Polyfluoroalkoxy phosphonic and phosphinic acid derivatives: II. Reversible esterase inhibitors

Article abstract of DOI:10.1134/S1070363210030102

Polyfluoroalkyl esters of phosphoric, alkylphosphonic and 1-hydroxypolyfluoroalkylphosphonic acids exhibited significant antiesterase activity against various esterases of animal and microbial origin. Moreover, with some compounds reversible inhibition of enzymes was observed due to the specific influence of hydrophobic fragments of the target products.

Full text of DOI:10.1134/S1070363210030102

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 3, pp. 434–439. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.V. Krutikova, V.I. Krutikov, A.V. Erkin, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 3, pp. 410–416.
Polyfluoroalkoxy Phosphonic
and Phosphinic Acid Derivatives:
1
II. Reversible Esterase Inhibitors
V. V. Krutikova, V. I. Krutikov, and A. V. Erkin
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
Received November 17, 2009
Abstract―Polyfluoroalkyl esters of phosphoric, alkylphosphonic and 1-hydroxypolyfluoroalkylphosphonic
acids exhibited significant antiesterase activity against various esterases of animal and microbial origin.
Moreover, with some compounds reversible inhibition of enzymes was observed due to the specific influence
of hydrophobic fragments of the target products.
DOI: 10.1134/S1070363210030102
In our previous communication [1] we reported on
a high level of antiesterase activity of (1-hydroxy-
esters, which is largely due to non-enzymatic dehyd-
rochlorination of these compounds to dichlorovinyl-
phosphates and -phosphonates (1):
2
,2,2-trichloroethyl)alkyl- and phenylphosphinic acid
δ−
R1
R1
R1
R1
O
O
O
O
O
O−
P
P
P
OH
δ+
R2O
P
−
Cl
(1)
R2O
R2O
R2O
CCl3
CCl3
CCl3
Cl
Such rearrangement is facilitated by the strong
hydroxy-2,2,2-trichloroethylphosphonates with anhydrides
or chlorides of polyhalogen carboxylic acids:
negative inductive effect of polyfluoroalkoxy residues
on the phosphorus atom. In addition, the introduction
of hydrophobic groups to eliminated or non eliminated
parts of inhibitor molecule increases its irreversible
inhibitory action towards esterases [2]. Therefore it is
interesting to find out what factor contributes most of
all to the influence of polyfluoroalkoxy groups on the
level of antienzyme activity. This problem can be
solved in two main ways. Firstly, the evaluation of
biological activity of the compounds with protected
hydroxy group. Secondly, the replacement of the
trichloromethyl group for the less reactive one.
R1
R1
O
O
(
R CO) O
3 2
P
OH
P
CCl + R COOH
3
3
R O
R O
2
2
(
2)
CCl3
OC(O)R3
Ia-Ig
The use of polyhalogen carboxylic acid derivatives
as acylating agents is caused by the need to maximally
prevent the process of releasing the hydroxy group of
compounds I in vitro and their subsequent dehydro-
chlorination.
In this paper, we report on the synthesis of 1-
acyloxy-2,2,2-trichloroethyl- phosphonates and phos-
phinates of general formula (I) (Table 1). The target
compounds were obtained by the reaction of 1-
The structure of compounds I was confirmed by IR,
P NMR, and F NMR spectroscopy (Table 2). IR
3
1
19
spectra contain no hydroxy absorption band.
Compounds I were tested for biological activity in
vitro against butyrylcholinesterase (BCHE, KF 3.1.1.8)
1
For communication I, see [1].
434

POLYFLUOROALKOXY PHOSPHONIC AND PHOSPHINIC ACID DERIVATIVES: II.
435
Table 1. Yields, boiling and melting points, elemental analysis data for 1-acyloxy-2,2,2-trichloroetyl-phosphonates and -
phosphinates I
а
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp or bp, °С
(p, mm Hg)
R
1
R
2
R
3
Formula
С
Н
С
Н
Iа
Ib
Ic
Id
Ie
If
C
C
C
C
6
6
6
6
H
H
H
H
5
5
5
5
OCH
OCH
OCH
OCH
OCH
OCH
OCH
2
2
2
2
3
3
3
CF
2
CF
2
H
CCl
CCl
CCl
CCl
3
3
3
3
85
89
92
89
72
70
68
86
28.3
28.0
27.4
27.7
20.5
21.6
21.0
1.55
1.42
1.11
1.48
2.05
2.12
1.64
C
C
C
C
C
C
C
13
15
17
12
H
H
H
H
9
9
9
8
Cl
Cl
Cl
Cl
6
6
6
6
F
F
F
F
4
8
O
4
P
28.5
27.8
27.3
27.9
20.4
21.8
21.2
1.65
1.40
1.21
1.56
2.00
2.09
1.56
(CF
(CF
2
2
CF
2
2
)
2
3
H
H
79
O
4
P
CF
)
73
12
O
4
P
CF
3
88
3
O
4
P
OCH
OCH
OCH
3
3
3
CF
CF
3
2
98 (0.06)
106 (0.1)
120 (0.05)
6
7
8
H
7
Cl
Cl
Cl
3
3
3
F
3
F
4
F
7
O
5
P
5
P
5
P
CF
2
H
H
8
O
O
Ig
C
3
F
7
H
7
a
Here and further, elemental analysis data are not given for phosphorus and fluorine, because of the distortion of the results due to the
joint presence of the elements.
from horse serum, acetylcholinesterase (ACHE, KF
.1.1.7) from human blood erythrocytes, and an
esterase isolated from a strain of Gram-positive soil
bacterium Bacillus subtilis (EBs). It is worth to
indicate the significantly higher level of antienzyme
activity of polyfluoroacyloxy derivatives Ia–Id
while improving the efficiency of irreversible esterase
suppression by 2-3 orders of magnitude is due to an
increase in the inhibitor molecule volume. The
aforementioned fact confirms the importance of
sorption of the compounds I on the hydrophobic region
between the histidine imidazole ring and the hydroxy
group of serine of the enzyme esterase center.
3
(
Table 3) compared to non-fluorinated analogs. It
should be emphasized that the enzyme inhibition
Sufficiently large values of k , at least an order of
II
constants k practically coincide with those for 1-hyd-
II
magnitude higher than the data for afos, have been
found for the suppression of EBs by the drugs I (Table 3).
However, the level of irreversible antiesterase action
does not depend on structural features of the inhibitors.
This is due, firstly, to the enzyme-resistant phos-
phorus–carbon bond for the bulky phenyl radicals of
compounds I. Secondly, to a noticeable difference
between the geometric dimensions of microbial
roxy derivatives [1]. It is also interesting that
“
2
polyfluoroacylated trichlorfons” (Ie, Ig, Ii) are by 1–
orders of magnitude more active than trichlorfon [1].
These facts allow us to suggest that the non-enzymatic
dehydrochlorination (1) is not the only and the main
reason of the high antiesterase activity of 1-
hydroxyphosphonates and -phosphinates. The increase
in the magnitude of k is likely due mainly to increased
II
hydrophobic adsorption of the inhibitor on the
enzyme’s surface.
Table 2. NMR data for compounds I
1
9
31
F NMR spectrum, δ, ppm
CF CF
Р NMR
The correlation analysis by Gancia method using
lipophilicity parameter log P and molecular volume
value V allowed us to obtain the dependence for the
suppression of BCHE by the drugs I:
Comp.
no.
spectrum,
OCH
2
2
2
HCF
2
δ, ppm
Ia
Ib
Ic
Id
Ie
If
–47.6
–41.5
–41.5
–60
–61.2
33.9
34
2
log kII = –2.85 + 0.940log P – 0.137(log P) + 0.00759V, (3)
–46.1; –51.1; –59.0 –60.5
–44.8; –50.7; –58.8 –60.1
r 0.975, s 0.36.
35
а
The optimal value of log P for this group of
inhibitors was 3.43, which is significantly less than
similar parameters for the 1-hydroxyphosphinates [1].
The reason is probably an additional and significant
influence of the value of the inhibitor molecule volume
on the level of biological activity. This is confirmed by
–2.3
–
–
–
–
34.2
9.6
9.8
9.3
b
–2.9
–
–44.9
–59.1
b
Ig
–3.4
–48.8; –41.0
–
a
b
Chemical shift of trifluoroethoxy group. Chemical shift of the
terminal trifluoromethyl group.
a sufficiently strict dependence of log k –V (Fig. 1),
II
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010

4
36
KRUTIKOVA et al.
Table 3. Antiesterase activity of 1-acyloxy-2,2,2-trichloroethylphosphonates and -phosphinates I
–
1
Enzyme inhibition constant, kII, l mol min
Comp.
no.
3
R
1
R
2
R
3
logP
V, Å
AChE
BCHE
EBs
6
7
7
6
4
5
4
5
3
5
5
5
5
Iа
Ib
Ic
Id
Ie
If
C
C
C
C
6
6
6
6
H
H
H
H
5
5
5
5
OCH
OCH
OCH
OCH
OCH
OCH
OCH
2
2
2
2
3
3
3
CF
2
CF
2
H
CCl
3
3
3
3
3.11
4.78
6.45
2.99
2.65
2.76
4.31
3.00
1.53
1022
1162
1297
1028
758
–
4.57×10
2.57×10
2.82×10
1.70×10
3.98×10
2.51×10
3.98×10
3.55×10
6.03×10
2.00×10
(CF
(CF
2
2
CF
2
2
)
2
3
H
H
CCl
CCl
CCl
–
–
4.47×10
CF
)
3.98×10
CF
3
–
1.78×10
4
5
4
OCH
OCH
OCH
3
3
3
CF
CF
3
2
2.51×10
3.24×10
3.02×10
–
–
CF
2
H
808
–
Ig
C
3
F
7
830
–
4.47×10
–
a
4
Ih
OC
6
H
5
OC
6
H
5
CH
CH
3
913
3
Ii
OCH
3
OCH
3
3
753
6.03×10
a
Compounds Ih и Ii are afos and acetyldipterex respectively [3].
esterase “pocket” containing active sites, from those of
BCHE.
F
(R O)
3
P + H(CF
2 2 2 2
CF ) CHO·H O
O
(
R O)
2 P
(CF CF ) H + R OH
(4)
To answer the question posed at the beginning of
this communication, we have synthesized a number of
F
2
2 2
F
OH
II
1
-hydroxyphosphonates containing not trichloromethyl
but octafluorobutyl group II. It becomes impossible to
split off a proton from the hydroxy group and therefore
it excluded metabolic conversion of phosphonates to
vinylphosphates [reaction (1)].
The analytical data for hydroxyphosphonates II and
their biological activity are presented in the Tables 4
and 5, respectively.
Compounds IIa–IIc were prepared according to a
known reaction [4, 5]:
1
-Hydroxyphosphonates and -phosphinates II are
weak inhibitors of cholinesterase. It should be noted
that an unexpected reversible inhibition of choli-
nesterase by 1-hydroxyphosphonate IIc is observed.
The explanation of such a phenomenon can be as
follows. It is known that in some cases combined
inhibition of cholinesterase by organophosphorus
compounds may occur [2]:
log kII
8
7
6
→
EIr ҙ E + In
←
EIn → EIn',
(5)
where E is enzyme, In is inhibitor, EIn is Michaelis–
Menten complex, EIn' is phosphorylated enzyme, EIr
is inhibitor complex, incapable to transform into EIn'.
5
4
3
log kII = –0.368 + 0.00642V
r 0.941, s 0.47.
Such scheme is common for reactions with
equilibrium formation of an intermediate product. In
this case the usual methods of studying the kinetics
often cannot determine whether the intermediate
product is on the reaction route, or formed in parallel
7
00 800 900 1000 1100 1200 1300
V, Å
[
6]. In our case, the change in the concentration of
Fig. 1. Effect of the molecular volume V of 1-acyloxy-
,2,2-trichloroethylphosphonates and -phosphinates I on
the level of antibutyrylcholinesterase activity.
2
inhibitor did not lead to a decrease of its activity,
which confirms the formation of the complex EIr.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010

POLYFLUOROALKOXY PHOSPHONIC AND PHOSPHINIC ACID DERIVATIVES: II.
437
Table 4. Yields, boiling and melting points, elemental analysis data for 1-hydroxyoctafluoropentylphosphonates II
O
(
RO)2P
(CF CF ) H
2 2 2
OH
Found, %
Calculated, %
Comp.
no.
Yield,
%
bp, °С
R
mp, °С
Formula
(p, mm Hg)
С
Н
С
Н
IIа
IIb
IIc
CF
3
CH
2
89
92
72
140 (0.1)
148 (0.3)
162 (0.08)
44
39
–
23.1
23.9
24.2
1.39
1.45
0.90
C
C
C
9
H
7
F
14
16
32
O
4
P
22.7
24.5
24.3
1.48
1.68
0.96
H(CF
H(CF
2
2
)
)
2
6
CH
2
2
11
19
H
9
F
O
4
P
CH
H
9
F
O
4
P
Combined inhibition of cholinesterase happens not
only if the phosphorus atom has bulky hydrophobic
radicals. This effect also occurs in those cases where
there are two alkoxy groups at the phosphorus atom,
with the reversible component more pronounced in
BCHE, not ACHE [2]. However, in our case, the
reversible nature of inhibition was observed for both
enzymes. This is due to the introduction of
hydrophobic groups into substrate molecule leading to
a weakening of anticholinesterase activity and the
appearance of a reversible component. It should be
particularly noted that the reversible inhibitor of
esterases IIc has a very high hydrophobicity and a
large volume of the molecule (Table 5). Therefore it is
interesting to evaluate the biological activity of the
compounds with easily cleaved hydrophobic groups.
For such a role polyfluoroalkylphosphates are the best
choice.
Parameters of the mixed phosphates and
phosphonates and their biological activity are given in
Tables 6 and 7, respectively. Analysis of the biological
activity of these compounds showed the low
irreversible inhibition of esterases, especially ACHE.
The following correlations have been found:
2
log kII = –3.30 – 0.671log P – 0.056(log P) + 0.0122V, (8)
r 0.916, s 0.46.
2
log k = 1.46 + 4.88log P – 0.350(log P) – 0.0124V,
II
(9)
r 0.998, s 0.12.
Correlation parameters [Eqs. (8), (9), Fig. 2] clearly
indicate the importance of hydrophobic and steric
parameters in evaluating the inhibitory activity of
polyfluoroalkylphosphates. In addition, there is a
coincidence of the main parameters of correlation
equations with those for 1-hydroxy-2,2,2-trichloro-
ethylphosphonates. In particular, the value of log Popt
was 5.09 [for a maximum of function, Eq. (9)], which
is in good agreement with the value obtained earlier
[1].
When 5-hydrooctafluoropentanal hydrate reacts
with trimethylphosphite the products are the cor-
responding mixed phosphates, formed through
phosphono-phosphate rearrangement of 1-hydroxy-
phosphonates [7]:
We also have found a reversible inhibition of
ACHE and BCHE by di(1,1,5-trihydrooctafluoro-
pentyl)ethylphosphonate IIIg, with the concentration
(
R
F
O)
(RO) P(O)OCH
IIIа, IIIb
3
P + H(CF
2
CF
2
)
2
CHO·H
2
O
→
2
2
(CF
2
CF
2
)
2
H + ROH.
(6)
Table 5. Biological activity of 1-hydroxyoctafluoropentyl-
phosphonates II
Other mixed phosphates and phosphonates were
obtained by the Todd–Atherton reaction from the cor-
responding incomplete phosphites or phosphonites:
Enzyme inhibition constant,
Comp.
no.
–1
3
k
II, l mol min
log P
V, Å
R (R O)P(O)H + R OH
AChE
BCHE
1
2
3
2
3
IVa, IVb
IIа
4.00×10
2.30×10
5.00×10
2.00×10
1.80×10
2.50×10
6.35
6.58
13.3
878
1004
1510
R1
2
6
O
IIb
NEt3, CCl4
+
CHCl + NEt3 HCl (7)
a
–4
–4
P
3
IIc
OR3
R O
2
a
For compound IIc values of IС50 causing 50% reversible
IIIc−IIIg
inhibition are given.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010

4
38
KRUTIKOVA et al.
Table 6. Yields, boiling and melting points of the mixed polyfluoroalkylphosphates and -phosphonates III
о
Comp. no.
R
1
R
2
R
3
Yield, %
bp, С (mm Hg)
а
IIIа
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
СH
3
3
О
СH
3
3
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
(CF
(CF
(CF
2
2
2
CF
CF
CF
2
2
2
)
)
)
2
3
2
H
H
H
78
69
70
65
74
62
71
60 (0.5)
89 (0.5)
69 (0.4)
72 (1)
СH
О
СH
b
C
2
H
5
О
2 5
C H
iso-C
3
3
H
7
7
O
iso-C
3
3
H
7
7
CF
2
CF
2
H
iso-C
H
О
iso-C
H
(CF
2
CF
2
)
3
H
80 (0.7)
109 (7)
141 (4)
C
2
2
H
5
5
CH
2
2
CF
CF
3
CF
CF
3
2
C
H
CH
2
CF
2
H
2
CF H
a
b
Compounds IIIa, IIIb were obtained by the reaction (5) and described earlier [7]. Compounds IIIc–IIIg were obtained by the reaction (6).
Table 7. Anticholinesterase activity of the mixed polyfluoroalkylphosphates and -phosphonates III
–
1
Enzyme inhibition constant, kII, l mol min
Comp.
no.
3
R
1
R
2
R
3
logP
V, Å
AChE
4.30×10
2.00×10
2.20×10
4.30×10
2.00×10
8.00×10
2.00×10
BCHE
2
4
IIIа
IIIb
IIIc
IIId
IIIe
IIIf
СH
3
3
О
СH
3
3
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
(CF
2
CF
CF
CF
2
2
2
)
)
)
2
3
2
H
H
H
4.79×10
1.51×10
3.98×10
2.53×10
7.94×10
4.27×10
2.00×10
3.31
4.98
4.00
3.16
6.49
2.27
5.84
724
879
2
6
СH
О
СH
(CF
(CF
2
2
3
5
C
2
H
5
О
C
2
H
5
799
3
3
iso-C
3
3
H
7
7
O
iso-C
3
3
H
7
CF
2
CF
2
H
805
4
3
iso-C
H
О
iso-C
H
7
(CF
2
CF
2
)
3
H
1170
658
2
2
C
2
2
H
5
5
CH
2
2
CF
CF
3
2
CF
CF
3
2
а
–6
–6
IIIg
C
H
CH
CF
2
H
CF
2
H
1137
a
For the compound IIIg values of IС50 causing 50% reversible inhibition are given.
of the substrate, providing 50% inhibition of the
enzyme by two orders of magnitude lower than for the
phosphonate IIc.
The molecular volumes V and lipophilicity
parameters log P for the target compounds were
calculated using the software package HyperChem™
Release 7.52 for Windows Molecular Modeling
System, after the geometric optimization of the
structure by Fletcher-Reeves method.
Thus, the studies of antiesterase activity of
polyfluoroalkoxy derivatives of phosphonic and
phosphoric acids revealed that the most significant
contribution to the level of enzyme inhibition make
polyfluoro ester fragments. Moreover, esterase of
microbial origin is more sensitive to hydrophobic
substrates. Finding among the studied range of organo-
phosphorus substances reversible inhibitors offers the
prospect of using them as low-toxicity antidotes.
The homogeneity of the compounds was confirmed
either by GLC (on a LKhM-8MD instrument,
stationary phase XE-60 10% on Chezasorb Inerton,
detector katharometer, carrier gas helium, 40 ml/min)
for liquid products or by TLC (on Silufol UV 254
plates, eluent acetone-hexane, 1:4) for solid products.
3
1
19
P and F NMR spectra were recorded on the
device, designed and built in St. Petersburg STI
operating frequency 16.2 and 37.6 MHz, external
standard 85% PO and trifluoroacetic acid,
EXPERIMENTAL
(
The antiesterase activity was evaluated by a
technique based on a comparison of the enzymatic
hydrolysis of chromogenic substrate indophenylacetate
before (v ) and after (v ) contact with the inhibitor with
H
3
4
respectively). IR spectra were recorded from mulls in
mineral oil Ia–Id, or from films Ie–Ig on an IKS-29
instrument. Elemental analyses were performed on a
CHN-3 analyzer.
0
τ
incubation time (t) from 1 to 10 minutes [1].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010

POLYFLUOROALKOXY PHOSPHONIC AND PHOSPHINIC ACID DERIVATIVES: II.
439
(
1,1,3-Trihydrotetrafluoropropyl)(1-trichloro-
log kII
6
6
.5
.0
acetoxy-2,2,2-trichloroethyl) phenylphosphinate (Ia).
To a solution of 2.68 g of 1,1,3-trihydrotetra-
fluoropropyl)(1-hydroxy-2,2,2trichloroethyl)phenyl-
phosphinate in 45 ml of dichloroethane, cooled to 0°C,
5
.5
0
.91 g of trichloroacetyl chloride was added dropwise
5.0
with stirring, followed by 3.2 ml of 25% aqueous
sodium hydroxide solution. The mixture was stirred at
room temperature for further 2 h. The organic layer
was separated, washed with water (3×25 ml), and dried
with calcium chloride. Removing solvent in vacuo
gave 3.1 g (85%) of the target product as a colorless
crystalline substance, mp 86°C.
4
4
.5
.0
3.5
log kII = 4.29 – 3.72log P +
2
3
3
2
.0
.5
1.70(log P) – 0.175(log P) , (10)
r 0.967, s 0.54.
Dimethyl-(1-trifluoroacetoxy-2,2,2-trichloro-
ethyl)phosphonate (Id). To a solution of 2.3 g of dime-
thyl(1-hydroxy-2,2,2-trichloroethyl)phosphonate in 40 ml
of dichloroethane 2.1 g of trifluoroacetic acid anhyd-
ride was added dropwise at room temperature. The
reaction mixture was heated at 40°C with stirring for 2 h.
Then the solvent and trifluoroacetic acid were distilled
off in a vacuum. Fractional distillation gave 2.3 g (72%)
of the target product. Polyfluoroacyloxy trichlorfon
derivatives If, Ig were obtained in a similar manner.
2
3
4
5
6
7
log P
Fig. 2 Effect of the lipophilicity of the phosphates III on
BCHE inhibition constant.
carbon tetrachloride 6.9 g of diethylphosphite was
added with stirring maintaining the temperature around
10 °C. Reaction mixture was stirred for 1 h at room
temperature and for 1 h at 35–40°C. The precipitate
formed was filtered off and the solvent was removed at
a reduced pressure. Fractional distillation of the
residue gave 12.9 g (70%) of the target product, bp
(1,1,3-Trihydrotetrafluoropropyl)ethylphosphonite.
1
3.2 g of 1,1,3-trihydrotetrafluoropropanol were placed
in a 4-neck flask equipped with a stirrer, a reflux
condenser, and a dropping funnel and cooled to 0°C.
6
9°C (0.4 mm Hg).
ACKNOWLEDGMENTS
The authors express their gratitude to S.F. Aleinikov
6
.6 g of ethylphosphonic acid dichloride was added
dropwise, maintaining the temperature in the flask
below 3°C. The reaction mixture was kept at room
temperature for 0.5 h, and then hydrogen chloride was
removed by bubbling dry air through it for 5 h.
Fractional distillation of the residue afforded 12.6 g
for the participation in the work and discussion of its
results.
REFERENCES
(
(
1
78%) of the product, bp 103°C (10 mm Hg). For
1,1,5-trihydrooctafluoropentyl)ethylphosphonite: bp
31°C (12 mm Hg).
1
2
.
.
Krutikova, V.V., Krutikov, V.I., and Erkin, A.V., Zh.
Obshch. Khim., 2010, vol. 80, no. 3, p. 403.
Brestkin, A.P. and Godovikov, N.N., Usp. Khim., 1978,
vol. 47, no. 9, p. 1609.
Di(1,1,7-trihydrododecafluoroheptyl)(1-hydroxy-
5
-hydrooctafluoropentyl)-phosphonate (IIb). To a
3. O’Brain, R., Toksichnye efiry kislot fosfora (Toxic
Esters of Phosphorus Acids), Moscow: Mir, 1964.
4. Fokin, A.V., Studnev, Yu.N., Rapkin, A.I., Pasevina, K.I.,
Verenikin, O.V., and Kolomiets, A.F., Izv. Akad. Nauk
SSSR, Ser. Khim., 1981, p. 1655.
solution of 2.5 g of 5-hydrooctafluoropentanal hydrate
in 40 ml of benzene 10.2 g of tris(1,1,7-trihydro-
dodecafluoroheptyl)phosphite was added dropwise
with stirring, keeping the temperature of the reaction
mixture in the range of 20–25°C. After stirring for
further 2 h solvent was distilled off and the residue
subjected to fractional distillation yielding 6.8 g of the
target product. Other phosphonates II were obtained in
the same way.
5
.
Aleinikov, S.F., Krutikov, V.I., Maslennikov, I.G.,
Kashkin, A.V., and Lavrent’ev, A.N., Zh. Obshch.
Khim., 1983, vol. 53, no. 7, p. 1537.
6
.
Gammet, L., Osnovy fizicheskoi organicheskoi khimii
(
Fundamentals of Physical Organic Chemistry),
Moscow: Mir, 1972.
1
,1,5-Trihydrooctafluoropentyldiethylphosphate
IIIc). To a mixture of 5 g of triethylamine and 11.5 g
of 1,1,5-trihydroperfluoropentanol-1 in 150 ml of
7. Aleinikov, S.F., Krutikov, V.I., Mikisheva, L.I., and
Lavrent’ev, A.N., Zh. Obshch. Khim., 1984, vol. 54,
no. 4, p. 968.
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010