Fluorinated tetraphosphonate cavitands

Article abstract of DOI:10.3390/molecules23102670

Two synthetic protocols for the introduction of fluorine atoms into resorcinarene-based cavitands, at the lower and upper rim, respectively, are reported. Cavitand 1, bearing four fluorocarbon tails, and cavitand 2, which presents a fluorine atom on the para position of a diester phosphonate phenyl substituent, were synthesized and their complexation abilities toward the model guest sarcosine methyl ester hydrochloride were evaluated via NMR titration experiments. The effect of complexation on the ¹⁹F NMR resonance of the probe is evident only in the case of cavitand 2, where the inset of the cation-dipole and H-bonding interactions between the P=O bridges and the guest is reflected in a sizable downfield shift of the fluorine probe.

Full text of DOI:10.3390/molecules23102670

molecules
Article
Fluorinated Tetraphosphonate Cavitands
Alessandro Pedrini , Federico Bertani and Enrico Dalcanale *
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle
Scienze 17/A, 43124 Parma, Italy; alessandro.pedrini@studenti.unipr.it (A.P.);
federico.bertani@studenti.unipr.it (F.B.)
*
Correspondence: enrico.dalcanale@unipr.it; Tel.: +39-0521-905463
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 28 September 2018; Accepted: 14 October 2018; Published: 17 October 2018
Abstract: Two synthetic protocols for the introduction of fluorine atoms into resorcinarene-based
cavitands, at the lower and upper rim, respectively, are reported. Cavitand , bearing four
fluorocarbon tails, and cavitand , which presents a fluorine atom on the para position of a diester
1
2
phosphonate phenyl substituent, were synthesized and their complexation abilities toward the model
guest sarcosine methyl ester hydrochloride were evaluated via NMR titration experiments. The effect
of complexation on the 19F NMR resonance of the probe is evident only in the case of cavitand
2,
where the inset of the cation-dipole and H-bonding interactions between the P=O bridges and the
guest is reflected in a sizable downfield shift of the fluorine probe.
Keywords: phosphonate cavitands; fluorine; molecular recognition; sarcosine methyl ester;
molecular probe
1
. Introduction
Cavitands [
through specific weak interactions, such as hydrogen bonding,
Their remarkable and versatile molecular recognition properties have been exploited in many different
fields, including catalysis [ ], crystal engineering [ ], molecular grippers [ ], protein recognition [ ],
responsive nanostructures [10,11], self-diagnostic polymers [12] and sensing [13,14].
1] are programmable abiotic receptors capable of hosting shape-complementary guests
π-π
stacking, CH- and cation- interactions.
π
π
2–5
6
7
8,9
Expanding further the application fields of cavitands requires the exploration of new synthetic
pathways for the introduction of specific reporting units. A potential but yet unexplored probe is
fluorine, with this nucleus being exceptionally sensitive toward molecular and micro-environmental
changes [15]. The lack of background interference makes fluorine-19 nuclear magnetic resonance
19
(
F NMR) spectroscopy an ideal tool for the study of complex matrices, in particular for in vivo
applications, where an endogenous signal from tissues is almost absent.
19
F NMR spectroscopy was first applied to the study of the complexation properties of
calix[4]arene-based molecular receptors by Swager and co-workers in 2013 [16]. Tungsten calix[4]arene
imido complexes were decorated with a fluorine atom to unambiguously detect targeted neutral
organic molecules. In their design, the perturbation of the electron density generated by the binding of
a Lewis basic molecule on tungsten induces a variation of the chemical shift of the π-conjugated fluorine,
with a response that highly depends on the electron donating ability of the analyte. The discrimination
between different analytes was possible only when the interactions with the tungsten were strong
enough to produce static structures on the NMR time scale and peaks at precise chemical shifts.
The same group further implemented this approach both by developing an array of fluorinated
receptors and by incorporating multiple nonequivalent fluorine atoms into a single receptor [17].
Fluorinated chiral palladium pincer complexes, instead, were successfully applied to an 19F
NMR-assisted simple and precise differentiation of chiral amines [18]. Diastereomeric complexes
Molecules 2018, 23, 2670; doi:10.3390/molecules23102670
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2670
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resulting from the bonding of enantiomers present a distinct and precise 19F NMR fingerprint even
in the presence of structurally similar analytes, allowing the simultaneous identification of multiple
species. The robustness of this chemosensory platform was demonstrated by the quantification of
caffeine content in coffee as well as by the identification of other ingredients in beverages [19].
More recently, Mancin et al. coated gold nanoparticles with fluorinated phenylboronic acids
and thioundecyl-D-glucopyranosides. The resulting chemosensor is able to detect dopamine in
human urine at physiologically relevant concentrations by means of 19F spectroscopic analysis via
displacement assay [20].
In view of their applications in biosensing [21], we selected the tetraphosphonate cavitands
(Tiiii) [13] as the most valuable receptors for the insertion of fluorine probes. Herein, we report two
synthetic protocols for the introduction of fluorine atoms into diester phosphonates [22 23] bridged
,
cavitand scaffolds at the lower and upper rim, respectively (Chart 1) and the response of the fluorine
probes toward the complexation of sarcosine methyl ester hydrochloride, as a proxy of sarcosine.
The early-stage detection of aggressive prostate cancer has been linked to the presence of sarcosine
in urine [24]. In detail, cavitand
fluorine containing nanoemulsions to impart molecular recognition properties [25], while cavitand
presenting a single fluorine atom on one phosphonate bridge, is considered a model system for
1 bearing four fluorocarbon tails is designed to be embedded in
2
,
molecular recognition via NMR using gold nanoparticles [20].
Chart 1. Structure of lower and upper rim fluorinated tetraphosphonate cavitands (
1 and 2 respectively)
and sarcosine methyl ester hydrochloride (G1).
2
. Results and Discussion
2
.1. Synthesis of Cavitand 1
Fluorocarbon-footed tetraphosphonate cavitand
1
was prepared from resorcinarene
4
, bearing
27],
required the acidic condensation of resorcinol and a fluorinated aldehyde.
was obtained via oxidation with Dess–Martin periodinane of the corresponding perfluorinated
four perfluorooctyl moieties. Following similar procedures to those reported in the literature [26
the synthesis of resorcinarene
Aldehyde
,
4
3
alcohol [28], which was obtained in two steps starting from heptadecafluoro-1-iodooctane [29].
The presence of three methylene groups mitigates the electron withdrawing effect of fluorides on aldehyde
reactivity. Aldehyde
resorcinarene (Scheme 1). Reaction with dichloroethylphosphine and the subsequent in situ oxidization
with hydrogen peroxide afforded diester phosphonate-bridged cavitand , with all P=O groups pointing
3 was reacted with an equimolar amount of resorcinol in acidic conditions, affording
4
1

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inward towards the cavity (hence the denomination Tiiii, where i stands for inward), which was
1
19 31
characterized by H, F, P NMR spectroscopy (Figures S1–S3) and matrix-assisted laser desorption
ionization time-of-flight (MALDI-TOF) spectrometry (Figures S7 and S8). As expected by the presence of
a relevant non-fluorinated part of the molecule, cavitand 1 was found to be insoluble in perfluorohexane,
but it presented a good solubility in fluorous hybrid solvents such as methoxyperfluorobutane (HFE-7100).
◦
Scheme 1. Synthesis of fluorinated tetraphosphonate cavitand
1: (
a
) resorcinol, HCl 37%, EtOH, 80 C,
◦
b) (1) EtPCl , pyridine/α,α,α-trifluorotoluene, 80 C, 3 h; (2) H O , r.t, 1 h, 23% (over
2 2 2
4
h, 23%; (
two steps).
2
.2. Synthesis of Cavitand 2
Asymmetric tetraphosphonate cavitand
strategy (Scheme 2). In the first step, dichloro(4-fluorophenyl)phosphine (
2
was prepared following a convergent synthetic
) was synthesized from
5
fluorobenzene via Friedel–Crafts reaction with phosphorous trichloride, using aluminum chloride
as a Lewis acid [30]. The subsequent addition of phosphorous oxychloride allowed the removal
1
of AlCl , that precipitated as AlCl
·
POCl complex [31]. Compound
5
was characterized via H,
3
3
3
19
31
F and P NMR; in particular, the presence of the phosphorous signal at 158.7 ppm confirmed
the isolation of the substituted phosphorous(III) dichloride species [30]. For its high reactivity
towards oxidation and hydrolysis, compound was maintained in solution under an inert atmosphere
and used without further purification in the next step. In principle, cavitand could be obtained
by the bridging of the corresponding resorcinarene scaffold with a mixture of phosphine and
5
2
5
unfunctionalized dichlorophenylphosphine. In our experience, the isolation of the desired product
from the mixture of statistical products is difficult [32], and therefore the bridging/excision protocol is
to be preferred. Following these considerations, pristine tetraphosphonate cavitand
from tetrahexyl-footed resorcinarene following previously reported procedures [33 34]. The bridging
reaction with dichloroethylphosphine in pyridine gave P(III) intermediate, which was oxidized
in situ with hydrogen peroxide to afford cavitands with the four diester phosphonate groups
directed towards the cavity. Adapting a published protocol [35], one of the four P=O bridges was
selectively removed using a stoichiometric amount of catechol as a scavenger and K CO as a base,
7 was prepared
6
,
7
2
3
affording triphosphonate cavitand diol (
phosphine
8
) in good yield. In the final reaction, a mixture of
8
and
◦
5
in pyridine was initially heated at 100 C for four hours to obtain a mixed-valence
phosphorous intermediate that was oxidized in situ to restore the diester phosphonate-decorated
rim with the four P=O directed inside the cavity. Fluorine-decorated tetraphosphonate cavitand
2
was isolated in low yield (10%) after column chromatography, as a consequence of the high
polarity of the product which hampers the purification step, and completely characterized via NMR
spectroscopy (Figures S4–S6) and MALDI-TOF spectrometry (Figures S9 and S10). As expected by
the desymmetrization of the cavity, 31P NMR spectrum of
2
presented three singlets at 4.4, 7.8 and
8
.9 ppm, respectively, with a 1:2:1 ratio of the integrals, while only one fluorine signal at 100.45 ppm
19
was detected with F NMR technique (Figure S6).

Molecules 2018, 23, 2670
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◦
a) (1) PCl , AlCl , 75 C, 4 h;
3 3
Scheme 2. Synthesis of fluorinated tetraphosphonate cavitand
2
: (
2) POCl , r.t., 0.5 h; (b) (1) PhPCl , pyridine, 80 C, 4 h; (2) H O , r.t, 0.5 h, 40% (over two steps);
3
◦
(
(
2
2
2
◦ ◦
) 1 eq. 1,2-dihydroxybenzene, K CO , DMF, 80 C, 5 h, 56%; (d) (1) 5, pyridine, 100 C, 2 h; (2) H O ,
2 3 2 2
c
r.t, 0.5 h, 10% (over two steps).
2
.3. NMR Titration Experiments
The effective variation of the 19F NMR chemical shift was evaluated upon complexation with
a well-studied guest, namely sarcosine methyl ester hydrochloride (G1), for both cavitands [36].
The design of cavitand requires the decoration of a diester phosphonate phenyl substituent
with fluorine in para position to ensure its -conjugation with the complexation active P=O group,
directly involved in the complexation via cation-dipole and H-bonding interactions. Cavitand instead
2
π
1
is designed to probe the complexation by sensing the presence of the chloride counterion, rather than
directly sensing the complexation of the protonated sarcosine G1. The typical positioning of the
chloride counterions in the complexation of sarcosine and related amino acids is between the alkyl feet
both in solution and in the solid state to minimize the ion pair distance [36].
To a solution of Tiiii
1 or 2 in deuterated chloroform at room temperature, four aliquots of
a solution of G1 in the same solvent were added to reach a guest/host molar ratio of 2. For each
1
19
31
addition, H, F and P NMR spectra were recorded and chemical shift variations for both host and
guest signals were analyzed. At the initial working concentration, cavitand signals in both proton
Figure S11a) and fluorine (Figure 1a) spectra are broadened. This behavior can be explained by the
1
(
low solubility of the receptor in the non-fluorinated solvent, which can give rise to the formation
of aggregates. Interestingly, upon the addition of the first aliquot of G1, a sensible sharpening of
the signals in the two spectra was observed, together with an upfield shift of the P=O singlet in 3
1
P
NMR spectrum (Figure S11b and Figure 1b, right). This is an unprecedented observation, as usually
complexation lowers the electron density on the phosphorous atom causing a downfield shift [37].
The reason for this unusual behavior can be traced in the 31P chemical shift of free cavitand
1, which is
unusually downfield-shifted with respect to the non-fluorinated analogues in CDCl (Figure S16),
3
while in the complexed form, the 31P chemical shift remains the same both for fluorinated and
non-fluorinated cavitands (27.7 ppm compared to 27.4 ppm).

Molecules 2018, 23, 2670
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Figure 1. 19F (376 MHz, CDCl , 298 K) and P NMR (162 MHz, CDCl , 298 K) spectra of free host
31
1
3
3
(
a),
1
+ 0.5 eq. of G1
(b
),
1
+ 1.0 eq. of G1
(c),
1
+ 1.5 eq. of G1
(d),
1
+ 2.0 eq. of G1 (e); on the right
cavitand 1 structure is reported.
Except for the line shape modification mentioned above, fluorocarbon-tail 19F NMR signals do not
experience any significant perturbation (Figure 1b, left). Guest proton signals, instead, present upfield
shits typical of N-methyl ammonium guest complexation in the electron rich cavity. The NCH3
triplet, in particular, experienced the highest complexation-induced shifts (from 2.38 to
−
1.11 ppm),
as expected by the deeper inclusion of this group in the cavity. Further additions of G1 (Figure S11c–e
and Figure 1c–e) did not alter significantly the position of both the host and the included guest signals
for all the studied nuclei, indicating a saturation of the receptor sites as consequence of the reduced
concentration of the free host in solution caused by the presence of aggregates.
The NMR titration experiment with cavitand
procedure. The H NMR spectra (Figures S12–S15) acquired during the titration shows reduced but
2 and G1 was performed following the same
1
detectable upfield shifts of the guest NCH group approaching 1 eq. of G1, with a reverse trend and
3
a signal broadening for further additions. This behavior is an indication of a fast exchange regime.
1
9
In F NMR spectra (Figure 2a–e, left) a 2.7 ppm upfield shift of the fluorine singlet (from
−
100.5 to
−
103.2 ppm) was detected. This result confirmed the effect of the -conjugation of the fluorine atom
π
31
with the P=O group through the aromatic ring. For the three singlets in P NMR spectra (Figure 2a–e,
right) different upfield shifts were observed, with appreciable higher values for the P=O group bearing
the fluorine-functionalized phenyl substituent and the one in the opposite position (red and green
lines in Figure 2).
Figure 2. 19F (376 MHz, CDCl , 298 K) and P NMR (162 MHz, CDCl , 298 K) spectra of free host
31
2
3
3
(
a),
2
+ 0.5 eq. of G1
(b
),
2
+ 1.0 eq. of G1
(c),
2
+ 1.5 eq. of G1
(d),
2
+ 2.0 eq. of G1
(e); on the right
chemical shift variations for the three phosphorus signals are reported.

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3
. Experimental
3
.1. Materials and Methods
Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere
of argon using anhydrous solvents (either freshly distilled or passed through activated alumina
columns). All commercially obtained reagents were used as received unless otherwise specified.
Silica column chromatography was performed using silica gel 60 (Fluka 230–400 mesh or Merck
7
0–230 mesh). NMR spectra were obtained using a Bruker AVANCE 400 (400 MHz) spectrometer
1
at 298 K. H NMR chemical shifts (
δ
) were reported in ppm relative to the proton resonances
19
resulting from incomplete deuteration of the NMR solvents.
F NMR chemical shifts (
) were reported in ppm
relative to external 85% H PO . High-resolution MALDI-TOF was performed on an AB SCIEX
δ) were
reported in ppm relative to external CF COOH. 31P NMR chemical shifts (
δ
3
3
4
MALDI TOF-TOF 4800 Plus (matrix:
Orbitrap MS analyses were performed with a Linear Trap Quadrupole-Orbitrap mass spectrometer.
H,1H,2H,2H,3H,3H-heptadecafluorododecanal ( ) [28] and resorcinarene 38] were prepared
according to methods in the literature. The adopted nomenclature follows an established rule [13].
α-cyano-4-hydroxycinnamic acid). High resolution ESI-LTQ
1
3
6 [
3
.2. Syntheses
.2.1. Synthesis of Resorcinarene [(CH ) (CF ) CF , H] (4)
3
2
3
2 7
3
To a solution of resorcinol (0.112 g, 1 mmol) in 2 mL of EtOH, a 37% solution of HCl (0.3 mL,
◦
4
mmol) was slowly added at 0 C. At the same temperature, a solution of aldehyde
3
(0.500 g, 1 mmol)
in 3 mL of EtOH was added dropwise. The mixture was allowed to warm over 90 min and then
◦
heated at 80 C for 4 h. After cooling, the solvent was removed and the crude was purified by flash
column chromatography (hexane/EtOAc 1:3). Resorcinarene
4
was obtained as a white solid (0.136 g,
0
.06 mmol, 23%).
1
H NMR (CD OD, 400 MHz):
δ (ppm) = 7.19 (s, 4H, ArHup), 6.27 (s, 4H, ArHdown), 4.37 (t, 4H,
3
19
J = 7.8 Hz, CH), 2.31–2.16 (m, 16H, CHCH + CH CF ), 1.61 (m, 8H, CH ); F NMR (CD OD, 376 MHz):
2
2
2
2
3
δ
(ppm) =
−
82.6 (t, 3F, JF-F = 10 Hz, CF3),
−
115.6 (t, 2F, JF-F = 15 Hz, CF CH ),
−
122.8 (m, 2F),
−
123.1 (m,
2
2
4
F),
−
123.9 (m, 2F),
−
124.8 (m, 2F),
−
127.5 (m, 2F); ESI-FT-Orbitrap-MS: calculated for C H F O
7
2
43 68
8
−
[M − H] m/z = 2327.187, found m/z = 2327.181.
3
.2.2. Synthesis of Tiiii [(CH ) (CF ) CF , H, Et] (1)
2 3 2 7 3
Resorcinarene
4 (0.060 g, 0.025 mmol) was suspended in 5 mL of a 2:1 mixture of pyridine/
α
,α,α-trifluorotoluene and dichloroethylphosphine (0.012 mL, 0.11 mmol) was added. The mixture
◦
◦
was heated at 80 C for 3 h. After cooling, 0.5 mL of aqueous 35% H O was added at 0 C and the
2
2
mixture was stirred for 1 h. The reaction was quenched with 20 mL of water and extracted with a 1:1
mixture of CHCl /HFE-7100. The organics were washed with water and the solvent was removed
3
under reduced pressure. Cavitand 1 (0.015 g, 0.006 mmol, 23%) was obtained as a white solid.
1
H NMR (CDCl , 400 MHz):
δ (ppm) = 8.88 (s, 4H, ArHup), 6.59 (s, 4H, ArHdown), 4.50 (t, 4H,
3
J = 8.0 Hz, CH), 3.11 (m, 8H, CHCH ), 2.36 (m, 8H, CH CF ), 2.21 (m, 8H, P(O)CH CH ), 1.62 (m, 8H,
2
2
2
2
3
19
CHCH CH ), 1.43 (m, 12H, P(O)CH CH ); F NMR (CD OD, 376 MHz):
δ
(ppm) =
−
80.9 (t, 3F,
123.3
2
2
2
3
3
JF-F = 10 Hz, CF3),
−
115.0 (m, 2F, CF CH ),
−
122.0 (m, 2F),
−
122.2 (m, 4F),
−
123.0 (m, 2F),
−
2
2
(
m, 2F),
−
126.3 (m, 2F); 31P NMR (CDCl , 162 MHz):
δ
(ppm) = 28.9 (s, 4P); MALDI-TOF: calculated
3
+
for C H F O P [M + H] m/z = 2625.171, found m/z = 2625.125; calculated for C H F O P Na
80
57 68 12
+
4
80 56 68 12
+
4
[
M + Na] m/z = 2647.153, found m/z = 2647.135; calculated for C H F O P K [M + K] m/z =
80 56 68 12 4
2
663.127, found m/z = 2663.124.

Molecules 2018, 23, 2670
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3
.2.3. Synthesis of Dichloro(4-fluorophenyl)phosphine (5)
A mixture of fluorobenzene (1.0 mL, 10.6 mmol), PCl (3.72 mL, 42.6 mmol) and AlCl (1.85 g,
3
3
◦
3.8 mmol) was heated at 75 C for 4 h. POCl (1.3 mL, 13.8 mmol) was carefully added to the hot
3
1
reaction mixture and the precipitate was filtered under an inert atmosphere and washed with diethyl
ether. Removal of the solvent under reduced pressure afforded phosphine 5, that was used without
purification for the next step.
1
H NMR (CDCl , 400 MHz):
δ
(ppm) = 7.93 (m, 2H, ArH3,5), 7.23 (t, 2H, J = 7.8 Hz, ArH2,6);
3
1
9
31
F NMR (CDCl , 376 MHz):
s, 1P).
δ
(ppm) =
−
105.2 (s, 1F); P NMR (CDCl , 162 MHz):
δ
(ppm) = 158.7
3
3
(
3
.2.4. Synthesis of Tiiii [C H , CH , Ph] (7)
6 13 3
Dichlorophenylphosphine (0.693 mL, 5.11 mmol) was added slowly at room temperature to
a solution of resorcinarene
was stirred at 80 C for 4 h. After cooling to room temperature, aqueous 35% H O (2 mL) was
6 (1.0 g, 1.14 mmol) in freshly distilled pyridine (30 mL). The mixture
◦
2
2
added and the resulting mixture was stirred for 30 min at room temperature. H O (200 mL) was
2
added and the precipitate was filtered, washed with water and dried. The crude was purified by flash
column chromatography (silica gel, CH Cl /EtOH 9:1) affording cavitand
7 as a white solid (0.622 g,
2
2
0
.45 mmol, 40%).
1
H NMR (CDCl , 400 MHz):
δ
(ppm) = 8.15 (m, 8H, ArH
o p
), 7.67 (m, 4H, ArH ), 7.57 (m, 8H,
3
ArH
m
), 7.17 (s, 4H, ArHdown), 4.82 (t, 4H, J = 7.9 Hz, CH), 2.37–2.28 (m, 20H, CHCH + ArCH ),
2
3
31
1.54–1.35 (m, 32H, CH ), 0.94 (t, 12H, J = 6.7 Hz, CH CH ); P NMR (CDCl , 162 MHz): δ (ppm) = 6.3
2 2 3 3
(s, 4P).
3
.2.5. Synthesis of Cavitand 3POiii [C H , CH , Ph] (8)
6 13 3
Catechol (0.036 g, 0.33 mmol) and K CO (0.454 g, 3.28 mmol) were added to a solution of
2
3
◦
cavitand
7 (0.45 g, 0.33 mmol) in 20 mL of DMF. The mixture was heated at 80 C under stirring
for 4 h. After cooling at room temperature, the solvent was removed under reduced pressure and
the residue was recovered with CH Cl washed with 1N aqueous solution of HCl, water and brine.
2
2,
The organic layer was dried over Na SO and evaporated to dryness. The crude product was purified
2
4
by flash column chromatography (silica gel, CH Cl /EtOH 95:5) to give cavitand
8
as an off-white
2
2
solid (0.210 g, 0.19 mmol, 56%).
1
H NMR (CDCl , 400 MHz):
δ
(ppm) = 8.11 (m, 6H, ArH
o
), 7.69 (m, 3H, ArH
p
), 7.59 (m, 6H,
3
ArHm), 7.23 (s, 2H, ArHdown), 7.10 (s, 2H, ArHdown), 4.74 (m, 3H, CH), 4.46 (m, 1H, CH), 2.32 (m, 6H,
31
CHCH ), 2.19 (m, 14H, ArCH + CHCH ), 1.52–1.30 (m, 32H, CH ), 0.93 (m, 12H, CH CH ); P NMR
2
3
2
2
2
3
(
CDCl , 162 MHz): δ (ppm) = 8.4 (s, 2P), 7.9 (s, 1P).
3
3
.2.6. Synthesis of Tiiii [C H , CH , 3Ph + 1PhFp] (2)
6 13 3
Cavitand
8
(0.200 g, 0.18 mmol) was dissolved in 10 mL of pyridine and phosphine
5
(0.18 mL,
◦
1
M solution in diethyl ether) was added. The mixture was heated at 100 C for 2 h under stirring.
After cooling to room temperature, aqueous 35% H O (1 mL) was added and the resulting mixture
2
2
was stirred for 30 min at room temperature. H O (100 mL) was added and the precipitate was filtered,
2
washed with water and dried. The crude mixture was purified by flash column chromatography
(
silica gel, CH Cl /EtOH 9:1) affording cavitand 2 as a white solid (0.016 g, 0.02 mmol, 10%).
2 2
1
H NMR (CDCl , 400 MHz, see supplementary material for signal attribution):
δ
(ppm) = 8.13
3
(
(
m, 2H, H ), 7.98 (m, 4H, H ), 7.72–7.46 (m, 9H, H + Hb’ + H + H ), 7.27 (s, 2H, Hdown’), 7.25
s, 2H, Hdown), 6.44 (m, 4H, H + H ), 4.91 (t, 1H, J = 6.6 Hz, H ) 4.77 (m, 3H, H + H ), 2.35 (m, 8H,
a
b d” d’ d
a”
a’
b”
c’
c”
CHCH ), 2.20 (s, 6H, H ), 1.66 (s, 6H, H ), 1.57–1.24 (m, 32H, CH ), 0.91 (t, 12H, J = 6.3 Hz, CH );
2
d’
d’
2
3
19
31
F NMR (CDCl , 376 MHz):
δ
(ppm) =
−
100.5 (s, 1F); P NMR (CDCl , 162 MHz):
δ
(ppm) = 8.9 (s, 1P),
3
3

Molecules 2018, 23, 2670
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+
7
=
.8 (s, 2P), 4.5 (s, 1P). MALDI-TOF: calculated for C H FO P [M + H] m/z = 1387.552, found m/z
80 92 12 4
+
1387.546; calculated for C H FO P Na [M + Na] m/z = 1409.534, found m/z = 1409.521.
80 91 12 4
4
. Conclusions
The present study describes two possible synthetic ways to introduce fluorine probes in
tetraphosphonate cavitands, at the lower and upper rim, respectively. In the first case, several fluorine
groups have been introduced as the final portion of the four alkyl feet of the cavitand , where the
key step is the synthesis of fluorinated resorcinarene . In the second case, a single fluorine group
has been introduced on the phenyl substituent of one P=O bridge to give cavitand . The preferred
synthetic approach turned out to be the excision of tetraphosphonate cavitand to give the tri-bridged
intermediate , which is then bridged with the phosphine and oxidized to give the desired cavitand
with all four P=O pointing toward the cavity.
1
4
2
7
8
5
2
The perturbation of the fluorine probe upon complexation was assessed in both cases using
sarcosine methyl ester hydrochloride (G1) as a prototype guest. The effect of complexation on the 1
9
F
NMR resonance of the probe is evident only in the case of cavitand 2, where the inset of cation-dipole
and H-bonding interactions between the P=O bridges and the guest is reflected in a sizable downfield
shift of the fluorine probe. The same complexation does not perturb the fluorine probes at the lower
rim of cavitand 1. The nesting of the chloride counterion between the alkyl feet in the complex [34]
does not affect the fluorine probes’ chemical shift, possibly because they are remote with respect to the
chloride position. The alternative of fully fluorinated alkyl feet is synthetically not viable, due to the
reduced reactivity of perfluorinated aldehydes. Therefore, the positioning of the fluorine probes on the
P=O bridges is the best option for potential biological applications.
Supplementary Materials: NMR spectra of cavitands
1
and
2
(Figures S1–S6), MALDI-TOF spectra of cavitands
1
1
and
2
(Figures S7–S10), H NMR titration spectra for complexation of cavitand
1
and with G1 (Figures S11–S16).
2
Author Contributions: E.D. and A.P. designed the investigation and wrote the paper; A.P. and F.B. synthetized
and characterized the cavitands and performed the complexation experiments. All authors read and approved
the final manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors thank G. Paredi of SITEIA, University of Parma, for high-resolution MALDI-TOF
MS analyses. Centro Interfacoltà di Misure “G. Casnati” of the University of Parma is acknowledged for the use
of NMR and HR-MS facilities. A.P. thanks INSTM for partial support of his Ph.D. scholarship.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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