Design of differently P-substituted 4i PO fluorescent tetraphosphonate cavitands

Article abstract of DOI:10.1080/10610278.2013.822975

Experimental approaches to tetraphosphonate cavitands bearing fluorenyl-phosphonate bridges are reported. Different routes are described depending on the substitution on the cavitand structure. Tetra-, tri- and di-bridged phosphonate cavitands have been p

Full text of DOI:10.1080/10610278.2013.822975

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Design of differently P-substituted 4iPO fluorescent
tetraphosphonate cavitands
Bastien Mettra a , Yann Bretonnière a , Jean-Christophe Mulatier a , Brigitte Bibal a b
Bernard Tinant c , Christophe Aronica a & Jean-Pierre Dutasta a
,
a Laboratoire de Chimie, ENS-Lyon, CNRS, Université de Lyon , 46 Allée d'Italie, F-69364 ,
Lyon , France
b Institut des Sciences Moléculaires, Université de Bordeaux , 351 Cours de la Libération,
F-33405 , Bordeaux , France
c Université Catholique de Louvain , MOST, 1 Place Louis Pasteur, B-1348 , Louvain-La-
Neuve , Belgium
Published online: 22 Aug 2013.
To cite this article: Bastien Mettra , Yann Bretonnière , Jean-Christophe Mulatier , Brigitte Bibal , Bernard Tinant ,
Christophe Aronica & Jean-Pierre Dutasta , Supramolecular Chemistry (2013): Design of differently P-substituted 4iPO
fluorescent tetraphosphonate cavitands, Supramolecular Chemistry, DOI: 10.1080/10610278.2013.822975
To link to this article: http://dx.doi.org/10.1080/10610278.2013.822975
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Supramolecular Chemistry, 2013
http://dx.doi.org/10.1080/10610278.2013.822975
Design of differently P-substituted 4i PO fluorescent tetraphosphonate cavitands
a
a
a
Bastien Mettra , Yann Bretonniere , Jean-Christophe Mulatier , Brigitte Bibala,b, Bernard Tinantc, Christophe Aronicaa and
`
Jean-Pierre Dutastaa*
a
b
Laboratoire de Chimie, ENS-Lyon, CNRS, Universite de Lyon, 46 Allee d’Italie, F-69364 Lyon, France; Institut des Sciences
´
Moleculaires, Universite de Bordeaux, 351 Cours de la Liberation, F-33405 Bordeaux, France; Universite Catholique de Louvain,
´
c
´
´
´
MOST, 1 Place Louis Pasteur, B-1348 Louvain-La-Neuve, Belgium
´
(Received 11 June 2013; final version received 26 June 2013)
Experimental approaches to tetraphosphonate cavitands bearing fluorenyl-phosphonate bridges are reported. Different routes
are described depending on the substitution on the cavitand structure. Tetra-, tri- and di-bridged phosphonate cavitands have
been prepared as precursors of fluorescent hosts, for which the stereochemistry is highly dependent on the substitution at the
wide rim of the resorcin[4]arene scaffold. The conformational change in 3io tetraphosphonate cavitands has been
characterised by X-ray diffraction. These new molecular receptors have been used for the recognition of acetylcholine.
Keywords: host–guest chemistry; molecular recognition; phosphonate cavitand; acetylcholine; fluorescence
1. Introduction
towards the molecular cavity giving them strong binding
capabilities (Figure 1). Nevertheless, partially bridged
compounds present interestingpropertiesduetothe presence
of free OH phenol groups that can be used to introduce
various bridging units. For instance, they have been used for
the design of supramolecular capsules (7) and chiral
molecular containers (8, 9).
Organic cage compounds are widely used as specific
sensors for a large variety of guest molecules of interest.
A particular attention is thus given to the design of
molecular hosts with structure and binding sites ideally
suited for the recognition of the target guests. The
phosphonate cavitands represent an original class of
molecular receptors, which have been actively studied
over the last decade (1–6). The most important feature,
which characterises these compounds, is the presence of an
aromatic cavity delineated at its wide rim by hard donor
phosphonate groups. This characteristic gives to these
molecules a strong capability to complex various guests
through cooperative interactions, including strong dipolar
interactions and H-bonding with the PO groups, and Van der
Waals interactions with the aromatic cavity. The phospho-
nate cavitands can exist under several configurations
depending on the orientation of the substituents at the
phosphorus atoms. Obviously, the inward (i) orientation of
the PvO groups is a prerequisite to optimise the
complexation properties. This has been demonstrated in
the past with tetra-bridged compounds bearing four
inwards-oriented PvO bonds (iiii or 4i isomer), and also
with partially bridged derivatives (Figure 1). For instance,
complexes with charged guests such as metal ions and
ammonium derivatives and neutral species such as alcohol
derivatives have been widely investigated. Most of these
studies are related to the so-called 4i derivatives that possess
four phosphonate bridges with the PvO bonds oriented
In this article, we demonstrated the versatility of the
synthesis of differently substituted phosphonate cavitands,
and we focused on fluorophoric derivatives that can be
useful to characterise the complexation of guests by means
of fluorescence spectroscopy (10). In the first approach, we
investigated the formation of tri-bridged 3i (iii) molecules
and discussed the different strategies that were used for
their syntheses. Similarly, di-bridged compounds (ABii
and ACii structures in Figure 1) were prepared following
known procedures. In the second step, the introduction of the
fluorenyl moiety in the structure of the cavitands gave rise
to new mono-, di- and tetra-fluorenyl 4iPO cavitand hosts
that are adequately suited for the recognition of natural
ammonium. This property is exemplified with acetylcholine
(AChþ) as guest by using fluorescence spectroscopy.
2. Results and discussion
2.1 Formation of tetraphosphonate 3io derivatives
Owing to the potential offered by the partially bridged
phosphonate cavitands, we have investigated different
*Corresponding author. Email: jean-pierre.dutasta@ens-lyon.fr
q 2013 Taylor & Francis

2
B. Mettra et al.
P
X
P
X
P
X
P
O
O
O
O
R
O
O
O
R
O
O
O
R
P
P
X
X
X
O
O
OH
OH
HO
HO
O
O
O
O
O
O
O
O
O
R
R
R
R
R
R
R
R
R
R
R
R
X
P
P
X
R
R
R
P
X
P
P
X
X
R
X
P
O
O
O
HO
OH
X
P
X
P
O
O
O
O
HO
HO
OH
OH
O
O
P
X
4i
3io
3i
ABii
ACii
Figure 1. Structures of the tetra-, tri- and di-bridged phosphonate cavitands (R ¼ alkyl chain; X ¼ S, O).
routes to access to these molecules, in particular starting
from derivatives with the 3io configuration. During the
synthesis of the phosphorylated cavitands, different
stereoisomers can be formed, due to the possible inwards
or outwards orientations of the PvO bonds. It has been
shown that the 4i stereoisomer, which is best suited for
intra-cavity complexation, is the main compound isolated
from the template-directed synthesis initially developed in
our laboratory (2, 11). For instance, the reaction of resorcin
[4]arene 1 with 4 equiv. of PhP(O)Cl2 mainly gave rise to
the 4i derivative 3 together with small quantities of the 3io
isomer 4 (6% yield) (Scheme 1). Starting from the
terabromo-resorcin[4]arene 2, the reaction with 4 equiv. of
PhP(O)Cl2 only afforded the 3io molecule 5 as the main
isolated product (52%). This result strongly differs from the
previous case without bromine atoms on the resorcin[4]
arene structure. However, the role of the bromine at the wide
rim of the cavitand in the stereoselectivity of the ring
closure reaction is not yet fully elucidated.
The solid-state structure of 4 was solved by single
crystal X-ray diffraction and shows the inward orientation
of one P-phenyl group that partially fills the molecular
cavity (Figure 2). It is interesting to note that the four
8-membered rings formed during the ring closure reaction
with PhP(O)Cl2 adopt the boat-chair conformation that
places the inward-oriented group on the phosphorus atom
in axial position and the outward-oriented group in
equatorial position. At room temperature (r.t.), the
1H NMR spectrum of 4 in CDCl3 solution shows
characteristic high-field shifted resonances for the protons
of the phenyl group oriented towards the cavity (Figure 3).
P
P
HO
OH
R
O
O
R
O
O
Z
Z
Z
Z
Z
O
R
R
Z
O
R
OH
OH
C6H5P(O)Cl2
(4 eq.)
HO
OH
OH
O
O
O
O
O
P
R
6
7
R
+
R
R
R
O
P
P
O
P
O
R
R
HO
O
O
O
O
Z
Z
O
P
Z
Z
Z
Z
HO
OH
O
O
O
O
P
1
Z = H; R = C11H23
Z = Br; R = C11H23
3
Z = H; R = C11H23
Z = Br; R = C11H23
4
O
2
5
1) 3 eq. C6H5PCl2
2) S8
3) [O]
P
P
P
O
O
O
O
O
O
Z
Z
O
Z
Z
Z
O
Z
O
Z
O
O
O
O
O
O
R
R
R
R
R
P
O
R
R
R
O
+
O
P
R
P
O
R
O
P
R
P
O
O
P
O
O
O
O
O
O
Z
Z
O
P
Z
Z
Z
HO
OH
O
O
O
P
P
6
7
Z = H; R = C11H23
Z = Br; R = C11H23
Cl
O
Cl
9
Z = H; R = C11H23 10
O
8
11 Z = Br; R = C11H23 12
Scheme 1. Syntheses of 3i, 4i and 3io phosphonate cavitands 3–7 from 1 (13) or 2 (14), and of the mono-fluorenyl-tetra-phosphonate
cavitands 9–12.

Supramolecular Chemistry
3
PhPCl2 with 1 equiv. of resorcin[4]arene 1 followed by a
sulphidation step, to give the trithiophosphonate 3i isomer
in moderate yields (25%), which is allowed to react with
m-chloro peroxybenzoic acid (m-MCPBA) or H2O2 to
afford the 3i compound 6 (74%) (Scheme 1) (12). It should
be noted that the step via the thiophosphonate derivatives
is often preferred to the direct oxidation because they are
more easily purified and the transformation to the oxide is
straightforward.
In the second approach, the 3i triphosphonate
cavitands were synthesised by reacting the corresponding
3io precursor with 1 equiv. of 1,2-dihydroxybenzene
(Scheme 1). This reaction scheme has been first proposed
by Castro et al. for the synthesis of tri- and di-quinoxaline
cavitands (15). Its efficient application to 4i tetrapho-
sphonate cavitands bearing ethyl R groups instead of
undecyl chains has been reported by Cantadori al. (16),
who obtained the 3i derivative in good yields (65%).
Starting from the 3io tetraphosphonate cavitand 4, the 3i
derivative 6 was only obtained in low yield. Surprisingly,
following this procedure with the 3io tetrabromo cavitand
5, the corresponding 3i derivative 7 was obtained
quantitatively. Therefore, the reaction is stereoselective
and the outward PO group in 5 is preferentially cleaved.
Compound 7 is thus obtained in two steps in 35–40%
overall yield from the resorcin[4]arene 2 and PhP(O)Cl2.
This has to be compared with the 19% overall yield
obtained previously for the related compound 6 in the
reaction of 1 with 3 equiv. of PhPCl2 followed by the
addition of sulphur and the subsequent oxidation with
MCPBA (12).
Figure 2. (Colour online) X-ray molecular structure of cavitand
3io 4 (the inward-oriented phenyl group is green coloured).
2.2 Syntheses of the partially bridged
phosphonatocavitands
The versatility of the bridging reactions encouraged us to
develop strategies for the synthesis of partially bridged
compounds because they open new possibilities to
introduce different bridging units for various applications.
To develop the synthesis of fluorescent-sensitive
cavitands, a 3i isomer with three phosphorylated bridges
and two free OH groups has been prepared. The first route
consists in the reaction of 3 equiv. of phosphorus reagent
Figure 3. (Colour online) 1H NMR spectrum (500.1 MHz; CDCl3; 298 K) of cavitand 3io 4 (aromatic protons: red, inward; green and
black, outward-oriented phenyl groups. Insert: methyne CH protons).

4
B. Mettra et al.
(a)
(b)
(c)
(d)
P
P
P
Cl
HO
Cl
OH
O
O
Br
Br
O
8
O
O
Scheme 2. Synthesis of fluorenyl-phosphonic dichloride 8: (a) n-BuN(Et)þ3 Cl2, aq NaOH, n-C6H13Br, dimethylsulfoxide (DMSO),
86% (17); (b) P(O-i-Pr)3, NiBr2, o-xylene, 98%; (c) HCl, 83% and (d) SOCl2, DMF, 100%.
2.3 Synthesis of the mono-fluorenyl derivatives 9–12
cavity, allowing the inclusion of an ethanol molecule
(Figure 4). This conformational change, compared with
the regular boat-chair conformation observed in the other
less constrained eight-membered rings in 11 (Figure 5), as
well as in other structures of phosphorylated cavitands
such as 4 described above, demonstrates the unexpected
flexibility of the cavitand structure under strong steric
hindrance.
The fluorescent probes based on the 3i cavitand structure
were obtained by reaction with the phosphorus reagent 8 that
was synthesised from P(OR)3 (R ¼ C2H5, i-C3H7) and
2-bromo-fluorene(Scheme 2). Bythisway, wethusexpected
the formation of the 4i tetraphosphorylated cavitands that are
known to form strong association with cationic species. The
reaction of 3i cavitand 6 with 8 gave rise to the 3io and 4i
isomers9and10, in9%and69%isolatedyields, respectively
(Table 1). Following the procedure that produced 9 and 10
from 6, the reaction of 7 with 8 afforded the P-fluorene
tetrabromo cavitand 11 (70% yield), where the fluorenyl
group is oriented inwards giving rise to a 3io structure
(Scheme 1). This result was unexpected according to the
hindrance induced by the fluorene moiety that would have
directed the bulky group outwards and thus favour the 4i
isomer 12, which was only recovered in small amounts and
characterised by mass spectrometry. However, this result is
in accord with the observation reported above about the
brominated and non-brominated derivatives, where the
reactionofthetetrabromo-resorcin[4]arene2with4equiv. of
PhP(O)Cl2 afforded only the 3io isomer 5.
2.4 Synthesis of poly-fluorenyl derivatives
The all inward-oriented PO groups of the tetraphosphonate
cavitands are a prerequisite for the efficient recognition of
guest substrates. Thus, we have been essentially interested
in the preparation of 4i isomers, and the following will
concern the non-brominated compounds. The ABiiPO (8)
and ACiiPO derivatives (Figure 1) can be synthesised in
good yields and are particularly attractive for the synthesis
of di-fluorenyl cavitands (Scheme 3). For instance, the
reaction of 2.5 equiv. of 8 with ABiiPO 13 allowed the
formation of the ABiiCDii bis-fluorene derivative 14 in
36% yield. Small amount (,12%) of the ABiiCDio bis-
fluorene compound 15 was also isolated. The same
procedure applied to the ACii derivative 16 afforded the
ACii BDii bis-fluorene 17 in 22% yield and the ACiiBDio
bis-fluorene 18 in 34% yield.
The structure of the mono-fluorenyl derivative 11 was
confirmed by an X-ray crystal structure determination
showing the outwards orientation of the PvO bond
attached to the fluorenyl group. As a consequence, a
distorted boat conformation of the appended eight-
membered ring maintains the fluorenyl group outside the
The strategy for the synthesis of the tetra-
fluorenyl cavitand is quite straightforward and follows
the sequence presented in Scheme 3 using 4 equiv. of the
Table 1. Yields and 31P NMR chemical shifts obtained for the mono-, di- and tetra-fluorenyl-phosphonate cavitands.
Cavitand
Isomer
H/Bra
No. fluob
Yield (%)
d 31P (ppm)c
9
3io
4i
3io
H
H
Br
H
H
H
H
H
H
1
1
1
2
2
2
2
4
4
9
69
70
36
12
22
34
35
9
9.54 (2P); 9.47 (1P); 8.04 (1P)
8.91 (1P); 7.39 (2P); 7.35 (1P)
9.05 (1P); 7.83 (1P); 7.65 (2P)
9.32 (2P); 7.77 (2P)
9.85 (1P); 9.15 (1P); 8.66 (1P); 8.59 (1P)
8.53 (2P); 6.85 (2P)
10.31 (1P); 9.28 (2P); 8.37 (1P)
8.78 (4P)
9.86 (3P); 9.50 (1P)
10
11
14
15
17
18
19
20
ABiiCDii
ABiiCDio
ACiiBDii
ACii BDio
4i
3io
a The substituent H or Br at the large rim.
b
Number of fluorenyl groups.
c CDCl3; 300 K.

Supramolecular Chemistry
5
maximum at 327 nm. Fluorescence quantum yields were
determined and are reported in Table 2. A decrease in the
quantum yield from 0.62 to 0.26 was observed when the
number of fluorenyl groups increases from one to four. This
may be explained by the close proximity of the fluorophores
at the wide rim of the cavitands, which facilitates self-
quenching and re-absorption of the emission.
To check the recognition properties of the new
fluorophoric cavitands, we used AChþ, which revealed to
be a suitable guest for the phosphonate cavitands due to its
cationic character and the favourable CHp interactions
between the methyl groups and the aromatic cavity. We
focused on the affinity of AChþ for the 4iPO derivatives 10,
14, 17and19. UpontheadditionofAchþ, thefluorescenceof
the host was dramatically quenched. The quantum yields F
for 10, 14, 17 and 19 obtained in the presence of AChþ guest
were identical to those of the free hosts and, compound 10
being chosen as an example, the fluorescence lifetime t
before and after the addition of guest remained constant.
These features are characteristic of a static quenching due to
theformationofanon-fluorescenthost–guestcomplexinthe
ground state. Job plots obtained by measuring the
fluorescence indicate the formation of 1:1 complexes for
all compounds (Figure 6). Then, titration experiments were
conducted in CHCl3 with measurement of the fluorescence
of the cavitands upon the addition of increasing quantity of
guest (Figure 7). By plotting the change in the emission
intensity I at 317 nm over the quantity of AChþ([AChþ])
added, a decrease was observed varying from 30% for
compound 17 to 40% for compounds 10, 14 and 19. The data
were then fitted by nonlinear regression analysis and least
squares fitting according to Equation (1) (18):
Figure 4. (Colour online) X-ray molecular structure of the
mono-fluorenyl tetraphosphonate cavitand 11.
fluorenyl-P(O)Cl2 derivative 8. Stereoisomers 4i 19 and 3io
20 have been isolated in 35% and 9% yields, respectively.
Table 1 sums up the different cavitands bearing fluorenyl-
phosphonate groups obtained in this work.
2.5 Recognition of ACh1 guest
ꢀ
ꢁ
Due to the presence of the fluorene core, the four
compounds 10, 14, 17 and 19 display an intense
fluorescence upon excitation in the main absorption band
(at 290 nm) characterised by a structured band with a
IF 2100
2Ka½AChþꢀ
I ¼
"
£ ðKa½hostꢀ½AChþꢀþ1Þ
#
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
þ
2
2
ðKa½hostꢀþKa½AChþꢀþ1Þ 24K2a½hostꢀ½ACh ꢀ
ð1Þ
þ100
where [host] and [AChþ] are, respectively, the cavitand host
and AChþ guest concentrations, Ka is the binding constant
and IF is the limiting value below which the fluorescencewill
not decrease due to the addition of AChþ. Equation (1) was
solved with IF and Ka as unknown parameters. The values of
the binding constants Ka determined are reported in Table 2
and are of the same order of magnitude ranging from 1.07
£ 106 for compound 19 to 9.28 £ 106 for compound 14. We
can notice that the Ka values are in the expected range for
ammonium guests and do not depend on the substitution of
the phosphorus atoms.
Figure 5. (Colour online) Part of the X-ray molecular structure
of 11 showing the two conformations adopted by the eight-
membered rings that delineate the aromatic cavity: (a) distorted
boat conformation and (b) boat-chair conformation.

6
B. Mettra et al.
P
P
P
O
O
O
O
O
O
O
O
R
R
P
O
Cl
Cl
O
13
O
O
OH
OH
O
P O
O
O P
O
R
R
R
R
R
R
P O
R
R
P
O
R
O P
O
O
O
O
O
O
P
HO
OH
O
O
O
O
P
13
14
15
O
P
O
P
O
P
O
O
O
O
O
O
O
R
R
P
Cl
Cl
O
8
O
O
O
O
HO
HO
OH
O
R
R
R
R
R
O
P
O
P
R
P
R
P O
O
R
R
O
O
O
OH
O
P
O
P
O
P
O
O
O
O
O
O
16
17
18
P
P
HO
OH
R
O
O
O
O
O
O
P
Cl
Cl
O
8
HO
HO
OH
OH
R
O
O
O
O
P
O
O P
R
R
R
R
O
R
P O
O
R
R
P
O
R
R
O
O
O
O
P
HO
OH
O
O
O
P
1
19
20
O
Scheme 3. Synthesis of the di- and tetra-fluorenyl-phosphonate cavitands.
3. Conclusions
behave differently from the non-brominated compounds.
In particular, the 3io isomer was the main compound
isolated, and it has been possible to obtain the 3i
derivative in almost quantitative yield by excision of the
outward-oriented PO group using 1,2-dihydroxy-benzene
under basic conditions. Fluorescence spectroscopy was
used to characterise the complexation of AChþ, a
biological relevant neurotransmitter. This highlights the
potentiality of these host molecules and opens new
opportunities for the development of original sensors.
More interestingly, this approach demonstrates the great
versatility of these molecules that can be differently
designed according to substituents and functions that can
be devoted to various specific guests and targeted
spectroscopic techniques.
Fluorescent tetraphosphonate cavitands have been
synthesised from readily accessible partially bridged
precursors. The brominated cavitands described herein
Table 2. Fluorescence quantum þyields F for hosts 10, 14, 17
and 19 and Ka values for the ACh complexes.
Hosta
F (t/ns)a
Ka (M21
)
10
14
17
19
0.62 (1.09)
0.46
0.56
1.82 £ 106
9.28 £ 106
1.55 £ 106
1.07 £ 106
0.26
a In CHCl3, using tryptophan in water (F ¼ 0.14) as reference,
lexc ¼ 290 nm.

Supramolecular Chemistry
7
measured using a Horiba-Jobin Yvon Fluorolog-3 spectro-
fluorometer, equipped with a red-sensitive Hamamatsu
R928 photomultiplier tube. Spectra were reference
corrected for both the excitation source light intensity
variation (lamp and grating) and the emission spectral
response (detector and grating). The fluorescence quantum
yields were determined in chloroform relative to tryptophan
in water (F ¼ 0.14) using Equation (2), where S is the slope
obtained by plotting the integrated area under the
fluorescence emission spectrum versus the absorbance at
lexc. Superscript ref and s correspond to the reference and
the sample, respectively. For each experiment, five points
were recorded, all corresponding to an absorbance at lexc
below 0.1.
ꢀ
ꢁ
2
Ss
Sref
nd
nrdef
Fs ¼ Fref
£
£
:
ð2Þ
Luminescence excited state lifetimes were recorded
using a Jobin Yvon IBH FluoroCube photon-counting
spectrometer as the detection unit. The system was
equipped with a TBX-04 picosecond photon detection
module for detection in the UV–vis region (300–800 nm).
A 290-nm Nano-LED was used as excitation source.
Figure 6. Job plots for the complexation of AChþ by cavitands
10, 14, 17 and 19.
4. Experimental
4.1 Materials and instrumentation
Solvents were of commercial grade or dried on GT S100
Dry Station columns; CDCl3 was stored over molecular
1
sieves. H, 13C and 31P NMR spectra were recorded at
4.3 Syntheses
298 K on a Bruker DPX 200 or Bruker Avance 500
spectrometers. NMR chemical shifts d are reported in ppm
referenced to the solvent signal (1H; 13C) or to external
85% H3PO4 (31P). Resorcin[4]arenes 1 and 2 were
synthesised according to the previously reported pro-
cedures (13, 14). 2-Bromo-9,9-di-n-hexyl-9H-fluorene
was prepared following the published procedure (17).
Diisopropyl (9,9-di-n-hexyl-9H-fluoren-2-yl)phosphonate
Tri-isopropyl phosphite (7.5 ml, 30.4 mmol) was added
dropwise to a solution of 2-bromo-9,9-di-n-hexylfluorene
(3 g, 6.52 mmol) and NiBr2 (0.32 g, 1.45 mmol) in
o-xylene (100 ml). The solution was stirred overnight at
1508C under argon. The solvent was evaporated under
vacuum, and the resulting oil was purified on a silica
column chromatography (CC) (CH2Cl2–AcOEt: 10:0 to
9:1) to give the desired product as a yellow oil (3.19 g,
98% yield). ESI-MS m/z 521.3161 [M þ Na]þ (calcd
4.2 Fluorescence
UV–vis absorption measurements were recorded on a
JASCO V670 spectrometer. Fluorescence spectra were
1
521.3161). H NMR (11.7 T, 300 K, CDCl3) d 7.81–7.68
Figure 7. Fluorescence quenching by increased [Ach]t: overall fluorescence decrease for 19 (left), and fluorescence quenching curves
(intensity at 317 nm normalised to 100 for [Ach]t ¼ 0 M) for 10, 14, 17 and 19 (right). Lines are fitted curves according to Equation (1).

8
B. Mettra et al.
(m, 4H); 7.32 (m, 3H); 4.61 (m, 2H); 1.97 (m, 4H); 1.35 (d,
6H); 1.17 (d, 6H); 1.10–0.98 (m, 12H); 0.71 (m, 6H); 0.52
(m, 4H). 13C NMR (11.7 T, 300 K, CDCl3) d 151.44,
150.74, 145.14, 130.94, 127.12, 126.34, 123.03, 120.55,
119.61, 70.62, 55.43, 53.52, 40.35, 31.57, 29.65, 24.21,
23.81, 22.56, 14.05. 31P NMR (4.7 T, 300 K, CDCl3) d
17.85 (s, 1P).
(s, 2P); 7.05 (s, 1P). 1H NMR (CDCl3, 200.13 MHz,
300 K) 8.35–8.21 (m, 6H); 7.98 (s, 2H); 7.70–7.50 (m,
9H); 7.14 (s, 2H); 4.79–4.72 (m, 3H); 4.52 (t, 1H); 2.26
(m, 8H); 1.37–1.25 (m, 72H); 0.87 (m, 12H).
Cavitand ACiiPO 16
To a chloroform solution of the parent thiophosphonate
cavitand ACii PS as previously described (8) (220 mg,
0.145 mmol), m-MCPBA (182 mg, 1.06 mmol, 7 equiv.)
was added. After stirring at r.t. overnight, the solvent was
evaporated and the residue was purified by silica gel CC
(CH2Cl2–THF, 1:0 to 4:1) to afford pure ACii PO
compound 16 as a white solid (210 mg, 0.14 mmol,
96%). ESI-MS 1371.8098 [M þ Na]þ (calcd 1371.8092).
31P NMR (CDCl3, 81.02 MHz, 300 K) 6.25 (s, 2P); 7.05 (s,
(9,9-Di-n-hexyl-9H-fluoren-2-yl)phosphonic acid
A mixture of di-isopropyl-9,9-di-n-hexylfluorene phos-
phonate (1.057 g, 2.12 mmol) in 37% HCl solution (10 ml)
was heated at reflux temperature overnight. The waxy
residue was washed with water and dissolved in CH2Cl2.
The organic solution was first washed with water until
neutrality, then with a saturated solution of NaCl and then
dried over Na2SO4. Evaporation of the solvent afforded the
phosphonic acid as a white powder (725 mg, 83% yield).
1
1P). H NMR (CDCl3, 500.1 MHz, 300 K) 9.49 (s, 4H);
8.08 (dd, 4H); 7.58 (m, 6H); 7.30 (m, 2H); 7.07 (s, 3H);
6.66 (s, 3H); 4.73 (t, 2H); 4.22 (t, 2H); 2.34 (m, 4H); 2.01
(m, 4H); 1.25 (m, 72H); 0.87 (s, 12H).
1
ESI-MS m/z 415.24 [M þ H]þ (calcd 415.52). H NMR
(11.7 T, 300 K, CDCl3) d 10.07 (s, 2H); 7.92–7.74 (m,
4H); 7.36 (m, 3H); 1.98 (m, 4H); 1.02 (m, 12H); 0.72 (m,
6H); 0.58 (m, 4H). 13C NMR (11.7 T, 300 K, CDCl3) d
151.64, 150.63, 144.38, 140.31, 130.38, 128.10, 126.90,
125.53, 123.21, 120.62, 119.81, 55.51, 40.24, 31.51,
29.76, 23.93, 22.64, 14.08. 31P NMR (4.7 T, 300 K,
CDCl3) d 24.63 (s, 1P).
General procedure for the synthesis of the fluorenyl-
phosphonate cavitands
The precursors 1, 6 (12), 7, 13 (8) and 16 were dissolved in
dry toluene and azeotropically distilled under argon to
eliminate traces of water. A solution of an excess of
N-methylpyrrolidine and (9,9-di-n-hexyl-9H-fluoren-2-yl)
phosphonic dichloride 8 in dry toluene was added. The
mixture was heated under reflux for 5–12 h. After
evaporation of the solvent, the residue was purified by
CC on silica gel to give the expected phosphonate
cavitand. A typical procedure was described for com-
pounds 9 and 10.
(9,9-Di-n-hexyl-9H-fluoren-2-yl)phosphonic dichloride 8
SOCl2 (4 ml) and dimethylformamide (DMF) (0.2 ml)
were added to (9,9-di-n-hexyl-9H-fluoren-2-yl)phospho-
nic acid (310 mg, 0.75 mmol) and heated at reflux
temperature overnight. After evaporation under vacuum,
8 was obtained as a brown oil (335 mg, 0.74 mmol, 100 %)
and immediately engaged in the next reaction without
1
further purification. H NMR (11.7 T, 300 K, CDCl3) d
7.79 (m, 1H); 7.70–7.60 (m, 3H); 7.32 (m, 2H); 7.09 (s,
1H); 1.84 (m, 4H); 0.87 (m, 12H); 0.58 (m, 6H); 0.41 (m,
4H). 31P NMR (4.7 T, 300 K, CDCl3) d 37.57 (s, 1P).
Mono-fluorenyl tetraphosphonatocavitands 9 and 10
Azeotropic distillation by means of a Dean-Stark
apparatus of 6 (295 mg, 0.20 mmol) in toluene (30 ml)
was performed overnight under dry argon to remove traces
of water. After cooling to r.t., N-methylpyrrolidine (three
drops) and (9,9-di-n-hexyl-9H-fluoren-2-yl)phosphonic
dichloride 8 (170 mg, 0.38 mmol) were added to the
toluene solution. The resultant mixture was heated at
reflux temperature for 5.5 h and then evaporated under
vacuum. The crude product was purified by silica gel
chromatography (CH2Cl2–THF 9:1, 7:1 and then 5:1) to
give successively the 3io derivative 9 (33 mg, 0.02 mmol,
9%) and the 4i derivative 10 (257 mg, 0.14 mmol, 69%). 9:
ESI-MS 1872.0139 [M þ Na]þ (calcd 1872.0132).
1H NMR (CDCl3, 200.13 MHz, 300 K) 8.14–7.79 (m,
8H); 7.69–7.30 (m, 17 H); 6.98 (s, 2H); 6.45 (s, 2H); 6.37
(m, 1H); 5.22 (t, 1H); 4.75 (m, 3H); 2.35 (m, 8H); 1.93
(m, 4H); 1.44–1.27 (m, 72H); 1.01–0.84 (m, 24H); 0.64
Cavitand 3i 7 (from 5)
Catechol (15 mg, 0.14 mmol) and K2CO3 (32 mg,
0.28 mmol) were added to a solution of cavitand 5
(265 mg, 0.14 mmol) in dry DMF (10 ml). The reaction
mixture was heated at 808C for 2 h. After cooling to r.t.,
water and few drops of aqueous 12N HCl and CH2Cl2 were
added, and the mixture was stirred for half an hour. The
organic layer was extracted and washed with brine, dried
over Na2SO4 and evaporated to dryness. The crude product
was purified by CC on silica gel (CH2Cl2–acetone 8:2,
then 1:1) to give cavitand 3i 7 as a beige solid (233 mg,
0.13 mmol, 94%). ESI-MS 1807.4449 [M þ Na]þ (calcd
1807.4424). 31P NMR (CDCl3, 81.02 MHz, 300 K) 7.99

Supramolecular Chemistry
(m, 6H); 0.52 (m, 4H). 31P NMR (CDCl3, 81.02 MHz,
9
ACiiPOBDioPO difluorene (18)
ESI-MS 2106.2407 [M]þ (calcd 2106.2498). 1H NMR
(500.1 MHz, 300 K, CDCl3) 8.00 (m, 4H); 7.88 (m, 4H);
8.03 (m, 4H); 7.82 (m, 1H); 7.75 (m, 1H); 7.55 (t, 2H);
7.45 (br m, 1H); 7.42 (m, 4H); 7.36 (s, 2H); 7.35 (m, 1H);
7.30 (br m, 5H); 7.27 (s, 2H); 7.00 (s, 2H); 6.65 (m, 1H);
6.54 (s, 2H); 5.32 (t, 1H); 4.86 (t, 1H); 4.77 (t, 2H); 2.35
(m, 8H); 2.09–1.85 (m, 8H); 1.55–1.37 (m, 12H); 1.37–
1.20 (br m, 60H); 1.10–0.90 (m, 24H); 0.86 (t, 12H); 0.71
(t, 6H); 0.65 (t, 6H); 0.65–0.45 (br m, 8H). 31P NMR
(81.02 MHz, 300 K, CDCl3) 10.31 (s, 1P); 9.28 (s, 2P);
8.37 (s, 1P).
300 K) 9.54 (s, 2P); 9.47 (s, 1P); 8.04 (s, 1P). 10: ESI-MS
1872.0119 [M þ Na]þ (calcd 1872.0132). 1H NMR
(CDCl3, 200.13 MHz, 300 K) 8.10–7.94 (m, 8H); 7.83–
7.72 (m, 2 H); 7.65–7.45 (m, 9 H); 7.36 (m, 3H); 7.26
(m, 4H); 7.02 (d, 4H); 4.82 (m, 4H); 2.35 (m, 8H); 1.99
(m, 4H); 1.45–1.27 (m, 72H); 1.08–1.01 (m, 12H); 0.71
(m, 12H); 0.71 (m, 6H); 0.57 (m, 4H). 31P NMR (CDCl3,
81.02 MHz, 300 K) 8.91 (s, 1P); 7.39 (s, 2P); 7.35 (s, 1P).
3ioPO(Br) monofluorene (11)
ESI-MS 2163.6750 [M þ H]þ (calcd 2163.6722). 1H NMR
(CDCl3, 200.13MHz, 300 K)8.36–7.93(m, 8H);7.70–7.45
(m, 10 H); 7.34–7.15 (m þ CHCl3); 6.37 (m, 1H); 5.84 (m,
1H); 4.82 (m, 3H); 2.32 (m, 8H); 1.89 (m, 4H); 1.48–1.28
(m, 72H); 1.08–0.76 (m, 24H); 0.64 (br m, 6H); 0.47
(m, 4H). 31P NMR (CDCl3, 81.02 MHz, 300 K) 9.05 (s, 1P);
7.83 (s, 1P); 7.65 (s, 2P).
4iPO tetrafluorene (19)
ESI-MS 2618.6972 [M]þ (calcd 2618.6880). 1H NMR
(500.1 MHz, 300 K, CDCl3) 8.02 (m, 8H); 7.80 (m, 4H);
7.75 (m, 4H); 7.37 (m, 10H); 7.30 (m, 6H); 7.09 (s, 4H);
4.91 (t, 4H); 2.39 (m, 8H); 2.00 (m, 16H); 1.61 (s, 8H);
1.50 (m, 8H); 1.29 (m, 56H); 1.03 (m, 48H); 0.88
4iPO(Br) monofluorene (12)
Not pure. ESI-MS 2163.6730 [M þ H]þ (calcd
Table 3. Crystallographic data for 4 and 11.
2163.6722); 2185.6580 [M þ Na]þ (calcd 2185.6542).
[4·CH2Cl2·H2O]
[11·2C2H5OH]
Formula
FW (g mol21
C97H126Cl2O13P4 C119H160Br4O14P4
)
1694.76
Monoclinic
P21/c
2258.08
Triclinic
P 2 1
ABiiPOCDiiPO difluorene (14)
Crystal system
Space group
Size (mm)
ESI-MS 2106.2593 [M]þ (calcd 2106.2498). 1H NMR
(500.1 MHz, 300 K, CDCl3) 8.00 (m, 7H); 7.84 (d, 2H);
7.78 (d, 2H); 7.64 (m, 2H); 7.54 (m, 4H); 7.39 (m, 6H);
7.33 (m, 4H); 7.07 (m, 7H); 4.91 (m, 2H); 4.86 (m, 2H);
2.40 (m, 8H); 2.04 (m, 8H); 1.76 (m, 8H); 1.52–1.37 (m,
66H); 1.06 (m, 22H); 0.90 (m, 12H); 0.74 (m, 12H); 0.60
(m, 8H). 31P NMR (81.02 MHz, 300 K, CDCl3) 9.32
(s, 2P); 7.77 (s, 2P).
0.2 £ 0.18 £ 0.18
14.857(6)
36.277(12)
17.309(7)
90.00
0.1 £ 0.1 £ 0.1
14.812(5)
19.791(5)
21.228(5)
109.64(5)
96.56(5)
99.33(4)
5687(3)
2
˚
a (A)
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
104.55(3)
90.00
9030(6)
4
1.247
0.204
3624
0.7107
293
3
˚
V (A )
Z
rcalcd (g cm23
)
1.319
1.532
2016
0.7107
293
m (mm21
F(0 0 0)
)
ABiiPOCDioPO difluorene (15)
˚
(A)
l
T (K)
Mo Ka
ESI-MS 2106.2433 [M þ H]þ (calcd 2106.2498). 1H
NMR (500.1 MHz, 300 K, CDCl3) 8.69–8.24 (m, 4H);
8.03 (m, 4H); 7.72 (m, 2H); 7.42 (m, 4H); 7.32; 6.95; 6.72;
6.53; 5.38 (t, 1H); 4.80 (t, 3H); 2.33 (m, 8H); 1.84 (m, 8H);
1.43 (m, 8H); 0.95 (m, 72H); 0.84 (m, 38H); 0.69–0.53
(m, 20H). 31P NMR (81.02 MHz, 300 K, CDCl3) 9.85 (s,
1P); 9.15 (s, 1P); 8.66 (s, 1P); 8.59 (s, 1P).
h
k
0 ! 14
0 ! 36
217 ! 16
20.81
30468
9135
7103
0 ! 19
225 ! 25
0 ! 27
27.98
25,184
22,927
9764
l
umax (8)
Reflections collected
Reflections independent
Reflections with
I . 2s(I)
No. parameters
No. restraints
Rint
1066
736
0.079
1270
303
0.053
ACiiPOBDiiPO difluorene (17)
R1[I . 2s(I)]
wR2[I . 2s(I)]
R1 (all data)
wR2 (all data)
Goodness of fit
Drmin /Drmax (e A
0.0885
0.2593
0.1057
0.2724
1.066
0.0972
0.1059
0.2056
0.1827
1.156
ESI-MS 2106.2583 [M]þ (calcd 2106.2498). 1H NMR
(500.1 MHz, 300 K, CDCl3) 8.09 (m, 4H); 7.91 (m, 5H);
7.88 (m, 2H); 7.57 (m, 3H); 7.44 (m, 7H); 7.36 (m, 6H);
7.06 (d, 2H); 6.51 (d, 3H). 31P NMR (81.02 MHz, 300 K,
CDCl3) 8.53 (s, 2P); 6.85 (s, 2P).
21
)
˚
21.047/0.530
21.07/1.65

10
B. Mettra et al.
(m, 12H); 0.71 (m, 12H); 0.59 (m, 16H). 31P NMR
(81.02 MHz, 300 K, CDCl3) 8.78 (s, 4P).
(4) Pinalli, R.; Suman, M.; Dalcanale, E. Eur. J. Org. Chem.
2004, 451–462.
(5) Pirondini, L.; Dalcanale, E. Chem. Soc. Rev. 2007, 36,
695–706.
(6) Melegari, M.; Suman, M.; Pirondini, L.; Moiani, D.;
Massera, C.; Ugozzoli, F.; Kalenius, E.; Vainiotalo, P.;
Mulatier, J.-C.; Dutasta, J.-P.; Dalcanale, E. Chem. Eur. J.
2008, 14, 5772–5779.
(7) Harthong, S.; Dubessy, B.; Vachon, J.; Aronica, C.;
Mulatier, J.-C.; Dutasta, J.-P. J. Am. Chem. Soc. 2010, 132,
15637–15643.
(8) Vachon, J.; Harthong, S.; Dubessy, B.; Dutasta, J.-P.;
Vanthuyne, N.; Roussel, C.; Naubron, J.-V. Tetrahedron
Asymmetr. 2010, 21, 1534–1541.
(9) Vachon, J.; Harthong, S.; Jeanneau, E.; Aronica, C.;
Vanthuyne, N.; Roussel, C.; Dutasta, J.-P. Org. Biomol.
Chem. 2011, 9, 5086–5091.
3ioPO tetrafluorene (20)
ESI-MS 2640.6574 [M þ Na]þ (calcd 2640.6700). 1H
NMR (500.1 MHz, 300 K, CDCl3) 8.1 (m, 2H); 8.0 (m,
2H); 7.9 (m, 4H); 7.7 (m, 1H); 7.6 (m, 4H); 7.5 (m, 4H);
7.4 (m, 8H); 7.3 (m, 1H); 7.2 (m, 10H); 7.0 (m, 2H); 6.5
(m, 2H); 5.3 (t, 1H); 4.6 (t, 3H); 2.4 (m, 8H); 2.0 (m, 8H);
1.5 (8,H); 1.4 (8,H); 1.3 (m, 64H); 1.1 (m, 8H); 0.9 (m,
12H); 0.8 (m, 12H); 0.5 (m, 8H). 31P NMR (81.02 MHz,
300 K, CDCl3) 9.86 (s, 3P); 9.50 (s, 1P).
4.4 X-ray crystallographic analysis
(10) Maffei, F.; Genovese, D.; Montalti, M.; De Zorzi, R.;
Geremia, S.; Dalcanale, E. Angew. Chem. Int. Ed. 2011, 50,
4654–4657.
(11) Delangle, P.; Dutasta, J.-P. Tetrahedron Lett. 1995, 36,
9325–9328.
Crystal data and details of structure refinement are
summarised in Table 3. The CCDC deposition numbers
are 937218 (4) and 937222 (11).
(12) Dubessy, B.; Harthong, S.; Aronica, C.; Bouchu, D.; Busi,
M.; Dalcanale, E.; Dutasta, J.-P. J. Org. Chem. 2009, 74,
3923–3926.
(13) Aoyama, Y.; Tanaka, Y.; Sugahara, S. J. Am. Chem. Soc.
1989, 111, 5397–5404.
(14) Timmerman, P.; Boerrigter, H.; Verboom, W.; Van
Hummel, G.J.; Harkema, S.; Reindhoudt, D.N. J. Inc.
Phenom. 1994, 19, 167–191.
Acknowledgements
The authors warmly thank B. Basler, E. Gaume and Dr A.-G.
Valade for their assistance in this project. Dr E. Jeanneau is
greatly acknowledged for his help in X-ray diffraction analysis.
(15) Castro, P.P.; Zhao, G.; Masangkay, G.A.; Hernandez, C.;
Gutierrez-Tunstad, L.M. Org. Lett. 2004, 6, 333–336.
(16) Cantadori, B.; Betti, P.; Boccini, F.; Massera, C.; Dalcanale,
E. Supramol. Chem. 2008, 20, 29–34.
References
(1) Dutasta, J.-P. Top. Curr. Chem. 2004, 232, 55–91.
(2) Delangle, P.; Mulatier, J.-C.; Tinant, B.; Declercq, J.-P.;
Dutasta, J.-P. Eur. J. Org. Chem. 2001, 3695–3704.
(3) Yebeutchou, R.M.; Tancini, F.; Demitri, N.; Geremia, S.;
Mendichi, R.; Dalcanale, E. Angew. Chem. Int. Ed. 2008,
47, 4504–4508.
´
´
(17) Anemian, R.; Mulatier, J.-C.; Andraud, C.; Stephan, O.;
Vial, J.-C. Chem. Commun. 2002, 1608–1609.
(18) Ryan, D.K.; Weber, J.H. Anal. Chem. 1982, 54, 986–990.

Supramolecular Chemistry
11
`
Bastien Mettra, Yann Bretonniere, Jean-Christophe Mulatier,
Brigitte Bibal, Bernard Tinant, Christophe Aronica and
Jean-Pierre Dutasta
Design of differently P-substituted 4i PO fluorescent tetrapho-
sphonate cavitands
1–11