Synthesis and phosphonate binding of guanidine-functionalized fluorinated amphiphiles

Article abstract of DOI:10.1016/j.jfluchem.2011.12.011

We report herein convenient procedures for the use of highly fluorinated α,ω-diols (e.g. 1) as building blocks for the rapid assembly of amphiphilic materials containing a fluorous phase region. We describe expedient conversion of the parent diols to both

Full text of DOI:10.1016/j.jfluchem.2011.12.011

Journal of Fluorine Chemistry 135 (2012) 292–302
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and phosphonate binding of guanidine-functionalized fluorinated
amphiphiles
Xinping Wu a, Emine Boz a, Amy M. Sirkis a, Andy Y. Chang b, Travis J. Williams a,
*
a Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, USA
b The Saban Research Institute of Children’s Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027-6062, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
We report herein convenient procedures for the use of highly fluorinated
a,v-diols (e.g. 1) as building
Received 6 October 2011
blocks for the rapid assembly of amphiphilic materials containing a fluorous phase region. We describe
expedient conversion of the parent diols to both symmetrically and asymmetrically substituted
amphiphiles via the installation of an intermediate trifluoromethanesulfonyl ester. These sulfonate
esters are versatile and easily manipulated intermediates, which can be readily converted to a variety of
nitrogen, halogen, and carbon groups. Moreover, we show that for guanidine-terminated fluorous
amphiphiles, these molecules can bind phosphonic acid groups in aqueous media. Thus, these materials
offer a new strategy for decorating phosphorylated biomolecules with fluorine-rich coatings.
ß 2012 Published by Elsevier B.V.
Received in revised form 15 December 2011
Accepted 19 December 2011
Available online 4 January 2012
Keywords:
Fluoroalkylation
Guanidines
Amphiphiles
1. Introduction
of convenient fluoroalkyl trifluoromethanesulfonate intermediates.
Thesynthesesproceedfromcommerciallyavailablefluorinateddiols,
We are developing a general and convenient synthetic route to
guanidine functionalized, fluorous-phase amphiphiles. Fluorinated
amphiphiles are important because of their tendency to self-
assemble into nanostructures such as monolayers [1,2], micelles,
or vesicles [3], in a fashion distinct from their hydrocarbon-based
counterparts [4]. Particularly, amine and guanidine-terminated
molecules in this class can potentially decorate phosphate-rich
biomolecules through selective non-covalent interactions such as
hydrogen bonding. While syntheses of several highly fluorinated
amphiphiles or surfactants have been reported [4–6], amine- and
guanidine-functionalized fluorocarbons remain largely under
addressed despite the potential synthetic utility of nitrogen-
containing groups as functionalization handles and biochemical
tools. The known synthetic routes to highly fluorinated amines
have drawbacks: for example, highly fluorinated amines can be
prepared from routes such as fluoroalkylation of ammonia with an
alkyl chloride [7], hydrogenation of fluoro-organic azides [8], and
the Gabriel synthesis [9], with the latter two involving high-
temperature displacement of fluoroalkyl tosylates. These methods
are of limited scope or involve harsh conditions incompatible with
some biologically relevant substrates.
which are available as byproducts of Teflon1 synthesis [10]. Carbon–
nitrogen bond formation is achieved through the intermediacy of
remarkably stable and versatile alkyl triflate intermediates, which
are prepared through a convenient sulfonation procedure. Both are
amenable to bidirectional syntheses of fluorocarbon-centered
moieties as well. Guanylation of the resulting fluoroalkyl amines
proceeds smoothly under mild conditions with practical yields.
These products are of the general structure guanidine-
fluorocarbon-poly(ethylene glycol), to allow for potential assem-
bly of a fluorous coating around a phosphate-coated surface. The
nearest known relatives to these structures are thiol-fluorocarbon-
poly(ethylene glycol) moieties that can decorate gold surfaces via
covalent S–Au bonds [5]. We will show with 31P NMR data that our
guanidine-fluorocarbon-poly(ethylene glycol) moieties can bind to
a phosphonic acid in aqueous solution, presumably through a
guanidinium–phosphonate double hydrogen bond.
2. Synthesis of fluorinated amphiphiles
We expected that fluorous amphiphiles could be constructed by
attaching a fluorous diol, such as 1, to a poly(ethylene glycol) (PEG)
fragment. A general outline of this operation is shown in Scheme 1.
Accordingly, a tosylate-functionalized PEG fragment (3) is used to
effect selective mono-alkylation of 1 in the presence of sodium
hydride. The resulting PEG-functionalized fluorous alcohol can be
further elaborated. We chose to install a triflate to mediate further
functionalization, although several sulfonate esters are known to
We present here a concise approach to the preparation of
guanidine-terminated fluorous amphiphiles based on displacement
* Corresponding author.
E-mail address: travisw@usc.edu (T.J. Williams).
0022-1139/$ – see front matter ß 2012 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2011.12.011

X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
293
1 HO
OH , NaH, dioxane
TsCl, pyr
DCM
n
FF
OH
4
OTs
4
O
O
- 20 oC, 12 hrs
94%
90 oC, 12 hrs
51-60%
2
3
FF
FF
TfCl, TEA
0 oC - rt, 19 hrs
60-93%
O
4
OTf
O
4
OH
O
O
n
n
4a n = 4
4b n = 3
4c n = 6
5a n = 4
5b n = 3
5c n = 6
Amine Synthesis via phthalimide:
O
KN
, DMF
O
FF
FF
O
O
4
N
O
4
OTf
O
O
65 oC
84%
4
4
O
5a
6
FF
4
H2NNH2
EtOH, 65 oC
93%
O
4
NH2
O
7a
Amine Synthesis via azide:
FF
O
4
OTf
O
n
5a-c
a. NaN3, DMF, 6.5 hrs
b. H2(balloon), Pd/C, DMF
65-70%
rt, 12 hrs
84-99%
NaN3, DMF
FF
FF
7a n = 4
7b n = 3
7c n = 6
H2(balloon), Pd/C,
DMF or EtOH, 3 hrs
68-72%
O
4
N3
O
4
NH2
O
O
3
n
8b
Guanylation:
NH
N
N
Cl
NH2
O
FF
FF
H
N
9a n = 4
9b n = 3
9c n = 6
O
NH2
O
4
NH2
NH
TFA
O
4
n
n
EtN (i-Pr)2, DMF
rt, 11 days
7a-c
56-92%
Scheme 1. Synthesis of PEG-functionalized amphiphiles from diols 1a–c.
transfer polyfluoroalkyl groups [11]. We presumed that the added
reactivity of the triflate would be important to effect efficient
displacement reactions. Sulfonation of fluorous alcohols is often
carried out in dichloromethane [12], yet sulfonation of 5a in
dichloromethane was relatively slow. A simple change of solvent to
tetrahydrofuran accelerated the rate of the reaction, affording
triflate 5a in excellent yield. C–N bond formation can be affected by
triflate displacement with either (i) potassium phthalimide or (ii)
sodium azide. Hydrogenation of the azide was more convenient in
our hands.
Guanylation of amines 7a–c is challenging because the
proximal fluorine atoms reduce the nucleophilicity of the
precursor amine [6]. Nonetheless, successful guanylation was
realized with an excess of guanylpyrazole and Hu¨nig’s base. We
chose 1H-pyrazole-1-carboximidamide due to its mild guanylation
conditions and ease of use [13,14]. Remarkably, these guanylation
reactions proceed to completion despite the attenuated nucleo-
philicity of the fluoroalkyl amines. This route can be generalized to
generate homologs of 9a featuring different lengths of the
fluorocarbon (Table 1, entries 16–18).

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X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
Table 1
Synthesis of fluorinated amphiphiles.
Entry
1
Starting material
Product
Conditions
Yield
94%
OTs
4
2
3
TsCl, pyridine, DCM, À20 8C
NaH, dioxane, 90 8C
O
FF
FF
2
3
4
5
6
7
1a
1b
1c
4a
4b
4c
4a
62%
51%
O
4
OH
OH
OH
O
O
O
4
4b
4c
5a
5b
5c
NaH, dioxane, 90 8C
NaH, dioxane, 90 8C
TfCl, THF, 0 8C–rt
TfCl, THF, 0 8C–rt
TfCl, THF, 0 8C–rt
O
4
3
6
4
FF
60%
O
4
FF
FF
81%a
60%
O
4
OTf
OTf
OTf
O
O
O
O
4
3
6
FF
93%a
O
4
O
FF
FF
8
9
5a
5a
5b
5c
6
6
KN(phthal), DMF, 85 8C
NaN3, DMF, rt
84%
84%
>99%
87%
93%
70%
O
4
N
O
O
4
4
3
O
8a
8b
8c
7a
7a
7b
7c
9a
O
4
N3
FF
10
11
12
13
14
15
16
NaN3, DMF, rt
O
4
N3
N3
O
O
O
O
FF
FF
NaN3, DMF, rt
O
4
6
H2NNH2, EtOH, 65 8C
a. NaN3, DMF, b. H2(balloon), Pd/C, rt
H2(balloon), Pd/C, rt
O
4
NH2
NH2
NH2
NH2
4
4
3
FF
FF
5a
6b
5c
7a
O
4
72%
65%
92%
O
4
O
FF
FF
a. NaN3, DMF, b. H2(balloon), Pd/C, rt
O
4
O
O
6
4
NH
N
HCl
N
H
N
NH2
TFA
O
4
NH2
NH
EtN(i-Pr)2,
DMF, rt

X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
295
Table 1 (Continued )
Entry
Starting material
Product
Conditions
Yield
FF
FF
NH
N
H
N
HCl
HCl
N
O
4
NH2
NH
TFA
TFA
17
7b
9b
57%
O
NH2
3
6
EtN(i-Pr)2,
DMF, rt
NH
N
N
H
N
NH2
O
4
NH2
NH
18
7c
9c
56%
O
EtN(i-Pr)2,
DMF, rt
a
95% conversion.
3. Binding of fluorinated amphiphiles to a phosphonic acid
Guanidinium binds to phosphonate through a salt bridge that is
buttressed by a bidentate hydrogen bonding system (Fig. 1). This
interaction is generally stable within a wide range of pH values
[15]. Thus, guanidinium-functionalized amphiphiles 9a–c should
form complexes with phosphonates in aqueous buffer. We show
here the interaction between 9a and MePO3K2 using 31P NMR
(Fig. 2, Table 2) [16], which has been used as a probe for phosphate
binding to several types of cations [17]. Fig. 2A shows that as 9a is
added to a solution of phosphonate, the 31P chemical shift of the
phosphonate moves only slightly, but broadens significantly. This
broadening effect is more pronounced as additional 9a is added.
The change in the shape of the peak is consistent with reduced
tumbling associated with increased size or reversible association of
9a with MePO3K2, which indicates complexation between the
guanidinium species and the phosphonate group. By contrast,
Fig. 2B shows that in the presence of HCl, a strong Brønsted acid,
protonated MePO3H2 remains sharp and shifts downfield to
30.4 ppm. Thus, guanidinium 9a is not merely protonating the
phosphonate in Fig. 2A. Treatment of MePO3K2 with NH4Cl resulted
in a small downfield shift like HCl, but did not broaden the signal
like 9a. Urea is structurally similar to guanidinium and can
potentially complex a phosphonate in a manner similar to 9a
(Fig. 1B). In the presence of HCl, similar chemical behavior is
expected when MePO3K2 is treated with urea as when it is treated
with 9a. Interestingly, these peaks do not broaden as is observed
with the apparent MePO3K2–9a complex (Fig. 2D). Overall, these
spectra show that 9a complexes methylphosphonate as indicated
by NMR properties which different from those of the correspond-
ing free phosphonate, phosphonic acid, or a putative urea-
phosphonate complex.
A. Guanidinium-Phosphonate Dimer
H
O
O
H N
H N
H3C
HO
P
NH2
H
B. Urea as a Guanidine Homolog
H
O
O
H N
H N
H3C
HO
P
O
H
Fig. 2. 31P NMR spectra showing chemical shift perturbation of samples delimited in
Table 2. Temp = 25 8C. [MePO3K2] = 25 mM. Solvent: 10% D2O/H2O.
Fig. 1. The guanidinium–phosphate interaction.

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X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
Table 2
NMR evidence for guanidinium–phosphate binding.
Spectrum
Content
Chemical shift (ppm)
Half-height width (Hz)
A, 4 equiv.
A, 2 equiv.
A, 1 equiv.
A, 0 equiv.
MePO3K2 + 4 equiv. 9a
MePO3K2 + 2 equiv. 9a
MePO3K2 + 1 equiv. 9a
MePO3K2
21.6
21.6
22.4
21.4
35.5
20.0
11.2
4.2
B, 3 equiv.
B, 2 equiv.
B, 1 equiv.
B, 4 equiv.
MePO3K2 + 3 equiv. HCl
MePO3K2 + 2 equiv. HCl
MePO3K2 + 1 equiv. HCl
MePO3K2
30.4
29.9
27.8
21.4
3.4
3.4
3.8
4.2
C, 1 equiv.
C, 0 equiv.
C, 0 equiv.
MePO3K2 + 4 equiv. NH4Cl
MePO3K2 + 1 equiv. NH4Cl
MePO3K2
22.1
21.8
21.4
4.2
3.6
4.2
D, 4 equiv.
D, 1 equiv.
D, 0 equiv.
MePO3K2 + 4 equiv. urea + 2 equiv. HCl
MePO3K2 + 1 equiv. urea + 2 equiv. HCl
MePO3K2
27.7
27.6
21.4
3.6
3.3
4.2
4. Bi-directional functionalization of fluorinated diols
building blocks. Entries 1–5 of Table 3 illustrate conditions for the
double displacement of triflate 10. Since dehydrofluorination is
facile in many fluorous compounds in the presence of stronger
bases, only weakly basic nucleophiles were used here [18]. For
example, bromide can displace the triflate easily to give 11a in 81%
yield. Treatment of 10 with potassium malonate results in selective
cyclization to give octa(fluoro)cycloheptane 11b. While fluorocar-
bon chains are known to be more rigid than their hydrocarbon
The methods developed above for the synthesis of fluorinated
amphiphiles also have utility in bidirectional applications. Our
general route to doubly functionalized fluorinated materials is
sketched in Table 3 [12]. Thus, treatment of diols such as 1 with
trifluoromethanesulfonyl chloride gives easy access to bis(sulfo-
nic) esters 10, which are remarkably stable and easily manipulated
Table 3
Synthesis and derivatization of fluorinated bis(sulfonic) ester 10.
TfCl
Et3N
F
F F
F
F
F F
F
Nu-
F F F F
F F F F
OH
OTf
Nu
HO
TfO
Nu
0 oC -> rt
94%
F
F F
10
F
F F F F
1
11
Entry
Starting material
Nucleophile or reagent
Conditions
Product
Yielda
81%
F
F F F
Br
Br
F
1
10
10
10
10
KBr
DMF, 18-crown-6, rt
F F
F
11a
MeO2C CO2Me
F
F
O
OK
OMe
2
3
4
DMF, rt
57%
F
F
MeO
F
F
FF
11b
O
O
KN
O
O
F
F F
F
N
N
DMF, 85 8C
89%
F
F F
F
O
O
11c
F F
F
F
N3
N3
NaN3
DMF, rt
>99%
F
F F F
11d

X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
297
Table 3 (Continued )
Entry
Starting material
Nucleophile or reagent
Conditions
Product
Yielda
F
F F F
5
11c
H2NNH2
EtOH, 65 8C
76%
NH2
H2N
F
F F F
12
6
7
11d
11d
H2
H2
H2(balloon), EtOH, Lindlar, rt
13%
59%
H2(ballon), EtOH, Lindlar, quinoline, rt
Ph
N
F
F F F
8
11d
DMF, CuI, 70 8C
85%
Ph
H
N
N
N
N
N
F
F F F
Ph
13
a
All yields are isolated yields.
counterparts [19], the formation of this seven-membered ring
indicates that the octafluoro-precursor is reasonably flexible [20].
We found C–N bond formation with 10 to proceed smoothly under
multiple conditions: both phthalimide and azide react with 10 to
generate the respective intermediates 11c and 11d in high yield
(entries 3 and 4). Compound 11d forms with less apparent
degradation of the fluorocarbon group. Installation of an interme-
diate triflate in the synthesis of 11d seems essential: attempts to
obtain 11d directly using diphenylphosphoryl azide left diol 1
unreacted [21]. Direct hydrogenation of 11d using Pd/C led to
extensive degradation while little or no product was formed. By
contrast, using the Lindlar catalyst afforded 12 with satisfying yield
in the presence of quinoline (entry 7). 11d participates in double
Hu¨isgen cycloaddition under traditional conditions in high yield
(entry 8).
reported as follows: chemical shift (ppm); multiplicity (s: singlet,
d: doublet, t: triplet, q: quartet, h: heptet, m: multiplet, br: broad,
tm: triplet of multiplet, tq: triplet of quintet); integration; coupling
constants (Hz); assignment. 13C NMR spectra were referenced to
the solvent chemical shift at 77.0 ppm for CDCl3. 19F NMR spectra
were referenced to CFCl3 as an external standard at 0.0 ppm. All
NMR spectra were taken at 25 8C unless otherwise indicated.
Mass spectra were obtained by electrospray ionization (ESI).
MALDI mass spectra were obtained on an Applied Biosystems
Voyager spectrometer using the evaporated drop method on a
coated 96 well plate. The 2,5-dihydroxybenzoic acid from Aldrich
was used as a matrix. In a standard preparation, ca. 1 mg of analyte
and ca. 20 mg of matrix were dissolved in a 1 mL of suitable solvent
and spotted on the plate with a micropipette.
6.2. PEG tosylate 3
5. Summary
To a solution of tetraethyleneglycol monomethyl ether (2)
(10.0 g, 48.0 mmol) and pyridine (84 mL) in CH2Cl2 (170 mL), solid
p-toluenesulfonyl chloride (22.0 g, 115.4 mmol) was added
portion-wise at À20 8C under nitrogen. The resulting reaction
mixture was stirred for 2 days at À20 8C. Then, the reaction
mixture was allowed to warm to room temperature and water
(200 mL) was added. The aqueous layer was extracted with CH2Cl2
(150 mL Â 3). The combined organic fractions were dried over
MgSO4 and the solvent was removed under reduced pressure. The
crude product was purified by chromatography on silica (1:1
EtOAc:hexanes; Rf = 0.3) to yield 3 as a colorless oil, 16.4 g, 94%.
Triflate esters, which are easily prepared from the correspond-
ing commercially available diols, are effective building blocks for
nitrogen substituted fluorous-phase amphiphiles that are not
easily prepared through other methods. These reactions are high
yielding, operationally simple, and afford easy access to highly
fluorinated materials. Among these compounds, guanidine-termi-
nated amphiphiles have special value because they present an
interesting approach to binding phosphate-covered molecules or
materials in aqueous solution. Ongoing research in our laboratories
involves the application of these materials to the control of
nanoparticle solubility and self-assembly.
1H NMR (500 MHz, CDCl3):
d = 7.80 (d, Ar, 2H), 7.34 (d, Ar, 2H),
4.16 (t, 2H), 3.66 (t, 2H), 3.62–3.65 (m, 6H), 3.58 (s, 4H), 3.532–3.56
(m, 2H), 3.34 (s, 3H), 2.43 (s, 3H). 13C NMR (125 MHz, CDCl3):
6. Experimental
d
= 144.71 (s, CSO2O), 132.94 (s, CH3CCH), 129.74 (s, CHCHCSO2),
6.1. General procedures
127.89 (s, CCHCH), 71.79, 70.57, 70.46, 70.44, 70.38, 70.36, 69.20,
68.52, 58.94 (CH3OCH2), 21.56 (CH3CHCH). Data was consistent
with a previously reported compound [5].
All water sensitive procedures were carried out using standard
Schlenk techniques under nitrogen when indicated. All reagents
were purchased from Alfa Aesar or TCI and used without further
purification. Dry solvents were obtained from EMD. All other
solvents were reagent grade and used as received. Distilled water
was purchased from Arrowhead.
Deuterated NMR solvents were purchased from Cambridge
Isotopes Labs.
Chloroform-d (CDCl3) was used as received; NMR spectra were
obtained on a Varian Mercury 400, Varian VNMRS 500, or Varian
VNMRS 600 MHz spectrometer. All chemical shifts are reported in
units of ppm and referenced to the residual 1H solvent. Data are
6.3. PEG-fluorinated alcohol 4abc
6.3.1. 4a
To a solution of diol 1 (10.85 g, 41.4 mmol) in dry dioxane
(236 mL), NaH powder (0.563 g, 23.46 mmol) was added under
nitrogen and stirred for 30 min at room temperature. The reaction
flask was then placed in 90 8C oil bath and continued to stir for 2 h.
A solution of 3 (5 g, 13.8 mmol) in dry dioxane (20 mL) was then
added drop wise. The mixture stirred overnight. Then the reaction
was cooled down and quenched by hydrochloric acid (2 M in

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X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
diethyl ether, 4.33 mL), and the solvent was removed under
reduced pressure. The crude compound was dissolved in
dichloromethane (200 mL) and a white precipitate was removed
via filtration. After solvent removal, the crude product was purified
by flash chromatography (1:2 ethyl acetate:hexanes, Rf = 0.5) to
yield the monosubstituted product as a clear oil, 3.86 g, 62%.
2JC,F = 24.9 Hz, CH2OCH2CF2), 58.9 (s, CH3O). 19F NMR (376 MHz,
CDCl3):
d
= À124.0 (m, 4F), À120.5 (p, 2F, 2JC,F = 12.4 Hz, OCH2CF2),
À120.3 (m, 2F, CF2CH2OTf), À74.6 (s, 3F, CF3SO2). FT-IR (cmÀ1, neat):
n
C
= 2885, 1428, 1215–1134, 1017, 958, 838, 611. MALDI-TOF for
16H23F11O8S [MNa]+: calculated 607.08 g/mol, found 606.85 g/mol.
1H NMR (400 MHz, CDCl3):
d
= 4.09–3.96 (m, 4H, OCH2(CF2)4-
6.4.2. 5b
5b was prepared in a similar way as 5a to afford 60% yield (100%
conversion).
1H NMR (500 MHz, CDCl3):
CH2OH), 3.78–3.74 (m, 2H), 3.67–3.61 (m, 12H), 3.55–3.52 (m, 2H),
3
3.36 (s, 3H, OCH3), 3.12 (t, JH,H = 7.2 Hz, 1H, CH2OH). 13C NMR
3
(125 MHz, CDCl3):
d
= 118.08–109.06 (m, CF2), 72.37, 72.00, 70.80,
d = 4.82 (t, JH,F = 13.2 Hz, 2H,
CF3SO2OCH2CF2), 4.03 (t, JH,F = 14.2 Hz, 2H, CH2OCH2CF2), 3.77–
70.77, 70.67, 70.63, 70.53, 68.3 (t, 2JC,F = 24.9 Hz, CF2CH2OCH2), 60.59
3
2
(t, JC,F = 25.4 Hz, CF2CH2OH), 59.07 (s, CH3O). 19F NMR (376 MHz,
3.76 (m, 2H), 3.67–3.63 (m, 12H), 3.55–3.53 (m, 2H), 3.37 (s, 3H,
1
CDCl3):
d
= À124.1 to À124.1 (m, 4F), À123.0 (p, 3JF,F = 214.8 Hz, 2F),
CH3O). 13C NMR (126 MHz, CDCl3):
d
= 118.57 (q, JC,F = 318.6 Hz,
3
À120.4 (p, JF,F = 13.3 Hz, 2F). FT-IR (cmÀ1, neat):
n
= 3415, 2882,
SO2CF3), 117.4–108.8 (m, CF2), 72.35, 72.07, 70.83, 70.76, 70.74,
2
1457, 1351, 1177–1119, 946, 865, 762. MALDI-TOF for C15H24F8O6
[MNa]+: calculated 475.13 g/mol, found 475.10 g/mol.
70.71, 70.65, 69.03 (t, JC,F = 26.4 Hz, CH2OTf), 68.14 (t,
2JC,F = 26.4 Hz, CH2OCH2CF2), 58.9 (s, CH3O). 19F NMR (470 MHz,
CDCl3):
d
= À123.9 to À124.1 (m, 4F, CF2CF2CH2), À120.5 (p, 2F,
6.3.2. 4b
3JC,F = 12.4 Hz, OCH2CF2), À120.2 to À120.35 (m, 2F, CF2CH2OTf),
4b was prepared in the same way as 4a with 51% yield.
À74.6 (s, 3F, CF3SO2). FT-IR (cmÀ1, neat):
n = 2878, 1427, 1216,
1H NMR (400 MHz, CDCl3):
d
= 4.07 (td, JH,F = 15.32 Hz,
1144 1008, 969, 613. MALDI-TOF for C15H23F9O8S [MNa]+:
calculated 557.09 g/mol, found 556.90 g/mol.
3
3JH,H = 7.3, 4H, HOCH2(CF2)3), 4.00 (t, JH,F = 14.3 Hz, 4H,
HOCH2(CF2)3CH2), 3.77–3.76 (m, 2H), 3.68–3.63 (m, 12H), 3.56–
3.54 (m, 2H), 3.38 (s, 3H, OCH3), 2.91 (t, 3JH,H = 7.3 Hz, 1H, CH2OH).
= 118.19–109. 41 (m, (CF2)3), 72.06,
71.94, 70.66–70.48 ((OCH2CH2O)4), 68.20 (t, JC,F = 25.4 Hz,
3
6.4.3. 5c
13C NMR (126 MHz, CDCl3):
d
5c was prepared in a similar way as 5a to afford 93% yield (95%
2
conversion).
2
3
CF2CH2OCH2), 60.31 (t, JC,F = 25.4 Hz, CF2CH2OH), 59.01 (s,
1H NMR (500 MHz, CDCl3):
d
= 4.80 (t, JH,F = 12.2 Hz, 2H,
CH3O). 19F NMR (376 MHz, CDCl3):
d
= À120.46 (m, 2F),
CF3SO2OCH2CF2), 4.02 (t, JH,F = 13.4 Hz, 2H, CH2OCH2CF2), 3.77–
3
À123.05 (m, 2F), À127.47 (m, 2F). FT-IR (cmÀ1, neat):
n
= 3421,
3.75 (m, 2H), 3.66–3.60 (m, 12H), 3.53–3.51 (m, 2H), 3.35 (s, 3H,
1
2881, 1460, 1350, 1285–1307, 937, 886, 850, 771, 668. MALDI-TOF
for C14H24F6O6 [MNa]+: 425.14 g/mol, found 425.03 g/mol.
CH3O). 13C NMR (126 MHz, CDCl3):
d
= 118.52 (q, JC,F = 320.7 Hz,
SO2CF3), 118.03–108.41 (m, CF2), 72.41, 72.02, 70.82–70.60, 68.37
3
3
(t, JC,F = 28.9 Hz, CH2OTf), 68.13 (t, JC,F = 28.9 Hz, CH2OCH2CF2),
59.0 (s, CH3O). 19F NMR (470 MHz, CDCl3):
= À120.16 (m, 4F),
À122.5 (m, 2F), À122.48 (m, 2F), À123.43 (m, 2F), À74.4 (s, 3F,
6.3.3. 4c
d
4c was prepared in the same way as 4a with 60% yield,
1H NMR (400 MHz, CDCl3):
3
d
= 4.09 (td, JH,F = 14.3 Hz,
CF3SO2). FT-IR (cmÀ1, neat):
n = 2884, 1427, 1203, 1142, 1012, 956,
3JH,H = 7.6, 4H, HOCH2(CF2)6), 4.04 (t, JH,F = 14.2 Hz, 4H,
HOCH2(CF2)6CH2), 3.79–3.77 (m, 2H), 3.69–3.63 (m, 12H), 3.56–
3.54 (m, 2H), 3.38 (s, 3H, OCH3), 2.19 (t, 3JH,H = 7.6 Hz, 1H, CH2OH).
821, 612. MALDI-TOF for C18H23F15O8S [MNa]+: calculated
707.08 g/mol, found 706.73 g/mol.
3
13C NMR (126 MHz, CDCl3):
72.00, 70.82–70.56 ((OCH2CH2O)4), 68.44 (t, JC,F = 24.4 Hz,
d
= 117.82–108. 76 (m, (CF2)3), 72.41,
6.5. PEG-fluorinated phthalimide 6
2
2
CF2CH2OCH2), 60.60 (t, JC,F = 25.4 Hz, CF2CH2OH), 59.08 (s,
Potassium phthalimide (4.12 g, 22.3 mmol) was added to a
solution of 5a (6.5 g, 11.1 mmol) in DMF (223 mL). The reaction
was stirred at 65 8C overnight under nitrogen. The reaction was
then cooled to room temperature and solvent was removed under
reduced pressure. Chloroform (200 mL) was added and a white
precipitate was filtered. The solvent was removed under reduce
pressure. The compound was then purified on a silica gel column
with a solvent gradient (in 4:1 ethyl acetate:hexanes Rf = 0.4) to
yield a clear oil 5.4 g, 84%.
CH3O). 19F NMR (470 MHz, CDCl3):
d
= À120.25 (m, 2F),
À122.60 (m, 4F), À122.83 (m, 2F), À124.08 (m, 4F). FT-IR (cmÀ1
,
neat):
n = 3408, 2884, 1645, 1457, 1197–1106, 944, 846, 758–726.
MALDI-TOF for C17H24F12O6 [MNa]+: 575.13 g/mol, found
575.08 g/mol.
6.4. PEG-fluorinated triflate 5
6.4.1. 5a
1H NMR (400 MHz, CDCl3): = 7.92 (q, 3JH,H = 2.8 Hz, Ar, 4H), 7.78
d
To a solution of 4a (1 g, 2.21 mmol) in dry THF (3.3 mL),
triethylamine (0.68 mL, 4.862 mmol) was added under N2 atmo-
sphere. The mixture was stirred for 10 min, after which the flask
was cooled to 0 8C. Trifluoromethanesulfonyl chloride (0.47 mL,
4.42 mmol) was then added and the reaction mixture was stirred
for 14 h. The solvent was removed under reduced pressure. The
crude product was dissolved in ether and filtered to remove a
white solid. The solvent of the filtrate was removed under reduced
pressure. The crude product was purified by flash chromatography
(2:1 ethyl acetate:hexanes, Rf = 0.42) to give 5a as a clear, oily
(q, 3JH,H = 2.8 Hz, Ar, 4H), 4.35 (t, 3JH,F = 15.8 Hz, 2H, NCH2CF2), 4.03
3
(t, JH,F = 14.4 Hz, 2H, CH2OCH2CF2), 3.80–3.75 (m, 2H), 3.69–3.61
(m, 12H), 3.56–3.51 (m, 2H), 3.36 (s, 3H, CH3O). 13C NMR (100 MHz,
CDCl3):
d = 166.9 (s, Ar), 134.5 (s, Ar), 131.6 (s, Ar), 123.9 (s, Ar),
118.4–109.2 (m, CF2), 72.3, 71.9, 70.71, 70.67, 70.64, 70.58, 70.56,
2
70.52, 70.48, 70.44, 68.3 (t, JC,F = 24.9 Hz, CF2CH2OCH2), 58.97 (s,
2
CH3O), 37.45 (t, JC,F = 23.5 Hz, CF2CH2N). 19F NMR (376 MHz,
CDCl3):
d
= À124.13 (m, 2F), À123.73 (m, 2F,), À120.35 (m, 2F),
À116.6 (m, 2F). FT-IR (cmÀ1, in CDCl3):
n = 3154, 2985, 2903, 2254,
1793,1472, 1378, 1382, 1099, 910, 733. MALDI-TOFforC23H27F8NO7
[MNa]+: calculated 604.1557 g/mol, found 603.8150 g/mol.
liquid (1.05 g). Yield: 81%, conversion: 95%.
1H NMR (400 MHz, CDCl3):
d
= 4.79 (t, JH,F = 12.6 Hz, 2H,
3
3
CF3SO2OCH2CF2), 4.01 (t, JH,F = 13.9 Hz, 2H, CH2OCH2CF2), 3.77–
6.6. PEG-fluorinated amine 7
3.73 (m, 2H), 3.66–3.59 (m, 12H), 3.53–3.50 (m, 2H), 3.35 (s, 3H,
1
CH3O). 13C NMR (100 MHz, CDCl3):
d
= 118.4 (q, JC,F = 318.9 Hz,
6.6.1. 7a
SO2CF3), 117.89–110.77 (m, CF2), 72.2, 71.8, 70.62, 70.59, 70.51,
70.49, 70.42, 68.45 (t, JC,F = 27.3 Hz, CH2OTf), 68.16 (t,
Compound 6 (3.8 g, 6.5 mmol) was treated with hydrazine
(2.05 mL, 65.2 mmol) in anhydrous ethanol (150 mL) at 65 8C and
2

X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
299
stirred overnight under nitrogen. The reaction was cooled to room
6.7. PEG-fluorinated azide 8
6.7.1. 8a
To a solution of 5a (194 mg, 0.34 mmol) in DMF (1.5 mL),
sodium azide (26.7 mg, 0.41 mmol) was added under nitrogen. The
reaction mixture was stirred for 6.5 h. The reaction mixture was
poured over H2O (2 mL) and extracted with Et2O (2 mL Â 3). The
combined organic fraction was washed with H2O (6 mL Â 3) and
dried over MgSO4. The solvent was removed under reduced
temperature. White precipitate was filtered and washed with
CHCl3. The solvent was removed under reduced pressure.
Chloroform (200 mL) was then added and stirred for 30 min. More
white precipitate was obtained, and the precipitate was filtered.
The solvent was removed to yield the product as light yellow oil,
2.74 g, 93%.
Alternative route to prepare 7a via a one-pot hydrogenation of
azide 8a: to a solution of 5a (190 mg, 0.33 mmol) in DMF (1.5 mL),
sodium azide (26.6 mg, 0.41 mmol) was added under nitrogen. The
reaction mixture was stirred for 6.5 h. Then Pd/C (2.4 mg, 10%, w/
w) was added and the reaction was purged under hydrogen gas. A
balloon filled with hydrogen gas was attached to the reaction,
which was then stirred for 3 h. Then the Pd/C was filtered out on a
pad of Celite. The reaction mixture was poured over 1 M aqueous
HCl (2 mL) and, washed with ether (1.5 mL Â 2). The pH of the
aqueous phase was adjusted to 12 with saturated NaOH solution,
and extracted with ether (2 mL Â 3). The combined organic
fractions were dried over MgSO4. The solvent was removed under
reduced pressure to afford 7a as a yellow, oily liquid (102.8 mg).
pressure to obtain 8a as a light-yellow liquid (136 mg, 84%).
1H NMR (500 MHz, CDCl3):
d
4.02 (t, JH,F = 14.3 Hz, 2H,
3
3
CH2OCH2CF2), 3.79–3.77 (m, 2H), 3.75 (t, JH,F = 14.6 Hz, 2H,
N3CH2CF2), 3.68–3.63 (m, 12H), 3.55–3.53 (m, 2H), 3.38 (s, 3H,
CH3O). 13C NMR (125 MHz, CDCl3):
d = 117.97–108.79 (m, CF2),
72.38, 72.00, 70.79, 70.75, 70.68, 70.66, 70.58, 68.38 (t,
3JC,F = 24.6 Hz, CF2CH2OCH2), 59.04 (s, CH3O), 50.18 (t,
3JC,F = 23.9 Hz, CH2N3). 19F NMR (470 MHz, CDCl3):
d
= À118.08
(m, 2F), À120.32 (m, 2F), À123.95 (m, 2F), À124.11 (m, 2F). FT-IR
(cmÀ1, in CDCl3):
n = 2881, 2113, 1456, 1123, 960, 857. MALDI-
TOF for C15H24F8N3O5 [MH]+, calculated 478.16 g/mol, found
478.02 g/mol.
Yield: 70%.
3
1H NMR (400 MHz, CDCl3):
d
4.02 (t, JH,F = 14.3 Hz, 2H,
CH2OCH2CF2), 3.80–3.75 (m, 2H), 3.69–3.61 (m, 12H), 3.56–3.51
(m, 2H), 3.37 (s, 3H, CH3O), 3.24 (t, JH,F = 15.8 Hz, 2H, NCH2CF2),
1.36–1.21 (br, 2H, CF2CH2NH2). 13C NMR (100 MHz, CDCl3):
6.7.2. 8b
3
8b was prepared in a similar way as 8a to afford >99% yield.
1H NMR (500 MHz, CDCl3):
CH2OCH2CF2), 3.78–3.75 (m, 2H), 3.77 (t, JH,F = 14.6 Hz, 2H,
N3CH2CF2), 3.68–3.63 (m, 12H), 3.55–3.53 (m, 2H), 3.37 (s, 3H,
CH3O). 13C NMR (125 MHz, CDCl3):
d = 117.97–108.58 (m, CF2),
3
d
4.01 (t, JH,F = 14.4 Hz, 2H,
3
d
= 118.4–109.6 (m, CF2), 72.3, 71.9, 70.71, 70.68, 70.65, 70.59,
70.57, 70.50, 68.3 (t, 3JC,F = 24.6 Hz, CF2CH2OCH2), 58.99 (s, CH3O),
42.92 (t, JC,F = 24.1 Hz, CF2CH2NH2). 19F NMR (376 MHz, CDCl3):
3
d
= À124.5 (m, 2F), À124.21 (m, 2F), À122.17 (m, 2F), À120.50 (m,
72.13, 71.84, 70.68, 70.60, 70.54, 70.51, 70.49, 70.41, 68.04 (t,
2F). FT-IR (cmÀ1, in CDCl3):
n
= 3409, 3340, 2878, 1632, 1460, 1352,
3JC,F = 24.9 Hz, CF2CH2OCH2), 58.83 (s, CH3O), 50.06 (t,
1232–1115, 956, 858. MALDI-TOF for C15H25F8NO5 [MH]+,
calculated 452.17 g/mol, found 451.96 g/mol.
3JC,F = 23.5 Hz, CH2N3). 19F NMR (470 MHz, CDCl3):
d
= À118.30
(m, 2F), À120.21 (m, 2F), À126.43 (m, 2F). FT-IR (cmÀ1, in CDCl3):
n
= 2881, 2114, 1653, 1457, 1306, 1148, 956. MALDI-TOF for
14H24F6N3O5 [MH]+,
6.6.2. 7b
C
calculated
428.1620 g/mol, found
7b was prepared from the azide precursor 8b, which was first
purified and subjected to two different conditions for hydrogena-
tion. Both conditions gave the product as a clear oil. Using EtOH as a
solvent gave 7b with 68% yield. Using DMF as a solvent gave 7b
428.1664 g/mol.
6.7.3. 8c
8c was prepared in a similar way as 8a to afford 87% yield.
1H NMR (500 MHz, CDCl3):
d 4.04 (t, JH,F = 14.0 Hz, 2H,
CH2OCH2CF2), 3.80–3.77 (m, 2H), 3.77 (t, JH,F = 15.6 Hz, 2H,
3
with 72% yield.
3
3
1H NMR (500 MHz, CDCl3):
d
3.99 (t, JH,F = 14.3 Hz, 2H,
CH2OCH2CF2), 3.78–3.76 (m, 2H), 3.70–3.63 (m, 12H), 3.56–3.54
(m, 2H), 3.39 (s, 3H, CH3O), 3.31 (t, JH,F = 15.3 Hz, 2H, NCH2CF2),
N3CH2CF2), 3.68–3.63 (m, 12H), 3.56–3.54 (m, 2H), 3.38 (s, 3H,
3
CH3O). 13C NMR (125 MHz, CDCl3):
d = 117.97–108.58 (m, CF2),
1.56 (br, 2H, CF2CH2NH2). 13C NMR (126 MHz, CDCl3):
d
= 120.26–
72.13, 71.84, 70.68, 70.60, 70.54, 70.51, 70.49, 70.41, 68.04 (t,
3JC,F = 24.9 Hz, CF2CH2OCH2), 58.83 (s, CH3O), 50.06 (t,
109.56 (m, CF2), 72.34, 72.02, 70.79–70.60, 68.36 (t, 2JC,F = 24.5 Hz,
CF2CH2OCH2), 59.08 (s, CH3O), 43.05 (t, 3JC,F = 24.6 Hz, CF2CH2NH2).
3JC,F = 23.5 Hz, CH2N3). 19F NMR (470 MHz, CDCl3):
d
= À117.88
19F NMR (470 MHz, CDCl3):
d
= À119.84 (m, 2F), À121.62 (m, 2F,),
(m, 2F), À120.19 (m, 2F), À122.30 (m, 2F), À122.50 (m, 2F),
À122.04 to 122.01 (m, 2F), À122.15 (m, 2F), À123.56 (m, 2F),
À123.66 (m, 2F), À123.88 (m, 2F). FT-IR (cmÀ1, in CDCl3):
n = 2881,
À123.70 (m, 2F). FT-IR (cmÀ1, in CHCl3):
n
= 3408, 3340, 2875,
2114, 1456, 1142, 958. MALDI-TOF for C17H24F12N3O5 [MH]+,
calculated 578.1524 g/mol, found 577.9730 g/mol.
1632, 1456, 1350, 1284, 1234, 1141, 956, 881. MALDI-TOF for
C
14H25F6NO5 [MH]+: calculated 402.17 g/mol, found 402.04 g/mol.
6.8. PEG-fluorinated-guanyldinium mono TFA salts 9
6.6.3. 7c
7c was prepared in the same way as 7a via one flask
6.8.1. 9b
hydrogenation of the corresponding azide, and was isolated as a
To a solution of compound 7b (161.6 mg, 0.4 mmol) in DMF
(0.4 mL), Hu¨nig’s base (0.14 mL, 0.8 mmol) and 1H-pyrazole-1-
carboxamidine hydrochloride (117.3 mg, 0.8 mmol) were added
and the reaction was stirred vigorously. Another addition of
Hu¨nig’s base and 1H-pyrazole-1-carboxamidine hydrochloride
was made at 72 h. Another aliquot of Hu¨nig’s base and 1Hpyrazole-
1-carboxamidine hydrochloride was added at 6 days and every
24 h thereafter to drive the reaction to completion. NMR and
MALDI confirmed the completion of the reaction at 11 days. The
solvent was removed under reduced pressure. The crude product
was obtained as a yellow gum, which was then suspended in H2O
and passed through an IRN-78 ion-exchange column to neutralize
the hydrochloride. The resulting crude product was separated with
yellow oil in 65% yield.
3
1H NMR (500 MHz, CDCl3):
d
4.02 (t, JH,F = 14.0 Hz, 2H,
CH2OCH2CF2), 3.77–3.75 (m, 2H), 3.66–3.61 (m, 12H), 3.53–3.52
(m, 2H), 3.36(s, 3H, CH3O), 3.24(t, 3JH,F = 15.8 Hz, 2H, NCH2CF2), 1.28
(br, 2H, CF2CH2NH2). 13C NMR (126 MHz, CDCl3):
d = 118.78–108.75
2
(m, CF2), 72.43, 72.03, 70.83–70.58, 68.43 (t, JC,F = 25.43 Hz,
CF2CH2OCH2), 59.08 (s, CH3O), 42.96 (t, 3JC,F = 23.5 Hz, CF2CH2NH2).
19F NMR (470 MHz, CDCl3):
d
= À119.84 (m, 2F), À121.62 (m, 2F,),
À122.04 to 122.01 (m, 2F), À122.15 (m, 2F), À123.56 (m, 2F),
À123.70 (m, 2F). FT-IR (cmÀ1, in CHCl3):
n = 3411, 3348, 2881, 1632,
1458, 1351, 1200–1141, 960, 840. MALDI-TOF for C17H25F12NO5
[MNa]+: calculated 574.14 g/mol, found 574.12 g/mol.

300
X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
reverse phase chromatography (MeOH/H2O, 0.1% TFA) to afford a
light yellow oil as the product in mono-TFA salt form (126.8 mg,
57%).
1JC,F = 320.1 Hz, CF3SO2), 115.5 (t, CF2), 113.6–112.6 (m, CF2),
111.3–109.9 (m, CF2), 108.0 (t, JC,F = 32.9 Hz, CF2), 68.07 (t,
2
2JC,F = 28.4 Hz, OCH2). 19F NMR (376 MHz, CDCl3):
d
= À123.35 (m,
4F, CF2CF2CH2), À120.1 (m, 4F, CF2CH2O), À74.3 (s, 6F, CF3SO2). FT-
IR (cmÀ1, in CHCl3):
= 3683, 3020, 2400, 1519, 1429, 1220, 931,
1H NMR (500 MHz, 55 8C, CDCl3):
d 8.62 (br, 1H, H2NCNHNH2),
7.37 (br, 4H, H2NCNHNH2), 3.96 (t, 3JH,F = 13.4 Hz, 2H,
CH2OCH2CF2), 3.92 (NHCH2CF2), 3.77–3.75 (m, 2H), 3.65–3.62
(m, 12H), 3.55–3.53 (m, 2H), 3.34 (s, 3H, CH3O). 13C NMR
n
761. Anal. Calc’d for C8H4F14O4S2: C, 18.26; H, 0.77. Found: C,
19.87; H, 0.77.
(126 MHz, CDCl3):
d = 158.9 (s, C55N), 117.9–109.2 (m, CF2CF2CF2),
72.3, 71.8, 70.5–70.2, 68.2 (t, 2JC,F = 26.0 Hz, CF2CH2OCH2), 58.7 (s,
6.10. Dibromide 11a
2
CH3O), 42.1 (t, JC,F = 22.1 Hz, CF2CH2NH2). 19F NMR (470 MHz,
CDCl3):
d
= À75.78 (s, 3F, HOOCCF3), À117.86 (m, 2F), À119.32 (m,
To a solution of compound 10 (100 mg, 0.18 mmol) in DMF
(1.2 mL), potassium bromide (50.8 mg, 0.43 mmol) and 18-crown-
6 (14.6 mg, 0.054 mmol) were added under N2 atmosphere. After
6 h of stirring, KBr (25 mg) was added and the reaction was
allowed to continue for another 26 h. The reaction mixture was
poured over H2O (3.6 mL), extracted with ether (2.4 mL Â 3),
washed with H2O (7.2 mL Â 3) and dried over MgSO4. Solvent was
removed under reduced pressure to afford the 3a as a clear oil
2F), À127.35 (m, 2F). FT-IR (cmÀ1, in CHCl3):
n = 3354–3015, 2921,
1684, 1457, 1204, 1150–1136, 755. MALDI-TOF for C15H27F6N3O5
[MH]+: calculated 444.19 g/mol, found 444.07 g/mol.
6.8.2. 9a
9a was prepared in
a way similar to 9b to give the
corresponding mono TFA salt product as a light yellow oil in
92% yield.
(56.1 mg, 81%).
1H NMR (500 MHz, 55 8C, CDCl3):
d
8.28 (br, 1H, H2NCNHNH2),
1H NMR (500 MHz, CDCl3):
d
= 3.76 (t, JH,F = 15.6 Hz, 4H,
3
7.34 (br, 4H, H2NCNHNH2), 3.97 (t, 3JH,F = 14.0 Hz, 2H,
CH2OCH2CF2), 3.93 (NHCH2CF2), 3.74–3.73 (m, 2H), 3.66–3.60
(m, 12H), 3.54–3.52 (m, 2H), 3.33 (s, 3H, CH3O). 13C NMR
BrCH2CF2). 13C NMR (126 MHz, CDCl3):
d
= 113.99 (tt, JC,F
1
2
1
= 257.25 Hz, JC,F = 31.8 Hz, CH2CF2), 110.91 (tq JC,F = 268.01 Hz,
2JC,F = 31.3 Hz, CH2CF2CF2), 26.05 (t, 2JC,F = 25.4 Hz, BrCH2). 19F NMR
(126 MHz, CDCl3):
d
= 158.72 (s, C55N), 117.82–108.96 (m,
(470 MHz, CDCl3):
d
= À113.10 (m, 4F, CF2CF2CH2), À122.03 (m, 4F,
2
CF2CF2CF2CF2), 72.21, 71.78, 70.50–70.13, 68.24 (t, JC,F = 24.3 Hz,
CF2CH2OCH2), 58.55 (s, CH3O), 41.84 (t, 2JC,F = 23.54 Hz,
CF2CH2NH2). 19F NMR (376 MHz, CDCl3):
CF2CF2CH2). FT-IR (cmÀ1, in CHCl3):
n
= 2987, 2961, 2932, 1727,
1428, 1287–1072, 875. EI GC/MS for C6H4Br2F8 [M]+: calculated
385.8552 g/mol, found 385.8544 g/mol.
d
= À75.98 (s, 3F,
HOOCCF3), À117.81 (m, 2F), À119.72 (m, 2F), À123.55 (m, 2F),
À123.58 (m, 2F,). FT-IR (cmÀ1, in CHCl3):
n
= 3356–3014, 2920,
6.11. Malonocycloheptane 11b
1684, 1457, 1177, 1132, 759. MALDI-TOF for C16H27F8N3O5
[MNa]+: calculated 494.19 g/mol, found 494.06 g/mol.
In a 3-neck round bottom flask, potassium hydride (26.8 mg,
0.67 mmol, in mineral oil) was washed with pentane. DMF (1.8 mL)
was then added. To this suspension of KH in DMF under vigorous
stirring, dimethylmalonate (88.2 mg, 0.67 mmol) was added
slowly. After 1 h, compound 10 (150 mg, 0.27 mmol) was added
to the resulting enolate and the reaction was stirred for 12 h. After
that, another aliquot of enolate was added, and the reaction was
allowed to stir for 24 h longer. The reaction mixture was poured
over H2O (3.6 mL) and extracted with ether (3.6 mL Â 3). The
combined organic fractions were washed with H2O (9 mL Â 3) and
dried over MgSO4. The solvent was removed under reduced
pressure. The crude product was purified by chromatography (7:1
benzene:ethyl acetate, Rf = 0.74) to separate unreacted starting
material, then further purified by a second chromatography (4:1
hexanes:ethyl acetate, Rf = 0.59) to obtain a clear liquid, which
crystallized on standing. The crystal sublimes at room tempera-
ture. Yield: 54.3 mg, 57%, mp. 67.5–69 8C.
6.8.3. 9c
9c was prepared in
a way similar to 9b to give the
corresponding mono TFA salt product as a light yellow oil in
56% yield.
1H NMR (500 MHz, 55 8C, CDCl3):
d
8.34 (br, 1H, HOOCCF3), 7.41
3
(br, 4H, H2NCNHNH2), 3.97 (t, JH,F = 13.4 Hz, 2H, CH2OCH2CF2),
3.93 (NHCH2CF2), 3.75–3.73 (m, 2H), 3.65–3.59 (m, 12H), 3.53–
3.51 (m, 2H), 3.33 (s, 3H, CH3O). 13C NMR (126 MHz, 55 8C, CDCl3):
d
= 158.88 (s, C55N), 118.15–108.56 (m, CF2CF2CF2CF2CF2CF2),
2
72.31, 71.86, 70.61–70.26, 68.33 (t, JC,F = 24.4 Hz, CF2CH2OCH2),
58.60 (s, CH3O), 41.75 (t, JC,F = 25.16 Hz, CF2CH2NH2). 19F NMR
(470 MHz, 55 8C, CDCl3):
2
d
= À76.07 (S, SCF3), À117.875 (m, 2F),
À119.74 (m, 2F), À121.81 (m, 2F), À122.02 (m, 2F), À123.22 (m,
2F), À123.57 (m, 2F). FT-IR (cmÀ1, in CHCl3):
n = 3360–3184, 3020,
2904, 1684, 1216–1144, 761. MALDI-TOF for C18H27F12N3O5
[MH]+: calculated 594.18 g/mol, found 593.99 g/mol.
1H NMR (400 MHz, CDCl3):
3JH,F = 15.1 Hz, 4H, CCH2CF2). 13C NMR (126 MHz, CDCl3):
d = 3.83 (s, 6H, CH3COC), 3.20 (t,
1
2
6.9. Triflate 10
d = 168.42 (s, CH3COC), 117.78–113.72 (tt, JC,F = 254.4 Hz, JC,F
1
2
= 27.9 Hz, CH2CF2), 111.38–107.08 (tq, JC,F = 229.8 Hz, JC,F
2
To a solution of diol 1 (5.0 g, 19.1 mmol) in dry dichloro-
methane (200 mL), trifluoromethanesulfonyl chloride (4.9 mL,
45.8 mmol) was added under nitrogen atmosphere in an ice bath.
Triethylamine (10.7 mL, 76.3 mmol) was then added drop wise. A
yellow precipitate was observed. The mixture was stirred at room
temperature overnight. The solvent was then removed and the
crude compound was dissolved in ethyl acetate (200 mL) and
washed twice with water (100 mL). The phases were separated,
and the organic phase was washed sequentially with 1 M HCl
(200 mL), NaHCO3 (200 mL), and brine and then dried with MgSO4
and filtered. The solvent was removed under reduced pressure to
yield a yellow oil. It was then crystallized from 3:1 hexanes:ethyl
= 27.8 Hz, CH2CF2CF2), 54.44 (s, CH3CO), 33.02 (t, JC,F = 24.7 Hz,
CH2CF2). 19F NMR (470 MHz, CDCl3):
d
= À111.41 (m, 4F,
CF2CF2CH2), À120.1 (m, 4F, CF2CH2O), À74.3 (s, 6F, CF3SO2). FT-
IR (cmÀ1, in CHCl3):
= 3021, 2958, 1748, 1438, 1345, 1282, 1216,
n
1180, 1117, 1076, 1016, 932, 756, 668. GC/MS for C10H7F8O3
[MÀOMe]+ calculated 327.03, found 327.08 g/mol; C9H7F8O2
+
[MÀCO2Me] calculated 299.03, found 299.08 g/mol.
6.12. Phthalimide 11c
To a solution of 10 (3.0 g, 5.7 mmol) in dry N,N-dimethylfor-
mamide (300 mL), potassium phthalimide (2.53 g, 13.7 mmol) was
added under nitrogen atmosphere. The mixture was stirred at
85 8C overnight. The reaction mixture was cooled down to room
temperature and 300 mL of brine was added. The product
acetate to yield 8 as clear crystals (9.4 g, 94%). Mp. 57.5–58.5 8C.
1H NMR (400 MHz, CDCl3):
d
= 4.82 (t, JH,F = 12.1 Hz, 4H,
3
CF3SO2OCH2CF2). 13C NMR (150 MHz, CDCl3):
d = 118.42 (q,

X. Wu et al. / Journal of Fluorine Chemistry 135 (2012) 292–302
301
precipitated as a white solid and was collected by filtration (2.6 g,
0.048 mmol) were added sequentially. The reaction was heated
at 70 8C for 12 h. The solution was cooled and the solvent was
removed under reduced pressure. The greenish crude product was
then re-dissolved in a minimal amount of acetone and passed
through a plug of silica gel. The eluent was collected and solvent
was removed under reduced pressure to obtain a yellowish solid,
which was then triturated with ethyl acetate and hexanes to obtain
13 as a white, fluffy solid, 147 mg, 89%. Mp. 242.5–245.5 8C.
89%). Decomp. temp and mp. 260.5–262 8C.
3
1H NMR (400 MHz, CDCl3):
d
= 7.93 (q, JH,H = 2.8 Hz, Ar, 4H),
7.78 (q, 3JH,H = 2.8 Hz, Ar, 4H), 4.38 (t, 3JH,F = 15.6 Hz, 4H, NCH2CF2).
13C NMR (100 MHz, CDCl3):
= 166.8 (s, Ar), 134.5 (s, Ar), 131.8 (s,
Ar), 123.9 (s, Ar), 37.6 (t, 3JC,F = 25.1 Hz, NCH2). 19F NMR (376 MHz,
CDCl3):
d
d
= À123.5 to À123.6 (m, 4F, CF2CF2CH2), À116.4 to À116.6
(m, 4F, CF2CH2N). Anal. Calc’d for C13H1304N: C, 50.78; H, 2.32; N,
5.38. Found: C, 50.73; H, 2.03; 5.05. FT-IR (cmÀ1, in CHCl3):
1H NMR (599.804 MHz, DMSO):
d = 8.74 (s, 1H, NCHC), 7.91–
n
= 3019, 2400, 1522, 1424, 1216, 930, 759.
Data are consistent with a previously reported compound [9].
7.90 (m, 2H, Ar, CHCHCH), 7.48–7.49 (m, 2H, Ar, CHCHCHN), 7.38–
3
7.36 (m, 1H, Ar, CHCHCH), 5.62 (t, 4H, JH,F = 15.9 Hz, 4H,
CH2CF2CF2). 13C NMR (150.837 MHz, DMSO):
d = 146.79 (s,
6.13. Diazide 11a
CCNCH), 130.02 (s, CHCC), 128.98 (s, Ar, CHCHCH), 128.25 (s, Ar,
CHCHCH), 125.34, (s, Ar, CHCHC), 123.50 (s, CCHN), 116.3–112.9
(tm, JC,F =260.5, CF2), 112.5–109.0 (tm, JC,F = 270.3, CF2), 48.5 (t,
1
1
To a solution of compound 10 (150 mg, 0.267 mmol) in DMF
(1.8 mL), NaN3 (41.6 mg, 0.64 mmol) was added under N2
atmosphere. The reaction was stirred for 3 h. The reaction mixture
was then poured over of H2O (3.6 mL) and extracted with ether
(3.6 mL Â 3). The combined organic fractions were then washed
with H2O (10 mL Â 3) and dried over MgSO4. The solvent was
removed under reduced pressure to yield a colorless oil (83.3 mg,
2JC,F = 22.5 Hz, CH2N). 19F NMR (470 MHz, DMSO):
d
= À115.93 (m,
4F, CF2CF2CH2), À122.43 (m, 4F, CF2CH2). FT-IR (cmÀ1, in CH2Cl2):
n
= 3052, 2988, 1419, 1265, 897, 737. MALDI-TOF for C22H17F8N6
[MH]+: calculated 517.14 g/mol, found 517.04 g/mol.
Acknowledgements
>99%).
1H NMR (500 MHz, CDCl3):
d
= 3.77 (t, JH,H = 14.7 Hz, 4H,
3
We thank the University of Southern California, the USC-
Zumberge Research and Innovation Fund, Robert and May Wright
foundation, the USC Women in Science and Engineering Fund
(fellowship to E.B.) and the NSF-REU (fellowship assistance for
A.M.S.) for funding. We appreciate Grants from the NSF (DBI-
0821671) and NIH (S10 RR25432) to support NMR spectrometers.
We thank Prof. G. K. S. Prakash for insightful discussions.
CH2CF2CF2). 13C NMR (150 MHz, CDCl3):
d = 115.73 (tt, JC,F =
1
2
1
258.9 Hz, JC,F = 30.1 Hz, N3CH2CF2), 111.82 (tq, JC,F = 265.87 Hz,
2JC,F = 33.52 Hz,NH2CH2CF2CF2),50.20(t,2JC,F = 24.3 Hz,CH2N3).Data
are consistent with a previously reported compound [8].
6.14. Diamine 12
Compound 11c (2.3 g, 4.4 mmol) was treated with hydrazine
(1.4 mL, 44.4 mmol) in anhydrous ethanol (300 mL) under reflux
overnight. After cooling to room temperature, the reaction mixture
was filtered to remove the white precipitate. The solvent was then
removed under vacuum. The crude product was then stirred in
200 mL chloroform and re-filtered to remove white precipitate.
Chloroform was removed by rotary evaporation, and the product
was obtained as a white solid. It was sublimated to obtain clear
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.12.011.
crystals, 0.87 g, 76%. Mp. 47–48 8C.
References
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1H NMR (400 MHz, CDCl3):
d
= 3.24 (t, JH,H = 16.0 Hz, 4H,
CH2CF2CF2), 1.35–1.18 (b, 4H, NH2CH2CF2). 13C NMR (150 MHz,
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6.15. (Bis)triazole 13
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