Fluoroalkene chemistry. Part 2. Reactions of thiols with some toxic 1,2-dichlorinated polyfluorocycloalkenes

Article abstract of DOI:10.1016/j.jfluchem.2004.02.009

1,2-Dichlorotetrafluorocyclobutene, 1,2-dichlorohexafluorocyclopentene and 1,2-dichlorooctafluorocyclohexene were treated with an equimolar amount of benzenethiol, 2-methoxybenzenethiol, 3-methoxybenzenethiol and 4-methoxybenzenethiol in acetonitrile with potassium carbonate. Each combination of fluoroalkene and thiol gave a mixture of mono and bis vinyl substitution products whose proportions depended on the ring size of the fluorocycloalkene and the size and electronic characteristics of the thiol. Treatment of 1,2-dichlorotetrafluorocyclobutene with one or two molar equivalents of N -acetylcysteine isopropyl ester in acetonitrile with potassium carbonate produced the mono and bis vinyl substitution products accordingly. The results support the contention that the high inhalation toxicity of the fluorocycloalkenes is due to reaction with two molar equivalents of biological thiols in the lung.

Full text of DOI:10.1016/j.jfluchem.2004.02.009

Journal of Fluorine Chemistry 125 (2004) 1265–1272
Fluoroalkene chemistry
Part 2. Reactions of thiols with some toxic 1,2-dichlorinated
polyfluorocycloalkenes
Christopher M. Timperley*
Defence Science and Technology Laboratory, Chemical and Biological Defence Sector,
Porton Down, Salisbury, Wiltshire SP40JQ, UK
Received 6 November 2003; received in revised form 30 January 2004; accepted 8 February 2004
Available online 19 June 2004
Abstract
1,2-Dichlorotetrafluorocyclobutene, 1,2-dichlorohexafluorocyclopentene and 1,2-dichlorooctafluorocyclohexene were treated with an
equimolar amount of benzenethiol, 2-methoxybenzenethiol, 3-methoxybenzenethiol and 4-methoxybenzenethiol in acetonitrile with
potassium carbonate. Each combination of fluoroalkene and thiol gave a mixture of mono and bis vinyl substitution products whose
proportions depended on the ring size of the fluorocycloalkene and the size and electronic characteristics of the thiol. Treatment of 1,2-
dichlorotetrafluorocyclobutene with one or two molar equivalents of N-acetylcysteine isopropyl ester in acetonitrile with potassium carbonate
produced the mono and bis vinyl substitution products accordingly. The results support the contention that the high inhalation toxicity of the
fluorocycloalkenes is due to reaction with two molar equivalents of biological thiols in the lung.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Benzenethiol; 1,2-Dichlorotetrafluorocyclobutene; 1,2-Dichlorohexafluorocyclopentene; 1,2-Dichlorooctafluorocyclohexene; Toxicity
1. Introduction
is influential, with the size and electronic properties of the R
group being important. The larger and more electron-donat-
ing the R group, the more difficult the second substitution
due to increased steric hindrance and negative charge at the
double bond. Also the smaller the fluorocycloalkene ring,
the greater its reactivity and toxicity [1].
Hexafluorocyclobutene (HFCB) and halogenated deriva-
tives are toxic by inhalation [1–4]. Such materials are
electrophilic gases or volatile liquids that are insoluble in
water. They are absorbed in the lung and can react with
cellular nucleophiles causing irreversible damage. The poi-
soned animal initially appears unaffected by a lethal dose
and death occurs 24–30 h later from pulmonary oedema [5].
There is convincing evidence that the mechanism of toxicity
is through reaction with thiols in the lung [6] as adminis-
tration of cysteine esters before exposure reduces deaths in
rodents [7].
Examples of the interaction of sulfur nucleophiles with
fluorocycloalkenes appear in the literature. Vinyl substitu-
tion products have been obtained from 1,2-dichlorodifluor-
ocyclopropene and potassium thiocyanate [9] and alkenes
E–G [10–17] and HFCB [18–20] with aromatic and alipha-
tic thiols. Several conclusions can be drawn: (a) sulfur
nucleophiles are more reactive than nitrogen or oxygen
nucleophiles, (b) vinyl substitution is preferred regardless
of the nature of the sulfur nucleophile and base employed,
and (c) double substitution with thiols is unusually facile.
Hexafluorocyclobutene can react with two molar equiva-
lents of thiol via an addition–elimination process (Fig. 1).
The diversity of products depends on the nucleophile and on
the reaction conditions. Addition products A and C are
rarely isolated. Mono-sulfide B is usually combines with
more thiol to give bis-sulfide D even when the ratio of HFCB
to thiol is equimolar [8]. The nature of the nucleophile RSH
* Tel.: þ44-1980-613566; fax: þ44-1980-613371.
E-mail address: cmtimperley@dstl.gov.uk (C.M. Timperley).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.02.009

1266
C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 1265–1272
F
F
F
F
F
F
F
2. Results and discussion
F
F
F
F
F
F
F
H
F
F
RSH
- HF
2.1. Reactions with arylthiols
SR
SR
F
Reactions between fluorocycloalkenes and arylthiols
were rapid at room temperature. The proportions of the
isolated products (Table 1) agreed with those found by
integration of the peaks in the gas chromatography–mass
spectrometry (GC–MS) spectra of the reaction mixtures, and
products were obtained as mobile liquids or low-melting
solids. Mono products 1a–8a, 10a and 12a contain a reactive
double bond and can undergo further nucleophilic substitu-
tion with loss of chloride (9a and 11a formed in insufficient
amounts to allow characterization). Few such compounds
are known and these contain alkylthio groups [13,17,21]. Bis
products from benzenethiol 1b, 5b and 9b have been pre-
pared before from perfluoro(1,2-dichlorocycloalkenes) and
the copper (I) mercaptides [14].
B
HFCB
A
RSH
F
F
F
F
F
SR
F
F
F
F
SR
SR
double vinylic
substitution
- HF
SR
H
D
C
Fig. 1. Reaction of hexafluorocyclobutene with two molar equivalents of
thiol. Under basic conditions, intermediates A and C will be transiently
carbanionic in nature, a negative charge residing where the proton is
drawn.
Factors that influence the reactions of nucleophiles with
fluorocycloalkenes are incompletely understood. The results
here clarify some of the factors and bring the goal of
formulating rules to predict products nearer. Effects that
operate are discussed in turn.
In this study, cycloalkenes E–G were treated with equi-
molar amounts of benzenethiol, 2-methoxybenzenethiol,
3-methoxybenzenethiol and 4-methoxybenzenethiol in
acetonitrile in the presence of potassium carbonate. Acid
dissociation constants of the thiols were measured to enable
the inductive effects of the arylthio groups to be ranked
to aid interpretation of the product distribution. Reactions of
1,2-dichlorotetrafluorobutene with N-acetyl L-cysteine iso-
propyl ester, which protects rodents against fluoroalkene
toxicity [20], were also investigated.
2.1.1. Effect of ring size on the reactivity of the
fluorocycloalkene
The combined yield of mono and bis products was highest
for the four membered ring (e.g. 1a þ 1b 75%) and lower for
the five and six membered rings (e.g. 5a þ 5b, 54% and
9a þ 9b, 45%). 1,2-Dichlorotetrafluorocyclobutene is more
Table 1
Product distributions after attack of thiol on cycloalkene (percentages refer to isolated yields)
Electrophile
Nucleophile
Mono product
Bis product
n ¼ 0
E
R ¼ H
1a, 40%
2a, 72%
3a, 53%
4a, 58%
1b, 35%
2b, 13%
3b, 23%
4b, 22%
20-OMe
30-OMe
40-OMe
n ¼ 1
F
H
5a, 17%
6a, 38%
7a, 14%
8a, 51%
5b, 37%
6b, 17%
7b, 36%
8b, 17%
20-OMe
30-OMe
40-OMe
n ¼ 2
G
H
9a, minor
10a, 10%
11a, minor
12a, 15%
9b, 45%
10b, 48%
11b, 50%
12b, 52%
20-OMe
30-OMe
40-OMe
Numbering system on starting materials extends to products and has been used for NMR assignments in the tables of spectroscopic data.

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 1265–1272
1267
reactive than larger homologues to thiols, which is consis-
F
F
Cl
F
F
tent with its toxicity: it is more toxic to rodents than 1,2-
dichlorohexafluorocyclopentene or 1,2-dichlorooctafluoro-
cyclohexene [1–3].
NCPE
2 K2CO3
MeCN
4 K2CO3
2 NCPE
SR
F
F
13 60%
Cl
Cl
F
F
2.1.2. Effect of ring size on the second substitution
For all the thiols studied, the first substitution is facile.
Attack of another thiol molecule takes place on the chlorine-
bearing carbon atom of the mono product, as this is the most
electron-deficient site. The difficulty of the second substitu-
tion depends on the ring size. In experiments with 2-meth-
oxybenzenethiol and 1,2-dichlorotetrafluorocyclobutene
(6:1, 2a:b) or 1,2-dichlorohexafluorocyclopentene (2:1,
6a:b) the mono product predominated. With 1,2-dichlor-
ooctafluorocyclohexene, the order reversed and the bis
product predominated (1:5, 10a:b). The stearic effect of
1,3-interactions between the ring fluorine atoms and the
chlorine atom of the mono product will most pronounced for
the four-membered ring, which may account for the lower
proportion of bis product observed in this case.
F
SR
F
F
E
SR
14 80%
F
Fig. 2. Products of reaction of one or two molar equivalents of N-
acetylcysteine isopropyl ester (NCPE) with 1,2-dichlorotetrafluorocyclo-
butene, where R equals CH2CH(NHAc)CO2-i-Pr.
whereas 2- and 4-methoxybenzenethiol (2:1, 6a:b and 3:1,
8a:b) gave mostly mono product. The same trends, but more
pronounced, were observed in the reactions of 1,2-dichlor-
ooctafluorocyclohexene. Benzenethiol and 3-methoxyben-
zenethiol gave bis product almost exclusively, while 2- and
4-methoxybenzenethiol (1:5, 10a:b and 1:3, 12a:b) gave
mainly mono products.
2.1.3. Effect of thio group on the second substitution
The ease of the second substitution depends also on the
size and electronic properties of the SR group in the mono
product. The larger or more electron-donating the R group,
the more difficult the second substitution. Steric hindrance is
important for the 2-methoxybenzenethio group but not for
the other arylthio groups. The acidity of the arylthio group is
also influential and can be assessed by examining the acid
dissociation constants of the thiols. Acid dissociation con-
stants of the arylthiols measured in 50% aqueous ethanol
using a known method [22] agreed with pKa data measured
in other solvent systems [23–25] and decreased in the order:
3-methoxybenzenethiol (7.60) < benzenethiol (7.82) < 4-
2.2. Reactions with N-acetylcysteine isopropyl ester
Treatment of a molar equivalent of N-acetyl L-cysteine
isopropyl ester with 1,2-dichlorotetrafluorocyclobutene gave
the mono vinyl product 13 (Fig. 2). In the carbon NMR
spectrum, the ring carbon atoms show as four distinct signals,
each as a triplet of triplets. The infrared spectrum contains a
peak at 1545 cmꢀ1 corresponding to the carbon-carbon dou-
ble bond stretch. Only a trace of bis-substituted product was
observed in the experiment, in contrast to the situation with
aromatic thiols, which gave mainly all bis-product, due to
lower acidity of the cysteine ester which renders the double
bond of the mono product less reactive; the a-carbanion is
stabilised less by aliphatic thio groups than by aromatic thio
groups in line with relative acidities (pKa values for N-
acetylcysteine isopropyl ester and the arylthiols were found
to be 10.8 and 8.2–7.6, respectively). Two molar equivalents
of thiol gave bis vinyl product 14 identical to a specimen
made earlier from hexafluorocyclobutene [20].
methoxybenzenethiol (8.06)
< 2-methoxybenzenethiol
(8.20). Second substitution is most difficult for 2-methox-
ybenzenethiol for steric and electronic reasons.
The ease of double vinyl substitution with thiols is caused
by stabilisation of the intermediate carbanion by the thio
substituent through pp–dp overlap [26] or through the
inductive and polarising effect of the sulfur atom [27].
The situation with thiols parallels that with phosphorus
nucleophiles which also add twice to perfluoro(1,2-dichlor-
ocycloalkenes) to give bis vinyl species due to similar
stabilisation of the carbanion intermediates [28].
2.1.4. Combined effect of ring size and the thio group on
the second substitution
3. Conclusion
Operation of electronic effects in the thio group was
observed, not in reactions with 1,2-dichlorotetrafluorocy-
clobutene (where mono products dominated), but in those
with 1,2-dichlorohexafluorocyclopentene or 1,2-dichlorooc-
tafluorocyclohexene (where mono or bis products dominated
according to the thio group). Reactions of 1,2-dichlorohex-
afluorocyclopentene with benzenethiol and 3-methoxyben-
zenethiol (1:2, 5a:b and 1:3, 7a:b) gave mostly bis product,
Perfluoro(1,2-dichlorocycloalkenes) reacted with thiols to
give a mixture of mono and bis vinyl substitution products
whose proportions depended on the ring size of the fluor-
ocycloalkene and the size and electronic characteristics of
the thiol. The results support the contention that the high
inhalation toxicity of the fluorocycloalkenes is linked to
their ability to react with two molecules of a biological thiol
(e.g. cysteine-containing peptides and proteins).

Table 2
Spectroscopic data for tetrafluorocyclobutenyl sulfides 1a–4a and 1b–4b (CDCl3 solvent)
Product
1H NMR d, J (Hz)
13C NMR d, J (Hz)
19F NMR d,
J (Hz)
IR n (cmꢀ1
)
EI-MS (mass, %)
Elemental analysis (%)
1a, colourless oil,
Rf 0.37a
7.62 (2H, d, J ¼ 8, 20- and
60-H), 7.49 (1H, t, J ¼ 8,
40-H), 7.42 (2H, br
147.1 (1C, s, C–Cl), 135.3 (2C, s, 20- and
60-C), 130.7 (1C, s, 40-C), 129.6 (2C, s, 30- and
50-C), 129.5 (1C, s, C–S), 123.7 (1C, s, 10-C),
118.9 and 118.1 (2C, m, J obs, CF2)
ꢀ114.1 (2F,
1323, 1255, 1123,
268 (Mþ, 100), 217
Calcd. for C10H5ClF4S:
C, 44.7; H, 1.9; S, 11.9.
Found: C, 44.8; H, 2.1;
S, 12.1
CF2CS), ꢀ112.1 860, 846, 741
(14), 183 (22), 128 (64)
(2F, CF2CCl)
dd, J ¼ 7, 30- and 50-H)
1b, white solid, mp
41–42 8Cb,
7.50 (4H, d, J ¼ 8, 20- and
60-H), 7.28 (2H, m, 40-H),
7.27 (4H, m, 30- and 50-H)
140.0 (2C, s, C–S), 134.6 (4C, s, 20- and
60-C), 129.9 (2C, s, 40-C), 129.3 (4C, s,
30- and 50-C), 125.9 (2C, s, 10-C), 118.6
(2C, m, J obs, CF2)
ꢀ109.8
1442, 1308, 1241,
1151, 1105, 855,
845, 747, 737, 688
342 (Mþ, 100), 278 (10),
258 (11), 201 (12), 183
(14), 171 (16), 127 (22)
Calcd. for C16H10F4S2:
C, 56.1; H, 2.9; S, 18.7.
Found: C, 55.7; H, 3.1;
S, 18.9
(4F, s, CF2)
Rf 0.24a
2a, colourless oil,
Rf 0.28a
7.55 (1H, dd, J ¼ 8 and 2,
60-H), 7.44 (1H, dd, J ¼ 8
and 2, 40-H), 6.96 (1H, dd,
J ¼ 8 and 2, 50-H), 6.92
(1H, dd, J ¼ 8 and 1, 30-H),
3.85 (3H, s, OMe)
159.9 (1C, s, 20-C), 141.6 (1C, s, C–Cl), 136.7
(1C, s, 60-C), 132.6 (1C, s, 40-C), 129.3 (1C, s,
C–S), 121.1 (1C, s, 50-C), 115.0 (1C, s, 10-C),
118 and 117.7 (2C, tt, J ¼ 289 and 24, CF2),
111.3 (1C, s, 30-C), 55.4 (1C, s, OMe)
ꢀ114.2 (2F,
1586 (C¼C), 1482,
1465, 1435, 1295,
1164, 1066, 1040,
1025, 845, 752
298 (Mþ, 100), 283 (10),
265 (16), 217 (18), 157
(20), 110 (12)
Calcd. for C11H7ClF4OS:
C, 44.2; H, 2.4; S, 10.7.
Found: C, 44.1; H, 2.6;
S, 10.5
CF2CS), ꢀ112.1
(2F, CF2CCl)
2b, white solid, mp
7.40 (2H, dd, J ¼ 8 and 2,
159.3 (2C, s, 20-C), 138.3 (2C, s, C–S), 135.0
(2C, s, 50-C), 131.3 (2C, s, 40-C), 120.9 (2C, s,
50-C), 115.2 (2C, s, 10-C), 115.0 (1C, tt,
J ¼ 262 and 25, 3-CF2), 111.2 (2C, s, 30-C),
108.2 (1C, tt, J ¼ 259 and 27, 5-CF2),
55.4 (1C, s, OMe)
ꢀ109.8
1585 (C¼C), 1479,
1466, 1433, 1275,
1250, 1160, 1087,
1065, 1025, 856,
841, 750
402 (Mþ, 100), 263 (10),
245 (14), 231 (10), 213
(18), 201 (20), 181 (12),
151 (30), 140 (25),
111 (42)
Calcd. for C18H14F4O2S2:
C, 53.7; H, 3.5; S, 15.9.
Found: C, 54.0; H, 3.6;
S, 16.3
67–68 8C, Rf 0.08a 60-H), 7.36 (2H, ddd, J ¼ 8
and 2, 40-H), 6.92 (2H, dd,
J ¼ 8 and 2, 50-H), 6.89
(4F, s, CF2)
(2H, br d, J ¼ 8, 30-H),
3.86 (6H, s, OMe)
3a, colourless oil,
Rf 0.21a
7.20 (1H, dd, J ¼ 8, 50-H),
7.08 (1H, dd, J ¼ 8, 60-H),
160.0 (1C, s, 30-C), 146.5 (1C, s, C–Cl), 130.5
(1C, s, 50-C), 128.9 (1C, s, C–S), 128.7 (1C, s,
ꢀ114.2
1593 (C¼C), 1578,
1480, 1466, 1429,
1322, 1286, 1254,
1236, 1122, 1041,
860, 845, 785
298 (Mþ, 100), 263 (22),
243 (12), 213 (56),
157 (25)
Calcd. for C11H7ClF4OS:
C, 44.2; H, 2.4; S, 10.7.
Found: C, 44.4; H, 2.0;
S, 10.5
(2F, CF2CS), ꢀ
112
7.03 (1H, br d, J ¼ 8, 20-H), 10-C), 127.3 (1C, s, 60-C), 120.5 (1C, s, 20-C),
6.90 (1H, dd, J ¼ 8 and 2,
117.8 (1C, s, 40-C), 118.0 and 117.7 (2C, tt,
(2F, CF2CCl)
40-H), 3.70 (3H, s, OMe)
J ¼ 289 and 24, CF2), 55.4 (1C, s, OMe)
159.8 (2C, s, 30-C), 139.9 (2C, s, C-S), 130.0
(2C, s, 50-C), 126.7 (2C, s, 10-C), 126.5 (2C, s,
3b, white solid, mp
54–55 8C, Rf 0.03a 7.05 (2H, d, J ¼ 8, 60-H),
7.25 (2H, dd, J ¼ 8, 50-H),
ꢀ109.7
1592 (C¼C), 1577,
1481, 1466, 1428,
1309, 1286, 1242,
1152, 1105, 1041,
856, 845
402 (Mþ, 100), 369 (12),
349 (32), 302 (18), 243
(42), 213 (22), 157
(22), 140 (60)
Calcd. for C18H14F4O2S2:
C, 53.7; H, 3.5; S, 15.9.
Found: C, 54.1; H, 3.9;
S, 16.2
(4F, s, CF2)
6.99 (2H, br d, J ¼ 8, 20-H), 60-C), 119.5 (2C, s, 20-C), 116.0 (2C, s, 40-C),
6.92 (2H, dd, J ¼ 8 and 2,
118.6 (2C, m, J obs, CF2), 55.4 (2C, s, OMe)
40-H), 3.83 (6H, s, OMe)
4a, colourless oil,
Rf 0.42c
7.54 (2H, d, J ¼ 9, 20- and
60-H), 6.89 (2H, d, J ¼ 9,
30- and 50-H), 3.81
140.7 (1C, s, C–Cl), 161.8 (1C, s, 40-C), 137.7
(3C, s, C–S and 20- and 60-C), 115.1 (2C, s,
30- and 50-C), 115.0 (1C, tt, J ¼ 262 and 25,
3-CF2), 108.2 (1C, tt, J ¼ 259 and 27, 5-CF2),
55.3 (1C, s, OMe)
ꢀ114.2
1593 (C¼C), 1496,
1322, 1294, 1253,
1175, 1121, 1031,
860, 845, 830
298 (Mþ, 56), 266 (10),
Calcd. for C11H7ClF4OS:
C, 44.2; H, 2.4; S, 10.7.
Found: C, 44.2; H, 2.3;
S, 10.5
(2F, CF2CS),
ꢀ112 (2F,
CF2CCl)
230 (10), 157 (100)
(3H, s, OMe)
4b, white solid,
mp 61–62 8C,
Rf 0.17c
7.53 (4H, d, J ¼ 9, 20- and
60-H), 6.89 (4H, d, J ¼ 9,
30- and 50-H), 3.81
161.1 (2C, s, 40-C), 137.8 (2C, s, C-S), 136.8
(4C, s, 20- and 60-C), 115.3 (4C, s, 30- and
50-C), 115.0 (2C, tt, J ¼ 259 and 24, 3-CF2),
110.8 (1C, t quin, J ¼ 275 and 25, 5-CF2),
55.3 (1C, s, OMe)
ꢀ109.7
1592 (C¼C), 1495,
1462, 1306, 1293,
1251, 1241, 1174,
1103, 1030, 854,
855, 828
402 (Mþ, 2), 231 (10),
213 (18), 201 (30),
157 (45), 140 (100),
43 (27)
Calcd. for C18H14F4O2S2:
C, 53.7; H, 3.5; S, 15.9.
Found: C, 53.1; H, 3.1;
S, 15.8
(4F, s, CF2)
(6H, s, OMe)
a Chromatographed in 100:1 hexane–acetone.
b Literature mp 45 8C [15].
c Chromatographed in 9:1 hexane–acetone.

Table 3
Spectroscopic data for hexafluorocyclopentenyl sulfides 5a–8a and 5b–8b (CDCl3 solvent)
Product
1H NMR d, J (Hz)
13C NMR d, J (Hz)
19F NMR d, J (Hz)
IR n (cmꢀ1
)
EI-MS (mass, %)
Elemental analysis (%)
5a, colourless
oil, Rf 0.46a
7.6 (2H, d, J ¼ 8, 20-
and 60-H), 7.45 (1H, dd,
J ¼ 7, 40-H), 7.39 (2H,
dd, J ¼ 8, 30- and 50-H)
140.6 (C–Cl), 135.6 (2C, s, 20- and 60-C), 130.6
(1C, s, 40-C), 129.9 (C-S), 129.5 (2C, s, 30- and
50-C), 124.5 (1C, s, 10-C), 115 (1C, tt, J ¼ 262
and 25, 3-CF2), 110.2 (1C, t quin, J ¼ 275 and
26, 4-CF2), 108.2 (1C, tt, J ¼ 259 and 27, 5-CF2)
ꢀ128.6 (2F,
1588 (C¼C), 1581,
1444, 1327, 1282,
1250, 1201, 1151,
1101, 1006, 884,
862, 846
318 (Mþ, 76),
283 (22), 264
(100), 183 (30),
52 (42), 42 (12)
Calcd. for C11H5ClF6S: C,
41.5; H, 1.6; S, 10.1. Found:
C, 41.1; H, 1.2; S, 10.4
4-CF2), ꢀ111.6
(2F, 5-CF2), ꢀ
106.4 (2F, 3-CF2)
5b, pale yellow
oil, Rf 20a
7.5 (4H, d, J ¼ 7, 20- and
60-H), 7.40 (2H, dd, J ¼ 7,
40-H), 7.35 (4H, dd, J ¼ 7,
30- and 50-H)
134.2 (4C, s, 20- and 60-C), 138.6 (2C, s, C–S),
129.7 (2C, s, 40-C), 129.3 (4C, s, 30- and 50-C),
126.9 (2C, s, 10-C), 115 (2C, tt, J ¼ 262 and 25,
CF2), 112.2 (1C, t quin, J ¼ 275 and 26, 4-CF2)
159.9 (1C, s, 20-C), 140.6 (1C, s, C–Cl), 136.7 (1C, s,
60-C), 132.6 (1C, s, 40-C), 129.3 (1C, s, C–S), 121.1
(1C, s, 50-C), 115 (1C, tt, J ¼ 262 and 25, 3-CF2),
112.4 (1C, s, 10-C), 111.3 (1C, s, 30-C), 110.2 (1C,
t quin, J ¼ 275 and 26, 4-CF2), 108.2 (1C, tt,
J ¼ 259 and 27, 5-CF2), 55.4 (1C, s, OMe)
159.3 (2C, s, 20-C), 138.3 (2C, s, C-S), 135 (2C,
s, 60-C), 131.3 (2C, s, 40-C), 121 (2C, s, 50-C),
115.2 (2C, s, 10-C), 115 (2C, tt, J ¼ 262 and 25,
CF2), 111.2 (2C, s, 30-C), 110.2 (1C, t quin,
J ¼ 275 and 26, 4-CF2), 55.4 (2C, s, OMe)
ꢀ129.3 (2F, quin,
J ¼ 4, CF2), ꢀ106.4
(4F, t, J ¼ 4, CF2)
1588 (C¼C), 1543, 1475,
1442, 1328, 1264, 1244,
1195, 1143, 1095, 1024,
1007, 876
392 (Mþ, 68),
263 (24), 183
(15), 110 (100)
Calcd. for C17H10F6S2: C,
52.0; H, 2.6; S, 16.3. Found:
C, 51.1; H, 2.4; S, 16.0
6a, colourless
7.55 (1H, dd, J ¼ 8 and 1,
60-H), 7.44 (1H, dd, J ¼ 7
and 7, 40-H), 6.96 (1H,
dd, J ¼ 7 and 7, 50-H),
6.92 (1H, dd, J ¼ 8 and
1, 30-H), 3.85 (3H, s, OMe)
ꢀ128.8 (2F,
4-CF2), ꢀ111.7
(2F, 5-CF2),
ꢀ108.3 (2F,
3-CF2)
1585 (C¼C), 1481,
1466, 1435, 1327,
1279, 1250, 1199,
1148, 1100, 1067,
1040, 1025, 1005,
884, 862, 845, 752
348 (Mþ, 100),
314 (12), 299 (18),
233 (14), 139 (10),
66 (10)
Calcd. for C12H7ClF6OS: C,
41.3; H, 2.0; S, 9.2. Found:
C, 40.8; H, 1.8; S, 8.9
b
oil, Rf 0.32
6b, white solid,
mp 43–44 8Cc,
Rf 0.08b
7.4 (2H, dd, J ¼ 8 and 2,
60-H), 7.36 (2H, dd, J ¼ 8
and 2, 40-H), 6.92 (2H,
dd, J ¼ 8 and 2, 50-H),
6.89 (2H, br d, J ¼ 8,
ꢀ129.6 (2F,
quin, J ¼ 4,
CF2), ꢀ108
(4F, t, J ¼ 4,
CF2)
1585 (C¼C), 1479,
1464, 1434, 1327,
1277, 1263, 1252,
1243, 1190, 1133,
1093, 1066, 1025,
1007, 875, 751
452 (Mþ, 6), 313
Calcd. for C19H14F6O2S2: C,
50.4; H, 3.1; S, 14.2. Found:
(14), 293 (18),
214 (30), 140 (100), C, 49.9; H, 3.1; S, 14.2
111 (28), 95 (10),
46 (14)
30-H), 3.86 (6H, s, OMe)
7a, colourless
oil, Rf 0.43d
7.30 (1H, dd, J ¼ 8,
50-H), 7.14 (1H, br d,
J ¼ 8, 60-H), 7.11 (1H,
br s, 20-H), 7.00 (1H, dd,
J ¼ 8, 40-H), 3.69
160.0 (1C, s, 30-C), 140.7 (1C, s, C–Cl), 130.3 (1C, s,
50-C), 130 (1C, s, C–S), 127.6 (1C, s, 60-C), 125.3
(1C, s, 10-C), 120.5 (1C, s, 20-C), 116.7 (1C, s, 40-C),
115.8 (1C, tt, J ¼ 262 and 25, 3-CF2), 110.2
ꢀ128.6 (2F,
4-CF2), ꢀ111.7
(2F, 5-CF2),
ꢀ106.5 (2F,
3-CF2)
1593 (C¼C), 1578,
1481, 1466, 1325,
1282, 1250, 1200,
1148, 1100, 1042,
1005, 884, 862, 847
348 (Mþ, 100), 313
(M–Cl, 100), 293
(24), 213 (50),
Calcd. for C12H7ClF6OS: C,
41.3; H, 2.0; S, 9.2. Found:
C, 41.0; H, 2.2; S, 9.3
63 (28), 51 (12)
(1C, quin, J ¼ 275 and 26, 4-CF2), 108.2 (1C, tt,
J ¼ 259 and 27, 5-CF2), 55.4 (1C, s, OMe)
(3H, s, OMe)
7b, white solid,
mp 56–58 8Cc,
Rf 0.27d
7.16 (2H, dd, J ¼ 8, 50-H),
6.96 (2H, d, J ¼ 8, 60-H),
6.90 (2H, br s, 20-H), 6.82
(2H, dd, J ¼ 8, 40-H), 3.69
(6H, s, OMe)
159.8 (2C, s, 30-C), 138.8 (2C, s, C-S), 130 (2C, s,
50-C), 126.0 (2C, s, 60-C), 127.8 (2C, s, 10-C), 118.9
(2C, s, 20-C), 115.6 (2C, s, 40-C), 115.0 (2C, tt, J ¼ 259
and 24, CF2), 110.8 (1C, t quin, J ¼ 275 and 25,
4-CF2), 55.4 (2C, s, OMe)
ꢀ129.5 (2F, quin,
J ¼ 4, CF2), ꢀ107.0
(4F, t, J ¼ 4, CF2)
1592 (C¼C), 1577, 1480,
1465, 1427, 1327, 1285,
1263, 1246, 1193, 1143,
1095, 1041, 1007, 876, 858
452 (Mþ, 5), 313
(12), 293 (10),
Calcd. for C19H14F6O2S2: C,
50.4; H, 3.1; S, 14.2. Found:
C, 50.5; H, 3.3; S, 14.0
213 (16), 141 (100)
8a, colourless
b
oil, Rf 0.21
7.54 (2H, d, J ¼ 9, 20-
and 60-H), 6.89 (2H,
d, J ¼ 9, 30- and 50-H),
3.81 (3H, s, OMe)
140.7 (1C, s, C–Cl), 161.8 (1C, s, 40-C),
137.7 (3C, s, C-S and 20- and 60-C), 116.5 (1C,
s, 10-C), 115.1 (2C, s, 30- and 50-C), 115 (1C, tt,
J ¼ 262 and 25, 3-CF2), 110.2 (1C, t quin, J ¼ 275 and
26, 4-CF2), 108.2 (1C, tt, J ¼ 259 and 27, 5-CF2),
55.3 (1C, s, OMe)
ꢀ128.4 (2F,
4-CF2), ꢀ111.4
(2F, 5-CF2),
ꢀ106.5 (2F,
3-CF2)
1593 (C¼C), 1574,
1496, 1464, 1443,
1325, 1283, 1250,
1199, 1182, 1175,
1146, 1102, 1032,
1005, 883
348 (Mþ, 100),
Calcd. for C12H7ClF6OS: C,
41.3; H, 2.0; S, 9.2. Found:
C, 41.7; H, 2.2; S, 9.1
333 (12), 64 (10)
8b, white solid,
mp 90–92 8Cc,
Rf 0.03b
7.54 (4H, d, J ¼ 9, 20-
and 60-H), 6.89 (4H, d,
J ¼ 9, 30- and 50-H),
3.81 (6H, s, OMe)
161.1 (2C, s, 40-C), 137.8 (2C, s, C-S), 136.8 (4C, s,
20- and 60-C), 115.3 (4C, s, 30- and 50-C), 116.8 (2C, s,
10-C), 115.0 (2C, tt, J ¼ 259 and 24, CF2), 110.8
(1C, t quin, J ¼ 275 and 25, 4-CF2), 55.3 (2C, s, OMe)
ꢀ129.5 (2F, quin,
J ¼ 4, CF2),
1594 (C¼C), 1574, 1374,
1546, 1495, 1313, 1293,
1267, 1253, 1197, 1184,
1174, 1129, 1108, 1092,
1029
452 (Mþ, 6), 333
Calcd. for C19H14F6O2S2: C,
50.4; H, 3.1; S, 14.2. Found:
C, 50.8; H, 3.3; S, 14.1
(14), 64 (12)
ꢀ105.9 (4F, t,
J ¼ 4, CF2)
a
Chromatographed in hexane.
b
c
Chromatographed in 100:1 hexane–acetone.
Recrystallised from hot ether to which was slowly added cold hexane.
d Chromatographed in 9:1 hexane–acetone.

Table 4
Spectroscopic data for octafluorocyclohexenyl sulfides 10a and 12a and 9b–12b (CDCl3 solvent)
Product
1H NMR d, J (Hz)
13C NMR d, J (Hz)
19F NMR d,
J (Hz)
IR n (cmꢀ1
)
EI-MS (mass, %)
Elemental analysis (%)
9b, yellow solid,
mp 55–57 8Ca,
Rf 0.37b
7.42 (4H, m, 10- and
50-H), 7.32 (4H, m, 20-
and 40-H), 7.32 (2H,
m, 30-H)
129.4 (2C, s, 10-C), 136.8 (2C, tt, J ¼ 27 and
4, C–S), 133 (4C, s, 20- and 60-C), 129.3 (4C,
s, 30- and 50-C), 129.2 (2C, s, 40-C), 110.3
(2C, tt, J ¼ 254 and 24, 3- and 6-CF2), 107.7
(2C, t quin, J ¼ 286 and 27, 4- and 5-CF2)
ꢀ132.8 (4F, m,
4- and 5-CF2),
ꢀ103.5 (4F, m,
3- and 6-CF2)
1580 (C¼C), 1545,
1479, 1442, 1340,
1220, 1200, 1163,
1111, 1037, 1024,
984, 867
442 (Mþ, 68), 369 (14),
333 (10), 313 (82), 293
(12), 263 (12), 244 (16),
185 (14), 154 (10),
111 (100)
Calcd. for C18H10F8S2: C,
48.9; H, 2.3; S, 14.5. Found:
C, 49.2; H, 2.5; S, 14.8
10a, colourless
oil, Rf 0.42b
7.48 (1H, d, J ¼ 8, 60-H),
7.39 (1H, dd, J ¼ 8 and
8, 40-H), 6.95 (1H, dd,
J ¼ 8, 50-H), 6.90 (1H,
br d, J ¼ 8, 30-H), 3.84
(3H, s, OMe)
159.4 (1C, s, 20-C), 135.8 (1C, tt, J ¼ 24 and 8, ꢀ133 and
1585 (C¼C), 1481,
1339, 1278, 1253,
1227, 1203, 1164,
1120, 1040, 1026,
986, 876, 827, 752
398 (Mþ, 100), 363 (35),
348 (45), 228 (12),
138 (12)
Calcd. for C13H7ClF8OS: C,
39.2; H, 1.8; S, 8.0. Found:
C, 40.1; H, 2.2; S, 8.2
C–Cl), 135.1 (1C, s, 60-C), 131.6 (1C, s,
40-C), 129.2 (1C, tt, J ¼ 28 and 6, C–S), 121.2
(1C, s, 50-C), 115.4 (1C, s, 10-C), 111.2 (1C, s,
30-C), 110.3 (1C, tt, J ¼ 256 and 24, 6-CF2),
108.3 (1C, tt, J ¼ 255 and 24, 3-CF2), 107.8
and 107.6 (2C, superimposed tt, 4- and 5-CF2),
53.6 (1C, s, OMe)
ꢀ132.4 (4F, m,
4- and 5-CF2),
ꢀ108 (2F, m,
6-CF2), ꢀ105.7
(2F, m, 3-CF2)
10b, yellow gum,
Rf 0.19b
7.35 (2H, d, J ¼ 7, 60-H),
7.32 (2H, dd, J ¼ 7,
158.7 (2C, s, 20-C), 136.2 (2C, tt, J ¼ 27 and 4, ꢀ132.9 (4F, m,
1584 (C¼C), 1479,
1434, 1339, 1277,
1251, 1219, 1197,
1163, 1107, 1065,
1037, 1026, 985
502 (Mþ, 55), 363 (14),
343 (24), 214 (84), 199
(15), 183 (10), 138
(100), 111 (65), 95
(18), 77 (28), 65 (15),
45 (30)
Calcd. for C20H14F8O2S2: C,
47.8; H, 2.8; S, 12.8. Found:
C, 47.6; H, 2.8; S, 12.4
C–S), 133.2 (2C, s, 60-C), 130.5 (2C, s, 40-C),
4- and 5-CF2),
ꢀ104.9 (4F, m,
3- and 6-CF2)
40-H), 6.92 (2H, dd, J ¼ 7,
121 (2C, s, 50-C), 117.6 (2C, s, 10-C), 111.2
50-H), 6.76 (2H, br d, J ¼ 7, (2C, s, 30-C), 110.1 (2C, br tt, J ¼ 254, 3-
30-H), 3.85 (6H, s, OMe)
and 6-CF2), 107.8 (2C, t quin, J ¼ 268 and
26, 4- and 5-CF2), 55.7 (2C, s, OMe)
11b, yellow gum,
Rf 0.28b
7.25 (2H, dd, J ¼ 9, 50-H),
160 (2C, s, 30-C), 137 (2C, tt, J ¼ 28 and
ꢀ132.8 (4F, m,
4- and 5-CF2),
ꢀ103.6 (4F, m,
3- and 6-CF2)
1591 (C¼C), 1577,
1480, 1466, 1428,
1339, 1317, 1286,
1250, 1233, 1220,
1162, 1111, 1037,
993, 984
502 (Mþ, 15), 363 (34),
343 (24), 245 (14), 141
(100), 125 (16)
Calcd. for C20H14F8O2S2: C,
47.8; H, 2.8; S, 12.8. Found:
C, 47.6; H, 2.6; S, 12.6
7.01 (2H, m, 60-H), 6.94
6, C-S), 130.5 (2C, s, 10-C), 130.1 (2C, s,
(2H, br m, 20-H), 6.85 (2H, 50-C), 125 (2C, s, 60-C), 117.7 (2C, s, 20-C),
dd, J ¼ 9 and 3, 40-H),
115.2 (2C, s, 40-C), 110.3 (2C, tt, J ¼ 254
and 26, 3- and 6-CF2), 107.8 (2C, t quin,
J ¼ 268 and 27, 4- and 5-CF2), 55.3
(2C, s, OMe)
3.78 (6H, s, OMe)
12a, yellow oil,
Rf 0.25c
7.52 (2H, d, J ¼ 9, 20- and
60-H), 6.9 (2H, d, J ¼ 9,
30- and 50-H), 3.83
137.4 (1C, obs m, C–S), 127.1 (1C, m,
C–Cl), 161.5 (1C, s, 40-C), 137.4 (2C, s, 20-
and 60-C), 116.9 (1C, s, 10-C), 114.8 (2C, s,
30- and 50-C), 109.8–107.8 (4C, m, CF2
groups), 55.4 (1C, s, OMe)
ꢀ132.8 and
1594 (C¼C), 1495,
1339, 1293, 1255,
1227, 1182, 1174,
1165, 1120, 1040,
986, 874
398 (Mþ, 100),
Calcd. for C13H7ClF8OS: C,
39.2; H, 1.8; S, 8.0. Found:
C, 40.0; H, 2.0; S, 7.8
ꢀ132.4 (4F, m,
4- and 5-CF2),
ꢀ108 (2F, m,
6-CF2), ꢀ104
(4F, m, 3-CF2)
363 (14), 343 (12),
320 (10), 139 (12)
(3H, s, OMe)
12b, yellow solid, 7.41 (4H, d, J ¼ 9, 20- and
160.8 (2C, s, 40-C), 136.1 (2C, m, C–S),
136.1 (2C, obs m, C–S), 136.1 (2C, s, 20- and
60-C), 119.5 (2C, s, 10-C), 114.9 (4C, s, 30-
and 50-C), 109.8–107.8 (4C, m, CF2
groups), 55.4 (2C, s, OMe)
ꢀ132.9 (4F, m,
4- and 5-CF2),
ꢀ103.3 (4F, m,
3- and 6-CF2)
1591 (C¼C), 1494,
1295, 1256, 1204,
1175, 1164, 1097,
1033
502 (Mþ, 48), 363 (15),
343 (28), 214 (100),
199 (58), 171 (16),
140 (100), 125 (15),
107 (14)
Calcd. for C20H14F8O2S2: C,
47.8; H, 2.8; S, 12.8. Found:
C, 47.3; H, 2.8; S, 12.5
mp 63–64 8Ca,
Rf 0.05
60-H), 6.86 (4H, d, J ¼ 9,
30- and 50-H), 3.84 (6H,
s, OMe)
a Recrystallized from hot ether, literature mp 60 8C [15].
b Chromatographed in 9:1 hexane–acetone.
c Chromatographed in 100:1 hexane–acetone.

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 1265–1272
1271
4. Experimental
J ¼ 13 and 5 Hz, HA), 3.51 (1H, dd, J ¼ 13 and 5 Hz, HB),
2.05 (3H, s, COCH3), 1.29 and 1.28 (6H, d, J ¼ 6 Hz, CH3).
13C NMR: d ¼ 170:2 and 168.9 (C¼O), 146 (tt, J ¼ 26 and
14 Hz, C–Cl), 130.1 (tt, J ¼ 28 and 21 Hz, C–S), 118.2 (tt,
J ¼ 286 and 23 Hz, CF2CCl), 117.5 (tt, J ¼ 288 and 24 Hz,
CF2CS), 70.9 (isopropyl CH), 52.1 (NCH), 32.7 (SCH2),
22.9 (acetyl CH3), 21.6 (isopropyl CH3). 19F NMR:
d ¼ ꢀ114:1 (2F, m, 3-CF2) and ꢀ111.4 (2F, m, 4-CF2).
IR (KBr disc): n ¼ 1741 and 1661 (C¼O), 1545 (C¼C),
1376, 1326, 1256, 1217, 1122, 862 cmꢀ1. CI-MS (m/z, %) ¼
364 (M þ 1, 36), 344 (M–F, 24), 322 (M–CH3CH¼CH2,
100), 302 (59), 280 (37), 260 (14), 234 (7), 214 (2). EI-MS
(m/z, %) ¼ 363 (Mþ, 7), 321 (M–CH3CH¼CH2, 5), 304 (26),
276 (15), 262 (45), 244 (6), 234 (100), 214 (15), 194 (41),
178 (4), 158 (42), 141 (7), 130 (8), 116 (29), 87 (48), 74 (33),
60 (28), 43 (i-Prþ, 32). Calcd. for C12H14ClF4NO3S: C, 39.6;
H, 3.9; N, 3.9; S, 8.8. Found: C, 40.1; H, 4.1; N, 4.3; S, 8.6%.
Fluorinated cycloalkenes were purchased from Apollo
Scientific Limited (Stockport, UK) and the thiols from
Aldrich (Gillingham, UK). They were used as received.
Anhydrous solvents were used throughout. Thin layer chro-
˚
matography plates, MK6F silica gel 60 A (2:5 cm ꢁ 7:5 cm,
layer thickness 250 mg), were obtained from Whatman
(Maidstone, UK). Monomer spots were visualised by expos-
ing the plates to iodine vapour or placing them under a UV
lamp (l ¼ 254 nm). Silica gel for flash chromatography was
from BDH Laboratory Supplies (Poole, UK). NMR spectra
were obtained on a JEOL Lambda 500 instrument (operating
at 500 MHz for 1H, 125 MHz for 13C and 470 MHz for 19F) as
solutions in CDCl3, with internal reference SiMe4 for 1H and
13C, and external CFCl3 for 19F spectra. Data are recorded as
follows: chemical shifts in ppm from reference on the d scale,
integration, multiplicity (s: singlet, d: doublet, t: triplet, q:
quartet, quin: quintet, m; multiplet, obs: obscured and br:
broad), coupling constant (J/Hz) and assignment. IR spectra
were recorded as films for liquids and on a KBr disc for solids
on a Nicolet SP210 instrument using Omnic software. Reac-
tion mixtures were monitored by gas chromatography–mass
spectrometry using a Finnigan MAT GCQ instrument with
chemical ionisation (CI) using methane as reagent gas.
Molecular masses of pure products were confirmed with
methane þve CI data (70 eV) and fragmentation patterns
obtained in electron impact (EI) mode.
4.3. Measurement of pKa values
The method used followed that of Bordwell and Anderson
[22]. A problem sometimes encountered with thiols is aerial
oxidation, especially under alkaline conditions. To suppress
this, all solutions were purged with nitrogen. Three samples of
thiol (0.2–0.4 g) were placed in separate 50 ml volumetric
flasks and absolute ethanol (25 ml) added to each flask. Each
mixture was swirled until the thiol dissolved. Sufficient 1 M
NaOH was added to each flask to neutralise between 20 and
60% of the thiol and each solution was then made up to a total
volume of 50 ml with distilled water. The concentration of
thiolate ions was therefore known. The pH of each partially
neutralised thiol was measured at 25 8C with a Jenway 3020
pH meter that had been calibrated with buffers of pH 4 and pH
7. The concentration of thiol was calculated by withdrawing
an aliquot (2 ml), adding it to an excess of aqueous iodine
(0.0255 M) and titrating the resultant solution, comprising
RSSR and HI, with aqueous sodium thiosulfate (0.024 M).
The acid dissociation constant was obtained using the Hen-
derson equation: pKa ¼ pH þ log10 [ArSH]/[ArSꢀ]. The var-
iation was generally no more than 0.05pKa units for the three
determinations whose average was taken.
Caution. Fluorocycloalkenes E–G are toxic by inhalation
and must be handled and used in an efficient fume cupboard.
Toxicity data are given elsewhere [6].
4.1. Reactions of thiols
The thiol (3.6 mmol) was added by syringe to a stirred
mixture of the fluoroalkene (3.6 mmol), acetonitrile (25 ml)
and anhydrous potassium carbonate (1 g, 7.2 mmol) at room
temperature. The mixture, which coloured yellow, was left
to stand for 12 h. Solid material was removed by filtration
and the filtrate concentrated to give a yellow gum. This was
dissolved in the minimum amount of chloroform and chro-
matographed on silica gel to give pure product/s. Experi-
mental and spectroscopic data appear in Tables 2–4. In the
infrared spectra, the carbon–carbon double bond stretch for
the mono and bis vinyl products appeared between 1594 and
1585 cmꢀ1 in agreement with literature data [19]. Electron
impact mass spectra of all products showed a molecular ion.
Acknowledgements
The author thanks the Porton scientists Rick Hall, Ian
Lawston and David Upshall for sharing their enthusiasm and
early experimental data on the reactions of fluoroalkenes,
which inspired this series of papers. # Crown Copyright
2003 Dstl.
4.2. 1-Chloro-2-[2-acetylamino-2-
(isopropoxycarbonyl)ethylthio]-3,3,4,4-
tetrafluorocyclobutene (13)
References
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1
60%). Mp 66–68 8C. H NMR (ABX cysteinyl system):
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OCH), 4.90 (1H, br ddd, J ¼ 7 and 5 Hz, CHx), 3.75 (1H, dd,

1272
C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 1265–1272
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