Synthesis and self-assembly of novel fluorous cationic amphiphiles with a 3,4-dihydro-2(1H)-pyridone spacer

Article abstract of DOI:10.1016/j.jfluchem.2011.04.008

The synthesis of fluorous (highly fluorinated) 3,4-dihydro-2(1H)-pyridone- 5-carboxylate cationic amphiphiles have been described, where the dihydropyridone serves as a spacer and either a pyridinium bromide or a triphenylphosphonium bromide form the pola

Full text of DOI:10.1016/j.jfluchem.2011.04.008

Journal of Fluorine Chemistry 132 (2011) 414–419
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and self-assembly of novel fluorous cationic amphiphiles with a
3,4-dihydro-2(1H)-pyridone spacer
a
a
a
b
Rufus Smits a, , Yelena Goncharenko , Iveta Vesere , Baiba Skrivele , Oksana Petrichenko ,
*
Brigita Vigante a, Marina Petrova a, Aiva Plotniece a, Gunars Duburs a
a Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga LV-1006, Latvia
b Faculty of Physics and Mathematics, University of Latvia, Zellu str. 8, Riga LV-1002, Latvia
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of fluorous (highly fluorinated) 3,4-dihydro-2(1H)-pyridone-5-carboxylate cationic
amphiphiles have been described, where the dihydropyridone serves as a spacer and either a pyridinium
bromide or a triphenylphosphonium bromide form the polar cationic head group. The in water self-
assembled aggregates have been observed by atomic force microscopy (AFM) and dynamic light
scattering (DLS).
Received 4 January 2011
Received in revised form 12 April 2011
Accepted 14 April 2011
Available online 22 April 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Fluorous cationic amphiphiles
Self-assembly
3,4-Dihydropyridone
1. Introduction
requires bicaudal (double chain) amphiphiles but, organized
supramolecular systems can be obtained from a single pure
The 3,4-dihydropyridone is a convenient scaffold for attaching
cationic head groups and fluorous long chain esters for the
construction of cationic amphiphiles. Also it is relatively straight
forward to synthesize from Meldrum’s acid as the second
dicarbonyl component in a Hantzsch-like reaction [1,2] and
recently by employing microwaves the yields have been boosted
substantially [3]. The 2-pyridones possess interesting pharmaco-
logical properties such as reverse transcriptase inhibition of
human immunodeficiency virus-1 (HIV-1) [4,5]. Milrinone, Amri-
none [6] and their analogs are cardiotonic agents for the treatment
of heart failure. They have also been reported to possess antitumor
[7,8], antibacterial [9] and other biological activities [10–12].
PreviouslyHyvonenet al.[13]havetestedaseriesofsymmetrical
cationic amphiphilic double-charged didodecyl 1,4-dihydropyri-
dine-3,5-dicarboxylate derivatives (1,4-DHP), which have self-
associating properties in aqueous media forming liposomes with
a mean diameter in the 50–130 nm range. The aim of this present
study is to combine the properties of DHP derived cationic
compounds with the stability imparted by fluorous groups and to
synthesize novel charged fluorous 6-methyl-3,4-dihydro-2(1H)-
pyridone-5-carboxylates which are 1,4-DHP analogs having a single
alkyl ester group. The formation of bilayers and vesicles usually
monocaudal nonrigid amphiphile by reinforcing the hydrophobic
interactions in the surfactant film through the use of a highly
perfluorinated tail, without recourse to classical steric effects or
intermolecular associations [14]. The force of this self-assembling
capacity is, illustrated by the ability of single chain F-surfactants to
form stable vesicles rather than micelles in water and as a rule, films
and membranes made of F-surfactants are more stable than those of
their hydrogenated analogs [15].
2. Results and discussion
The 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluoro-
dodecanol was synthesized using perfluorooctyliodide in a radical
reaction with 3-buten-1-ol initiated by sodium dithionite and
deiodinated with tributyltin according to a literature procedure
[16]. This alcohol was further reacted with 2,2,6-trimethyl-4H-1,3-
dioxin-4-one in refluxing p-xylene. The xylene was evaporated
under reduced pressure and the residual oil was purified by silica
gel flash chromatography using 10% ethylacetate in hexane as
eluent to furnish the fluorous acetoacetate 1 as a white waxy solid
in good yield Scheme 1.
The fluorous 3,4-dihydropyridone-5-carboxylate was synthe-
sized employing a four component reaction developed by Suarez
et al. [17], which involves using Meldrum’s acid, a b-ketoester, and
benzaldehyde in the presence of ammonium acetate in acetic acid
as solvent, providing the dihydropyridone in reasonable yields.
* Corresponding author. Tel.: +371 27006957.
E-mail address: rusmits@gmail.com (R. Smits).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.04.008

R. Smits et al. / Journal of Fluorine Chemistry 132 (2011) 414–419
415
I
Na2S2O4
(Bu)3SnH
AIBN
(CF2)7CF3
CF3(CF2)7I
H2C
+
OH
HO
NaHCO3
H3C CH3
O
O
(CF2)7CF3
HO
O
O
H3C
O
(CF2)7CF3
H3C
O
Xylene
Δ
1
Scheme 1. Synthesis of a fluorous acetoacetate.
H3C CH3
O
O
O
O
O
4
(CF2)7CF3
Δ
H3C
O
O
O
1
O
O
(CF2)7CF3
(CF2)7CF3
Br2
O
O
Chloroform
O
3
N
H
O
N
H
CH3
2
Br
Scheme 2. Four component synthesis of 3,4-dihydropyridone and bromination of the 6-methyl group with bromine.
Thus by using the fluorous acetoacetate 1 as the
b
-ketoester
The bromine of 6-bromomethyl-3,4-dihydropyridone (3) was
substituted with pyridine in dry acetone by stirring at room
temperature overnight. The precipitated solids were filtered and
washed with ethyl ether providing a white powder of the
pyridinium bromide 4a in 79% yield. The dodecyl ester analog
4b of 4a was also synthesized for comparison and its synthesis will
be reported elsewhere. The substitution with triphenylphosphine
was accomplished by warming in dry acetonitrile for 2 h when
noticeable amounts of the triphenylphosphonium bromide 5
precipitated as a yellowish solid in 82% yield Scheme 3.
The determination of the structures of the synthesized
compounds 1–5 were accomplished on the basis of 1D-1H, 13C,
19F, 31P and 2D-NMR 1H-1H, 19F-19F and 1H-13C spectra recorded in
chloroform-d1 solution. The 1H, 13C, 19F and 31P chemical shifts are
in full agreement with the proposed structures.
Scheme 2, and after refluxing in glacial acetic acid for 6.5 h the
reaction contents was poured in ice-water giving an orange
syrup which after extraction with ethyl acetate and recrystalli-
zation from ethanol furnished the fluorous 3,4-dihydropyri-
done-5-carboxylate 2 as a yellow powder in 31% yield. Unlike
the methyl ester dihydropyridones which give yields of around
60%, the fluorous ester seems to somehow interfere with the
reactive centers in the reaction mixture reducing the yield quite
substantially. The bromination of the 6-methyl group of 4-
aryldihydropyridones described in the literature has been
accomplished with N-bromosuccinimide (NBS) in refluxing
chloroform for 10–14 h [17]. Although the 6-bromomethyl
compound was not isolated its presence as intermediate was
suggested by the subsequent lactonization producing
g-lactone
fused 3,4-dihydropyridones. Another report on the 6-methyl
group bromination utilized bromine in chloroform and irradia-
tion with a 500 W lamp [18], in this case only the crude
compound was isolated and not further characterized. In our
case the 6-methyl group was brominated by dissolving the
dihydropyridone in chloroform and simple drop-wise addition
of a bromine chloroform solution with stirring. The reaction took
place readily as indicated by the rapid discoloration of the
bromine solution. After solvent removal the compound was
dissolved in methanol and allowed to slowly crystallize in the
dark, providing the light yellow compound 3 in 72% yield which
could be fully characterized.
Atomic force microscopy (AFM) and dynamic light scattering
(DLS) were employed to observe the self-assembly of compounds
4a, 4b and 5. The samples were prepared in a dilute (0.03%, w/v)
aqueous dispersion by sonication using a probe type sonicator.
Compounds 4a and 4b were readily soluble in water and were
sonicated for only 5 min but, compound 5 was quite insoluble and
needed 25 min sonication for full dispersion. Using a longer
sonification time, it is possible to obtain nanoparticles with a
narrow size distribution, while after a short sonification time
nanoparticles were quite different in their sizes and shapes. For
AFM observation freshly cleaved mica plates were dipped into the
solution and kept for 30 s to allow the nanoaggregates to stick to

416
R. Smits et al. / Journal of Fluorine Chemistry 132 (2011) 414–419
O
(CF2)7CF3
O
dry Py
Acetone
Br-
O
N
H
O
4a
N+
(CF2)7CF3
O
3
O
N
H
O
PPh3
Br
(CF2)7CF3
Acetonitrile 40 oC
O
5
O
N
H
P+Ph3Br-
Scheme 3. Synthesis of fluorous 3,4-dihydropyridone cationic amphiphiles.
the negatively charged surface. The mica samples were dried at
room temperature and observed by AFM in tapping mode. AFM is a
well established method for the characterization of nanoscale drug
delivery systems (DDS) [19], enabling the direct observation of
very small objects without the need of cumbersome and
potentially contaminating sample preparation. Tapping mode
AFM allows the investigation of soft samples with minimal sample
alteration with a lateral resolution of several nanometers and
height resolution of 0.1 nm [20]. Compound 5 formed nanoag-
gregates with a diameter of approximately 150 nm and height of
20 nm at the specified preparation conditions Fig. 1. Compounds
4a and 4b also formed similar aggregates but, the AFM images
which we have obtain to date are not of publishable quality.
This is consistent with the observations of Damas et al. that
fluorinated surfactants with even a single chain can form bilayer
aggregates or vesicles, although this is usually unfavorable for single
chain hydrocarbon ones [21] however, since compound 4b being the
nonfluorinated analog of 4a, also formed similar nanoaggregates it
warrants further research on the nature of the aggregates formed,
which could be provided by freeze-fracture electron microscopy.
The hydrodynamic diameters of the nanoparticles (NPs) suspended
inwaterweredeterminedbyDLS, Fig. 2and thevaluesarepresented
in Table 1. The advantages of DLS are rapidity of analysis, no
requirement for calibration, and sensitivity [22].
The mean diameter represents the average diameter of all
nanoaggregates in the sample and the most expected diameter
depicts the diameter of the main population (or tip of the peak) of
the nanoaggregate sample. The NPs from compound 4a had the
largest hydrodynamic diameter or approximately 250 nm and the
nonfluorinated analog 4b had a smaller diameter of approximately
165 nm. Both of the compounds formed NPs in a relatively narrow
size distribution range. For the phosphonium amphiphile 5 two
populations of NPs were observed, one at about 90 nm and the
other at 395 nm diameters in approximately 3:1 ratio (Table 1,
entry 3). Since micelle diameters are usually not more than about
30 nm these NPs could not be micelles, they could be liposomes or
some other nanoaggregates but, without freeze-fracture electron
microscopy it cannot be proved conclusively. There is a slight
Fig. 1. AFM image of the self-assembled structures of fluorous 3,4-dihydropyridone
triphenylphosphonium bromide amphiphile (5) adsorbed on a mica surface from
aqueous solution with the corresponding height profiles (bottom).
Fig. 2. Representative dynamic light scattering spectrum of NPs obtained from
compounds 4a; 4b and 5 in distilled water.

R. Smits et al. / Journal of Fluorine Chemistry 132 (2011) 414–419
417
Table 1
one 1.86 g (0.0131 mol) in 50 mL p-xylene were heated in an oil
bath and stirred at 160 8C for 2 h. The solvent was removed on a
rotary evaporator to give 6.89 g of a light yellow oil. The oil was
purified by a silica gel column using EtOAc/hexane as eluent
800 mL 5% and 500 mL 10% in EtOAc, the fractions were monitored
on silica TLC plates with phosphomolybdic acid developer.
Fractions with Rf = 0.1 were collected and concentrated to give
Characteristic hydrodynamic diameters of NPs determined by DLS.
Nr.
Comp.
DLS
Most expected
Mean
d[H], nm
d[H], nm (%)
Peak 1
Peak 2
Peak 1
Peak 2
1.
2.
3.
4a
4b
5
255
164
59
–
–
249 (100)
164 (100)
87 (75)
–
4.43 g 64% yield of oil which solidified, to a white powder, mp 76–
–
3
79 8C. 1H NMR, 400 MHz (CDCl3):
d
= 4.17 (t, JHH = 6.2 Hz, 2H,
396
395 (25)
OCH2), 3.46 (s, 2H, COCH2CO), 2.21 (s, 3H, COCH3), 2.10 (m, 2H,
CH2CF2), 1.63–1.73 (m, 4H, CH2CH2CH2CF2). 13C NMR, 100.61 MHz
diameter size discrepancy between the AFM and DLS methods as
observed for compound 5. This could be due to the fact that DLS is
performed on NPs in water which makes them fully hydrated,
whereas, in AFM the samples are dried on a mica slide surface
which may influence the size and shape of NPs. The polydispersity
of the sample for compound 5 is explained by recognizing that DSL
measures average size ranges whereas AFM visualizes only a small
number of NPs.
(CDCl3): d = 200.26 (CO), 167.02 (COO), 121–108 (six m, 8CF2’s),
64.47 (OCH2), 49.91 (COCH2), 30.39 (t, JCF = 22.5 Hz, CH2CF2),
30.04 (s, 3H, CH3), 27.90 (OCH2CH2), 16.91 (CH2CH2CF2). 19F NMR,
2
376.2 MHz (CDCl3):
d
= À80.99 (t, 3JFF = 9.67 Hz, 3F, CF3), À114.58
(m, 2F, CH2CF2), À121.81 (m, 2F, CH2CF2CF2), À121.06 (m, 4F,
CF2C2F5 and CH2C2F4CF2), À122.86 (m, 2F, CF3CF2), À123.61 (m, 2F,
CF2C3F7), À126.27 (m, 2F, CF2C4F9). LC–MS: MS(+ESI) m/z (relative
intensity): 599 ([M+Na]+ 100) actual C16H13F17O3 MW 576.25.
3. Experimental
3.3. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyl
2-methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate
3.1. General
(2)
All reagents were purchased from Aldrich, Acros, Fluka or Merck
and used without further purification. TLC was performed on
20 cm  20 cm Silica gel TLC-PET F254 foils (Fluka). The one-
dimensional 1H (400 MHz), 19F (376.2 MHz), 31P (161.86 MHz)
An RB flask fitted with a water cooled condenser and a CaCl2
guard tube was charged with Meldrum’s acid 1.03 g (7.2 mmol),
benzaldehyde 0.76 g (7.2 mmol), the above perfluoroalkyl acet-
oacetate (1) 4.13 g (7.2 mmol), ammonium acetate 0.83 g
(10 mmol), and 12 mL glacial acetic acid. The reaction mixture
was stirred magnetically and heated to reflux in an oil bath for
6.5 h, after which the heating was stopped and left stirring
overnight. The reaction mixture was poured into ice water and
extracted with 3Â 50 mL EtOAc, and washed with brine, dried with
Na2SO4 filtered and concentrated on the rotary evaporator to a
light brown mass and after addition of 10 mL EtOH was left in the
ice box to crystallize. The crystals were filtered on a sintered glass
frit funnel and washed with cold EtOH to yield a light yellow
compound 1.59 g 31% yield with Rf = 0.36 on a silica TLC in 9:7:1
chloroform:petroleum ether:acetone under UV light mp 114–
and 13C (100.61 MHz) and two dimensional 1H–1H COSY, 19F–19
F
COSY, 13C–1H HMBC, 13C–1H HSQC NMR spectra of compounds were
recorded on a Varian-Mercury BB 400 MHz. The 1H–13C-HMBC
spectra were recorded with the evolution time of 62.5 s delay for the
generation of long-range correlations. For all two dimensional
13C–1H HMBC, 13C–1H HSQC spectra 4096 Â 1024 data matrix was
used, which ensured t t C
2max = 100 ms for 1H and 2max = 50 ms for 13
along the F1 and F2 axes, correspondingly. In order to improve the
signal-noiseratio, thedatamatrixbeforeFouriertransformationwas
zero-filled twiceandmultipliedwitha cosinefunction. Thechemical
shifts of the hydrogen and carbon atoms are presented in parts per
million and referred to the residual signals of the CDCl3 solvent 7.25
(1H) and 77.0 ppm (13C) ppm respectively. The chemical shifts of
fluorine and phosphorus atoms were referred to internal software
standards CFCl3 and H3PO4 correspondingly. Mass spectral data
were determined on an Acquity UPLC system (Waters) connected to
a Q-TOF micro hybrid quadrupole time of flight mass spectrometer
(Micromass) operatingin the ESI positive or negative ion mode onan
120 8C. 1H NMR, 400 MHz (CDCl3):
d = 7.53 (br s 1H, NH), 7.26 (t,
3
3JHH = 7.8 Hz, 2H, m-Ph), 7.19 (t, JHH = 7.8 Hz, 1H, p-Ph), 7.15 (d,
3JHH = 7,8 Hz, 2H, o-Ph), 4.23 (dm, 3JHH = 8.1 Hz, 1H, C4H), 4.11 and
2
3
4.03 (dt, JHH = 11.5 Hz, JHH = 6.0 Hz, 2H, AB-sys, OCH2) 2.71 (dd,
3
2
2JHH = 16.5 Hz, JHH = 8 Hz, C5HA), 2.94 (ddd, JHH = 16.5 Hz,
3JHH = 2 Hz, JHH = 0.9 Hz, C5HB), 2.43 (s, 3H, CH3), 1.96 (m, 2H,
4
CH2CF2), 1.59 (m, 2H, OCH2CH2), 1.47 (m, 2H, CH2CH2CF2).13
C
Acquity UPLC BEH C18 column (1.7
m
m, 2.1 mm  50 mm) using a
NMR, 100.61 MHz (CDCl3): d = 170.04 (C6), 166.65 (COO), 146.40
gradient elution with acetonitrile/phosphate buffer (pH 2.2; 0.05 M)
in water (10:90 by volume) at a flow rate of 1 mL/min. Peak areas
were determined electronically with a DP-800 (GBC Scientific
Equipment). Melting points were determined on an OptiMelt (SRS
Stanford Research Systems). The nanoaggregates were prepared by
dispersing the compounds in water using a Cole Parmer probe type
ultrasonic processor CPX 130W, U.S.A. and observed with MFP-3D-
BIOTM atomic force microscope in dynamic mode using Olympus
AC240TM tips. The characteristics of the formed nanoaggregates
were determined by the Dynamic Light Scattering technique (DLS).
For DLS measurements, we employed a Zetasizer Nano instrument.
(C2), 141.95 (i-Ph), 128.79 (m-Ph), 127.05 (p-Ph), 126.50 (o-Ph),
120–108 (six m, 8CF’s), 106.84 (C3), 63.21 OCH2), 38.23(C4),
2
38.16(C5), 30.50 (t, JCF = 23 Hz, CH2CF2), 28.10 (OCH2CH2), 19.23
(CH3), 16.93 (CH2CH2CF2). 19F NMR (CDCl3):
d
= À80.76 (t,
3JFF = 10.4 Hz, 3F, CF3), À114.4 (m, 2F, CH2CF2), À121.72 (m, 2F,
CH2CF2CF2), À121.91 (m, 4F, CF2C2F5 and CH2C2F4CF2), À122.69
(m, 2F, CF3CF2), À123.51 (m, 2F, C3F7CF2), À126.1 (m, 2F, C4F9CF2).
LC–MS: MS(+ESI) m/z (relative intensity): 728 ([M+Na]+ 100)
actual C25H20F15NO3 MW 705.40.
3.4. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyl
2-(bromomethyl)-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-
carboxylate (3)
Nano–Nano S90: size range 1 nm–3
of Malvern Instruments Ltd.
mm. Laser 633 nm and software
3.2. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyl
The above dihydropyridone (2) 0.71 g (1.0 mmol) was dissolved
in 5 mL chloroform. While stirring magnetically 0.7 mL of a
0.232 g/mL Br2 solution in chloroform (1.0 mmol) was added drop-
wise and the flask was stoppered and stirred 30 min. Then the flask
contents were transferred to a 100 mL round bottom flask with an
3-oxobutanoate (1)
5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorodode-
canol 6.45 g (0.0131 mol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-

418
R. Smits et al. / Journal of Fluorine Chemistry 132 (2011) 414–419
3
additional chloroform wash and the solvent was removed on a
rotary evaporator (foaming) and dissolved in about 1 mL MeOH
and left to crystallize in the dark. The precipitated solid was filtered
after 3 days as a light yellow solid powder 0.57 g, 72% yield and mp
4JHP = 3.7 Hz, 6H, m-Ph), 7.20 (t, JHH = 7.6 Hz, 2H, m-Ph), 7.16 (t,
3
3JHH = 7.6 Hz, 1H, p-Ph), 7.04 (d, JHH = 7.6 Hz, 2H, o-Ph) 5.86 and
2
2
5.66 (two dt, JHH = 14.9 Hz, JHP = 14.7 Hz, 2H, AB-syst., C2CH2),
3.90 (m, 1H, C4H), 3.75 and 3.52 (two dt, 2JHH = 11 Hz, 3JHH = 6.2 Hz,
2H, OCH2), 2.70 (dd, 2JHH = 16 Hz, 3JHH = 8.7 Hz, 1H, C5HA), 2.42 (dd,
100–104 8C. 1H NMR 400 MHz (CDCl3):
d = 7.95 (br s 1H, NH), 7.28
(t, 3JHH = 7,8 Hz, 2H, m-Ph), 7.21 (t, 3JHH = 7.8 Hz, 1H, p-Ph), 7.15 (d,
2JHH = 16 Hz, JHH = 1.9 Hz, 1H, C5HB), 1.87 (m, 2H, CH2CF2), 1.35
2
3JHH = 7,8 Hz, 2H, o-Ph), 4.88 (d, JHH = 11.2 Hz, 1H, CHABr), 4.57
(m, 2H, OCH2CH2), 1.27 (m, 2H, CH2CH2CF2). 13C NMR 100.6 MHz
2
(dd, 2JHH = 11.2 Hz, 4JHH = 0.7 Hz, 1H, CHBBr), 4.26 (dd, 3JHH = 8 Hz,
3JHH = 1.8 Hz, C4H) 4.15 and 4.07 (two dt, 2JHH = 11.3, 3JHH = 6.1 Hz,
(CDCl3):
d
= 167.92 (C6), 165.96 (d, JCP = 3 Hz, COO), 141.21 (d,
3
2
5JCP = 3.9 Hz, i-Ph), 140.96 (d, JCP = 11.3 Hz, C2), 135.24 (d,
2
3
2
2H, OCH2) 2.95 (dd, JHH = 16.5, JHH = 8.3, C5HA), 2.72 (ddd,
2JHH = 16.5, 3JHH = 2.1, 4JHH = 0.9, C5HB), 1.96 (m, 2H, CH2CF2), 1.60
(m, 2H, OCH2CH2), 1.47 (m, 2H, CH2CH2CF2). 13C NMR 100.61 MHz
4JCP = 3.3 Hz, 3 C, p-Ph) 134.62 (d, JCP = 10.4 Hz, 6 C, o-Ph),
3
130.01 (d, JCP = 13.2 Hz, 6 C, m-Ph), 128.9 (m-Ph), 127.26 (p-
1
Ph), 126.62 (o-Ph), 117.43 (d, JCP = 86.6 Hz, 3 C, i-Ph), 111.41 (d,
(CDCl3):
d
= 169.60 (C6), 165.57 (COO), 144.46 (C2), 141.01 (i-Ph),
3JCP = 9.3 Hz, C3), 120–108 (six br m, 8CF’s), 63.57 (OCH2), 38.33 (d,
4JCP = 2.4 Hz, C4), 38.04 (C5), 30.21 (t, 2JCF = 23.2 Hz, CH2CF2), 27.73
129.02 (m-Ph), 127.38 (o-Ph), 126.44 (o-Ph), 120–108 (six br.m,
8CF’s), 109.41 (C3), 63.95 OCH2), 38.33(C4), 38.04 (C5), 30.34 (t,
2JCF = 22.5 Hz, CH2CF2), 27.93 (OCH2CH2), 26.16 (CH2Br), 16.90
(OCH2CH2), 27.32 (d, 1JCP = 48.9 Hz, CH2Br), 16.78 (CH2CH2CF2). 19
F
3
NMR 376.2 MHz (CDCl3):
d
= À80.79 (t, JFF = 9.74 Hz, 3F, CF3),
(CH2CH2CF2). 19F NMR 376.2 MHz (CDCl3):
d
= À80.78 (t,
À114.32 (m, 2F, CH2CF2), À121.72 (m, 2F, CH2CF2CF2), À121.92 (m,
4F, CF2C2F5 and CH2C2F4CF2), À122.71 (m, 2F, CF3CF2), À123.52 (m,
2F, C3F7CF2), À126.11 (m, 2F, C4F9CF2). 31P NMR 161.86 MHz
3JFF = 10.4 Hz, 3F, CF3), À114.34 (m, 2F, CH2CF2), À121.73 (m, 2F,
CH2CF2CF2), À121.91 (m, 4F, CF2C2F5 and CH2C2F4CF2), À122.71
(m, 2F, CF3CF2), À123.51 (m, 2F, C3F7CF2), À126.1 (m, 2F, C4F9CF2).
LC–MS: MS(+ESI) m/z (relative intensity): 806 ([M+Na]+ 100)
actual C25H19BrF15NO3 MW 784.30.
(CDCl3)
d = 24.77 ppm. LC–MS: MS(+ESI) m/z (relative intensity):
966 ([MÀBr]+ 100) actual C43H34BrF17NO3P MW 1046.59.
3.7. Sample preparation for AFM and DLS observations
3.5. 1-[3-(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluoro-
dodecyloxycarbonyl)-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridin-2-
ylmethyl]-pyridinium bromide (4)
Compound 4a, 4b, or 5 was dispersed in an aqueous solution at
a concentration of 0.3 mg/mL by sonication using a probe type
sonicator, Cole Palmer ultrasonic processor CPX 130 (W), ampli-
tude 30%, pulse 15 s on, 15 s off, 5 min. – compound 4a and 4b and
25 min. – compound 5. Freshly cleaved mica plates were dipped
into the solutions and kept for 30 s to allow the nanoaggregates to
stick to the negatively charged surface. The mica samples were
dried at room temperature and observed by AFM in tapping mode.
The DLS measurements on the same aqueous samples were
recorded on a Zetasizer Nano S90 instrument.
0.30 g (0.38 mmol) of the above compound 3 was dissolved in
0.5 mL dry acetone and while stirring magnetically (0.40 mmol)
0.032 g of dry pyridine were added and the flask was stoppered.
The reaction mixture was left stirring overnight, filtered and the
solid was washed with diethyl ether to provide 0.26 g of a white
powder in 79% yield, mp 145–151 8C. 1H NMR 400 MHz (CDCl3):
3
d
= 10.56 (br s, 1H, NH), 9.51 (d, JHH = 5.6 Hz, 2H, o-Py), 8.42 (t,
3
3
3JHH = 7.6 Hz, 1H, p-Py), 8.12 (dd, JHH = 7.6 Hz, JHH = 5.6 Hz, 2H,
m-Py), 7.25 (t, 3JHH = 7.6 Hz, 1H, m-Ph), 7.21 (t, 3JHH = 7.6 Hz, 1H, p-
4. Conclusion
3
Ph), 7.14 (d, JHH = 7.6 Hz, 2H, o-Ph), 6.39 and 6.25 (two d,
2JHH = 13.5 Hz, 2H, AB-syst, CH2Py), 4.18 (dd, JHH = 6.4 Hz,
3
A fluorous 3,4-dihydro-2(1H)-pyridone-5-carboxylate has been
synthesized and further elaborated to yield two cationic amphi-
philes with either a pyridinium bromide or triphenylphosphonium
bromide polar head group. These amphiphiles self-assembled in
aqueous solution and as observed by AFM formed nanoaggregates.
The hydrodynamic diameters ranging from 90 to 395 nm were
determined by DLS measurements. NPs with a diameter range
100–200 nm are good candidates for cellular transport applica-
tions, and further studies to this end are continuing in our lab.
4JHH = 1.5 Hz, 1H, C4H), 4.06 and 4.02 (two dt, JHH = 11.3 Hz,
2
3JHH = 5.4 Hz, 2H, AB-syst, OCH2), 3.16 (dd, JHH = 16.1 Hz,
2
3JHH = 7.7 Hz, 1H, CHACOO), 2.57 (d, JHH = 16.1 Hz, 1H, CHBCOO),
2
1.94 (m, 2H, CH2CF2), 1.54 (m, 2H, CH2CH2O), 1.37 (m, 2H,
CH2CH2CF2). 13C NMR, 100.6 MHz (CDCl3):
d = 169.29 (C6), 166.47
(COO), 145.97 (p-Py), 145.40 (o-Py), 141.74 (C2), 141.14 (i-Ph),
129.0.5 (m-Ph), 128.56 (m-Py), 127.39 (p-Ph), 126.53 (o-Ph), 120–
108 (six br m, 8CF’s), 112.78 (C3), 64.33 (OCH2), 57.42 (C2CH2),
2
38.59 (C4), 38.29 (C5), 30.28 (t, JCF = 22.3 Hz, CH2CF2), 27.87
(OCH2CH2), 16.83 (CH2CH2CF2). 19F NMR, 376.2 MHz (CDCl3):
Acknowledgements
3
d
= À80.78 (t, JFF = 9.3 Hz, 3F, CF3), À114.32 (m, 2F, CH2CF2),
121.73 (m, 2F, CH2CF2CF2), À121.91 (m, 4F, CF2C2F5 and
CH2C2F4CF2), À122.71 (m, 2F, CF3CF2), À123.51 (m, 2F, C3F7CF2),
À126.11 (m, 2F, C4F9CF2). LC–MS: MS(+ESI) m/z (relative intensi-
ty): 784 ([MÀBr]+ 100) actual C30H24BrF17N2O3 MW 863.40.
This work was supported by the ESF project No. 2009/0197/
1DP/1.1.1.2.0/09/APIA/VIAA/014.
We are also grateful to Mr. Pavel Biryukov and Dr. Donats Erts of
the Institute of Chemical Physics, University of Latvia for the use
and assistance with the AFM equipment and Institute of Physics,
University of Latvia for the use and assistance with the DLS
equipment.
3.6. 1-[3-(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluoro-
dodecyloxycarbonyl)-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridin-2-
ylmethyl]-triphenylphosphonium bromide (5)
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triphenylphosphine were dissolved in 5 mL of dry acetonitrile. The
yellow solution was stirred magnetically at 40 8C for 2 h and then
cooled in the fridge. The precipitated product filtered and washed
with diethyl ether to give 0.55 g (82%) of a yellowish powder mp
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