Fluorinated phosphorus compounds: Part 10. Bis(fluoroalkyl) S-alkyl phosphorothiolates and tris(fluoroalkyl) phosphorothionates

Article abstract of DOI:10.1016/j.jfluchem.2005.03.026

Treatment of bis(fluoroalkyl) phosphites (R_FCH ₂O)₂P(O)H, where R_F was CF₃ or C₂F₅ with sulfur in pyridine at 80 °C gave salts of structure [(R_FCH₂O)₂P(O)SH]NC₅H ₅ in 90 and 88% yield, respectively. The salts reacted with alkyl iodides in acetonitrile at 50 °C to furnish bis(fluoroalkyl) S-alkyl phosphorothiolates (R_FCH₂O)₂P(O)SR, where R was Me, Et, n- and i-Pr (when R_F = CF₃) and Me (when R _F = C₂F₅). Yields ranged from 21 to 57%. Bis(trifluoroethyl) S-methyl phosphorothiolate (CF₃CH ₂O)₂P(O)SMe underwent fluorination by silver(I) fluoride in acetonitrile at room temperature to yield the phosphorofluoridate (CF ₃CH₂O)₂P(O)F in 75% yield. Tris(fluoroalkyl) phosphorothionates (R_FCH₂O)₃P = S, where R _F was CF₃, C₂F₅ and C ₃F₇, were prepared in 30-34% yield by heating the tris(fluoroalkyl) phosphites (R_FCH₂O)₃P and sulfur to 200 °C in a sealed tube for 8 h. Crown Copyright

Full text of DOI:10.1016/j.jfluchem.2005.03.026

Journal of Fluorine Chemistry 126 (2005) 902–906
www.elsevier.com/locate/fluor
Fluorinated phosphorus compounds
Part 10. Bis(fluoroalkyl) S-alkyl phosphorothiolates
and tris(fluoroalkyl) phosphorothionates
*
Christopher M. Timperley , Sue Kirkpatrick,
Mark Sandford, Matthew J. Waters
Defence Science and Technology Laboratory, Chemical and Biological Sciences,
Porton Down, Salisbury, Wiltshire SP4 0JQ, UK
Received 13 January 2005; received in revised form 21 March 2005; accepted 24 March 2005
Available online 9 June 2005
Abstract
Treatment of bis(fluoroalkyl) phosphites (R
structure [(R CH O) P(O)SH]NC in 90 and 88% yield, respectively. The salts reacted with alkyl iodides in acetonitrile at 50 8C to furnish
bis(fluoroalkyl) S-alkyl phosphorothiolates (R CH O) P(O)SR, where R was Me, Et, n- and i-Pr (when R = CF ) and Me (when R = C F ).
F 2 2 F 3 2 5
CH O) P(O)H, where R was CF or C F with sulfur in pyridine at 80 8C gave salts of
F
2
2
5 5
H
F
2
2
F
3
F
2 5
Yields ranged from 21 to 57%. Bis(trifluoroethyl) S-methyl phosphorothiolate (CF
fluoride in acetonitrile at room temperature to yield the phosphorofluoridate (CF CH
othionates (R CH O) P = S, where R was CF , C F and C F , were prepared in 30–34% yield by heating the tris(fluoroalkyl) phosphites
3
CH
2
2
O) P(O)SMe underwent fluorination by silver(I)
3
O)
2 2
P(O)F in 75% yield. Tris(fluoroalkyl) phosphor-
F
2
3
F
3
2
5
3 7
F 2 3
(R CH O) P and sulfur to 200 8C in a sealed tube for 8 h.
Crown Copyright # 2005 Published by Elsevier B.V. All rights reserved.
Keywords: Bis(fluoroalkyl) S-alkyl phosphorothiolate; Bis(fluoroalkyl) phosphite; Bis(trifluoroethyl) phosphorofluoridate; Tris(fluoroalkyl) phosphite;
Tris(fluoroalkyl) phosphorothionate
1
. Introduction
homologues, where R equalled Me could not be prepared
from methanethiol and triethylamine.
Two retrosynthetic pathways to bis(fluoroalkyl) S-alkyl
In this paper, we report a more versatile route to
bis(fluoroalkyl) S-alkyl phosphorothiolates based on the
second retrosynthetic pathway. We also describe the
synthesis of bis(trifluoroethyl) phosphorofluoridate
(CF CH O) P(O)F from one of the thiolates, and the
phosphorothiolates A can be devised. The first involves the
reaction between bis(fluoroalkyl) phosphorohalidates and
thiols, the second the reaction between bis(fluoroalkyl)
phosphorothioates and alkyl halides (Scheme 1). In Part 8,
we used the former route to prepare a selection of
phosphorothiolates A, where R included CF and C F ,
3
2
2
isolation of some new tris(fluoroalkyl) phosphorothionates
1
(R CH O) P S, where R equals CF , C F and C F .
F
F
3
2
5
F
2
3
3
2
5
3 7
and R was Et or n-Pr [1]. A disadvantage of this route was the
low reactivity of the thiols towards the phosphorochlori-
dates and low yields of product (13–21%). The simplest
1
The nomenclature of phosphorus compounds can be confusing and the
names used in the text were chosen for clarity. For details on the naming of
phosphorus–sulfur compounds, see ref. [1]. The terms thiolo and thiono
describe sulfur singly (P–S) or doubly (P S) bonded to the phosphorus
atom.
*
Corresponding author. Tel.: +44 1980 613 566; fax: +44 1980 613 834.
E-mail address: cmtimperley@dstl.gov.uk (C.M. Timperley).
0022-1139/$ – see front matter. Crown Copyright # 2005 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.03.026

C.M. Timperley et al. / Journal of Fluorine Chemistry 126 (2005) 902–906
903
The isolated yields are based on products >98% pure
from small-scale experiments and after fractionation using
micro-distillation apparatus. Material obtained below this
purity was not included in the calculation of yields. Larger
scale experiments, using larger fractionation equipment,
would be expected to lead to increased yields.
All the products obtained had chemical shifts d in the
P
Scheme 1. Retrosynthetic pathways to bis(fluoroalkyl) S-alkyl phosphor-
othiolates A where R = fluoroalkyl, R = alkyl and X = halide (usually Cl or
Br in the case of the phosphorohalidate and I in the case of the alkyl halide).
region of 30 ppm, which is typical for dialkyl S-alkyl
phosphorothiolates [2]. In the proton NMR spectrum, a
characteristic difference in the values of the spin–spin
coupling constants was observed: JHCSP (15–17 Hz) was
greater than JHCOP (8 Hz).
F
2
. Results and discussion
In summary, the new route has permitted the synthesis of
the S-methyl and S-isopropyl analogues for the first time
and should be viewed as complementary to the earlier
explored route. Starting from the fluoroalcohol, it is now
possible to construct bis(fluoroalkyl) phosphorothiolates in
three steps from simple and commonly available precursors
2
.1. Bis(fluoroalkyl) S-alkyl phosphorothiolates
We found that bis(trifluoroethyl) phosphite and bis(pen-
tafluoropropyl) phosphite reacted with sulfur in pyridine to
yield the pyridinium salts 1 and 2.
(
Scheme 2).
2.2. Bis(trifluoroethyl) phosphorofluoridate
The phosphorus–sulfur bond can be cleaved by fluorinat-
ing agents such as l-fluoro-2,4-dinitrobenzene [4], 2,4,6-
trinitrofluorobenzene [5] or triethylamine tris(hydrofluor-
ide) in the presence of iodine [6]. However, one of the most
effective and convenient fluorinating agents for this purpose
is silver(I) fluoride [7,8]. We found that treatment of
bis(trifluoroethyl) S-methyl phosphorothiolate 3 with sil-
ver(I) fluoride in acetonitrile at room temperature resulted in
efficient conversion to the bis(trifluoroethyl) phosphoro-
fluoridate 8.
Salt 1 was obtained as a white solid with mp 53–56 8C
from isopropanol, whereas salt 2 was a pale yellow liquid
that resisted crystallization. Structures of the salts were
confirmed by multinuclear NMR spectroscopy, the value of
the chemical shift d at 59 ppm being diagnostic for thiono
P
compounds [2].
Alkylation of salts of phosphorothioic acid is known to
yield products of thiolic structure [3]. We found that salts 1
and 2 reacted with alkyl iodides in warm acetonitrile to give
the desired phosphorothiolates 3–7 as colourless or pale
yellow liquids. Although the pyridinium salts are potentially
capable of reacting via the oxo or thiolo anion, reaction took
place via the latter because of its greater reactivity towards
the alkyl iodide.
This example was chosen to illustrate the synthetic
potential of the new bis(fluoroalkyl) S-alkyl phosphorothio-
lates: the fluoridate had been prepared previously in 84%
yield by fluorinating the corresponding phosphorochloridate
with potassium fluoride in warm dichloromethane in the
presence of trifluoroacetic acid catalyst [9].
2.3. Tris(fluoroalkyl) phosphorothionates
Compounds of structure (R O) P S appear to be very
F
3
rare. Reference to only four could be found: (CF3-
CH O) P S, prepared in 53% yield by treatment of
2
3
thiophosphoryl chloride with sodium trifluoroethoxide
10], [(CF ) CHO] P S, prepared in 73% by treatment of
[
3
2
3
thiophosphoryl chloride with lithium hexafluoroisoprop-
oxide [11] and [H(CF ) CH O] P S, where n equalled 2
and 4, prepared in 95 and 83% yield, respectively, by adding
2
n
2
3
sulfur to the tris(fluoroalkyl) phosphites [12]. Tertiary

904
C.M. Timperley et al. / Journal of Fluorine Chemistry 126 (2005) 902–906
Scheme 2. Two routes to bis(fluoroalkyl) S-alkyl phosphorothiolates A having the same number of stages.
phosphites usually add sulfur readily on warming in inert
solvents but those with b-fluorine atoms react less easily as
the nucleophilicity of the phosphorus atom is reduced. Thus,
inappreciable conversion of the two fluorinated phosphites
occurred after prolonged boiling with excess sulfur in
dioxane in the presence of triethylamine catalyst [12].
However, the reaction proceeded, under anhydrous condi-
tions in the absence of solvent, on heating to 190–210 8C in a
sealed glass tube for over 8 h.
4. Experimental
The bis(fluoroalkyl) phosphites were prepared in high
purity using a reported method [9]. Fluoroalcohols from
Apollo Scientific Ltd. (Stockport, UK) and other reagents
from Aldrich (Gillingham, UK) were used as received.
Anhydrous solvents were used in all experiments. Thin layer
˚
chromatography (TLC) plates, MK6F silica gel 60 A
(2.5 cm  7.5 cm) were obtained from Whatman (Maid-
stone, UK). Spots were visualised by iodine vapour. Silica
gel for column chromatography was obtained from BDH
Laboratory Supplies (Poole, UK). NMR spectra were
obtained on a JEOL Lambda 500 instrument (operating at
We found that the related tris(fluoroalkyl) phosphites 9–
1
1 added sulfur under comparable conditions, although
conversion to product could only partially be effected. The
tris(fluoroalkyl) phosphorothionates 12–14 were isolated as
yellow liquids in greater than 98% purity after column
chromatography.
1
13
19
500 MHz for H, 125 MHz for C, 470 MHz for F and
3
202 MHz for P spectra) or a JEOL Lambda 300 instrument
1
1
operating at 300 MHz for H, 75 MHz for C, 282 MHz for
13
(
1
9
31
F and 121.5 MHz for P spectra) as solutions in CDCl ,
3
1
with internal reference SiMe for H and C, external CFCl
13
4
3
1
for F and external (MeO) P (d 140 ppm) for P spectra.
9
31
3
Data were recorded as follows: chemical shifts in ppm from
reference on the d scale, integration, multiplicity, coupling
constant and assignment. IR spectra were recorded as liquid
films on a Nicolet SP210 instrument using Omnic software.
Reaction mixtures were monitored by gas chromatography–
mass spectrometry (GC–MS) using a Finnigan MAT GCQ
instrument with chemical ionisation (CI) using methane as
reagent gas. Molecular weights of pure products were
confirmed with methane +ve CI data (70 eV).
The phosphorothionates had chemical shifts d in the
P
region of 68 ppm which is characteristic for compounds of
this structure [2]. In the infrared spectra, two strong bands at
À1
908 and 738–734 cm were present, indicative of the P S
bond [13].
4.1. Pyridinium bis(2,2,2-trifluoroethyl)
phosphorothioate (1)
3
. Conclusion
Pyridine (4.9 ml, 60.98 mmol) was added dropwise to a
stirred mixture of finely divided sulfur (1.3 g, 40.65 mmol)
and bis(2,2,2-trifluoroethyl) phosphite (10 g, 40.65 mmol)
at room temperature. The temperature was increased to
80 8C and the sulfur aggregated into solid lumps. The
mixture was maintained at this temperature for 8 h. Solids
were filtered off and the filtrate was concentrated by rotary
Some novel bis(fluoroalkyl) S-alkyl phosphorothiolates
and tris(fluoroalkyl) phosphorothionates have been pre-
pared. Although the yields were not high, sufficient amounts
have now been obtained to permit their chemistry to be
explored for the first time.

C.M. Timperley et al. / Journal of Fluorine Chemistry 126 (2005) 902–906
905
evaporation to remove residual pyridine. The resultant
yellow oil was dissolved in isopropanol and concentrated
again to reveal the title compound as white crystals (13.1 g,
1
9
0%); mp 53–56 8C. H NMR: d = 8.87 (2H, dd, J = 2 and
Hz, pyridine 2- and 6-H), 8.40 (1H, dt, J = 2 and 8 Hz,
pyridine 4-H), 7.91 (2H, dt, J = 1 and 8 Hz, pyridine 3- and
5
1
3
5
4
5
-H), 4.36 (4H, m, OCH2). C NMR: d = 144.5 (s, pyridine
-C), 142.5 (s, pyridine 2- and 6-C), 126.7 (s, pyridine 3- and
1
9
-C), 63.3 (dq, J = 4 and 37 Hz, OCH ). F NMR:
2
3
1
d = À73.8 (t, J = 9 Hz, CF ). P NMR: d = 59.6. The
3
product was analytically pure by TLC analysis.
4.2. Pyridinium bis(2,2,3,3,3-pentafluoropropyl)
phosphorothioate (2)
The above procedure was followed, starting with
bis(2,2,3,3,3-pentafluoropropyl)
phosphite (14.06 g,
0.65 mmol). The title compound was obtained as a pale
4
1
yellow liquid that failed to crystallize (16.3 g, 88%). H
NMR: d = 8.81 (2H, dd, J = 2 and 5 Hz, pyridine 2- and 6-
H), 8.15 (1H, dt, J = 2 and 8 Hz, pyridine 4-H), 7.68 (2H, dt,
J = 1 and 8 Hz, pyridine 3- and 5-H), 4.41 (4H, m, OCH ).
2
1
3
C NMR: d = 143.9 (s, pyridine 4-C), 141.5 (s, pyridine 2-
and 6-C), 126.4 (s, pyridine 3- and 5-C), 63.1 (dq, J = 4 and
1
9
3
7 Hz, OCH2). F NMR: d = À123.28 (4F, m, CF ), À82.6
2
3
6F, m, CF3). P NMR: d = 59.6. The product was
1
(
analytically pure by TLC analysis.
4
.3. Bis(fluoroalkyl) S-alkyl phosphorothiolates (3–7)
The appropriate alkyl iodide (35 mmol) was added in one
portion to a stirred solution of pyridinium salt 1 (5 g,
4 mmol) or 2 (6.4 g, 14 mmol) in acetonitrile (15 ml). The
1
mixture was stirred at 50 8C for 1 h, during which pyridine
hydroiodide precipitated. The mixture was allowed to cool
to room temperature. Removal of the solids by filtration
through a Pasteur pipette containing a small plug of cotton
wool and rotary evaporation of the filtrate gave crude
product (generally 92% pure by multinuclear NMR
analyses) which was fractionated under reduced pressure
to yield the title compounds as colourless or pale yellow
liquids. Physical constants and analytical data appear in
Table 1.
4
.4. Bis(trifluoroethyl) phosphorofluoridate (8)
Silver(I) fluoride (1.68 g, 13.22 mmol), a brown powder,
was added in one portion via a funnel to a stirred solution of
bis(2,2,2-trifluoroethyl) S-methyl phosphorothiolate
1.93 g, 6.61 mmol) at room temperature. The solution
assumed a yellow colour. The suspension was stirred for
2 h. The solids were removed by filtration through a short
(
1
column of silica gel. The filtrate was concentrated to give a
liquid. Distillation under reduced pressure gave the title
compound as a colourless liquid (1.3 g, 75%); bp 46–47 8C/
1
0 mmHg (oil bath temperature ꢀ100 8C). Spectroscopic

906
C.M. Timperley et al. / Journal of Fluorine Chemistry 126 (2005) 902–906
3
1
details were the same as those for a specimen of the same
compound prepared by a different route [9].
À83.3 (9F, m, CF ). P NMR d = À68.0. Calculated for
3
C H F O PS: C, 21.2; H, 1.2; S, 6.3. Found: C, 21.1; H, 1.1;
9
6 15 3
S, 6.3%.
Compound 14. H NMR d = 4.51 (6H, dt, J = 10 and
1
4
.5. Tris(fluoroalkyl) phosphites (9–11)
1
3
1
3 Hz, OCH2). C NMR d = 114.1 (tq, J = 34 and 287 Hz,
CF ), 108.5 (m, OCH CF ), 108.5 (t, J = 265 Hz, CF CF ),
These were isolated in 60–70% yield by heating the
3
2
2
2
3
1
9
respective fluoroalcohol with phosphorus trichloride in a 3:1
molar ratio, according to the method of Krogh et al. [14].
Boiling points for phosphites 9, 10 and 11 were 43 8C/
63.8 (t, J = 28 Hz, OCH2). F NMR d = À127.4 (6F, m,
2 2 2 3 3
3
1
CH CF ), À121.1 (6F, m, CF CF ), À80.8 (9F, m, CF ).
P
NMR d = À68.1. Calculated for C H F O PS: C, 21.8; H,
1
2 6 21 3
1
0 mmHg,38 8C/2 mmHgand96 8C/16 mmHg,respectively.
0.9; S, 4.9. Found: C, 21.8; H, 0.8; S, 5.0%.
After careful fractionation, they were obtained as colourless
liquids of purity no greater than 90–95%. The impurities
comprised the bis(fluoroalkyl) phosphites (R CH O)P(O)H,
F
2
which presumably arose from HCl-promoted dealkylation of
the tris(fluoroalkyl) phosphite in the reaction mixture. These
impurities co-distilled with the desired phosphites; further
fractionationgenerallyresultedinmaterialoflowerpurity.For
example, repeat fractionation of tris(trifluoroethyl) phosphite
Acknowledgements
Many thanks to Owen Morris for conducting preliminary
experiments on the synthesis of the tris(fluoroalkyl)
phosphorothionates. #Crown copyright 2005 published
with the permission of the Controller HMSO.
(dP 138.2 ppm) always gave a product contaminated with
about5%(CF CH O) P(O)H(d 6.9,comparedto7.0 ppmfor
3
2
2
P
a pure specimen, ref. [9]). The phosphite mixtures were used
for the sulfur addition experiments.
References
4
.6. Tris(fluoroalkyl) phosphorothionates (12–14)
[
[
1] C.M. Timperley, S.A. Saunders, J. Szpalek, M.J. Waters, J. Fluorine
Chem. 119 (2003) 161–171.
The appropriate tris(fluoroalkyl) phosphite (20 mmol)
2] M.M. Crutchfield, C.H. Dungan, J.H. Letcher, V. Mark, J.R. Van
Wazer, in: M. Grayson, E.J. Griffith (Eds.), Topics in Phosphorus
Chemistry, vol. 5, Wiley/Interscience, London, 1967.
was placed in a borosilicate glass tube (Pierce vacuum
hydrolysis tube, Rockford, IL, USA) and finely divided
sulfur (2.56 g, 80 mmol) added. The tube was sealed by
[3] I.G. Maslennikov, S.V. Mayakova, A.N. Lavrentev, Zh. Obshch. Khim.
3 (1993) 1540–1543;
1
6
tightening the Teflon screw valve at the top and heated in
TM
Russ. J. Gen. Chem. 63 (1993) 1077–1078.
an aluminium block (Reacti-Therm
heating module,
[
4] A. Bebbington, R.V. Ley, J. Chem. Soc. (C) (1966) 1410–1412.
5] H.L. Boter, G.R. Van den Berg, Rec. Trav. Chim. Pays-Bas 85 (1966)
Rockford, IL, USA) at 200 8C for 8 h. The mixture was
allowed to cool to room temperature and an aliquot
withdrawn. Analysis by GC–MS showed no greater than
[
9
19–927.
[6] M. Bollmark, J. Stawinski, J. Chem. Soc., Chem. Commun. (1997)
91–992.
9
5
0% conversion to product. Excess sulfur was removed from
[
[
[
7] B. Saville, J. Chem. Soc. (1961) 4062–4068.
8] B. Saville, J. Chem. Soc. (1961) 4624–4630.
9] C.M. Timperley, R.E. Arbon, S.A. Saunders, M.J. Waters, J. Fluorine
Chem. 113 (2002) 65–78.
the reaction mixture by filtration and the filtrate concentrated
by rotary evaporation. Chromatography of the residue over
silica gel, eluting with 20:1 hexane–acetone, gave the title
compounds as yellow liquids.
[10] A.P. Breau, W.M. Mitchell, J. Swinson, L. Field, J. Toxicol. Environ.
Health 16 (1985) 403–413.
1
Compound 12. H NMR d = 4.42 (6H, dq, J = 8 and
1
2 Hz, OCH2). C NMR d = 124.5 (dq, J = 11 and 277 Hz,
3
[11] D. Dakternieks, G.V. Roschenthaler, R. Schmutzler, J. Fluorine Chem.
1
1
1 (1978) 387–398.
1
9
CF ), 64.5 (dq, J = 3 and 38 Hz, OCH ). F NMR d = À74
3
2
[
12] A.V. Fokin, A.F. Kolomiets, V.A. Komarov, A.I. Rapkin, K.I. Pasevina,
O.V. Verenikin, Izv. Akad. Nauk. SSSR, Ser. Khim. (1979) 152–158
(English translation).
3
1
(9F, t, J = 9 Hz, CF3). P NMR d = À68.5. Calculated for
C H F O PS: C, 20.0; H, 1.7; S, 8.9. Found: C, 20.1; H, 1.7;
6
6 9 3
[
13] L.C. Thomas, Functional groups containing bonds between phosphorus
and sulfur atoms, in: The Identification of Functional Groups in Orga-
nophosphorus Compounds, Academic Press, London, 1974,pp. 98–99
S, 8.8%.
Compound 13. H NMR d = 4.48 (6H, q, J = 12 Hz,
1
1
OCH2). C NMR d = 118.2 (tq, J = 34 and 286 Hz, CF3),
3
(
Chapter 9).
1
2
11.7 (dtq, J = 10, 257 and 34 Hz, CF ), 63.6 (dt, J = 4 and
2
[14] L.C. Krogh, T.S. Reid, H.A. Brown, J. Org. Chem. 19 (1954) 1124–
1
9
9 Hz, OCH2). F NMR d = À124.1 (6F, t, J = 12 Hz, CF2),
1126.