Fluoroalkene chemistry Part 1. Highly-toxic fluorobutenes and their mode of toxicity: Reactions of perfluoroisobutene and polyfluorinated cyclobutenes with thiols

Article abstract of DOI:10.1016/j.jfluchem.2003.11.021

The reactions of four highly-toxic fluorobutenes - perfluoroisobutene (PFIB), 1-hydropentafluorocyclobutene (1-H), hexafluorocyclobutene (HFCB) and 3-chloropentafluorocyclobutene (3-Cl)-with propanethiol, 2,6-dimethoxybenzenethiol and N -acetylcysteine is

Full text of DOI:10.1016/j.jfluchem.2003.11.021

Journal of Fluorine Chemistry 125 (2004) 685–693
Fluoroalkene chemistry
Part 1. Highly-toxic fluorobutenes and their mode of toxicity:
reactions of perfluoroisobutene and polyfluorinated
cyclobutenes with thiols
Christopher M. Timperley*
Defence Science and Technology Laboratory (Dstl), Room 2/6A, Bldg 383B, Chemical and Biological Defence Sector,
Porton Down, Salisbury, Wiltshire SP4 0JQ, UK
Received 2 October 2002; received in revised form 24 November 2003; accepted 25 November 2003
Available online 16 January 2004
Abstract
The reactions of four highly-toxic fluorobutenes – perfluoroisobutene (PFIB), 1-hydropentafluorocyclobutene (1-H), hexafluorocyclobu-
tene (HFCB) and 3-chloropentafluorocyclobutene (3-Cl)—with propanethiol, 2,6-dimethoxybenzenethiol and N-acetylcysteine isopropyl
ester were studied. PFIB and HFCB reacted with two molar equivalents of the aliphatic thiols, but with only one molar equivalent of the
aromatic thiol (presumably due to steric hindrance) and resembled phosgene in their reactivity. The fluorocyclobutenes 1-H and 3-Cl reacted
with one and up to three molar equivalents of the aliphatic thiols, respectively, but with only one molar equivalent of the aromatic thiol. The
products of allyl and vinyl substitution were isolated and characterised as fully as possible. The inhalation toxicities of the fluorocyclobutenes
to rodents correlated with the number of easily-displaceable fluorine substituents, supporting the contention that toxicity is due to reaction
with biological thiols in the lung.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Fluorinated alkenes and cycloalkenes; Hexafluorocyclobutene; Perfluoroisobutene; Phosgene; Nucleophilic reactions; Thiol; Toxicity
1. Introduction
Many monofluorinated compounds are highly toxic by
metabolism to 2R,3R-2-fluorocitrate or by inhibition of the
enzyme acetylcholinesterase, but some polyfluorinated
materials such as highly fluorinated alkenes are also poiso-
nous [1–4]. One of the most toxic is perfluoroisobutene
(PFIB),1 a by-product of TeflonTM manufacture whose
The ability of fluoroalkenes to react easily with nucleo-
toxicity is legendary [8–14]. Other fluorinated alkenes such
philes distinguishes them from alkenes and is pronounced in
as hexafluorocyclobutene (HFCB) are also toxic by inhala-
the case of PFIB and HFCB [17]. Comparative data on rates
tion. Once inhaled, PFIB and HFCB produce a potentially
of reaction of the fluoroalkenes with nucleophiles are un-
lethal build up of fluid in the lung ‘pulmonary oedema’ after
available, although from experience PFIB appears more
a latent period of many hours [15,16].
reactive than HFCB; the reactivity of acyclic fluoroalkenes
declines in the order (RF)2C¼CF2 > RFCF¼CFRF [18].
Additiontothedoublebondoccurswithnucleophilesunder
acidic or neutral conditions. Under basic conditions, addition
is usually accompanied by dehydrofluorination (this distin-
guishes PFIB and HFCB from less fluorinated alkenes for
which addition is to a large extent characteristic). The carba-
nion intermediates can eliminate fluoride from the carbon
bonded to the nucleophile giving the vinyl substitution pro-
* Tel.: þ44-1980-613566/613302; fax: þ44-1980-613834.
E-mail address: cmtimperley@dstl.gov.uk (C.M. Timperley).
1 PFIB is included in Schedule 2B of the Chemical Weapons Convention
(CWC) which entered into force on 29 April 1997 and bans the
development, production, stockpiling and use of chemical weapons [5].
PFIB was incorporated into the final text of the CWC after prompting by
one delegation during the Conference on Disarmament [6]. Concern was
raised over the potential military utility of PFIB [7] and related highly-
toxic fluorinated gases.
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.021

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C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
Table 1
Inhalation toxicities of fluorobutene analogues in mice and rats [4,25]
Fluorobutene Designation LCt50 micea
(mg min mÀ3
LCt50 ratsa
Toxicity
)
(mg min mÀ3 groupb
)
1-H
10,000–20,000 >80,000
I
1-Cl
1-Br
HFCB
3-Cl
3-Br
6000
>6750
6000
10,630
6460
4410
1910
1310
II
II
II
III
III
1930
1890
PFIB
880c
1800
1200
3000
–
–
Phosgene
a The LCt50 is the lethal concentration that kills 50% of a group of
animals and is expressed in milligrams of fluoroalkene per metre cubed
multiplied by the exposure time t in minutes (mg min mÀ3). It is based on
deaths occurring up to 14 days following exposures of 10 min duration.
95% confidence limits can be found elsewhere [25].
Fig. 1. Carbanions from attack of a nucleophile on PFIB and HFCB and
possible products arising from loss of vinylic (a) or allylic (b) fluorine as
fluoride.
b For an explanation of the toxicity groups, see Section 2.6.
c The preliminary LCt50 of PFIB in mice was reported as
980 mg min mÀ3 in an earlier paper [24]; the revised figure is now
880 mg min mÀ3
.
duct, or from the CF3 group (PFIB) or the CF2 group (HFCB)
giving the allyl substitution product (Fig. 1). The relationship
between vinyl and allyl substitution is determined by the
nature of the nucleophile and the reaction conditions. Vinyl
substitution usually predominates unless the allylic position
contains a good leaving group (e.g. a halogen atom other than
fluorine). In this case, allyl substitution can occur more easily,
sometimes to the exclusion of vinyl substitution. Often vinyl
and allyl products can undergo further addition–elimination
to give poly-substituted products.
Highly-toxic fluoroalkenes such as PFIB are essentially
insoluble in water [19] and have a high affinity for thiols in
the lung. A rapid fall in lung cysteine and glutathione levels
was observed in rodents exposed to PFIB [20]. Cysteine
esters administered as pretreatments increased intracellular
thiol levels and protected against lethal doses, presumably
by reacting with the fluoroalkene in preference to cellular
components [21–23]. Cysteine isopropyl ester was later
shown to combine with PFIB in aqueous solution to give
a thiazole [24], implicating direct reaction as part of the
protective mechanism. We showed that the acute inhalation
toxicity towards rodents of PFIB, HFCB and close structural
analogues correlated with their reactivities towards thiols in
the lung [25]. Inhalation toxicity data appear in Table 1.
Several structure-toxicity relationships are evident:
ꢀ Vinyl chloro and bromo analogues are less toxic than allyl
isomers (1-Cl versus 3-Cl and 1-Br versus 3-Br).
ꢀ Allyl chloro and bromo analogues are more toxic than
HFCB (3-Cl and 3-Br versus HFCB).
ꢀ The most toxic fluoroalkene tested was PFIB, which is
more toxic than phosgene.
The purpose of the work described here was to examine the
reactions of some toxic fluorobutenes with model biological
thiols and to use the results to explain the toxicity order. Few
additions of thiols to PFIB and HFCB appear in the literature.
Mono or bis-vinyl substitution products have been obtained
by treating PFIB with thiophenols in the presence of a tertiary
amine [24] or with alkali-metal mercaptides [26,27] or thio-
phenoxides [28]. Disubstituted products have been obtained
from the reaction of HFCB with butanethiol or mercapto-
acetic acid with Triton B as base [29] or with toluene-3,4-
dithiolwithpotassiumcarbonateasbase[30]. Inthisstudy, the
reactions of PFIB and three fluorocyclobutanes (1-H, HFCB,
3-Cl) with propanethiol, 2,6-dimethoxybenzenethiol and N-
acetylcysteine isopropyl ester were examined. Propanethiol
and N-acetylcysteine isopropyl ester, with accessible SH
groups, have reactivities comparable to those of the lung
thiols cysteine and glutathione.2 Steric hindrance of the thiol
ꢀ Vinyl hydro analogues have low toxicity (1-H versus
HFCB).
2 The tripeptide glutathione (g-glutamylcysteineglycine) is the most
common intracellular thiol; it contains a primary SH group and is present
in mammalian cells in concentrations between 0.5–10 mM.
ꢀ Vinyl chloro and bromo analogues are less toxic than the
perfluoro prototype (1-Cl and 1-Br versus HFCB).

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
687
groupoften lowers reactivity, and 2,6-dimethoxybenzenethiol
models a biological thiol that is part of a larger structure such
as a protein.
In the two cases presented, attack on PFIB takes place at
the difluoromethylene group as this is the most electrophilic
site. Likewise attack by nucleophiles on substituted fluoro-
cyclobutenes occurs on the most positive carbon atom of
the double bond, as will now be seen.
2. Results and discussion
2.2. 1-Hydropentafluorocyclobutene (1-H)
2.1. Perfluoroisobutene and phosgene
1-Hydropentafluorocyclobutene has only one displace-
able leaving group on the double bond and reacts with
nucleophiles such as alcohols to give mono products arising
from displacement of vinyl fluoride [35]. A similar outcome
occurred with thiol nucleophiles, with propanethiol reacting
to give a mixture of isomers: vinyl sulfide 4a and a trace of
allyl sulfide 4b, which could not be separated by chromato-
graphy or by distillation. Use of 2,6-dimethoxybenzenethiol
gave vinyl sulfide 5 in moderate yield; allylic substitution
was not detected in this instance.
The hallmark of acute lung injury caused by PFIB is a
breach in the permeability characteristics of the air–blood
barrier of the lung that manifests itself as pulmonary oedema.
The symptoms are very similar to those caused by inhalation
of phosgene [31–33], so it is possible that both PFIB and
phosgene share a common mechanism of action. Therefore,
both were treated with two molar equivalents of propanethiol
to compare their behaviour under the same conditions.3
In line with previous results [24], PFIB gave the ketene
dithioacetal 1. The IR stretching frequency of the double
bond in 1 (1526 cmÀ1) was much lower than that in PFIB
(1751 cmÀ1). Phosgene gave the dithiocarbonate 2 whose
carbonyl stretch appeared at 1647 cmÀ1. The (CF3)2C¼C
group of PFIB is isoelectronic with the O¼C group of
phosgene and both gases react similarly with thiols, suggest-
ing a common mechanism of action. Successful use of
N-acetylcysteine to alleviate the symptoms of both PFIB
[20–23] and phosgene poisoning [34] supports this theory.
2.3. Hexafluorocyclobutene (HFCB)
Two equivalents of propanethiol gave the 1,2-bis(sulfide)
6a (double vinyl substitution) and a trace of its 1,3-isomer 6b
(allyl substitution then either allyl or vinyl substitution).
Even with a two molar proportion of 2,6-dimethoxybenzene-
thiol only the mono-substituted product was obtained.
Further reaction was presumably precluded by steric hin-
drance.
Treatment of PFIB with two molar equivalents of 2,6-
dimethoxybenzenethiol (DMBT) led to the isolation of only
the mono-vinyl species 3. Here a second nucleophilic attack
was probably prevented by electron-donation from the 2,6-
dimethoxybenzenethio substituent to the double bond and
steric hindrance. Allylic substitution was not detected in this
case.
3 Additions of fluoroalkenes to the thiols were carried out at À78 8C.
After addition, reaction mixtures were allowed to warm up to room
temperature and were left for 12 h prior to work up. This procedure was
used throughout.
Thus, in its behaviour towards thiols, HFCB showed
analogous reactivity to PFIB (see Section 2.1) and can

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C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
therefore be regarded, in terms of its ability to damage the
lung, as an analogue of phosgene, which it also resembles in
its toxic effect and symptoms.
2.4. 3-Chloropentafluorocyclobut-1-ene (3-Cl)
3-Chloropentafluorocyclobutene (bp 31–33 8C) was
synthesised in 65% yield by heating 3-(fluorosulfato)penta-
fluorocyclobutene with potassium chloride in diglyme (see
Section 3.3). It reacted with an excess of propanethiol to give
a mixture of bis vinyl sulfide 8a and tris sulfide 8b. The
presence of the latter is explained by initial allylic substitu-
tion (with loss of chloride), followed by vinyl or allyl
substitution, then a final vinyl substitution (with loss of
fluoride).
Fig. 2. Products of reaction of fluorobutenes with N-acetylcysteine
isopropyl ester (NCPE) where R ¼ CH2CHðNHAcÞCO2Pr-i.
previous experiments, 1-H combining with one molar
equivalent of thiol, and PFIB and HFCB combining with
two. It is likely that some of the protective action of cysteine
esters administered as pretreatments in animals prior to
fluorobutene exposure will be due to reaction of the thiol
with the incoming gas.
Reaction of 3-chloropentafluorocyclobutene with an
excess of 2,6-dimethoxybenzenethiol resulted in displace-
ment of the allylic chlorine, giving sulfide 9; no evidence
was found for further attack at the double bond (a trace of an
isomer, presumed to be the vinylic product, was detected in
the reaction mixture, but could not be isolated in a pure state
by chromatography).4 The result is useful from a synthetic
viewpoint, vinyl sulfide 7 (1674 cmÀ1) made by treating
HFCB with 2,6-dimethoxybenzenethiol is isomeric with
allyl sulfide 9 (1784 cmÀ1) which displays a C¼C stretch
close to that for HFCB (1798 cmÀ1) and for 3-Cl
(1795 cmÀ1) confirming that the arylthio group is not
attached to the double bond.
2.6. Discussion
The susceptibility of fluorobutenes towards attack by
biological nucleophiles, such as thiols, accounts for their
toxicity, and the author has classified them into Toxicity
Groups (I-III) according to their observed alkylating abil-
ities. Group I fluoroalkenes can condense with one molar
equivalent of thiol, Group II fluoroalkenes with two, and
Group III fluoroalkenes with three. In the absence of special
effects, toxicity increases on progressing from Group I
through Group II to Group III (Table 1). The toxicities of
the fluorobutenes correlate with their susceptibilities
towards attack by thiols. 1-Hydropentafluorocyclobutene,
which reacts with thiols to give mono-substituted products
(A), is the least toxic compound of the series. The similar
toxicities of HFCB and its 1-chloro and 1-bromo analogues
can be rationalised on the basis of their similar electrophili-
cities and the fact that they are all bis-alkylating agents,
giving disubstituted products (B) with thiols. The greater
toxicities of the 3-chloro and 3-bromopentafluorocylobu-
tenes are ascribable to their ability to act as tris-alkylating
agents, giving trisubstituted products (C).
2.5. Reactions with N-acetylcysteine isopropyl ester
Perfluoroisobutene, 1-hydropentafluorocyclobutene and
hexafluorocyclobutene reacted with N-acetylcysteine iso-
propyl ester under mild conditions to give vinyl substitution
products (Fig. 2). The substitution pattern was the same as in
4 Other polyfluorocyclobutenes with an allylic leaving group undergo
similar reaction with oxygen nucleophiles; methanolysis of 3-(fluorosul-
fato)pentafluorocyclobutene yielded the corresponding 3-methoxy ether in
80% yield [36].

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
689
Further evidence that biological activity correlates
with fluorocycloalkene reactivity was provided by a study
of the effect of ring size on toxicity. It was found that
inhalation toxicity to mice decreased in the order
perfluorocyclopropene > HFCB > perfluorocyclopentene
[4]. Perfluorocyclopropene is the most toxic cycloalkene
examined to date, its toxicity approaching that of PFIB. It is
highly electrophilic and reacts violently with nucleophiles,
often with ring opening, to give polysubstituted adducts
[37].
ꢀ Group II fluorocyclopentenes should be more toxic than
the corresponding Group II fluorocyclohexenes (as they
are more reactive).
ꢀ Group II fluoroalkenes having a 1,2-difluoro substitution
pattern are expected to be more toxic than 1,2-dichloro
analogues (as they are more reactive).
3. Experimental
The following were made using literature procedures—N-
acetylcysteine isopropyl ester (method similar to that for
cysteine isopropyl ester [20]), 1-hydropentafluorocyclobu-
tene [40], PFIB [41] and 2,6-dimethoxybenzenethiol [42].
HFCB was obtained from Apollo Scientific Ltd (Derbyshire,
UK). N,N-Diisopropylethylamine was obtained from
Aldrich (Gillingham, UK) and used as received. Anhydrous
solvents were used for reactions: THF was distilled from
sodium/benzophenone. Petroleum ether refers to the fraction
with boiling range between 40–60 8C. TLC was performed
Several cyclic fluoroalkenes previously shown to be toxic
are listed in Table 2. They are ranked into toxicity groups
according to their projected ability to act as mono- or bis-
alkylating agents. Such classification gives rise to the fol-
lowing predictions:
˚
on MK6F silica gel 60 A plates (Whatman, USA) with
detection by UV light (l ¼ 254 nm) and I2 vapour. Sorbsil
C30 40/60 silica was used for column chromatography.
Melting points were determined on an Electrothermal appa-
ratus and are uncorrected. IR spectra were recorded on a
Nicolet SP210 instrument using Omnic software. NMR
spectra were obtained on a Jeol Lambda 500 instrument
(operating at 470 MHz for 19F, 500 MHz for 1H, and
125 MHz for 13C spectra); products were examined as
solutions in CDCl3, with CFCl3 and SiMe4 as external
ꢀ Group I cycloalkenes having a 1-OCH2RF substituent are
likely to be more toxic than analogues with a 1-OCH2R
substituent (as vinyl fluoroalkoxy groups can stabilise
carbanionic intermediates derived from nucleophilic
attack better than alkoxy groups; there is also the possi-
bility that the fluoroalkoxy substituent could be displaced
by thiols).
1
references for 19F and H, respectively. Data are recorded
Table 2
Previously reported biological activities of toxic fluorocycloalkenes [38,39]
Fluoroalkene
Species
Mice
Dose
1–2%
3–7%
Biological effects
Toxicity group
Slow induction and recovery; one out of three mice died
Convulsive movements; all mice died within 6 min
I
Mice
II
Rats
2 ml
Analgesia and respiratory depression; animals died within 18 h
No anaesthesia; all mice died
II
I
Mice
Mice
Mice
Mice
Mice
0.8–3.4%
0.1–0.6%
1.9–2.8%
0.8–1.5%
–
Poor anaesthesia; one out of two mice died
All mice died in 3 h after 15 min exposure
No anaesthesia; all mice died after 20 min
LCt50 for mice is 109,622 mg min mÀ3 (2 h exposure)
I
Ia
II
II
a If the 2,2,2-trifluoroethoxy group can act as a leaving group, then this compound will belong to toxicity group II.

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C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
as follows—chemical shift in ppm from reference on the d
scale, integration, multiplicity (br ¼ broad, s ¼ singlet, d ¼
doublet, t ¼ triplet, tt ¼ triplet of triplets, q ¼ quartet and m
¼ multiplet), coupling constant (Hz) and assignment. Mass
spectra were recorded on a Finnigan MAT GCQ instrument
using a direct insertion probe; electron impact (EI) with
methane as reagent gas or chemical ionisation (CI) in the
presence of ammonia.
Caution. Owing to the high inhalation toxicities of the
fluoroalkenes, the chemistry described requires a high level
of awareness. Experiments must be performed in an effi-
cient, dedicated fume-cupboard. The safest way to handle
the toxic gases is to inflate a polypropylene gas bag with a
resealing syringe port via a lecture bottle and a short length
of rubber tubing; a known volume of gas can then be
removed from the bag, as required, using a large gas-tight
syringe. Gas bags of 1 liter capacity supplied by SKC
Limited (Unit 11, Sunrise Park, Higher Shaftesbury Road,
Blandford Forum, Dorset DT11 8ST, UK; Catalogue No.
232-01) are ideal for this type of work and were used for
experiments involving PFIB and HFCB.
and a magnetic stirrer bar were placed in a 250 ml round-
bottomed flask fitted with a rubber septum. Approximately
300 ml of air was removed from the headspace using a gas-
tight syringe. The mixture was cooled to À78 8C and
phosgene (328 ml, 14.6 mmol) added via the syringe. A
heavy precipitate of N,N-diisopropylethylamine hydrochlor-
ide formed. The reaction was left for 12 h at room tem-
perature to ensure completion. Water (50 ml) was added
and the mixture transferred to a separating funnel. The
organic layer was separated, the aqueous layer extracted
with ether (2 ꢁ 50 ml) and the ether extracts combined
and dried (MgSO4). The drying agent was filtered off and
the filtrate concentrated to give a yellow liquid. Chromato-
graphy on silica gel, eluting with 9:1 hexane–acetone,
gave the title compound as a colourless liquid (2.2 g,
1
85%). H NMR d ¼ 3:58 (4H, t, J ¼ 7 Hz, SCH2), 2.47
(4H, m, CH2), 1.17 (6H, J ¼ 7, CH3). 13C NMR d ¼ 189:74
(C¼O), 32.48 (SCH2), 23.24 (CH2), 15.28 (CH3). IR (film)
n ¼ 2967, 2933, 2873, 2799, 1647 (C¼O), 1457, 1410,
1379, 1340, 1291, 1239, 1204, 1070, 873, 782, 734 cmÀ1
.
CI–MS: m=z ¼ 179 (M þ 1, 100), 150 (22). Calcd. for
C7H14OS2: C, 47.1; H, 7.9; S, 36.0. Found: C, 47; H, 7.7;
S, 36.1%.
3.1. 1,1-Bis(propylthio)-2-(trifluoromethyl)-3,3,3-
trifluoroprop-1-ene (1)
3.3. Synthesis of 3-chloropentafluorocyclobutene (3-Cl)
A solution of propanethiol (2.64 ml, 29.2 mmol) and N,N-
diisopropylethylamine (5.1 ml, 29.2 mmol) in THF (50 ml)
and a magnetic stirrer bar were placed in a 250 ml round-
bottomed flask fitted with a rubber septum. Approximately
300 ml of air were removed from the headspace using a gas-
tight syringe. The mixture was cooled to À78 8C and per-
fluoroisobutene (328 ml, 14.6 mmol) added via the syringe.
A slight precipitate of N,N-diisopropylethylamine hydro-
fluoride formed. The reaction was left for 12 h at room
temperature to ensure completion. Water (50 ml) was added
and the mixture transferred to a separating funnel. The
organic layer was separated, the aqueous layer extracted
with ether (2 ꢁ 50 ml) and the ether extracts combined and
dried (MgSO4). The drying agent was filtered off and the
filtrate concentrated to give a yellow liquid. Chromatogra-
phy on silica gel, eluting with 9:1 hexane–acetone, gave the
title compound as a colourless liquid (4.23 g, 92%). 1H
NMR d ¼ 2:9 (4H, t, J ¼ 7 Hz, SCH2), 1.15 (4H, m, CH2),
0.96 (6H, J ¼ 7, CH3). 13C NMR d ¼ 162:3 (s, C-CF3),
121.43 (q, J ¼ 277 Hz, CF3), 117.91 (s, C-S), 37.99 (SCH2),
23.13 (CH2), 15.25 (s, CH3). 19F NMR d ¼ À56:09 (6F, s,
CF3). IR (film) n ¼ 2970, 2937, 2878, 1526 (C¼C), 1460,
1412, 1382, 1307, 1228, 1207, 1149, 992, 879, 843, 810,
783, 715, 699 cmÀ1. CI–MS: m=z ¼ 312 (M þ 1, 32), 293
(M-HF, 100), 269 (45). Calcd. for C10H14F6S2: C, 38.5; H,
4.5; S, 20.5. Found: C, 38.4; H, 4.5; S, 20.3%.
3-(Fluorosulfato)pentafluorocyclobutene [36] (16 g,
0.07 mol) was added dropwise to a stirred suspension of
dried powdered KCl (5.2 g, 0.07 mol) in diglyme (50 ml).
When the addition was complete, the mixture was heated to
80–90 8C (external bath temperature) for 2 h. The product
was distilled from the mixture and fractionated to give the
title compound as a colourless mobile liquid (8 g, 65%); bp
31–33 8C. IR (film): n ¼ 1795 cmÀ1 (C¼C). EI–MS:
m=z ¼ 180, (Mþ C4F537Clþ, 9), 178 (Mþ C4F535Clþ, 28),
161 (1), 159 (4), 143 (64), 124 (5), 118 (4), 116 (12), 111
(35), 109 (100).5 HRMS: calculated C4ClF5 178.492, found
178.482 (error 0.3).
3.4. Reactions with propanethiol and 2,6-
dimethoxybenzenethiol
Hexafluorocyclobutene (224 ml, 10 mmol) was removed
from a gas bag using a gas-tight syringe. In a flask sealed with
a septum, a mixture of the appropriate thiol (20 mmol) and
N,N-diisopropylethylamine (20 mmol) in THF (15 ml) was
cooled to À78 8C and stirred under argon. The syringe needle
was inserted through the septum. Contraction due to cooling
caused the syringe plunger to deliver the fluoroalkene into
5 A gas chromatogram showing the fluoroalkene to be 98% pure
(retention time 1.6 min) was obtained using a 2 m ꢁ 4 mm internal
diameter glass column packed with 10% SE-30 on Chromosorb WHP (80–
100 mesh) at 30 8C with 25 ml minÀ1 nitrogen as carrier gas. GC–MS
spectra were obtained using the same column at the same temperature and
15 ml minÀ1 helium as carrier gas.
3.2. S,S-Dipropyl dithiocarbonate (2)
A solution of propanethiol (2.64 ml, 29.2 mmol) and N,N-
diisopropylethylamine (5.1 ml, 29.2 mmol) in THF (50 ml)

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
691
the flask. The liquid fluoroalkenes 1-H and 3-Cl were
added dropwise via cannula as a solution in THF (15 ml)
to a stirred solution of the thiol (1 M or 3 M equivalents)
and tertiary amine (1 M or 3 M equivalents) at À78 8C.
Reaction occurred immediately and TLC after 1 h con-
firmed the disappearance of the thiol. The mixture was
allowed to warm to room temperature. Products were
isolated by (A) removing the solvent and chromatography
of the residue on silica using 4:1 petrol–ethyl acetate or
petrol–ether as eluent (except where stated otherwise), or
(B) washing with saturated aqueous NaHCO3 (2 ꢁ 5 ml),
extracting with dichloromethane (3 ꢁ 10 ml), drying
(MgSO4), filtering, removing the solvent and distilling
the residue under reduced pressure in a Kugelrohr appa-
ratus (oven temperatures quoted).
3.7. 1,3-Dimethoxy-2-[(3,3,4,4-tetrafluorocyclobut-1-en-1-
yl)thio]benzene (5)
Work-up A gave the title compound as fine white crystals
that were recrystallised from 1:1 petrol–ether (69%); mp 63–
65 8C. 1H NMR: d ¼ 7:4 (1H, t, J ¼ 9 Hz, 4-H), 6.61 (2H, d,
J ¼ 9 Hz, 3- and 5-H), 5.95 (1H, tt, J ¼ 11 and 2 Hz, ¼CH),
3.89 (6H, s, OCH3). 13C NMR: d ¼ 160:7 (2- and 6-C),
153.6 (m, 1-C), 132.6 (4-C), 128.6 (pseudo tt, J ¼ 12 Hz,
¼CH and ¼CS), 118.7 and 118.4 (tt, J ¼ 282 and 24 Hz,
CF2 groups), 104.3 (3- and 5-C), 56.1 (OCH3). 19F NMR:
d ¼ À112:3 (2F, m, 4-CF2), À107.7 (2F, m, 3-CF2). IR
(KBr): n ¼ 1589 (C¼C), 1549, 1476, 1435, 1341, 1277,
1256, 1169, 1096, 843, 770 cmÀ1. EI–MS: m=z ¼ 294 (Mþ,
100), 279 (8), 259 (4), 239 (2), 228 (4), 213 (4), 187 (23),
179 (2), 167 (4), 154 (5), 139 (2), 123 (5), 109 (39), 91 (8),
69 (7), 51 (5). Calcd. C12H10F4O2S: C, 49; H, 3.4; S, 10.9.
Found: C, 49.1; H, 3.6; S, 10.8%.
3.5. 1,3-Dimethoxy-2-{[1,3,3,3-tetrafluoro-2-
(trifluoromethyl)prop-1-en-1-yl]thio}benzene (3)
Work-up A (with hexane, followed by 15:1 hexane–
acetone as eluents), gave the title compound as a pale yellow
liquid (58%). Rf 0.1 in hexane. H NMR d ¼ 7:4 (1H, dd,
3.8. 3,3,4,4-Tetrafluoro-1,2-bis(propylthio)cyclobutene
(6a)
1
each J ¼ 8, 4-H), 6.6 (2H, d, J ¼ 8 Hz, 3- and 5-H), 3.9 (6H,
s, OCH3). 13C NMR d ¼ 170:9 (m, CF), 160.9 (s, 2- and 6-
C), 132.9 (s, 4-C), 123 (1-C), 104.2 (s, 3- and 5-C), 102.4 (s,
C-CF3), 120.5 (low intensity and complex, CF3 groups), 56.2
(s, OCH3). 19F NMR d ¼ À64:7 (1F, m, CF), À57 (3F, dq,
J ¼ 24 and 8 Hz, CF3 trans to dimethoxybenzenethio
group), À56.3 (3F, dq, J ¼ 8 Hz, CF3 cis to dimethoxyben-
zenethio group). IR (film) n ¼ 2254, 1622 (C¼C), 1583,
1475, 1432, 1348, 1298, 1269, 1257, 1213, 1157, 1111, 987,
908, 862, 775, 735, 704, 650 cmÀ1. CI–MS: m=z ¼ 351
(M þ 1, 35), 331 (M-F, 100), 168 (82). Calcd. for
C12H9F7O2S: C, 41.1; H, 2.6; S, 9.2. Found: C, 41.2; H,
2.5; S, 9.1%.
Work-up B gave the title compound as a colourless mobile
oil (66%); bp 65 8C/10 mm. 1H NMR: d ¼ 2:9 (4H, t,
J ¼ 7 Hz, SCH2), 1.65 (4H, qt, J ¼ 7 Hz, CH2) and 0.95
(6H, t, J ¼ 7 Hz, CH3). 13C NMR: d ¼ 140:2 (pseudo
quintet, J ¼ 21 Hz, ¼CS), 119.2 (ddt, J ¼ 17, 25 and
279 Hz, CF2), 33.2 (SCH2), 23.6 (CH2) and 12.8 (CH3).
19F NMR: d ¼ À108:6 (4F, s, CF2). IR (film) n ¼ 1458
(C¼C), 1310, 1238, 1157, 1098, 860 cmÀ1. EI-MS:
m=z ¼ 274 (Mþ, 87), 255 (4), 232 (50), 213 (3), 190
(100), 183 (2), 171 (7), 153 (2), 139 (12), 125 (4), 107
(8), 93 (3), 88 (9), 74 (5). The product contained a trace of
3,4,4-trifluoro-1,3-bis(propylthio)cyclobutene 6b. EI–MS:
m=z ¼ 274 (Mþ, 100), 255 (2), 232 (27), 212 (4), 203
(8), 190 (60), 183 (5), 170 (15), 157 (5), 139 (8), 125
(11), 107 (5), 93 (1), 87 (7), 74 (5), 63 (3), 45 (6).
3.6. 3,3,4,4-Tetrafluoro-1-(propylthio)cyclobutene (4a)
Work-up B gave the title compound as a colourless
mobile liquid (54%); bp 41 8C/12 mm Hg. 1H NMR:
d ¼ 6:23 (1H, tt, J ¼ 11 and 2 Hz, ¼CH), 2.82 (2H, t,
J ¼ 7 Hz, SCH2), 1.68 (2H, qt, each J ¼ 7 Hz, CH2), 0.97
(3H, t, J ¼ 7 H, CH3). 13C NMR: d ¼ 154:5 (m, ¼CS),
128.9 (pseudo tt, J ¼ 13 Hz, ¼CH), 118.7 and 119 (each tt,
J ¼ 289 and 26 Hz, CF2 groups), 33.3 (SCH2), 23.4 (CH2)
and 13 (CH3). 19F NMR: d ¼ À111:8 (2F, m, 3-CF2),
À107.5 (2F, m, 4-CF2). IR (film): n ¼ 1543 (C¼C),
1460, 1371, 1335, 1281, 1244, 1167, 1128, 1098, 849,
747 cmÀ1. EI–MS: m=z ¼ 200 (Mþ, 100), 181 (3), 171 (7),
158 (83), 151 (5), 139 (12), 125 (6), 107 (87), 100 (4), 94
(23), 87 (8), 75 (30), 69 (11), 63 (9), 58 (20), 45 (16). The
product contained a trace of 1,3,4,4-tetrafluoro-3-(pro-
pylthio)cyclobutene 4b. EI–MS: m=z ¼ 200 (Mþ, 100),
181 (2), 171 (3), 158 (55), 151 (3), 139 (8), 125 (25),
121 (2), 107 (14), 102 (1), 95 (2), 89 (17), 75 (27), 69 (9),
63 (5), 57 (2), 51 (1), 45 (6).
3.9. 1,3-Dimethoxy-2-[(2,3,3,4,4-pentafluorocyclobut-1-
en-1-yl)thio]benzene (7)
Work-up A gave the title as white prisms that were
recrystallized from petrol–ether (50%); mp 64 8C. 1H
NMR: d ¼ 7:4 (2H, t, J ¼ 8 Hz, 3- and 5-H), 6.6 (1H, d,
J ¼ 8 Hz, 4-H), 3.92 (6H, s, OCH3). 13C NMR: d ¼ 160:8
(2- and 6-C), 150 (m, 1-C), 148 (¼CF), 132.4 (4-C), 116
(CF2 groups), 104.1 (3- and 5-C), 56.2 (OCH3); one signal
obscured in background noise (C-S). 19F NMR (AA’BB’X
system): d ¼ À120:1, À114.8, À114.8, À114.6 (four reso-
nances for CF) and À120.5 (1F, m, ¼CF). IR (KBr)
n ¼ 1674 (C¼C), 1582, 1478, 1456, 1435, 1364, 1287,
1260, 1217, 1113, 1028, 955, 855, 816, 772 cmÀ1. EI-
MS: m=z ¼ 312 (Mþ, 100), 297 (4), 277 (11), 264 (2),
246 (7), 200 (2), 187 (9), 168 (4), 154 (6), 123 (4), 109
(20), 95 (7), 77 (5), 51 (4). Calcd. for C12H9F5O2S: C, 46.2;
H, 2.9; S, 10.3. Found: C, 46; H, 3; S, 10.2%.

692
C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
3.10. 3-Chloro-3,4,4-trifluoro-1,2-
bis(propylthio)cyclobutene (8a) and 3,3,4-trifluoro-1,2,4-
tris(propylthio)cyclobutene (8b)
tography on silica gel gave the following pure products as
white solids.
3.13. 1,1-Bis[2-acetylamino-2-
(isopropoxycarbonyl)ethylthio]-2-(trifluoromethyl)-3,3,3-
trifluoroprop-1-ene (10)
Work-up B gave an inseparable mixture of the title
compounds 8a (20%) and 8b (60%) as a colourless mobile
oil; bp 95 8C/12 mm Hg. 1H NMR: d ¼ 2:3–2.6 (m, SCH2),
1.7 (m, CH2), 1.1 (m, CH3). 19F NMR (spectra taken as
AMX system, ie. treated as first order) for adduct 8a:
d ¼ À106:9 (1F, m, J ¼ 20 and 183 Hz, 4-F), À102.2
(1F, m, J ¼ 23 and 183 Hz, 4-F) and À101.2 (1F, m,
J ¼ 20 and 23 Hz, 3-F) and for adduct 8b: d ¼ À122:3
(1F, m, J ¼ 22 and 27 Hz, 4-F), À105.5 (J ¼ 22 and 183 Hz,
3-F) and À102.2 (J ¼ 27 and 183 Hz, 3-F). EI–MS for 8a:
m=z ¼ 290 (Mþ, 100), 271 (1), 248 (75), 206 (100), 183 (6),
171 (29), 155 (4), 139 (6), 125 (11), 107 (7), 87 (12), 74 (7),
63 (3). EI-MS for 8b: m=z ¼ 330 (Mþ, 46), 312 (1), 287
(27), 269 (2), 255 (100), 245 (25), 225 (3), 213 (52), 203
(18), 193 (4), 184 (7), 171 (20), 139 (5), 117 (6), 107 (6), 87
(5), 75 (4), 59 (3), 47 (5).
Chromatography eluent: 6:1 hexane–acetone (yield 66%);
mp 157–158 8C. 1H NMR (ABX cysteinyl system): d ¼ 6:4
(2H, d, J ¼ 6 Hz, NH), 5.05 (2H, septet, J ¼ 6 Hz, OCH),
4.77 (2H, dd, J ¼ 6 and 4 Hz, HX), 3.63 (2H, dd, J ¼ 14 and
5 Hz, HA), 3.42 (2H, dd, J ¼ 14 and 3 Hz, HB), 1.95 (6H, s,
COCH3), 1.25 (12H, d, J ¼ 6 Hz, CH3). 13C NMR:
d ¼ 170:1 and 168.7 (C¼O), 161.5 (m, ¼CS2), 124.6 (q,
JCF ¼ 276 Hz, CF3), 119 (m, JCF ¼ 33 Hz, CF3C), 70.7
(OCH), 52.8 (NCH), 36.8 (SCH2), 22.7 (acetyl CH3),
21.5 (isopropyl CH3). 19F NMR; d ¼ À56:1 (6F, s, CF3).
IR (KBr): n ¼ 1734 and 1654 (C¼O), 1536 (C¼C), 1532,
1375, 1314, 1245, 1220, 1108, 1092 cmÀ1. CI–MS:
m=z ¼ 571 (M þ 1, 10), 551 (M-F, 3), 400 (10), 358 (16),
206 (32), 172 (46), 164 (74), 149 (28), 130 (62), 122 (24), 91
(32), 73 (28), 60 (47). Calcd. for C20H28F6N2O6S2: C, 42.1;
H, 4.9; S, 11.2. Found: C, 41.9; H, 4.9; S, 11.3%.
3.11. 1,3-Dimethoxy-2-[(1,2,3,4,4-pentafluorocyclobut-2-
en-1-yl)thio]benzene (9)
Work-up A gave the title compound as a white solid (53%);
mp 66–67 8C. 1H NMR: d ¼ 7:38 (1H, t, J ¼ 9 Hz, 4-H), 6.6
(2H, d, J ¼ 9 Hz, 3- and 5-H), 3.9 (6H, s, OCH3). 13C NMR
(some resonances obscured): d ¼ 162:2 (2- and 6-C), 132.6
(4-C), 104.3 (3- and 5-C), 56.4 (OCH3). 19F NMR:
d ¼ À131:3 (1F, m, ¼CF-CFS), -130.5 (1F, m, ¼CF-CF2),
–124.3 (1F, m, CFS), À115.7 and À112.4 (both 1F, m, CF2).
IR (KBr) n ¼ 1784 (C¼C), 1582, 1476, 1431, 1381, 1327,
1317, 1294, 1256, 1196, 1134, 1109, 1080, 1030, 1003, 924,
866, 818, 774 cmÀ1. EI–MS: m=z ¼ 312 (Mþ, 100), 297 (5),
281 (9), 249 (4), 231 (28), 215 (14), 200 (3), 187 (8), 167 (7),
154 (18), 141 (15), 123 (19), 109 (21), 95 (15), 69 (9), 51 (5).
Calcd. for C12H9F5O2S: C, 46.2; H, 2.9; S, 10.3. Found: C,
46.1; H, 2.9; S, 10.5%.
3.14. 1-[2-Acetylamino-2-(isopropoxycarbonyl)ethylthio]-
3,3,4,4-tetrafluorocyclobutene (11)
Chromatography eluent: 9:1 hexane–acetone (yield 44%);
1
mp 44–46 8C. H NMR (ABX cysteinyl system): d ¼ 6:53
(1H, tt, JHF ¼ 11 and 2 Hz, ¼CH), 6.51 (1H, br s, NH), 5.1
(1H, septet, J ¼ 5 Hz, OCH), 4.84 (1H, ddd, J ¼ 7 and
5 Hz, HX), 3.5 (1H, dd, J ¼ 14 and 6 Hz, HA), 3.38 (1H, dd,
J ¼ 14 and 4 Hz, HB), 2.04 (3H, s, COCH3), 1.29 and 1.28
(6H, d, J ¼ 6 and 5 Hz, CH3). 13C NMR: d ¼ 170:3 and
168.9 (C¼O), 153.1 (m, ¼CS), 129.6 (m, ¼CH), 118.2 and
118 (m, 3- and 4-CF2), 70.9 (OCH), 51.9 (NCH), 33.1
(SCH2), 22.9 (acetyl CH3), 21.5 (isopropyl CH3). 19F
NMR: d ¼ À112 (2F, m, 4-CF2), À108 (2F, m, 3-CF2).
IR (KBr): n ¼ 1737 and 1661 (C¼O), 1543 (C¼C), 1376,
1335, 1280, 1216, 1167, 1129, 1101, 847 cmÀ1. CI–MS:
m=z ¼ 330 (Mþ þ 1, 48), 310 (84), 288 (54), 268 (100), 246
(16), 226 (23). EI-MS: m=z ¼ 329 (Mþ, 8), 296 (2), 287 (6),
270 (Mþ-OPr-i, 36), 242 (Mþ-CO2i-Pr, 16), 228 (40), 200
(100), 180 (12), 160 (27), 133 (14), 113 (21), 87 (37), 74
(31), 60 (18), 43 (i-Prþ, 27). Calcd. for C12H15F4NO3S: C,
43.8; H, 4.6; S, 9.7. Found: C, 43.9; H, 4.4; S, 9.6%.
3.12. Reactions with N-acetylcysteine isopropyl ester
A solution of N-acetylcysteine isopropyl ester (6.15 g,
30 mmol) in acetonitrile (25 ml) containing anhydrous
potassium carbonate (8.28 g, 60 mmol) and a magnetic
stirrer bar was placed in a 250 ml round-bottomed flask
fitted with a rubber septum. Approximately 300 ml of air
were removed from the headspce using a gas-tight syringe.
The mixture was cooled to À78 8C and PFIB or HFCB
(336 ml, 15 mmol) added via the syringe. The suspension
was stirred for 12 h. The inorganic solid was removed
by filtration and the filtrate concentrated to give a yellow
liquid. The experiment with 1-hydropentafluorocyclobutene
(2.16 g, 15 mmol) involved dropwise addition of a solution
in acetonitrile (25 ml) via cannula to a stirred mixture of the
thiol (3.08 g, 15 mmol) and potassium carbonate (4.14 g,
30 mmol). The mixture was worked up as before. Chroma-
3.15. 1,2-Bis[S-(N-acetylcysteinyl isopropyl ester)]-
3,3,4,4-tetrafluorocyclobutene (12)
Chromatography eluent: 6:1 hexane–acetone (yield 70%);
mp 132 8C (dec.). 1H NMR (ABX cysteinyl system):
d ¼ 6:85 (2H, d, J ¼ 6 Hz, NH), 5.15 (2H, septet,
J ¼ 6 Hz, OCH), 5.9 (2H, m, HX), 3.65 (2H, dd, J ¼ 14
and 4 Hz, HA), 3.45 (2H, dd, J ¼ 14 and 5 Hz, HB), 2.2 (6H,
s, COCH3), 1.4 (12H, d, J ¼ 6 Hz, CH3). 13C NMR:

C.M. Timperley / Journal of Fluorine Chemistry 125 (2004) 685–693
693
[8] J. Patocka, J. Bajgar, Toxicology of perfluoroisobutene, Appl. Sci.
Anal. Newslett. 98 (5) (2002) 16–18.
d ¼ 170:6 and 169.5 (C¼O), 142 (‘quintet’, JCF ¼ 21 Hz,
C¼C), 119 (tt, JCF ¼ 286 and 27 Hz, CF2), 70.8 (OCH),
52.6 (NCH), 33.5 (SCH2), 23.1 (acetyl CH3), 21.9 (isopropyl
CH3). 19F NMR: d ¼ À111:9 (AA’BB’ system, 4F, m, CF2).
IR (KBr): n ¼ 1736 and 1654 (C¼O), 1529 (C¼C), 1377,
1309, 1231, 1137 and 1126 cmÀ1. CI–MS: m=z ¼ 533
(M þ 1, 100), 513 (M-HF, 34), 493 (14), 471 (16), 451
(6), 172 (49), 130 (62), 112 (26), 86 (28), 73 (12), 60 (21), 49
(14), 43 (i-Prþ, 52). Calcd. for C20H28F4N2O6S2: C, 45.1; H,
5.3; S, 12. Found: C, 44.8; H, 5.1; S, 11.7%.
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fluorobutenes correlated with their susceptibility to nucleo-
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