Meso-piperidine calix[4]pyrrole: Synthesis, structure and ion binding studies

Article abstract of DOI:10.1016/j.tet.2015.08.032

We report the synthesis, structure and preliminary solution phase ion binding properties of the calix[4]pyrrole 3a-c. Calix[4]pyrrole 3a and 3b, the first to be prepared via one-pot reaction, were obtained by reacting the ketone 7 with pyrrole in the presence of an acid catalyst. On the basis of ¹H NMR spectroscopic analyses and the titrations of UV spectrophotometry, it was concluded that compound 3a possesses significantly enhanced selectivity for fluoride anion in chloroform, and formes 1:1 (ligand: anion) complexes with fluoride and chloride anions.

Full text of DOI:10.1016/j.tet.2015.08.032

Tetrahedron 71 (2015) 8208e8212
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Meso-piperidine calix[4]pyrrole: synthesis, structure and ion
binding studies
*
Ying-Chun He, Ji-Gang Pan
College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2015
Received in revised form 27 July 2015
Accepted 10 August 2015
Available online 17 August 2015
We report the synthesis, structure and preliminary solution phase ion binding properties of the calix[4]
pyrrole 3aec. Calix[4]pyrrole 3a and 3b, the first to be prepared via one-pot reaction, were obtained by
reacting the ketone 7 with pyrrole in the presence of an acid catalyst. On the basis of 1H NMR spec-
troscopic analyses and the titrations of UV spectrophotometry, it was concluded that compound 3a
possesses significantly enhanced selectivity for fluoride anion in chloroform, and formes 1:1 (ligand:
anion) complexes with fluoride and chloride anions.
Keywords:
Calix[4]pyrrole
Synthesis
Ó 2015 Elsevier Ltd. All rights reserved.
Macrocycle
Anion
Crystal structure
1. Introduction
enhance affinity and selectivity towards anions, all the meso posi-
tions of calix[4]pyrroles were substituted by aryl groups (2aeb) to
Meso-octamethylcalix[4]pyrrole 1, a tetrapyrrolic macrocycle,
was found in 1996 by Sessler and co-workers to act as an efficient
receptor for anionic and electron-rich neutral guests in organic
solvents,1 though it has been synthesized in 1886 by Baeyer.2 Since
that time, calix[4]pyrrole 1 caused great interest as an anion re-
ceptor with considerable effort having been devoted to produce
a number of calix[4]pyrroles and study their binding affinity and
selectivity for specific anionic guests.3e7 In addition, calix[4]pyr-
roles adapt their core conformation (Fig. 2) in order to bind strongly
with a variety of hydrogen bond acceptor substrates, ranging from
neutral aprotic molecules to halide ions and oxyanions.8 To
achieve a deep cavity and resulted in the formation of four con-
figurational isomers (see Fig. 1).9
However, all of these isomeric receptors displayed a negative
selectivity towards anions, compared to 1 owing to steric conges-
tion.10 Separately, meso-tetramethyltetrakis(3-hydroxyphenyl)calix
[4]pyrrole 2c was synthesized by Namor and co-workers, and its
aabb and abab isomers also were isolated. The aabb isomer shows
higher affinity for H2POꢀ4 in acetonitrile while the abab derivative
prefers the Fꢀ ion.11 To achieve selectively binding anion, we de-
cided to synthesize aabb derivatives possessing functionality pe-
riphery. Herein we report one-pot synthesis of calix[4]pyrrole 3a
and 3b, in addition to their solid state structure and anion binding
studies. To date and to the best of our knowledge, there are no
examples reported in the literature for the synthesis of 3aec.
2. Results and discussion
The synthesis of 3aec is outlined in Scheme 1. They started with
1-Boc-piperidine-4-carboxylic acid 4, which was subjected to
condensation by treating with Meldrum’s acid. Then 5 was heated
in ethanol under reflux, the ethanolysis took place smoothly with
Fig. 1. Structures of meso-octamethylcalix[4]pyrrole 1 and deep cavity calixpyrroles 2.
the evolution of carbon dioxide to afford
b-Keto Esters 6. Hydrolysis
of this latter -Keto Esters with the solution of 6.0 M NaOH gave the
b
ketone 7. Condensation of this latter ketone with pyrrole in the
presence of 1.5 equiv of Methanesulfonic acid (MSA), then gave the
desired calix[4]pyrrole derivatives 3a in 19.7% yield and 3b in 26.6%
* Corresponding author. Tel.: þ86 13700501929; e-mail address: panjigang_sxu@
163.com (J.-G. Pan).
http://dx.doi.org/10.1016/j.tet.2015.08.032
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

Y.-C. He, J.-G. Pan / Tetrahedron 71 (2015) 8208e8212
8209
Fig. 2. Conformational isomers of calix[4]pyrroles (left) and Structural isomers of calix[4]pyrroles (right).
yield. Treatment of 3b with excess potassium carbonate in water
served to remove the Methanesulfonic acid, this gave calix[4]pyr-
role 3 in 95.7% yield. The acidification of 3 with 4.0 M hydrogen
chloride solution in dioxane gave 3c in 92.4% yield.
are hydrogen bonded, one above and one below, with the adjacent
pyrrole-NH groups of the calix[4]pyrrole donor in the 1, 2-alternate
conformation. In contrast, In Fig. 4, the resulting structure revealed
that calix[4]pyrrole 3b adopts the so-called partial cone confor-
Scheme 1. Synthesis of compound 3aec.
Calix[4]pyrrole 3aec were characterized by single-crystal X-ray
diffraction analysis. Single crystals of 3aec suitable for X-ray dif-
fraction were grown from DMF/CH2Cl2 (4/1) and CH3CN/H2O (10/1).
Then, the resulting structures revealed that in the solid state calix
[4]pyrrole 3aec adopts the so-called 1, 2-alternate conformation
and parcial cone. In 3a$(DMF)2, Fig. 3, the two DMF guest molecules
mation in the solid state with one CH3SOꢀ3 bound to the pyrrolic NH
protons. The included CH3SOꢀ3 is held within this cleft by a series of
NeH/O hydrogen bonding interactions involving the three NeH
groups of the four pyrrole rings. To study the complex with Clꢀ,
however, single crystal of 3c$(H2O)2 is obtained through slow
evaporation of the mixture of 3c and TBACl made up in CH3CN/H2O

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Y.-C. He, J.-G. Pan / Tetrahedron 71 (2015) 8208e8212
(10/1). Unfortunately, in the case of 3c$(H2O)2, four Clꢀ are dis-
persed around the macrocycle periphery, two H2O guest molecules
are hydrogen bonded, one above and one below, with the adjacent
pyrrole-NH groups of the calix[4]pyrrole donor in the 1, 2-alternate
conformation, and excess Clꢀ failed in bounding to the pyrrolic NH
protons. Simultaneously, it means that Clꢀ failed in the competition
with H2O. Compared to CH3SOꢀ3 , parent 3 possesses lower affinity
to Clꢀ (at least in the solid state) (see Fig. 5).
for NH, and an upfield shift for b-CH proton signals with gradual
addition of fluoride anion. It also displayed evidence of very fast
complexationedecomplexation equilibrium in the case of 3a-Fꢀ
complex, since the addition of approximately 0.15 equiv of TBAF
resulted in the broadening of the pyrrole NH signals until addition
of w1 equiv of the salt and subsequent becoming singlet (Fig. S1 in
the Supplementary data).
Fig. 3. Side and top views of the X-ray structures of DMF33a. Displacement ellipsoids are scaled to the 50% probability level. Hydrogen atoms have been removed for clarity. Colour
code: red: O, blue: N, grey: C.
Fig. 4. Side and top views of the X-ray structures of 3b. Displacement ellipsoids are scaled to the 50% probability level. Hydrogen atoms have been removed for clarity. Colour code:
red: O, blue: N, grey: C.
Fig. 5. Side and top views of the X-ray structures of H2O33c. Displacement ellipsoids are scaled to the 50% probability level. Hydrogen atoms have been removed for clarity. Colour
code: red: O, blue: N, grey: C, green: Cl.
Proton NMR spectroscopy was used to probe the effect of anion
binding in solution. Preliminary anion binding studies were carried
out on 3a using 1H NMR titration studies in CDCl3 (due to the poor
solubility of 3a in acetonitrile) with various anions (Fꢀ, Clꢀ, Brꢀ) as
their tetrabutyl ammonium (TBA) salts. Here, it was found that
under conditions of strong binding, such as proved true for fluoride
interacting with 3a, addition of the substrate served to lock the
system into the expected3 cone conformation. As expected, quan-
titative 1H NMR titration studies showed a distinct downfield shift
On the other hand, in the case of Clꢀ and Brꢀ, the NH signal and
-CH proton signals remain intact under low concentrations of
b
chloride and bromide anions. This lack of change is ascribed to the
fact that the chloride and bromide are bound only weakly and that
calix[4]pyrrole undergoes fast conformational ‘flipping’ in the
presence of the anions. Support for this conclusion comes from the
fact that only relatively small downfield shifts in the NH proton
resonance are seen upon the addition of TBACl and TBABr (Fig. 6A,
Fig. S2 and S3 in the Supplementary data). Simultaneously, The

Y.-C. He, J.-G. Pan / Tetrahedron 71 (2015) 8208e8212
8211
changing for the pyrrole NH signals under high concentrations of
chloride and bromide anions is consistent with the aabb isomer of
2b with high concentrations of fluoride anion and displaying weak
binding. And high concentrations of chloride and bromide anions
served to lock the system into the separate, well-defined confor-
mation that, on the basis of symmetry considerations, was assigned
as being the conformationally accessible cone like form.3
donor solvents, such as water and methanol, because strong hy-
drogen bonding to the solvent should lower the available fluoride
ion.12 Unfortunately, in the case of the calix[4]pyrroles 3a and 3c,
the NH signal and b-CH proton signal remain intact for accurate
NMR titrations with halide ion for high concentrations in water.
This suggests the presence of water could serve to reduce the
strength of the presumed receptor-anion interactions.
Fig. 6. Proton NMR spectra of 3a recorded at room temperature in CDCl3 before and after the addition tetrabutylammonium salts of different anions: (A) low concentrations of
fluoride, chloride and bromide anions. (B) high concentrations of fluoride, chloride and bromide anions. (Tetrabutylammonium fluoride was added as the trihydrate.).
In an effort to test the above assumption, UV spectroscopy was
used. The CDCl3 solution of 3a (1.5ꢁ10ꢀ4 M) was mixed with anions
(1.5ꢁ10ꢀ4 M) such as fluoride and chloride. The UV spectroscopy
revealed that 3a bind fluoride and chloride with 1:1 stoichiometry.
Because the absorption of the parent OMCP macrocycle generally
occurs in the deep UV region, the investigation of binding affinity
for anions is generally carried out by NMR and ITC. Here, however,
the calix[4]pyrrole 3a possesses piperidine side-arms that absorb
light in the near-UV. This allows performing anion titrations using
a UV spectroscopy. Fig. 7 shows UV spectra of 3a upon the addition
of fluoride and chloride in CHCl3 (The changing for UV spectroscopy
upon the addition of bromide wasn’t obvious). Calix[4]pyrrole 3a
exhibited a distinctly increasing of absorbance upon fluoride ad-
dition, but a negligible change upon chloride addition, which sug-
gests that the affinity and selectivity of 3a for fluoride anion are
3. Conclusions
In summary, three new aabb derivatives 3a, 3b and 3c have been
synthesized, and their structure unambiguously characterized by
X-ray crystallography. The binding stoichiometry of 3a and anions
was investigated by UV spectroscopy. It was concluded that 3a
possesses significantly enhanced selectivity for fluoride anion in
chloroform. And it was also concluded that 3a formes 1:1 (ligan-
d:anion) complexes with fluoride and chloride anions. Also we
have illustrated the first example of a one-pot synthesis of func-
tionalized derivatives. Presently, we are exploring whether flexible
anchors endowed with suitable functionality at the calix[4]pyrrole
periphery may enhance the affinity towards suitable anions. This
may spur the development of new functionalized building blocks
leading to interesting porphyrinoids.
Fig. 7. Absorption spectra of 3a upon the addition of tetrabutylammonium fluoride (A), tetrabutylammonium chloride (B) in CHCl3 at rt, [Fluoride]/[chloride]¼0e300
(at 260 nm): Fitting of UV/Vis titration data. Tetra-butylammonium fluoride was added as the trihydrate.
mM. Bottom
stronger than for chloride anion in chloroform. The binding affin-
ities of 3a for fluoride is >103 Mꢀ1 and chloride is <5 Mꢀ1 (UV).
Compared to 1, calix[4]pyrrole 3a exhibited higher selectivity for
fluoride.1
As mentioned in the recent report, the theoretical predictions
suggest that the relative fluoride ion to chloride ion affinities of
calix[4]pyrrole 1 should reverse [i.e., K(Cl)>K(F)] in hydrogen bond
4. Experimental section
4.1. General
Methods and Materials. 1H NMR and 13C NMR spectra were
recorded on a 300 MHz and 75 MHz spectrometer. All solvents
were dried prior to use. 1-Boc-piperidine-4-carboxylic acid

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Y.-C. He, J.-G. Pan / Tetrahedron 71 (2015) 8208e8212
was commercially available and used without further
purification.
which was recrystallized by methanol, affording 1.60 g (26.6% yield)
of a white solid, 3b. 1H NMR (300 MHz, D2O):
6.09e6.12 (d, 2H),
d
3.42 (m, 2H), 3.00 (m, 2H), 2.82 (s, 3H), 2.36 (m, 1H),1.76e1.88 (m,
4.2. Synthesis of 5
2H), 1.52 (s, 3H), 1.30e1.45 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
144.1, 142.6, 112.2, 110.8, 51.4, 51.2, 48.8, 47.7, 45.5, 32.1, 31.1, 29.4.
To an oven-dried 250 mL round-bottomed flask containing 1-
MS (m/z): HRMS (ESI) calcd for
1087.4700, found: 1087.4693.
C
48H79N8O12S4 ([MꢀH]ꢀ):
Boc-piperidine-4-carboxylic acid (9.20
g
40.0 mmol), DMAP
(7.70 g 63.0 mmol), Meldrum’s acid (6.40 g 44.4 mmol) was added
dry dichloromethane (100 mL). The mixture of DCC (9.50 g
46.0 mmol) and dichloromethane (50 mL) was added dropwise
through a dropping funnel. From the last addition, the reaction was
kept at room for a further 24 h. The reaction mixture was filtered
and the filtrate was quenched by addition of a solution of 1 M HCl.
The collected organic layers were washed with brine and dried over
sodium sulfate. The solvent was removed under reduced pressure,
affording 14.0 g (98.7% yield) of a light yellow solid that was used
4.6. Synthesis of 3c
To a 10 mL round-bottomed flask containing a solution of K2CO3
(0.13 g, 0.94 mmol) in water (5 mL) was added 3b (0.50 g
0.46 mmol). A white precipitate formed, which was collected by
filtration, washed with water until being colourless, and dried to
afford 0.31 g (95.7% yield) 3.
To a 10 mL round-bottomed flask filled with MeOH (2 mL) was
added 3 (0.10 g 0.14 mmol), then add 4.0 M hydrogen chloride
solution in 1,4-dioxane to pH 2. A white precipitate was formed,
which was collected by filtration, washed with ethanol until col-
ourless, and dried to afford 0.11 g (92.4% yield) of a white solid, 3c.
without further purification. 1H NMR (300 MHz, CDCl3):
d 4.22 (br
m, 2H), 3.95 (m, 1H), 2.82 (br m, 2H), 1.75e1.80 (m, 10H), 1.48 (s,
9H).
4.3. Synthesis of 6
1H NMR (300 MHz, D2O):
d 5.97e6.01 (d, 2H), 3.31e3.35 (m, 2H),
2.85e2.93 (m, 2H), 2.21e2.29 (m, 1H), 1.69e1.78 (m, 2H), 1.41 (s,
3H), 1.19e1.34 (m, 2H). MS (m/z): HRMS (ESI) calcd for C44H65N8
([Mþ H]þ): 705.5332, found: 705.5330 (3c was decomposed to 3
under the condition of MS).
In a 250 mL round-bottomed flask filled with dry ethanol
(70 mL) was added 5 (13.0 g 36.7 mmol). The reaction mixture was
heated under reflux for 8 h, then the solvent was evaporated,
affording 10.9 g (99.5% yield) light yellow liquid. 1H NMR (300 MHz,
CDCl3):
d 12.09 (s, 0.14H, enol OH), 4.89 (s, 0.14H, enol CeH),
Acknowledgements
4.13e4.20 (m, 4H), 3.47 (s, 2H), 2.63e2.74 (m, 2H), 2.55e2.60 (m,
1H), 1.80 (m, 2H), 1.48e1.57 (m, 2H),1.45 (s, 9H), 1.26e1.28 (t, 3H).
This work was supported by College of Chemistry and Chemical
Engineering, Shanxi University, Taiyuan, Chao Jianbin (for NMR
measurements) and Tong Hongbo (for the X-ray diffractometer).
4.4. Synthesis of 7
In a 100 mL round-bottomed flask filled with a solution of 6.0 M
NaOH (50 mL) was added 6 (9.00 g 30.2 mmol). The reaction
mixture was heated under reflux for 20 h, then diluted with 300 mL
water and was quenched by addition 240 mL dichloromethane. The
collected organic layers were washed with brine and dried over
sodium sulfate. The solvent was removed under reduced pressure,
affording 6.42 g (94.0% yield) light yellow liquid. 1H NMR (300 MHz,
Supplementary data
Supplementary data (NMR spectroscopic data, UV absorption
and X-ray structural data are available. Single crystal data for
compounds 3a (CCDC 1047323), 3b (CCDC 1047324), and 3c (CCDC
1047325) have been deposited in the Cambridge Crystallographic
Data Center.) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.08.032. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
CDCl3):
d 4.07e4.11 (m, 2H), 2.74e2.81 (m, 2H), 2.41e2.48 (m, 1H),
2.15 (s, 3H), 1.81e1.84 (m, 2H), 1.48e1.57 (m, 2H), 1.44 (s, 9H).
4.5. Synthesis of calixpyrrole 3a and 3b
To a 100 mL round-bottomed flask containing a solution of
pyrrole (1.53 mL 22.1 mmol) in MeOH (50 mL) was added ketone 7
(5.00 g 22.1 mmol). The mixture was stirred for 5 min, then
methanesulfonic acid (3.18 g 33.2 mmol) was added slowly, and the
reaction was left at rt overnight. A pink precipitate formed, which
was collected by filtration, washed with methanol until being col-
ourless, and dried to afford a white microcrystalline solid, then
subjected to column chromatography (SiO2, MeOH: CH2Cl2, 1:30) to
afford 1.19 g (19.7% yield) white solid, 3a, and the filtrate was col-
References and notes
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(d, 2H), 4.08e4.13 (m, 2H), 2.60 (m, 2H), 1.85e1.89 (m, 1H),
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(75 MHz, CDCl3):
d 154.2, 135.6, 135.3, 104.2, 103.8, 78.8, 43.7, 41.6,
27.9, 27.7, 27.4. Elem. Anal. Calcd for 3a$H2O: C 68.42; H 8.79; N
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