Convenient synthesis of thiols and disulfides in the polyfluorinated series incorporating a butylic spacer

Article abstract of DOI:10.1016/S0040-4039(00)00303-8

New fluorinated thiols R(F)(CH₂)(p)SH and disulfides [R(F)(CH₂)(p)S]₂ containing a butylic spacer (p=4) between the perfluorinated part and the thiol (or disulfide) function were easily obtained in good yields with a purity higher than 98%. This allows us to obtain homologues (p>4) for their use as synthetic intermediates or as constituents for molecular organized systems. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00303-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2885–2889
Convenient synthesis of thiols and disulfides in the
polyfluorinated series incorporating a butylic spacer
Natacha Mureau, Frédéric Guittard ∗ and Serge Géribaldi
GRECFO, Chimie Organique du Fluor, Université de Nice-Sophia Antipolis, Faculté des Sciences, 06108 Nice Cedex 2,
France
Received 15 December 1999; accepted 17 February 2000
Abstract
New fluorinated thiols RF(CH2)pSH and disulfides [RF(CH2)pS]2 containing a butylic spacer (p=4) between the
perfluorinated part and the thiol (or disulfide) function were easily obtained in good yields with a purity higher
than 98%. This allows us to obtain homologues (p>4) for their use as synthetic intermediates or as constituents for
molecular organized systems. © 2000 Elsevier Science Ltd. All rights reserved.
The association of a perfluorinated tail with a thiol or disulfide functional group within the same
molecular shape leads to the conjugation of the intrinsic properties of these two parts (the specific
reactivity of the mercaptan function and its affinity for metallic substrates on one hand, and the chemical
and thermal inertness with hydrophobic and oleophobic properties of the perfluorinated tail on the other
hand), in order to use these thiol or disulfide compounds as part of a highly fluorinated series in the field
of materials and to investigate their physical properties. The use of perfluorinated thiols or disulfides
results from the fact that they form self-assembled organic monolayers.1 These materials are used in
electronic devices (as low voltage connector coatings), in electronics (for hard disk lubrification) or else
in biology, including the development and understanding of membrane models. The resulting materials
show improved performance: better chemical and thermal stability,2 a decrease of the surface tension
of the coating surface and low wetting,3 and an increase of the resistance against frictional forces.4
Moreover, mercaptans also have the advantage of showing excellent properties as intermediates for the
synthesis of a large range of elaborated molecules, such as surfactants5,6 or polymers for fire retardants,7,8
liquid crystals,9 biocides10–12 or blood substitutes,13 etc.
However, even if the presence of the thiol function gives remarkable and unique properties for
obtaining molecular or supramolecular organized systems, it is worth noting that these properties are
exacerbated by the nature and the lengthening of the hydrocarbon spacer (CH2)p bonding the thiol
function to the perfluorinated tail (RF).14 In fact, the interaction between perfluorinated tails is relatively
weak compared to their homologous hydrocarbon tails, and the order obtained in the layer within
∗
Corresponding author. E-mail: guittard@unice.fr (F. Guittard)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00303-8
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organized systems is, in this case, governed, amongst others, by the lengthening of this methylenic spacer
which induces a favourable phase microsegregation. Therefore, it is necessary to control and to develop
new strategies for obtaining thiols or disulfides within a perfluorinated series showing a variable number
of methylene moieties. The aim of this work is to describe a reliable method for obtaining fluorinated
thiols or disulfides with the general formula RF(CH2)pSH and [RF(CH2)pS]2 where RF=F-butyl, F-hexyl
or F-octyl and with p=4 but also to give the possibility of reaching higher homologues (p>4).
In spite of the increasing interest in highly fluorinated thiols and disulfides, their preparation has
received, until now, little attention. Numerous difficulties have arisen against the lengthening of the
hydrocarbon segment to be introduced between the sulfur atom and the perfluorinated chain (p value).
Furthermore, these difficulties are increased by the small number of available raw materials within the
F-alkyl series. The available structures described up to now are developed principally from two raw
materials (cf. Scheme 1):
– either perfluorinated iodides (RF-I) into which the introduction of the methylenic spacer is achieved
from a radical reaction,15 and which are then converted into the thiol. This leads to the possibility of
reaching a methylenic moiety number (p) superior to 916,17 (cf. pathway i);
Scheme 1.
– or the 2-F-alkylethyliodides which lead directly to the thiols, either with p=2,18 cf. pathway ii, under
phase transfer catalysis19 conditions, or with p=3 via the acids obtained by the Grignard reaction (cf.
pathway iii).20
Hence, the increase in length of the methylenic spacer in the fluorinated series is a relatively delicate
procedure. The strategy of the synthesis involved is based upon the malonic ester condensation. In order
to carry out this first step we have improved, and rendered specific, the malonic ester condensation within
the fluorinated series; this requires some particular specifications.21–25 The overall steps are described in
Scheme 2.
Scheme 2. a,b,c=RF value, i.e. C4F9, C6F13, C8F17; (i) CH2(CO2Et)2/THF/K2CO3, 70°C, 24 h; (ii) KOH/EtOHabs, 10–15
h, 80°C; (iii) 195°C, 3 h; (iv) Et2O/AlLiH4, 40°C, 12 h; (v) 0°C, PBr3/Et2O, 40°C, 12 h; (vi) TsCl/EtOH, 70°C, 1 h; (vii)
thiourea/EtOHabs., 80°C, 20 h; (viii) NaOH (2 equiv.), N2, 70°C, 2 h; (ix) NaOH (10 equiv.), 70°C, 12 h
The monosubstituted malonic diesters (65–70%) are obtained by nucleophilic substitution between
2-F-alkylethyliodides, 1a–c and the dialkyl malonate, according to the reaction plan. In opposition to
previous work described in the literature,21,22 it appears a necessary condition to use a weak alkaline
medium in order to minimize the formation of byproducts. The presence of a strong base promotes

2887
the elimination reaction and the possibility of a second alkylation of the malonate. Hence, anhydrous
potassium carbonate was used in order to avoid the elimination of hydrogen iodide from the starting
materials, which would lead to the build-up in formation of 2-F-alkylethene. It is important to work with
highly anhydrous solvents and reagents under an inert atmosphere to avoid the build-up in the reaction
medium of hydroxyl ions liable to lead to the byproducts previously cited. The formation of disubstituted
compounds (8–10%) is not, however, to be completely avoided. It is worth noting with regard to this
nucleophilic substitution reaction that it is also possible to use 18-crown as a crown ether catalyst,26,27 to
significantly reduce the reaction time (6 h compared to 24 h for the non-catalyzed reaction). The diacid
salts (89–93%) are easily obtained by saponification of the corresponding monosubstituted malonic
diesters, in an alkaline medium under controlled heating conditions.27 Acidic hydrolysis of the salts
allows us to obtain the corresponding carboxylic diacids (2a–c). The 4-F-alkylbutanoic acids (3a–c)
are obtained in high yield (97–98%) by decarboxylation of the corresponding geminated diacid at high
temperature. The alcohols (4a–c) are obtained by the reduction of the previous acids (96–97%) using
lithium aluminium hydride. These alcohols allow us to obtain the corresponding bromides (64–72%,
5a–c) or tosylates (6a–c).
The production of thiols (8a–c) can be carried out according to several routes. Most of the methods
used for the synthesis of thiols, and without spacers different from the methylenic unit,28 either within
the hydrocarbon or fluorinated series, involve the high nucleophilicity of the sulfide ion. The action
of sodium thiosulfate on the halogenated compounds,29 or of thioacetic acid on the alkene in a two-
step process,30 or on 2-F-alkylethyliodide,18 gives thiols within controlled pressure and temperature
conditions. The disulfides can also be reduced to thiols with mild reducing reagents such as zinc in
a diluted acid media,31 by heating in alkaline media,32 or by hydrogenolysis.33 The yields of thiol
conversion are mainly dependent on the method employed but it is possible in some cases to record the
competitive formation of sulfide or disulfide byproducts. We have, therefore, chosen a reliable method
from an industrial point of view which allows us to obtain high yields. Moreover, this method allows the
use of phase transfer catalysis, previously described by our team, to improve the access to functionalized
2-F-alkylethyl compounds.19 The action of thiourea on the brominated or tosylated derivatives within an
anhydrous ethanolic medium leads to the obtention of the isothiouronium salts (95–96%, 7a–c).
Hydrolysis of isothiouronium salts in alkaline medium (2 equiv.) under a controlled atmosphere gives
thiols (88–90%) which can be considered as new raw materials within the F-alkylated series. In spite
of precautions taken, however, this method does not allow the formation of disulfide in low proportions
(<5%) easily separable by distillation. Hydrolysis of these isothiouronium salts in an excess of base
(10 equiv.) over atmospheric oxygen and with an increased heating time (overnight), compared to
the thiol procedures (2 h), leads to disulfides (9a–c) in higher yields (93–96%). The physicochemical
characteristics of thiols and disulfides are reported in Table 1.
Table 1
Preparation of thiols and disulfides with a butylic spacer

2888
Lastly, the achievement of higher homologues with p>4 is effective when using a similar pathway of a
recurrent34 synthetic nature, as summarized in Scheme 3.
Scheme 3. X=I, Br or OTs, (i) see Refs. 18 and 19 and this work; (ii) see Ref. 20; (iii) this work
Acknowledgements
The authors thank Atochem who provided the 2-F-alkylethyliodides.
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