an emulsion.
The stationary emulsion separated into two phases. With the aid of a funnel, the mixture
was poured into a 4-L separatory funnel. The upper aqueous phase is a MgCl2 solution (ca.
2 mol•L–1). The lower phase is virtually pure ESF (ca. 600 mL), which was drained into a 1000
mL Erlenmeyer flask, dried over anhydrous MgSO4 (10 g), and filtered, giving neat 1 (0.85 kg,
7.7 mol). Three 500 mL portions of methylene chloride were used to wash the reaction
vessel and the MgSO4 used to dry the neat 1, and to extract the aqueous phase. The
combined organic phase was washed with brine (1 L), dried over anhydrous MgSO4 (50 g),
and filtered through a 600-mL sintered glass Buchner funnel. The filtrate was concentrated
by rotary evaporation (18 ºC, 0.05 bar) to afford an additional 0.10 kg of 1.16 Totally, 1 (0.94
1
kg, 8.6 mol, 98%) was obtained as a slightly yellow liquid, which was judged pure by H
4
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
1
2
3
4
NMR. Further short-path distillation under reduced pressure (85 ºC, 0.53 bar) helped to
5
6
7
remove the color and gave 0.90 kg colorless 1.
8
9
In conclusion, 1.42 kg 2-chloroethanesulfonyl chloride (2) was converted to 0.94 kg
ethenesulfonyl fluoride (ESF, 1, 98% overall yield). This interfacial, on-water sequence, which
requires little more than stirring and liquid-liquid phase separation, should be practical on a
commercial scale. However, our present goal is just to increase access to ESF by the
chemical research community.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
Caution! ESF is a toxic substance, which has a pungent odor and strong tear-exciting action.
All operations handling ESF and precursors should be performed in a well vented hood.
Glassware used in this process should be soaked in 3 mol•L–1 NaOH solution or aqueous
ammonia overnight to remove any remaining sulfonyl halide (1, 2 or 3) before normal
cleaning. John Hyatt and co-workers illustrated that ESF is highly toxic orally and extremely
toxic intraperitoneal to laboratory animals. The oral LD50 is approximately 50 mg/kg for rats
and approximately 10 mg/kg for mice. The intraperitoneal LD50 is 1–5 mg/kg for rats and <
5 mg/kg for mice. The liquid was absorbed through the intact skin, the skin absorption LD50
is 1–5 mL/kg. The material acts as a severe lachrymator.
1
2-Chloroethanesulfonyl fluoride (
3
). bp 171 °C (1 atm). H NMR (500 MHz, CDCl3):
δ
3.94–
3.90 (m, 2H), 3.83–3.78 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ
52.7 (d, J = 7.2 Hz), 35.0. 19F
NMR (376 MHz, CDCl3):
δ
56.7. GC-MS tR = 3.624 min (flow rate 2 mL/min; column
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
1
2
3
4
5
6
7
8
9
temperature 50 ºC for 4 min, then 20 ºC/min to 280 ºC, then hold 2 min), EI (70 eV)-
quadrupole MS calcd for C2H4ClFO2S [M+] 145.96, m/z (%) 62.0 (70), 63.0 (100), 64.0 (32),
65.0 (32), 67.0 (24), 83.0 (10), 146.0 (0.3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethenesulfonyl fluoride (
1
). bp 119 °C (1 atm). 1H NMR (500 MHz, CDCl3):
δ
6.82 (ddd,
J =
16.6, 9.1, 2.1 Hz, 1H), 6.76 (d,
J
= 16.5 Hz, 1H), 6.47 (dd, J
= 9.2, 5.2 Hz, 1H). 13C NMR (126
3
2
MHz, CDCl3):
CDCl3): 56.8.
δ
134.5 (d, JC–F = 3.0 Hz), 130.2 (d, JC–F = 28.2 Hz). 19F NMR (376 MHz,
δ
Author Information
Corresponding Author
*E-mail: sharples@scripps.edu
Present Address
†
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Acknowledgement
Financial support was provided by the National Institutes of Health (R01GM117145).
Associated Content
Supporting Information
6
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
1
2
3
4
The supporting information is available free of charge on the ACS Publications website.
5
6
7
1H, 13C and 19F NMR spectra for compounds 3 and 1.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
References
(1) Hedrick, R. M. Ethylene Sulfonyl Fluoride and Its Method of Preparation. U.S. Patent
2,653,973, Sept. 29, 1953.
(2) (a) Krutak, J. J.; Burpitt, R. D. 2-(Fluorosulfonyl)ethylamino Anthraquinones. U.S. Patent
3,952,029, Apr. 20, 1976. (b) Weaver, M. A.; Coates, C. A.; Fleischer, J. C. Azo Dyes
Derived from 3-Amino-2,1-benzisothiazoles and Aromatic Amine Couplers Containing
Sulfo Groups, or Salts thereof. U.S. Patent 4,265,812, May 5, 1981. (c) Mischke, P.; Fuchs,
H. Water-Soluble Monoazo Compounds Containing a N-(sulfoalkyl)-aniline Coupling
Component and a Fiber-Reactive Group of the Vinylsulfonyl Series in the Phenyl or
Benzothiazole Fiber-Reactive Dyestuffs. U.S. Patent 4,652,634, Mar. 24, 1987. (d) Seiler,
H. Reactive Dyes Containing Fluorotriazine and Vinylsulfonyl Radicals. U.S. Patent,
5,298,607, Mar. 29, 1994.
(3) Mark, Jr. H. B.; Czerwinski, A.; Caia, J. Thin Layer Electrode and Cell. U.S. Patent,
4,310,400, Jan. 12, 1982.
(4) Fujigaya, T.; Shibasaki, Y.; Ando, S.; Kishimura, S.; Endo, M.; Sasago, M.; Ueda, M. Chem.
Mater. 2003, 15, 1512.
(5) Vries, L. Hydrocarbylethyl Sulfonyl Fluoride. U.S. Patent, 4,269,790, May 26, 1981.
(6) (a) Champseix, A.; Chanet, J.; Etienne, A.; Le Berre, A.; Masson, J. C.; Napierala, C.;
Vessiere, R. Bull. Soc. Chim. Fr. 1985, 463. (b) Russell, R. K. Ethanesulfonamide
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
1
2
3
4
5
6
7
8
9
Derivatives. U.S. Patent, 4,874,771, Oct. 17, 1989. (c) Russell, R. K. Ethanesulfonamide
Derivatives. U.S. Patent, May 12, 1992. (d) Jimonet, P.; Audiau, F.; Barreau, M.; Blanchard,
J.-C.; Boireau, A.; Bour, Y.; Coleno, M.-A.; Doble, A.; Doerflinger, G.; Huu, C. D.; Donat,
M.-H.; Duchesne, J. M.; Ganil, P.; Gueremy, C.; Honore, E.; Just, B.; Kerphirique, R.;
Gontier, S.; Hubert, P.; Laduron, P. M.; Blevec, J. L.; Meunier, M.; Miquet, J.-M.; Nemecek,
C.; Pasquet, M.; Piot, O.; Pratt, J.; Rataud, J.; Reibaud, M.; Stutzmann, J.-M.; Mignani, S. J.
Med. Chem. 1999, 42, 2828. (e) Kreimeyer, A.; Laube, B.; Sturgess, M.; Goeldner, M.;
Foucaud, B. J. Med. Chem. 1999, 28, 4394. (f) Aguilar, B.; Amissah, F.; Duverna, R.;
Lamango, N. S. Curr. Cancer Drug Targets 2011, 11, 752.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2014, 53
9430. (b) Chen, Q.; Mayer, P.; Mayr, H. Angew. Chem. Int. Ed. 2016, 55, 12664.
,
(8) Krutak, J. J.; Burpitt, R. D.; Moore, W. H.; Hyatt, J. A. J. Org. Chem. 1979, 44, 3847.
(9) (a) Sharpless, K. B.; Kolb, H. C. Book of Abstracts, 217th ACS National Meeting,
Anaheim, CA, March 21–25, 1999; ORGN-105, Accession Number 199:145537; ꢀ(b)
Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
(10) (a) Scherer, O.; Schacher, P. F. Process of Preparing Vinylsulfofluoride. U.S. Patent,
2,783,275, Feb. 26, 1957. (b) Scherer, O.; Schacher, P. F. Vinylsulfonyl Fluoride and
Preparation thereof. U.S. Patent, 2,884,452, Apr. 28, 1959.
(11) The carboy used in this experiment has a bottom spigot. Which is beneficial for the
easy isolation of the desired organic phase without a separatory funnel.
(12) The solubility of potassium bifluoride in water at 20 ºC is 39.2 g/100 mL. The pH of the
near saturated potassium bifluoride solution used in this experiment was 3.0, as
measured by a pH test strip (1–14 range, 1.0 precision).
8
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
1
2
3
4
5
6
(13) Little exotherm was noted. Hence, no heat control is needed, at least at the present
scale.
7
8
9
(14) This aqueous solution contained potassium bifluoride [K(FHF), 4.37 mol], potassium
dihydrogen trifluoride [K(FHFHF), 8.73 mol], and potassium chloride (KCl, 8.73 mol). The
pH of this solution was 1.0, as measured by a pH test strip (1–14 range, 1.0 precision).
To minimize fluoride waste, the solution for sulfonyl chloride-fluoride transformation
can be regenerated by adding potassium fluoride (508 g, 8.73 mol) to this solution. A
rapid exotherm is observed. After cooling to room temperature, the pH of this solution
is again 3.0. This regenerated bifluoride solution can be used in the preparation of a
new batch of ESF. We found this K(FHF)-K(FHFHF) solution could be used for at least
three cycles without apparent change in the effectiveness of the reaction.
(15) Magnesium oxide has poor solubility in water, see: Roy, D. M.; Roy, R. Am. J. Sci. 1957,
255, 573. Hence, this “slurry” condition approximated “slow addition”, which simplifies
the operation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Alternatively, this combined organic phase can be used as a stock solution of ESF in
methylene chloride. In this case, it was determined by quantitative NMR that the
solution (3.91 kg) contained 0.10 kg ESF. The concentration could be further confirmed
by a “titration” using an equimolar reaction between ESF and 1-phenylpiperazine.
9
ACS Paragon Plus Environment