Synthesis of symmetric and dissymetric bisperfluoroalkanesulfonylimides and evaluation of their inhibition on bovine carbonic anhydrase

Article abstract of DOI:10.1002/hc.20452

This study describes a synthesis of symmetric and dissymmetric bis[(perfluoroalkane)-sulfonyl]imides by the reaction of the sodium salt of perfluoroalkanesulfonamide R_FSO₂NH^-Na ⁺ (R_F = C₄F₉, C₆F ₁₃, C₈F₁₇) with hexamethyldisilazane and perfluoroalkanesulfonylfluoride R_FSO₂F (R_F - C₄F₉, C₆F₁₃, C₈F ₁₇). They are obtained, in two steps, in moderate overall yield. Moreover, this paper provides a study of their inhibition on bovine carbonic anhydrase.

Full text of DOI:10.1002/hc.20452

Heteroatom Chemistry
Volume 19, Number 5, 2008
Synthesis of Symmetric and Dissymetric
Bisperfluoroalkanesulfonylimides and
Evaluation of Their Inhibition
on Bovine Carbonic Anhydrase
Zohra Benfodda, Franck Guillen, and Hubert Blancou
Institut des Biomole´cules Max Mousseron (IBMM), UMR CNRS 5247, Universite´ de Montpellier
I et de Montpellier II, Universite´ de Montpellier II CC017, Place Euge`ne Bataillon 34095,
Montpellier cedex 05, France
Received 15 November 2007; revised 21 February 2008
Perfluoroalkanesulfonimides are of increasing
ABSTRACT: This study describes a synthesis of
interest for their high Bro¨nsted acidity, electro-
symmetric and dissymmetric bis[(perfluoroalkane)-
chemical properties, and high thermal and chemical
sulfonyl]imides by the reaction of the sodium
stability.
salt of perfluoroalkanesulfonamide RF SO2NH−Na+
Salts of anions of bis[(perfluoroalkane)sulfonyl]-
(RF = C4F9, C6F13, C8F17) with hexamethyldisi-
imides have been found to serve as solutes for poly-
lazane and perfluoroalkanesulfonylfluoride RF SO2F
mer electrolytes leading to dramatically improved
(RF = C4F9, C6F13, C8F17). They are obtained, in two
performance in lithium batteries and fuel cells
steps, in moderate overall yield. Moreover, this paper
[4–6]. They also present a significant interest as in-
provides a study of their inhibition on bovine car-
termediates of electrophilic fluorinating agents [7,8],
ꢀ
C
bonic anhydrase.
2008 Wiley Periodicals, Inc. Het-
in ionic liquids [9], as Lewis acid catalysts do for
Diels Alder [10] and Friedel–Crafts acylation [11].
However, until now they have never been studied
for their biological properties, in particular for their
activity on bovine carbonic anhydrase (bCA).
eroatom Chem 19:542–548, 2008; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20452
Our research team has developed new method-
ologies of syntheses and aim at reaching to var-
ious families of fluorinated molecules, in particu-
lar those comprising the following sulfur functions:
sulfonic acids and sulfinic acids derivatives [12–
14]. We were interested with the perfluoroalkane-
sulfonimides because it is known that sulfonamides
[15,16], in particular trifluoromethanesulfonamide
was an inhibitor of bCA [17]. Because of the analogy
of structure of perfluoroalkanesulfonylimides with
perfluoroalkanesulfonamides, we thought that these
compounds could inhibit the bCA enzyme.
INTRODUCTION
It has been known for a few years that the substitu-
tion of a hydrogen atom by a fluorine atom in organic
compounds can modify their physical, chemical, and
biological properties. Consequently, the synthesis of
organofluorine compounds has become an impor-
tant area of chemistry both in academia and industry
[1–3].
Correspondence to: Hubert Blancou; e-mail: hubert.blancou@
The perfluoroalkanesulfonimides could be pre-
pared by different methods. They involve a multistep
univ-montp2.fr.
c
ꢀ
2008 Wiley Periodicals, Inc.
542

Synthesis of Symmetric and Dissymetric Bisperfluoroalkanesulfonylimides and Evaluation of Their Inhibition on bCA 543
reaction using sodium perfluoroalkanesulfonamides
the reaction media. Finally, the N-silyl form (2) re-
act with an excess of perfluoroalkanesulfonylfluo-
ride, in THF at 70◦C from 12 to 24 h, and lead to
bis[(perfluoroalkane)sulfonyl]imides (3) after acidi-
fication by aqueous solution of HCl in a range vary-
ing from 46% to 62% yield based on starting amount
of 1.
In the last reaction described in Scheme 1, three
different products were obtained. In the first part,
there was the formation of the expected product:
the perfluoroalkanesulfonylimide (3), in the second
part the formation of the perfluoroalkanesulfonic
acid (4), and in the third part perfluoroalkanesulfon-
amides (5). These compounds were identified and
characterized by 19F NMR spectroscopy and FAB
spectroscopy.
with hexamethyldisilizane and perfluoroalkanesul-
fonylfluorides [18–20], or a one-pot synthesis by
the reaction of perfluoroalkanesulfonylfluoride with
liquid NH3 in the presence of triethylamine as a
base under −40◦C [21]. Also the reaction could be
made from perfluoroalkanesulfonamides with per-
fluoroalkanesulfonylhalides in the presence of non-
nucleophilic base such as lithium carbonate [22], or
a one-pot reaction of perfluoroalkanesulfonylhalides
with acetamide derivatives in the presence of K2CO3
[23], or a protonation of N-sulfonyl trichlorophosp-
hazenes with sulfonic acids [24].
In the present paper, we describe the synthesis
of symmetric and dissymmetric bis[(perfluoro-
alkane)sulfonyl]imides using a sodium salt of per-
fluoroalkanesulfonamides,
(HMDS), and perfluoroalkanesulfonylfluoride.
Then, we have evaluated their inhibition in vitro on
bCA.
hexamethyldisilazane
We determined the conversion of each chemical
species by 19F NMR spectroscopy (Table 1).
We can note that the formation of the perfluo-
roalkanesulfonamides (5) was probably due to the
hydrolysis of the N-silyl form (2) at the time of the
acid treatment, which can be interpreted by the fact
that the N-silyl form intermediate did not completely
react.
The formation of the perfluoroalkanesulfonic
acid (4) was probably related to the hydrolysis of
the perfluoroalkanesulfonylfluoride (in excess in the
reaction), which did not react.
RESULTS AND DISCUSSION
Chemistry
In our experiments, the method was based on that
used by Desmarteau et al. to prepare perfluoroalka-
nesulfonylimides [18,19]. The procedure to synthe-
size bis[(perfluoroalkane)sulfonyl]imides is shown
in Scheme 1.
The sodium perfluoroalkanesulfonamides (1)
were synthesized starting from perfluoroalkanesul-
fonamides and sodium methylate; their synthesis
was previously described [25].
The perfluoroalkanesulfonylimides (3) were pu-
rified by silica gel chromatography and were char-
acterized by 19F NMR spectroscopy and HRMS.
Carbonic Anhydrase Inhibition
The N-silyl form (2) was prepared by the reac-
tion of sodium perfluoroalkanesulfonamide (1) with
an excess of HMDS in acetonitrile at 110◦C for 24 h.
In our experiment, it was difficult to analyze this in-
termediate (2) by NMR spectroscopy or mass spec-
troscopy because of its great moisture sensitivity.
We considered that compound 2 was formed in
Carbonic anhydrases (CAs) are zinc metalloen-
zymes, which catalyze the reversible hydration of
carbon dioxide into bicarbonate and therefore are vi-
tal to many biological and physical functions. The in-
hibition of these enzymes may be clinically exploited
in the treatment or prevention of a variety of disor-
ders. In consequence, CA inhibitors (CAIs) possess
a variety of applications in therapy. CA inhibition
with sulfanilamide discovered by Mann and Keilin
was the beginning of a great scientific adventure
that led to important drugs such as the antihyper-
tensives of benzothiadiazine and high-ceiling-type
diuretics, the sulfonamides with CA inhibitory prop-
erties are mainly used as antiglaucoma agents, some
antithyroid drugs, hypoglycemic sulfonamides, and
ultimately some novel types of anticancer agents
[15,26,27].
In this paper, we prepared bis[(perfluoroalkane)-
sulfonyl]imides and they were evaluated for inhi-
bition on bCA. Not only does CA catalyze the re-
versible hydration of CO2 and dehydration of HCO3−
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

544 Benfodda, Guillen, and Blancou
TABLE 1 Determination of the Conversion of Each Species by 19F NMR Spectroscopy
Reactants
RF SO2F
Products
Yieldsa
1
3
Yieldsa
4
5
Yieldsa
1a
1a
1b
1b
1c
1c
C4F9SO2F
C8F17SO2F
C6F13SO2F
C4F9SO2F
C8F17SO2F
C6F13SO2F
a
b
c
d
e
f
64
61
69
78
58
66
A
C
B
A
C
B
23
25
25
13
19
24
a
a
b
b
c
c
13
14
6
9
23
10
aThe conversions were determined by 19F NMR spectroscopy (d6-acetone) after treatment of the crude product (the residue was dissolved in
Et2O and washed with 1 N HCl and water). They were also determined by the relative integration of the functional CF signal of compounds 3, 4,
2
5 by the formula (f i/Ni)/(ꢀf i/Ni) × 100, where f i represent the height integration of the functional CF signal and Ni the number of corresponding
2
atom.
but also the hydrolysis of many esters. We assayed
the enzyme activity both with respect to hydra-
tion of CO2 and to hydrolysis of an ester, namely
p-nitrophenylacetate (NPA). Although the esterase
activity of these enzymes was very weak, by com-
parison with the CA activity, it could be determined
with greater ease and accuracy [28,29]. We deter-
mined esterase activity spectrophotometrically with
NPA as substrate in routine assays (Fig. 1). Hydroly-
sis Kinetics of NPA by bCA was calculated from the
tangents at time zero minute in the presence and in
the absence of perfluoroalkanesulfonylimides.
It is interesting to note that we used a constant
concentration of NPA (7.5 × 10−4 M) and a constant
concentration of bCA (2.9 × 10−6 M) for this study.
We followed the rate of the hydrolysis of the NPA
by measurements of the absorbance at 348 nm, and
we deduced the rate of inhibition of the different
compounds previously prepared on bCA. The results
are shown in Table 2.
We thought that the sulfonimide function would
complex the zinc ion of the active site like the sulfon-
amide function does it. Moreover, we had imagined
that the F-alkylated chain of the perfluoroalkanesul-
fonylimides, which are known to be very hydropho-
bic could push back the water, which is formed at
the time of the enzymatic catalysis. Unfortunately,
we did not obtain the expected results.
At a concentration of 1.35 × 10−4 M, we found for
the symmetric perfluoroalkanesulfonylimides (3a,
3c, 3e) that the compound with the C4F9 chain in-
hibits less than the compound with the C6F13 and
C8F17 chains. These two last compounds inhibit the
bCA in an equivalent way. For the dissymmetric per-
fluoroalkanesulfonylimides (3b, 3d, 3f), the inhibi-
tion properties are similar.
At a concentration of 1.35 × 10−6 M, we see that
the inhibition properties disappear for all perflu-
oroalkanesulfonimides, whereas for acetazolamide
and trifluoromethanesulfonamide, there is a good
inhibition of the hydrolysis of NPA. Because of the
weak inhibition properties of the perfluoroalkane-
sulfonylimides, we do not determinate the inhibition
constants (Ki).
Tangent 1
DO
We may suppose on the one hand that the two
F-alkylated chains were rigid and could prevent the
access to the active site of the enzyme, and on the
other hand that the sulfonylimide function could not
complex enough the Zn metal present in the catalytic
site.
a
Tangent 2
b
Time (min)
CONCLUSION
FIGURE 1 Determination of the rate of the hydrolysis of NPA
by measurements of the absorbance at 348 nm. Note that
curve a represents the hydrolysis of NPA (7.5 × 10−4 M) by
bCA without any compound and curve b represents the hy-
drolysis of NPA in presence of perfluoroalkanesulfonylimides.
In summary, we prepared a symmetric and dis-
symmetric perfluoroalkanesulfonimides starting
from sodium salts of perfluoroalkanesulfonamides,
HMDS, and perfluoroalkanesulfonylfluorides and
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Symmetric and Dissymetric Bisperfluoroalkanesulfonylimides and Evaluation of Their Inhibition on bCA 545
TABLE 2 Determination of the percent Inhibition of the Hydrolysis of the NPA on bCA by Different Compounds
Inhibition of Hydrolysis (%) Compounds
Compound Concentrations Tested
3a
3b
3c
3d
3e
3f
CF3SO2NH2
Acetazolamide
1.35 × 10−4
M
M
65
0
97
0
85
0
87
0
89
0
87
0
87
85
85
85
1.35 × 10−6
NPA = p-nitrophenylacetate.
we assayed their inhibition on bCA. In spite of their
current interest, perfluoroalkanesulfonylimides
have not been studied for their biological properties.
In consequence, we found that these compounds in-
mixture of 10 g of perfluorohexanesulfonamide
(25 mmol) and 1.28 of sodium methylate
g
(23.68 mmol) dissolved, respectively, in 40 mL of
anhydrous diethyl ether, and 5 mL of methanol was
refluxed for 3 h and then filtered. The filtrate was
evaporated in vacuo, and the residue was washed
three times with 30 mL of diethyl ether to remove
the excess of perfluorohexanesulfonamide and then
dried under vacuum. An amount of 9.7 g of 2b was
obtained (92%).
hibit this enzyme at a concentration of 1.35 × 10−4
M
and do not inhibit it at concentration of 1.35 ×
10−6 M. Further studies of Docking could help
us to understand the favorable positioning of the
perfluoroalkanesulfonylimides in the enzymatic site.
19F NMR (282.37 MHz, d6-acetone):
δ
EXPERIMENTAL
Chemistry
−125.93 (m, 2F, CF3CF2(CF2)4), −122.46 (m, 2F,
CF3CF2CF2(CF2)3), −121.56 (m, 2F, CF3(CF2)2CF2
(CF2)2), −120.06 (m, 2F, CF3(CF2)3CF2CF2), −113.55
(m, 2F, CF3(CF2)4CF2), −80.83 (m, 3F, CF3(CF2)5);
MS (FAB−): 398; HRMS Calcd for C6HO2NF13S:
397.9482; found 397.9492.
Moisture-sensitive reactions were carried out un-
der dry nitrogen. The trifluoromethanesulfonimide
and the acetazolamide were purchased from Aldrich
(Saint Quentin Fallavier, France). HMDS was pur-
chased from Aldrich and distilled once before use.
Solvents were distilled from the appropriate dry-
ing agents immediately prior to use. Reactions were
monitored on TLC on silica gel 60 F254 and visualized
under iodine. For column chromatography, silica gel
(Kieselgel 60) was employed.
General Procedure for the Synthesis
of N-Trimethylsilane Sodium Salts
of Perfluoroalkanesulfonamides
RF SO2NNaSi(CH3)3 (2a, 2b, 2c)
Freshly distilled HN[Si(Me)3]2 (25 eq.) was added to
a stirred solution of dry powdered RFSO2NH− Na+
(1 eq.) dissolved in dry CH3CN. The reaction mixture
was refluxed at 110◦C for 24 h. The solvent and excess
of HMDS were then removed by vacuum distillation.
Owing to the moisture sensitivity of the compound,
the remaining solid was used directly without any
further characterization and the yield was not deter-
mined.
1H and 19F, spectra were recorded respectively at
300.13 MHz, 282.37 MHz with a Brucker Avance 300
spectrometer, therefore chemical shifts are given in
parts per million relative to Me4Si, CCl3F, respec-
tively, as internal standards. Coupling constants are
given in Hz. Mass spectra and HRMS were recorded
on a Jeol SX 102 spectrometer.
Melting points were recorded at atmospheric
pressure unless otherwise stated on a Stuart sci-
entific SMP3 apparatus and remained without any
correction.
Synthesis of N-Timethylsilane Sodium Salts of
Perfluorobutanesulfonamide (2a). A total of 3 g
(9.3 mmol) of 1a was dissolved in CH3CN (15 mL),
and HMDS (49 mL) was added. In all, 3.6 g of 2a
obtained.
Synthesis of Sodium Perfluoroalkanesulfon-
amides (1a, 1b, 1c)
The synthesis of sodium perfluorobutanesulfon-
amide (1a) and sodium perfluorooctanesulfonamide
(1c) were described previously [25].
Synthesis of N-Trimethylsilane Sodium Salts
of Perfluorohexanesulfonamide (2b). A measure of
9.7 g (23 mmol) of 1b was dissolved in CH3CN
(37 mL), and HMDS (120 mL) was added. In all,
11 g of 2b was obtained.
Synthesis of Sodium 1,1,2,2,3,3,4,4,5,5,6,6,6-
Tridecafluorohexane-n-hexanesulfonamide (1b). A
Heteroatom Chemistry DOI 10.1002/hc

546 Benfodda, Guillen, and Blancou
Synthesis of N-Trimethylsilane Sodium Salts of
Perfluorooctanesulfonamide (2c). A total of 12 g
(23 mmol) of 1c were dissolved in CH3CN (38 mL)
and HMDS (122 mL) was added. In all, 13.4 g of 2c
were obtained.
Synthesis of Bis((1,1,2,2,3,3,4,4,5,5,6,6,6-Tride-
cafluorohexane)sulfonyl)imide (3c). 2b (3.42 g,
6.94 mmol) and C6F13SO2F (3.21 g, 7.98 mmol) dis-
solved in CH3CN (20 mL) were refluxed for 24 h.
The crude product was purified by silica gel chro-
matography (AcOEt/petroleum ether = 6/4) to give
3c (2.98 g) in a 54% overall yield based on the start-
ing amount of 1b.
General Procedure for the Synthesis of
Perfluoroalkanesulfonylimides (3a, 3b, 3c)
mp: 132.5◦C; 19F NMR (282.37 MHz, d6-acet-
one): δ −125.8 (m, 4F, (CF3CF2(CF2)4SO2)2NH),
−122.4 (m, 4F, (CF3CF2CF2(CF2)3SO2)2NH), −121.4
(m, 4F, (CF3(CF2)2CF2(CF2)2SO2)2NH), −119.7 (m,
4F, (CF3(CF2)3CF2CF2SO2)2NH), −112.8 (m, 4F, (CF3
(CF2)4CF2SO2)2NH), −80.7 (m, 6F, (CF3(CF2)5SO2)2
NH); MS (FAB−): 780; HRMS calcd for C12NO4
F26S2 779.8854; found 779.8840.
RFSO2F (1.15 eq) was added to a stirred solution of
dry powdered RFSO2N−NaSi(CH3)3 (1 eq.) dissolved
in dry THF. The reaction mixture was refluxed from
12 to 24 ho at 70◦C. After cooling, all volatile parts of
the mixture were removed in vacuo. The residue was
dissolved in Et2O and washed once with an aque-
ous solution of HCl (1 N) and twice with water.
The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure. Silica gel
chromatography (AcOEt/petroleum ether = 6/4 (v/v))
yielded perfluoroalkanesulfonylimides 3.
Synthesis of S-(1,1,2,2,3,3,4,4,5,5,6,6,6 Trideca-
fluorohexane), Sꢁ-(1,1,2,2,3,3,4,4,4-Nonafluorobut-
ane)sulfonylimide (3d). 2b (5.68 g, 11.5 mmol) and
C4F9SO2F (4 g, 13.2 mmol) dissolved in CH3CN
(20 mL) were refluxed for 24 h. The crude prod-
uct was purified by silica gel chromatography
(AcOEt/petroleum ether = 6/4) to give 3d (4.93 g) in
a 61% overall yield based on the starting amount of
1b.
Synthesis of Bis((1,1,2,2,3,3,4,4,4-Nonafluoro-
butane)sulfonyl)imide (3a). 2a (1.21 g, 3.1 mmol)
and C4F9SO2F (1.07 g, 3.56 mmol) dissolved in
CH3CN (10 mL) were refluxed for 12 h. The crude
product was purified by silica gel chromatography
(AcOEt/petroleum ether = 6/4) to give 3a (1 g) in a
55% overall yield based on the starting amount of
1a.
mp: 127.2◦C; 19F NMR (282.37 MHz, d6-acetone):
δ −125.8 (m, 4F, CF3CF2(CF2)4SO2NHSO2CF2),
−122.5 (m, 2F, CF3CF2CF2(CF2)3SO2), −121.4 (m,
2F, CF3(CF2)2CF2(CF2)2SO2), −120.7 (m, 2F, SO2
CF2CF2CF2CF3), −113.0 (m, 2F, CF3(CF2)4CF2SO2),
−112.9 (m, 2F, SO2CF2(CF2)2CF3), −80.7 (m, 6F, CF3
(CF2)5SO2NHSO2(CF2)3CF3); MS (FAB−): 680;
HRMS calcd for C10NO4F22S2: 679.8917; found
679.8922.
mp: 120.7◦C; 19F NMR (282.37 MHz, d6-
acetone): δ −125.7 (m, 4F, (CF3CF2(CF2)2SO2)2NH),
−120.7 (m, 4F, (CF3CF2CF2CF2SO2)2NH), −113.0
(m, 4F, (CF3(CF2)2CF2SO2)2NH), −80.8 (m, 6F,
(CF3(CF2)3SO2)2NH); MS (FAB−): 580; HRMS Calcd
for C8NO4F18S2: 579.8981; found 579.8968.
Synthesis of S-(1,1,2,2,3,3,4,4,4-Nonafluorobut-
ane), Sꢁ-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Heptadeca-
fluorooctane)sulfonylimide (3b). 2a (1.18 g,
3 mmol) and C8F17SO2F (1.73 g, 3.45 mmol)
dissolved in CH3CN (10 mL) were refluxed for
12 h. The crude product was purified by silica gel
chromatography (AcOEt/petroleum ether = 6/4) to
give 3b (1.22 g) in a 51% overall yield based on the
starting amount of 1a.
Synthesis of Bis((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
Heptadecafluorooctane)sulfonyl)imide
(3e). 2c
(6.63 g, 11.1 mmol) and C8F17SO2F (6.45 g,
12.8 mmol) dissolved in CH3CN (20 mL) were
refluxed for 24 h. The crude product was purified
by silica gel chromatography (AcOEt/petroleum
ether = 6/4) to give 3e (5.2 g) in a 46% overall yield
based on the starting amount of 1c.
mp: 143.3◦C; 19F NMR (282.37 MHz, d6-acetone):
δ −125.8 (m, 4F, (CF3CF2(CF2)6SO2)2NH), −122.3
(m, 4F, (CF3CF2CF2(CF2)5SO2)2NH), −121.4 (m,
12F, (CF3(CF2)2(CF2)3(CF2)2SO2)2NH), −119.6 (m,
4F, (CF3(CF2)5CF2CF2SO2)2NH), −112.8 (m, 4F, (CF3
(CF2)6CF2SO2)2NH), −80.7 (m, 6F, (CF3(CF2)7SO2)2
NH), MS (FAB−): 980; HRMS Calcd for C16NO4F34S2:
979.8726; found 979.8703.
mp: 130.3◦C; 19F NMR (282.37 MHz, d6-
acetone): δ −125.7 (m, 4F, CF3CF2(CF2)2SO2NHSO2
(CF2)6CF2CF3), −122.3 (m, 2F, SO2(CF2)5CF2CF2
CF3), −121.4 (m, 6F, SO2(CF2)3(CF2)3CF2CF3),
−120.7 (m, 2F, CF3CF2CF2CF2SO2), −119.6 (m, 2F,
SO2CF2CF2(CF2)5CF3), −113.0 (m, 2F, CF3(CF2)2
CF2SO2), −112.9 (m, 2F, SO2CF2CF2(CF2)5CF3),
−80.8 (m, 6F, CF3(CF2)3SO2NHSO2(CF2)7CF3); MS
(FAB−): 780; HRMS calcd for C12NO4F26S2: 779.8854;
found 779.8844.
Synthesis of S-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
Heptadecafluorooctane), Sꢁ-(1,1,2,2,3,3,4,4,5,5,6,6,6-
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Symmetric and Dissymetric Bisperfluoroalkanesulfonylimides and Evaluation of Their Inhibition on bCA 547
1
5c (C8F17SO2NH2). mp: 154.6◦C. H NMR (300.13
MHz, d6-acetone): δ 8.2 (m, 2H, SO2NH2); 19F
NMR (282.37 MHz, d6-acetone): δ −125.8 (m,
2F, CF3CF2(CF2)6), −122.3 (m, 2F, CF3CF2CF2
(CF2)5), −121.4 (m, 6F, CF3(CF2)2(CF2)3(CF2)2),
−119.9 (m, 2F, CF3(CF2)5CF2CF2), −113.5 (m,
2F, CF3(CF2)6CF2), −80.7 (m, 3F, CF3(CF2)7); MS
(FAB−): 498.
Tridecafluorohexane)sulfonylimide (3f). 2c (4.51 g,
7.6 mmol) and C6F13SO2F (3.51 g, 8.7 mmol) dis-
solved in CH3CN (20 mL) were refluxed for 24 h.
The crude product was purified by silica gel chro-
matography (AcOEt/petroleum ether = 6/4) to give 3f
(3.55 g) in a 52% overall yield based on the starting
amount of 1c.
mp: 137.5◦C; 19F NMR (282.37 MHz, d6-acetone):
δ −125.8 (m, 4F, CF3CF2(CF2)6SO2NHSO2(CF2)4
CF2CF3), −122.3 (m, 4F, CF3CF2CF2(CF2)5SO2NH
SO2(CF2)3CF2CF2CF3), −121.4 (m, 8F, CF3CF2CF2
(CF2)3(CF2)2SO2NHSO2(CF2)2CF2(CF2)2CF3), −119.7
(m, 4F, CF3(CF2)5CF2CF2SO2NHSO2CF2CF2(CF2)3
CF3), −112.8 (m, 4F, CF3(CF2)6CF2SO2NHSO2CF2
(CF2)4CF3), −80.7 (m, 6F, CF3(CF2)7SO2NHSO2
(CF2)5CF3); MS (FAB−): 880; HRMS Calcd for
C14NO4F30S2: 879.8790; found 879.8774.
BIOLOGICAL
bCA was purchased as a lyophilized powder from
Sigma Chemical Co. (Saint Quentin Fallavier,
France) All the reagents that were used were of an-
alytical grade. Acetazolamide was purchased from
Aldrich. Native enzyme concentrations were deter-
mined from the absorbance at 280 nm, using a mo-
lar absorbance of 5.7 × 104 M−1 cm−1 for bCA. All en-
zyme preparations were stored in 0.05 M TrisSO42+
1
Byproducts. Perfluoroalkanesulfonic Acids
mM mercaptoethanol (pH 8.7) at 4◦C. Enzyme con-
centration was 2.9 × 10−6 M for the bCA.
4a (C4F9SO3H) 19F NMR (282.37 MHz, d6-acetone):
δ −126.8 (m, 2F, CF3CF2(CF2)2); −122.2 (m, 2F,
CF3CF2CF2CF2); −115.5 (m, 2F, CF3(CF2)2CF2);
−81.9 (m, 3F, CF3(CF2)2); MS (FAB−) 299.
Initial rates of 4-nitrophenyl acetate hydrolysis
were estimated by a modification of the method of
Verpoorte et al. [28]. The increase in absorbance
was followed at 348 nm for approximately 20 min.
Steady-state measurements were made at 25◦C in
a Kontron Uvikon 860 spectrophotometer. The so-
lution of substrate was prepared in acetone/H2O
media (1/50, v/v); the substrate concentration used
was 7.5 × 10−4 M for the bCA. A molar absorption
coefficient ε of 16.3 × 103 M−1 cm−1 was used for
4-nitrophenolate formed by hydrolysis, in the con-
ditions of the experiments (pH 8). Nonenzymatic
hydrolysis rates were always subtracted from the
observed rates. Triplicate experiments were con-
ducted for each substrate concentration and for
each inhibitor concentration. Inhibitor solutions
were prepared in distilled-deionized water with
10% (v/v) DMSO (which is not inhibitory at these
concentrations), and dilutions were done there-
after with distilled-deionized water; the inhibitor
concentrations varied between 1.35 × 10−4 M and
1.35 × 10−6 M. Inhibitor and enzyme solutions were
preincubated together for 5 min at room temper-
ature prior to assay. Acetazolamide was used as a
specific inhibitor in our studies, its inhibitory ef-
4b (C6F13SO3H) 19F NMR (282.37 MHz, d6-acetone):
δ −125.8 (m, 2F, CF3CF2(CF2)4SO3H); −122.4
(m, 2F, CF3CF2CF2(CF2)3SO3H); −121.4 (m, 2F,
CF3(CF2)2CF2(CF2)2SO3H); −120.2 (m, 2F, CF3
(CF2)3CF2CF2SO3H); −114.3 (m, 2F, CF3(CF2)4
CF2SO3H); −80.8 (m, 3F, CF3(CF2)5SO3H); MS
(FAB−) 399.
4c (C8F17SO3H) 19F NMR (282.37 MHz, d6-acetone):
δ −125.8 (m, 2F, CF3CF2(CF2)6SO3H); −122.3
(m, 2F, CF3CF2CF2(CF2)5SO3H); −121.3 (m,
6F, CF3(CF2)2(CF2)3(CF2)2SO3H); −120.2 (m, 2F,
CF3(CF2)5CF2CF2SO3H); −114.3 (m, 2F, CF3
(CF2)6CF2SO3H); −80.7 (m, 3F, CF3(CF2)7SO3H);
MS (FAB−) 499.
Perfluoroalkanesulfonamides
5a (C4F9SO2NH2). mp: 67.5◦C, 1H NMR (300.13
MHz, d6-acetone): δ 8.2 (m, 2H, SO2NH2); 19F
NMR (282.37 MHz, d6-acetone): δ −125.8 (m, 2F,
CF3CF2(CF2)2), −121.0 (m, 2F, CF3CF2CF2CF2),
−113.7 (m, 2F, CF3(CF2)2CF2), −80.8 (m, 3F,
CF3(CF2)3); MS (FAB−) 298.
fectiveness was determined by using 2.9 × 10−6
M
1
5b (C6F13SO2NH2). mp: 119.8◦C; H NMR (300.13
bCA and varying acetazolamide concentrations from
1.35 × 10−4 M to 1.35 × 10−6 M.
MHz, d6-acetone): δ 4.90 (m, 2H, SO2NH2);
19F NMR (282.37 MHz, d6-acetone): δ −125.8
(m, 2F, (CF3CF2(CF2)4); −122.3 (m, 2F, (CF3CF2
CF2(CF2)3); −121.4 (m, 2F, (CF3(CF2)2CF2(CF2)2);
−119.8 (m, 2F, (CF3(CF2)3CF2CF2); −113.8 (m,
2F, (CF3(CF2)4CF2); −80.8 (m, 3F, (CF3(CF2)5);
MS (FAB−): 398.
REFERENCES
[1] Be´gue´, J. P.; Bonnet-Delpon, D. Chimie bioorganique
et me´decinale du fluor; EDp sciences/CNRS: Paris,
2005.
Heteroatom Chemistry DOI 10.1002/hc

548 Benfodda, Guillen, and Blancou
[2] Kirk, K. J Fluorine Chem 2006, 127, 1013–1029.
[3] Banks, R. E.; Smart, B. E.; Tatlow, J. C. (Eds.); Prin-
ciples and Commercial Applications; Plenum press:
New York, 1994.
[4] Armand, M.; Gorecki, W.; Andreani, R. In: Interna-
tional Symposium On polymer Electrolytes; Swosati,
B. (Ed.); Elsevier: New York, 1990; p. 91.
[5] Nowinsky, J. L.; Lightfoot, P.; Bruce, P. G. J Mater
Chem 1994, 4, 1579–1580.
[6] Atkins, J. R.; Sides, C. R.; Creager, S. E.; Harris, J. L.;
Pennington, W. T.; Thomas, B. H.; Desmarteau, D. D.
J N Mater Electr Syst 2003, 6, 9–15.
[7] Lal, G. S.; Pez, J. P.; Syvret, R. G. Chem Rev 1996, 96,
1737–1755.
[8] Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron
1999, 55, 12431–12477.
[9] Xue, H.; Verma, R.; Shreeve, J. N. M. J Fluorine Chem
2006, 127, 159–176.
[10] Kobayashi, H.; Nie, J.; Sonoda, T. Chem Lett 1995,
24(3), 307–308.
[11] Earle, M. J.; Hakala, U.; McAuley, B. J.; Nieuwen-
huyzen, M.; Ramani, A.; Seddon, K. R. Chem Com-
mun 2004, 12, 1368–1369.
[16] Supuran, C. T.; Scozzafava, A.; Casini, A. Med Res
Rev 2003, 23, 146–189.
[17] Maren, Th.; Conroy, C. W. J Biol Chem 1968, 35,
26233–26239.
[18] Hu, L. Q.; DesMarteau, D. D. Inorg Chem 1993, 32,
5007–5010.
[19] Foropoulos, J, Jr.; DesMarteau, D. D. Inorg Chem
1984, 23, 3720–3723.
[20] Meussdorfer, J. N.; Niederprum, H. Chem Ztg 1972,
96, 582.
[21] Howells, R. D.; Lamanna, W. M.; Fanta, A. D.;
Waddell, J. E. WO 9723448; Chem. Abstr.
127:136181.
[22] Sakaguchi, H.; Fujii, K.; Sakai, S.; Kobayashi, Y.;
Kita, Y. DE19533711; Chem. Abstr. 124:342658.
[23] Sogabe, K.; Hasegawa, Y.; Wada, Y.; Kitamura, T.;
Yanagida, S. Chem Lett 2000, 8, 944–945.
[24] Xu, K.; Day, N. D.; Austen Angell, C. Inorg Chem
Commun 1999, 2(6), 261–264.
[25] Benfodda, Z.; Delon, L.; Guillen, F.; Blancou, H. J
Fluorine Chem 2007, 128(11), 1353–1358.
[26] Chegwidden, W. R.; Dodgson, S. J.; Spencer, I. M.
In: The Carbonic Anhydrases; Chegwidden, W. R.;
Carter, N. D.; Edwards, Y. H. (Eds.); Birkha¨user-
Verlag: Basel, Switzerland 2000; pp. 343–363.
[27] Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran,
C. T. Curr Med Chem 2003, 10, 925–953.
[28] Verpoorte, J. A.; Mehta, S.; Edsall, J. T. J Biol Chem
1967, 242, 4221–4229.
[12] Blancou, H.; Moreau, P.; Commeyras, A. J Chem Soc,
Chem Commun 1976, 21, 885–886.
[13] Benefice-Malouet, S.; Blancou, H.; Teissedre, R.;
Commeyras, A. J Fluorine Chem 1986, 31, 319–332.
[14] Commeyras, A.; Blancou, H. J.; Lantz, A. DE 2756169;
Chem. Abstr. 89:108161.
[15] Supuran, C. T.; Scozzafava, A. Expert Opin Ther
Patents 2000, 10, 575–600.
[29] Shelton, J. B.; Chegwidden, W. R. Comp Biochem
Physiol, A: Physiol 1996, 114, 283–289.
Heteroatom Chemistry DOI 10.1002/hc