Fluorinated phosphorus compounds: Part 2. The synthesis of some bis(fluoroalkyl) alkylphosphonates

Article abstract of DOI:10.1016/S0022-1139(00)00284-0

Twenty bis(fluoroalkyl) alkylphosphonates of structure (R_FO)₂P(O)R were prepared in 28-69% yields by treatment of alkylphosphonic dichlorides Cl₂P(O)R [R=Me, Et, n-Pr, i-Pr] with fluoroalcohols R_FOH [R_F=CF₃CH₂, H(CF₂)₂CH₂, C₂F₅CH₂, C₃H₇CH₂, (CF₃)₂CH] in diethyl ether in the presence of triethylamine. Reactions of isopropylphosphonic dichloride with two molar equivalents of alcohols and fluoroalcohols were compared. After 12h at room temperature, the alcohols EtOH, n-PrOH, i-PrOH and n-BuOH gave mixtures of monoesters and diesters, except isopropanol, which gave the monoester exclusively. Electronic and steric effects caused by the alkoxy substituents satisfactorily account for the product ratios. With the fluoroalcohols CF₃CH₂OH, C₂F₅CH₂OH, C₃F₇CH₂OH and (CF₃)₂CHOH, the diesters predominated. Here the electronic effects of the fluoroalkoxy substituents stabilise the intermediate phosphoranes, eg. Cl₂(R_FO)P(OH)i-Pr and Cl(R_FO)₂P(OH)i-Pr, and drive the reactions to completion. Steric effects are clearly much less important in the case of attack by fluorinated alcohols.

Full text of DOI:10.1016/S0022-1139(00)00284-0

Journal of Fluorine Chemistry 106 (2000) 43±52
Fluorinated phosphorus compounds
Part 2. The synthesis of some bis(¯uoroalkyl)
alkylphosphonates
Christopher M. Timperley*, John F. Broderick, Ian Holden,
Ian J. Morton, Matthew J. Waters
Chemical and Biological Defence Sector, Defence Evaluation and Research Agency,
Porton Down, Salisbury, Wiltshire SP4 0JQ, UK
Received 29 February 2000; accepted 6 April 2000
Abstract
Twenty bis(¯uoroalkyl) alkylphosphonates of structure (RFO)2P(O)R were prepared in 28±69% yields by treatment of alkylphosphonic
dichlorides Cl2P(O)R [RˆMe, Et, n-Pr, i-Pr] with ¯uoroalcohols RFOH [RFˆCF3CH2, H(CF2)2CH2, C2F5CH2, C3H7CH2, (CF3)2CH] in
diethyl ether in the presence of triethylamine. Reactions of isopropylphosphonic dichloride with two molar equivalents of alcohols and
¯uoroalcohols were compared. After 12 h at room temperature, the alcohols EtOH, n-PrOH, i-PrOH and n-BuOH gave mixtures of
monoesters and diesters, except isopropanol, which gave the monoester exclusively. Electronic and steric effects caused by the alkoxy
substituents satisfactorily account for the product ratios. With the ¯uoroalcohols CF3CH2OH, C2F5CH2OH, C3F7CH2OH and (CF3)2CHOH,
the diesters predominated. Here the electronic effects of the ¯uoroalkoxy substituents stabilise the intermediate phosphoranes, eg.
Cl2(RFO)P(OH)i-Pr and Cl(RFO)2P(OH)i-Pr, and drive the reactions to completion. Steric effects are clearly much less important in the
case of attack by ¯uorinated alcohols. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Alkylphosphonic dichlorides; Bis(¯uoroalkyl) alkylphosphonates; Fluorinated phosphonates; Fluoroalcohol; Phosphonate
1. Introduction
is that classical routes to dialkyl alkylphosphonates work
poorly for ¯uorinated systems [4±9].
The synthesis of ¯uoroalkoxy phosphorus compounds
was pioneered by F. Swarts. In 1909, he described the
One of the commonest routes to dialkyl phosphonates is
the Arbusov reaction of trisubstituted esters of phosphorous
acid with alkyl halides [10]. Trivalent phosphorus com-
pounds having ¯uorine bound to phosphorus, or ¯uorine
within an ester group, enter such reactions with dif®culty
due to their reduced nucleophilicity. For example, triisopro-
pyl phosphite (i-PrO)3P reacts readily with boiling methyl
iodide to give diisopropyl methylphosphonate (i-PrO)2-
P(O)Me in 95% yield [11], but diisopropyl phosphoro¯uor-
idite (i-PrO)2PF requires a temperature of 1008C for 7 h in a
sealed tube to produce a 44% yield of isopropyl methylpho-
sphono¯uoridate (i-PrO)P(O)MeF [12]. The presence of one
b-¯uorine atom in trialkyl phosphites also retards pro-
foundly the rate of the Arbusov reaction. Whereas triethyl
phosphite isomerises quantitatively to diethyl ethylphospho-
nate in boiling ethyl iodide [11], diethyl 2-¯uoroethyl
phosphite reacts only on heating to 1308C for 5 h in a sealed
tube, giving ethyl 2-¯uoroethyl ethylphosphonate (pathway
a) and diethyl ethylphosphonate (pathway b) [9].
preparation
of
tris(2,2-di¯uoroethyl)
phosphate,
(HCF2CH2O)3P=O, the ®rst phosphorus molecule to contain
a ¯uoroalkoxy group [1]. Since then, relatively few ¯uor-
oalkoxy phosphorus compounds have been made, and little
attention has been paid to their physical and chemical
properties. As part of a study of ¯uorinated phosphorus
compounds in progress in this laboratory [2,3], the synthesis
of bis(¯uoroalkyl) alkylphosphonates of general structure
(RFO)2P(O)R became of interest.1 Few substances of this
type are described in the literature. The main reason for this
* Corresponding author.
1 Organic phosphorus compounds are named after the corresponding
parent acids. The compounds described in this paper are diesters of
alkylphosphonic acids (HO)2P(O)R and are therefore called dialkyl
alkylphosphonates. Similarly, compounds of type Cl2P(O)R are called
alkylphosphonic dichlorides, and those of type Cl(R0O)P(O)R are called
alkyl alkylphosphonochloridates.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 8 4 - 0

44
C.M. Timperley et al. / Journal of Fluorine Chemistry 106 (2000) 43±52
these include the oxidation of phosphonites (route B), the
substitution of phosphorochloridates by Grignard reagents
(route C), and the Michaelis±Becker reaction of sodium
dialkyl phosphonates with alkyl halides (route D). Some
improved approaches involve the reactions of alkylpho-
sphonic dichlorides with ¯uoroalcohols promoted by metal
chloride catalysts (route E) or by tertiary amines (route F).
The last two methods have been applied only to methylpho-
sphonic dichloride.
In this paper, we report the reactions of various alkylpho-
sphonic dichlorides Cl2P(O)R [RˆMe, Et, n-Pr, i-Pr] with
¯uoroalcohols and triethylamine. Stereoelectronic in¯u-
ences on the reaction pathway were studied by treating
isopropylphosphonic dichloride with the alcohols EtOH,
n-PrOH, n-BuOH and i-PrOH, and the ¯uoroalcohols
CF3CH2OH, C2F5CH2OH, C3F7CH2OH and (CF3)2CHOH.
Some methods that have been used to make bis(¯uor-
oalkyl) alkylphosphonates are shown in Fig. 1. The harsh
conditions necessary for the Arbusov reactions of poly¯uori-
nated phosphites (route A) render this chemistry unsuitable
for routine use. Other approaches are often low yielding and
2. Results and discussion
2.1. Synthesis of bis(fluoroalkyl) alkylphosphonates
Bis(¯uoroalkyl) alkylphosphonates 1±20 (Table 1) were
prepared by ¯uoroalcoholysis of methyl, ethyl, propyl or
isopropylphosphonic dichloride. They were isolated as
mobile colourless liquids; some of them solidi®ed to low-
melting white solids on standing in a refrigerator. Yields and
physical constants are presented in Table 2 and spectro-
scopic data in Tables 3±6.
2.2. NMR spectra of bis(hexafluoroisopropyl)
alkylphosphonates
The ¯uorine spectra of the bis(hexa¯uoroisopropyl) alkyl-
phosphonates 5, 10, 15 and 20 in deuterated chloroform are
complex (assignments are given in Tables 3±6). For bis(hex-
a¯uoroisopropyl) n-propylphosphonate 15, two broad reso-
nances having ®ne structure were observed at about
dˆ 72.6 and 72.8 (Fig. 2). In the proton spectrum, the
methine resonance appeared as a doublet of septets corre-
3
3
sponding to JHP and JHF. The ¯uorine spectrum in d8-
tetrahydrofuran gave a simple doublet at dˆ 72.2 with a
coupling constant of 5 Hz (Fig. 2). Dissolution of the
compound in d4-dichlorobenzene, and heating to a max-
imum of 1208C, caused a gradual loss of ®ne structure in the
¯uorine spectrum, but no coalescence. Additionally the
¯uorine spectra showed the same chemical shift difference
when recorded at a frequency of 470 or 282 MHz.
Bis(hexa¯uoroisopropyl) alkylphosphonates probably
exist in chloroform in a high-energy state, with the ester
groups conformationally locked due to high intramolecular
repulsive forces: either two pairs of non-equivalent tri¯uor-
omethyl groups, or one pair of non-equivalent hexa¯uor-
oisopropyl groups, are present. The repulsive forces are
expected to be reduced in tetrahydrofuran, the solvent
perhaps hydrogen bonding to the hexa¯uoroisopropoxy
Fig. 1. Literature routes to bis(fluoroalkyl) alkylphosphonates.

C.M. Timperley et al. / Journal of Fluorine Chemistry 106 (2000) 43±52
45
Table 1
R
Fluoroalkyl group RF
Compound
Fluoroalkyl group RF
Compound
Fluoroalkyl group RF
C2F5CH2
Compound
Me
CF3CH2
C3F7CH2
CF3CH2
C3F7CH2
CF3CH2
C3F7CH2
CF3CH2
C3F7CH2
1
HCF2CF2CH2
(CF3)2CH
2
3
4
5
Et
6
HCF2CF2CH2
(CF3)2CH
7
C2F5CH2
C2F5CH2
C2F5CH2
8
9
10
12
15
17
20
n-Pr
i-Pr
11
14
16
19
HCF2CF2CH2
(CF3)2CH
13
18
HCF2CF2CH2
(CF3)2CH
protons; many highly-¯uorinated branched alcohols form
strong hydrogen bonds with ether or other substrates that
contain oxygen atoms [13].
The structures of the alkylphosphonic dichloride and
intermediate chloridate, and the nature of the alcohol, are
some of the features that affect the reaction pathway.
Although steric and electronic in¯uences on the process
have been elucidated for alcohols [15], the relative con-
tribution of such effects for ¯uoroalcohols is unknown.
The inductive effect of the alkyl group on phosphorus
varies little in going from methyl through to isopropyl [16]
and therefore all the alkylphosphonic dichlorides studied are
similar electronically. However, the role of steric factors in
2.3. Factors affecting the alcoholysis of alkylphosphonic
dichlorides
The interaction of alkylphosphonic dichlorides with oxy-
gen nucleophiles proceeds with formation of alkyl alkylpho-
sphonochloridates that react further to give disubstituted
products. In both stages, the alcohol adds to a phosphorus
chloride to give a trigonal bipyramidal phosphorane inter-
mediate that eliminates HCl (SN2P mechanism) [14].
Table 2
Experimental data for bis(fluoroalkyl) alkylphosphonates RP(O)(ORF)2
Compound
R
RF
Yield (%)
Bp (8C/mmHg)
1
2
Me
Me
Me
Me
Me
Et
CF3CH2
69
58
37
52
48
67
58
28
49
52
66
48
39
48
67
69
57
35
40
54
55/4 (mp 228C)a
97/0.015b
45/1 (mp 158C)
73/0.02 (mp 208C)c
38/2.5
H(CF2)2CH2
C2F5CH2
C3F7CH2
(CF3)2CH
CF3CH2
3
4
5
6
59/4d
7
Et
H(CF2)2CH2
C2F5CH2
C3F7CH2
(CF3)2CH
CF3CH2
98/0.015
35/0.1 (mp 198C)
73/0.015
41/0.15
8
Et
9
Et
10
11
12
13
14
15
16
17
18
19
20
Et
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
47/1e
H(CF2)2CH2
C2F5CH2
C3F7CH2
(CF3)2CH
CF3CH2
95/0.015
49/0.5
80/0.015
34/0.3
57/0.04
H(CF2)2CH2
C2F5CH2
C3F7CH2
(CF3)2CH
91/0.015
64/3
71/0.02
46/0.8
a 51±528C/4 mmHg [5] or 70±718C/8 mmHg [7].
b 102±1038C/3 mmHg [4], 114±1158C/6 mmHg [7] (these figures are too high and suggest either impure products or wrong pressure readings).
c 92±938C/9 mmHg [8].
d 418C/1 mmHg [5].
e 50±538C/1 mmHg [5].

Table 3
Spectroscopic data for bis(fluoroalkyl) methylphosphonates (RFO)2P(O)Me (NMR data measured in CDCl3)
1
Compound
1H NMR d, J (Hz)
13C NMR d, J (Hz)
19F NMR d, J (Hz)
31P NMR d
IR n (cm
)
HRMS analysis
1
4.39 (4H, complex m, OCH2), 122.3 (dq, Jˆ9, 278, CF3),
74.4 (6F, t, Jˆ7, CF3)
33.5
1403, 1296 (P=O), 1252, 1175,
1108, 1077, 966, 923, 903, 845
Calculated C5H7F6O3P 260.004,
found 259.996 (error 29.1 ppm)
1.68 (3H, d, Jˆ19, P±CH3)
61.7 (dq, Jˆ6, 37, OCH2), 11.1
(d, Jˆ148, P±CH3)
2
3
5.91 (2H, tt, Jˆ4, 53, CF2H),
4.42 (4H, br m, OCH2), 1.65
(3H, d, Jˆ18, P±CH3)
113.7 (dtt, Jˆ7, 29, 250, CF2),
109 (tt, Jˆ37, 251, CF2H), 61.1
(dt, Jˆ6, 30, OCH2), 11.1
(d, Jˆ148, P±CH3)
137.1 (4F, d, Jˆ53, CF2H),
124.3 (4F, t, Jˆ13, CF2)
33.2
33.5
1460, 1420, 1321 (P=O), 1255,
1236, 1211, 1109, 1065, 920,
903, 831
Calculated C7H9F8O3P 324.016
‡
([M HF] ˆ304.010), found
304.010 (error 0.8 ppm)
4.46 (4H, br m, OCH2), 1.67
118.2 (tq, Jˆ34, 286, CF3),
111.7 (dqt, Jˆ7, 45, 255, CF2),
60.9 (dt, Jˆ6, 28, OCH2), 11
(d, Jˆ147, P±CH3)
123.8 (4F, t, Jˆ13, CF2),
1460, 1407, 1376, 1355, 1320
(P=O), 1267, 1204, 1157, 1110,
1069, 1028, 936, 921, 839
Calculated C7H7F10O3P 359.997,
found 359.996 (error 2.3 ppm)
(3H, d, Jˆ18, P±CH3)
82.7 (6F, m, CF3)
4
5
4.50 (4H, m, OCH2), 1.65
117±105 (complex m, J obscured,
CF2CF2CF3), 61.1 (dt, Jˆ5, 28,
OCH2), 11.1 (d, Jˆ148, P±CH3)
120 (dq, Jˆ20, 284, CF3),
70 (dsep, Jˆ7, 38, OCH),
11.9 (d, Jˆ146, P±CH3)
127.2 (4F, m, CF2),
121.3 (4F, m, CH2CF2),
80.6 (6F, m, CF3)
33.7
36.5
1460, 1408, 1358, 1321 (P=O),
1300, 1230, 1186, 1132, 1080,
1018, 966, 926, 841
Calculated C9H7F14O3P 459.991,
found 459.991 (error 0.6 ppm)
(3H, d, Jˆ18, P±CH3)
5.18 (2H, dsep, Jˆ6 each,
OCH), 1.84 (3H, d, Jˆ18,
P±CH3)
73.9 (6F, br, CF3),
1383, 1324 (P=O), 1305, 1262,
1230, 1202, 1130, 1091, 931,
870
Calculated C7H5F12O3P 395.978,
found 395.979 (error 0.8 ppm)
73.7 (6F, Jˆ6±7, CF3)

Table 4
Spectroscopic data for bis(fluoroalkyl) ethylphosphonates (RFO)2P(O)Et (NMR data measured in CDCl3)
1
)
Compound
1H NMR d, J (Hz)
13C NMR d, J (Hz)
19F NMR d, J (Hz)
31P NMR d
IR n (cm
HRMS analysis
6
4.38 (4H, complex m, OCH2), 122.8 (dq, Jˆ7, 272, CF3), 62
1.93 (2H, dq, Jˆ19, 8, P±CH2), (dq, Jˆ5, 37, OCH2), 19.2
74.4 (6F, t, Jˆ8, CF3)
36.1
1462, 1419, 1288 (P=O),
1255, 1174, 1109, 1080,
1036, 1016, 964, 845
Calculated C6H9F6O3P 274.019,
found 274.017 (error 7.3 ppm)
1.23 (3H, dt, Jˆ19, 8, CH3)
(d, Jˆ144, P±CH2), 6.05
(d, Jˆ6, CH3)
7
8
5.91 (2H, tt, Jˆ4, 53, CF2H),
4.42 (4H, br m, OCH2), 1.91
(2H, dq, Jˆ19, 8, P±CH2),
1.21 (3H, dt, Jˆ19, 8, CH3)
113.7 (dtt, Jˆ7, 28, 251, CF2),
109.1 (tt, Jˆ36, 251, CF2H),
61.1 (dt, Jˆ5, 23, OCH2),
18.7 (d, Jˆ143, P±CH2),
5.9 (d, Jˆ7, CH3)
136.6 (4F, d, Jˆ53, CF2H),
123.8 (4F, t, Jˆ11, CF2)
35.5
36.2
1462, 1411, 1291 (P=O),
1258, 1232, 1212, 1109,
1069, 1034, 964, 950, 864
Calculated C8H11F8O3P 338.032,
found 338.032 (error 0.1 ppm)
4.48 (4H, m, OCH2), 1.93
(2H, dq, Jˆ19, 8, P±CH2),
1.22 (3H, dt, Jˆ19, 8, CH3)
118.1 (tq, Jˆ35, 286, CF3), 111.6
(dqt, Jˆ7, 38, 256, CF2), 60.8
(dt, Jˆ6, 29, OCH2), 18.8
(d, Jˆ44, P±CH2), 5.5
123.8 (4F, br t, CF2),
82.7 (6F, m, CF3)
1464, 1410, 1375, 1355,
Calculated C8H9F10O3P 374.013,
found 374.013 (error 0.4 ppm)
1302 (P=O), 1270, 1201, 1158,
1111, 1073, 1029, 957, 866
(d, Jˆ8, CH3)
9
4.5 (4H, m, OCH2), 1.94
(2H, dq, Jˆ19, 8, P±CH2),
1.22 (3H, dt, Jˆ19, 8, CH3)
117±109 (complex m, J obscured,
CF2CF2CF3), 60.9 (dt, Jˆ5, 28,
OCH2), 18.6 (d, Jˆ143, P±CH2),
5.6 (d, Jˆ7, CH3)
126.6 (4F, m, CF2),
120.7 (4F, m, CH2CF2),
79.9 (6F, m, CF3)
36.3
38.8
1464, 1410, 1356, 1300 (P=O),
1230, 1186, 1132, 1082, 1014,
966, 924, 864
Calculated C10H9F14O3P
474.007, found 474.007
(error 0.8 ppm)
10
5.17 (2H, dsep, Jˆ6, OCH),
120 (dq, Jˆ11, 286, CF3), 70
73.9 (6F, d, Jˆ66, CF3),
73.7 (6F, d, Jˆ66, CF3)
1466, 1383, 1294 (P=O),
1234, 1203, 1130, 1113,
1093, 1038, 1018, 903, 866
Calculated C8H7F12O3P 409.994,
found 409.994 (error 0.5 ppm)
2.07 (2H, dq, Jˆ23, 8, P±CH2), (dsep, Jˆ6, 35, OCH), 19.5
1.28 (3H, dt, Jˆ23, 8, CH3)
(d, Jˆ140, P±CH2), 5.5
(d, Jˆ8, CH3)

Table 5
Spectroscopic data for bis(fluoroalkyl) propylphosphonates (RFO)2P(O)n-Pr (NMR data measured in CDCl3)
1
Compound 1H NMR d, J (Hz)a
13C NMR d, J (Hz)
19F NMR d, J (Hz)
31P NMR d
IR n (cm
)
HRMS analysis
11
12
4.36 (4H, m, Jꢀ8, OCH2), 1.91
122.5 (dq, Jˆ7, 277, CF3), 61.8
(dq, Jˆ6, 37, OCH2), 27.5
74.4 (6F, t, Jˆ7, CF3)
35.2
1412, 1293 (P=O), 1261,
1239, 1174, 1109, 1070,
1042, 965, 872
Calculated C7H11F6O3P 288.035,
found 288.035 (error 1 ppm)
(2H, m, Jꢀ8, P±CH2), 1.69
(2H, m, Jꢀ8, CH2), 1.06
(3H, dt, Jˆ2, 8, CH3)
(d, Jˆ140, P±CH2), 15.6 (d, Jˆ5,
CH2), 14.9 (d, Jˆ18, CH3)
5.9 (2H, tt, Jˆ4, 53, CF2H),
4.4 (4H, m, Jꢀ8, OCH2), 1.85
(2H, br m, Jꢀ8, P±CH2), 1.67
(2H, br m, Jꢀ8, CH2), 1.05
(3H, dt, Jˆ1, 7, CH3)
113.8 (dtt, Jˆ8, 29, 247, CF2),
109.1 (tt, Jˆ36, 251, CF2H), 61.1
137.1 (4F, d, Jˆ52,
34.6
1460, 1408, 1290 (P=O),
1263, 1236, 1213, 1109,
1063, 951, 935, 870, 835
Calculated C9H13F8O3P 352.047,
found 352.046 (error 3 ppm)
CF2H), 124.3
(dt, Jˆ6, 25, OCH2), 27.6 (d, Jˆ140, (4F, t, Jˆ13, CF2)
P±CH2), 15.6 (d, Jˆ6, CH2),
14.9 (d, Jˆ18, CH3)
13
14
15
4.47 (4H, m, Jꢀ7, OCH2),
1.68 (2H, m, Jꢀ7, P±CH2),
1.90 (2H, m, Jꢀ7, CH2), 1.05
(3H, dt, Jˆ2, 7, CH3)
118.3 (qt, Jˆ286, 34, CF3), 111.8
(dqt, Jˆ7, 38, 255, CF2), 60.8
(dt, Jˆ6, 29, OCH2), 27.5 (d, Jˆ141,
P±CH2), 15.4 (d, Jˆ6, CH2), 14.7
(d, Jˆ18, CH3)
124.4 (4F, t, Jˆ7, CF2), 35.0
1462, 1408, 1354, 1306 (P=O), Calculated C9H11F10O3P
83.3 (6F, m, CF3)
1275, 1209, 1157, 1128,
1066, 1028, 958, 935, 872
388.029, found 388.029
(error 1.8 ppm)
4.55 (4H, m, Jꢀ8, OCH2),
1.92 (2H, dt, Jˆ10, 8, P±CH2),
1.69 (2H, m, Jꢀ8, CH2),
117.4 (qt, Jˆ287, 33, CF3), 113.6
(dtt, Jˆ7, 31, 257, CH2CF2), 108.5
(qt, Jˆ266, 34, CF2), 61 (dt, Jˆ5, 27,
OCH2), 27.6 (d, Jˆ141, P±CH2), 15.5
(d, Jˆ6, CH2), 14.8 (d, Jˆ18, CH3)
120.1 (dq, Jˆ16, 285, CF3), 69.9
126.6 (4F, m, CF2),
120.7 (4F, m, CH2CF2),
80 (6F, m, CF3)
35.0
37.5
1462, 1408, 1356, 1300 (P=O), Calculated C11H11F14O3P
1230, 1186, 1132, 1072, 1016,
966, 924, 870
488.022, found 488.022
(error 0 ppm)
1.05 (3H, dt, Jˆ2, 8, CH3)
5.17 (2H, dsep, Jˆ6 each,
73.9 (6F, br, CF3),
73.7 (6F, complex m,
Jꢀ6, CF3)b
1462, 1382, 1300 (P=O), 1272, Calculated C9H9F12O3P 424.010,
1243, 1206, 1129, 1077, 1043,
904, 883, 866
OCH), 2.03 (2H, m, Jꢀ8, P±CH2), (dsep, Jˆ6, 37, OCH), 28 (d,
found 424.009 (error 0.9 ppm)
1.73 (2H, tq, Jˆ8, CH2), 1.08
(3H, dt, Jˆ2, 8, CH3)
Jˆ137, P±CH2), 15.3 (d, Jˆ6,
CH2), 14.7 (d, Jˆ19, CH3)
a The P±OCH2 proton resonances are second order; hence coupling constants are only approximate.
b
ꢀ80 Hz apart at 470 MHz and ꢀ44 Hz apart at 282 MHz.

Table 6
Spectroscopic data for bis(fluoroalkyl) isopropylphosphonates (RFO)2P(O)i-Pr (NMR data measured in CDCl3)
1
Compound 1H NMR d, J (Hz)a
13C NMR d, J (Hz)
19F NMR d, J (Hz)
31P NMR d
IR n (cm
)
HRMS analysis
16
17
4.38 (4H, dq, Jˆ8, OCH2), 2.15
122.7 (dq, Jˆ7, 277, CF3),
62 (dq, Jˆ3, 38, OCH2), 26.6
(d, Jˆ43, P±CH), 15.5
74.4 (6F, t, Jˆ7, CF3)
37.7
1421, 1287 (P=O), 1240,
1174, 1110, 1094, 1075,
1046, 964, 868
Calculated C7H11F6O3P 288.035,
found 288.035 (error 1.1 ppm)
(1H, dsep, Jˆ19, 7, P±CH),
1.25 (6H, dd, Jˆ7, 20, CH3)
(d, Jˆ5, CH3)
5.9 (2H, tt, Jˆ4, 53, CF2H), 4.41
(4H, br m, Jꢀ8, ꢀ13, OCH2),
2.13 (1H, dsep, Jˆ19, 7, P±CH),
1.24 (6H, dd, Jˆ7, 19, CH3)
113.8 (dtt, Jˆ7, 27, 251, CF2),
109.1 (tt, Jˆ37, 251, CF2H),
61.3 (dt, Jˆ6, 29, OCH2),
26 (d, Jˆ42, P±CH), 15.5
(d, Jˆ6, CH3)
137.1 (4F, d, Jˆ52, CF2H),37.4
124.3 (4F, t, Jˆ13, CF2)
1471, 1292 (P=O), 1234,
1213, 1109, 1065, 1043,
951, 935, 891, 864, 837
Calculated C9H13F8O3P 352.047,
found 352.048 (error 0.1 ppm)
18
19
20
4.46 (4H, m, OCH2), 2.15
(1H, dsep, Jˆ21, 7, OCH), 1.25
(6H, dd, Jˆ7, 19, CH3)
118.2 (tq, Jˆ34, 285, CF3),
111.8 (dqt, Jˆ7, 38, 256, CF2),
61 (dt, Jˆ6, 29, OCH2), 25.9
(d, Jˆ42, OCH), 15.2 (d, Jˆ3, CH3)
117.4 (tq, Jˆ34, 287, CF3), 113.7
123.8 (4F, br m, CF2),37.7
82.7 (6F, m, CF3)
1471, 1395, 1375, 1354,
1297 (P=O), 1270, 1205,
1156, 1127, 1070, 1043,
958, 936, 892, 865, 823
1471, 1356, 1296 (P=O),
1230, 1184, 1132, 1076,
1016, 966, 924, 891, 862
Calculated C9H11F10O3P 388.029,
found 388.029 (error 0.6 ppm)
4.5 (4H, m, Jꢀ8, OCH2), 2.15
(1H, dsep, Jˆ19, 7, P±CH),
1.25 (6H, dd, Jˆ7, 19, CH3)
126.6 (4F, m, CF2), 120.737.8
Calculated C11H11F14O3P 488.022,
found 488.023 (error 0.8 ppm)
and 108a (m, CF2CF2), 61.2 (dt, Jˆ8, (4F, m, CH2CF2), 79.9 (6F,
44, OCH2), 26.3 (d, Jˆ44, P±CH),
15.3 (d, Jˆ5, CH3)
m, CF3)
5.17 (2H, dsep, Jˆ6 each,
OCH), 2.26 (2H, dsep, Jˆ21
and 7, P±CH), 1.32 (6H, dd,
Jˆ7, 21, CH3)
120.1 (dq, Jˆ16, 284, CF3), 70
(dsep, Jˆ7, 37, OCH), 27 (d, Jˆ138,
P±CH), 15.1 (d, Jˆ5, CH3)
73.6 (12F, d, Jˆ66, CF3) 39.9
1471, 1375, 1292 (P=O),
1246, 1205, 1128, 1113,
1086, 1047, 891, 877, 854
Calculated C9H9F12O3P 424.010,
found 424.009 (error 1.8 ppm)
a Coupling constants obscured because of CF2 overlap.

50
C.M. Timperley et al. / Journal of Fluorine Chemistry 106 (2000) 43±52
is also important, particularly in the case of the isopropoxy
group. A similar interplay between steric and electronic
effects accounts for differences in the rates of hydrolysis of
alkyl alkylphosphonochloridates. For example, in the
methylphosphonochloridate series Cl(RO)P(O)Me, the
methyl ester hydrolyses twice as fast as the ethyl ester
and four times faster than the isopropyl ester [20]. In the
ethylphosphonochloridate series Cl(RO)P(O)Et, the methyl
ester hydrolyses about three times faster than the ethyl ester,
but almost 13 times faster than the isopropyl ester [20].
Similarly, Cl(n-PrO)P(O)n-Pr hydrolyses one and a half
times faster, and Cl(n-PrO)P(O)i-Pr approximately two
times faster, than the corresponding isopropyl esters [21].
Fluoroalcohols are more reactive towards alkylphospho-
nic dichlorides than their hydrogen counterparts owing to
the ability of ¯uorine to stabilise the alkoxide form, which is
a better nucleophile, and to increase inductively the electro-
philicity of the intermediate phosphonochloridates. Fluor-
oalcoholysis of isopropylphosphonic dichloride led to
almost exclusive production of bis(¯uoroalkyl) isopropyl-
phosphonates of type B. The low percentage or absence of
any intermediate phosphonochloridates must be a conse-
quence of the unusually rapid rate of the second substitution.
This phenomenon is anomalous as products of type A and B
(Table 7) were formed when un¯uorinated primary alcohols
reacted with isopropylphosphonic dichloride. The product
differences in the two cases can be ascribed to a difference in
the electronic effect of a ¯uoroalkoxy group (electron-with-
drawing) relative to an alkoxy group (electron-donating). A
kinetic acceleration of the second substitution occurs for
¯uoroalkyl phosphonochloridates Cl(RFO)P(O)R0 but not
for alkyl phosphonochloridates Cl(RO)P(O)R0. Alterna-
tively, thermodynamic stabilisation of the intermediate
phosphorane C, formed in the ¯uoroalcoholysis reactions,
could lead to the same phenomenon.
Fig. 2. The 19F spectra of bis(hexafluoroisopropyl) n-propylphosphonate
[(CF3)2CHO]2P(O)n-Pr 15, showing the signals corresponding to the
trifluoromethyl groups; recorded in deuterated chloroform (left) and
tetrahydrofuran (right) at 470 MHz; the chemical shift on the horizontal
axis is relative to external CFCl3 standard.
determining their reactivity is profound. For example,
MeP(O)Cl2 hydrolyses ®ve times faster than EtP(O)Cl2 or
n-PrP(O)Cl2, and over a hundred times faster than i-
PrP(O)Cl2 in ice-cold acetone containing 5% water [17].
Isopropylphosphonic dichloride was the least reactive of
the alkylphosphonic dichlorides investigated and is the
best model for studying differences in the rates of alcoho-
lysis. The reactivities of some alcohols and ¯uoroalcohols
towards isopropylphosphonic dichloride were therefore
compared.
After 12 h at room temperature, two molar equivalents of
alcohol reacted to give mixtures of mono and disubstituted
products A and B (Table 7), but in the case of isopropanol,
one product only. The increase in monosubstituted product
with lengthening of the alkyl chain of the alcohols can be
ascribed to electron release to the phosphorus atom (in
agreement with pKa values), reducing the reactivity of the
phosphonochloridate towards further nucleophilic attack.
However, the steric effect of the newly formed ester function
Table 7
Composition of reaction mixtures after 12 h at 258C as determined by GC-
MS
It is well established that the stabilities of pentacoordinate
phosphorus compounds increase with the electronegativity
of the ligand (e.g. PF5 is very stable, PCl5 dissociates, and
PH5 and PMe5 are unknown) [22]. Consequently reaction
intermediates with the most electronegative ligands are the
most stable; the slightly higher rate of hydrolysis of (i-
PrO)2P(O)F compared to (i-PrO)2P(O)Cl has been attributed
to the greater stability of the intermediate (i-PrO)2P(OH)2F
versus (i-PrO)2P(OH)2Cl [23]. Fluoroalkoxy groups also
stabilise the pentavalent state. For example, the ¯uoroalk-
a
a
Alcohol pKa
%A
%B
Fluoroalcohol pKa
%A %B
MeOH
EtOH
15.1
15.9
29
50
68
75
98
70
48
29
23
±
CF3CH2OH
C2F5CH2OH
C3F7CH2OH
(CF3)2CHOH
12.4
5
5
±
±
94
93
98
98
oxyphosphoranes
(CF3CH2O)3P(CN)2
[24]
and
n-PrOH 16.1
n-BuOH 16.1
±
(HCF2CF2CH2O)3P(CN)2 [25] are liquids of relatively high
stability - they can be distilled without decomposition unlike
related alkoxyphosphoranes which usually undergo rapid
Arbusov rearrangement. The hexa¯uoroisopropyl group is
11.4
9.3
i-PrOH
17.1
a pKa values for alcohols obtained from [18] and for fluoroalcohols
from [19].

C.M. Timperley et al. / Journal of Fluorine Chemistry 106 (2000) 43±52
51
particularly good at stabilising the pentavalent state. Its
strong electron-acceptor ability and bulkiness hinder trans-
formation of dihalophosphoranes by the Arbusov reaction,
(MeO)3P (dˆ140 ppm) for 31P spectra. Data in Tables 3±6
are recorded as follows: chemical shifts in ppm from refer-
ence on the d scale, integration, multiplicity (sˆsinglet,
dˆdoublet, tˆtriplet, qˆquartet, mˆmultiplet and
sepˆseptet; brˆbroad), coupling constant (Hz) and assign-
ment. IR spectra were recorded as liquid ®lms 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 and
chemical ionisation (CI) using methane as reagent gas.
Molecular masses of pure products were con®rmed with
methane ‡ve CI data. Elemental analysis was carried out on
the largest stable fragment ion, using high resolution mass
spectrometry (HRMS) on a Micromass Autospec SQ Double
Focusing Magnetic Sector instrument. Mode: ‡ve ion elec-
tron impact, magnet scan m/z 400 to 100 s per decade,
resolution 2900. Inlet: septum (1608C), 0.2 ml introduced.
Source conditions: temperature 2008C, electron energy
70 eV, and accelerating voltage 8000 V.
and
stable
covalent
derivatives
of
structure
[(CF3)2CHO]3PX2 (XˆF, Cl or Br) can be isolated [26].
Such a stabilising effect may explain why bis(hexa¯uoroi-
sopropyl) isopropylphosphonate [(CF3)2CHO]2P(O)i-Pr 20
formed exclusively in the reaction between hexa¯uoroiso-
propanol and isopropylphosphonic dichloride. On steric
grounds, only monosubstitution to give Cl[(CF3)2CHO]-
P(O)i-Pr was expected, hexa¯uoroisopropanol being
assumed to be roughly the same size as 2,4-dimethyl-3-
pentanol (i-Pr)2CHOH; the tri¯uoromethyl group is con-
siderably larger than a methyl group and is estimated to be at
least as large as an isopropyl group [27]. Thermodynamic
stabilisation of the phosphorane intermediate to account for
the formation of bis(hexa¯uoroisopropyl) isopropylphos-
phonate 20 is supported by the steric congestion of the
molecule, as indicated by NMR studies (refer to Section
2.2), and the ®nding that disubstitution of isopropylpho-
sphonic dichloride with an excess of isopropanol could not
be achieved with triethylamine as base, even on prolonged
re¯ux in ether (see Section 4.2).
4.1. General method for bis(fluoroalkyl)
alkylphosphonates
A solution of ¯uoroalcohol (0.14 mol) and triethylamine
(0.14 mol) in diethyl ether (50 ml) was added dropwise to a
magnetically stirred solution of alkylphosphonic dichloride
(0.07 mol) in diethyl ether (50 ml) at 0±58C. After addition,
the mixture was re¯uxed for 2 h. Analysis by GC-MS
indicated that the reaction had gone to completion. The
precipitate was removed by ®ltration and the ®ltrate con-
centrated to an oil. Fractionation under reduced pressure
(0.015±4 mmHg) gave the title compounds as colourless
mobile liquids. Yields and physical constants are given in
Table 2 and spectroscopic data in Tables 3±6. In the reac-
tions of H(CF2)2CH2OH with the alkylphosphonic dichlor-
ides, i.e. for the synthesis of 2, 7, 12 and 17, the procedure
differed: the reaction mixture was treated with water
(100 ml), the organic layer separated, dried (MgSO4) and
concentrated to a mobile oil which was then fractionated
under reduced pressure.
3. Conclusion
The base-promoted reaction of ¯uoroalcohols with alkyl-
phosphonic dichlorides is one of the best methods available
for the synthesis of bis(¯uoroalkyl) alkylphosphonates.
Unlike most literature methods, this approach is mild and
of general applicability. Now that bis(¯uoroalkyl) alkylpho-
sphonates can be prepared in good yield, the path is laid for a
systematic study of their chemistry.
4. Experimental details
All reagents were of commercial quality: ¯uoroalcohols
were purchased from Apollo Scienti®c Ltd (Derbyshire,
UK). Methylphosphonic dichloride was puri®ed by distilla-
tion; bp 1638C (lit. bp 1638C [28]). Ethyl and n-propylpho-
sphonic dichlorides were purchased from Aldrich (the latter
was of technical grade, i.e. 95% pure). Isopropylphosphonic
dichloride was obtained from the Friedel±Crafts reaction
between isopropyl chloride and phosphorus trichloride
[29,30]; bp 808C/15 mmHg (lit. bp 77±798C/14 mmHg
[30]). Anhydrous ether and triethylamine (distilled from
CaH2 and stored over CaH2) were used for the alcoholysis
experiments. NMR spectra were obtained on a JEOL
Lambda 500 instrument (operating at 500 MHz for 1H,
125 MHz for 13C, 470 MHz for 19F, and 202 MHz for 31P
spectra) or a JEOL instrument (operating at 300 MHz for 1H,
75 MHz for 13C, 282 MHz for 19F, and 121.5 MHz for 31P
spectra) as solutions in CDCl3, with internal reference
4.2. Reactions of alcohols with isopropylphosphonic
dichloride
The molar ratios of reactants were as before but the
reaction mixtures were left for 12 h at room temperature,
then analysed by GC-MS. The product/s that formed are
given in Table 7. The reaction between isopropylphosphonic
dichloride and isopropanol yielded only isopropyl isopro-
pylphosphonochloridate Cl(i-PrO)P(O)i-Pr. This could be
isolated by ®ltration, evaporation of the ®ltrate to an oil
and fractionation under reduced pressure (bp 42±448C/
0.1 mmHg). Alternatively, re¯uxing for several days
produced a 2:1 mixture of isopropyl isopropylphosphono-
chloridate, Cl(i-PrO)P(O)i-Pr, and diisopropyl isopropyl-
phosphonochloridate, (i-PrO)2P(O)i-Pr.
1
SiMe4 for H and 13C, external CFCl3 for 19F and external

52
C.M. Timperley et al. / Journal of Fluorine Chemistry 106 (2000) 43±52
[14] R.F. Hudson, Structure and Mechanism in Organophosphorus
Acknowledgements
Chemistry, Academic Press, London, 1965.
[15] R.F. Hudson, L. Keay, J. Chem. Soc. (1960) 1865.
[16] V.V. Sheluchenko, M.A. Landau, S.S. Dubov, A.A. Neimysheva, I.L.
Knunyants, Dokl. Akad. Nauk. SSSR, Ser. Khim. (in English) 177
(1967) 1050.
Many thanks to Alison Bussey and Steve Marriott for their
excellent technical support. We also wish to thank DERA
Haslar (Environmental Sciences) for funding the work.
[17] A.A. Neimysheva, I.L. Knunyants, Zh. Obshch. Khim. (in English)
38 (1968) 575.
[18] S.G. Wilkinson, in: J.F. Stoddart (Ed.), Comprehensive Organic
Chemistry, Pergamon Press, Oxford, Vol. 1, Part 4.1, 1979, p. 584.
[19] B.E. Smart, Characteristics of C±F systems, in: R.E. Banks, B.E.
Smart, J.C. Tatlow (Eds.), Organofluorine Chemistry Ð Principles
and Commercial Applications, Plenum Press, London, 1994, Chapter
3, p. 57.
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