CHAPTER 1
INTRODUCTION
Introduction
Chapter 1 Page 2
RESUME The literature on functionalized supramolecules like calixpyrrole and their
analytical applications has been comprehensively covered. The aim and scope of the
present work has been discussed.
Introduction
Chapter 1 Page 3
TABLE OF CONTENTS
1. Introduction to Supramolecular Chemistry 004
2. The Chemistry of Calixpyrrole 008
2.1. Historical development 009
2.2. Mechanism 011
2.3. Different conformers of calix[4]pyrrole cycles formed 012
3. Various Synthetic Techniques for Calix[4]pyrrole Macrocycles 013
3.1. One-pot [1+1+1+1] condensation 013
3.2. [2+2] Condensation 016
3.3. [3+1] Condensation 017
3.4. Eco-friendly synthesis of calix[4]pyrroles using different catalysts 019
4. Modification in Calix[4]pyrrole by Functionalization 021
4.1. Modification at the N-rim 021
4.2. Functionalization at the β-position (C-rim) 022
4.3. Functionalization at the meso-position (bridge position) 027
5. Functionalized Calix[4]pyrroles and their Applications 039
5.1. Calix[4]pyrrole-based optical sensors 040
5.2. Calix[4]pyrrole-based electrochemical sensors 052
5.3. Calix[4]pyrrole-based HPLC support 057
5.4. Polymer-bonded calix[4]pyrrole and their chelating properties 058
5.5. Miscellaneous applications of calix[4]pyrrole macrocycles 060
6. Synthesis of Higher order Calixpyrroles 063
Aim and Scope 065
References 067
Introduction
Chapter 1 Page 4
1. INTRODUCTION TO SUPRAMOLECULAR CHEMISTRY
Supramolecular chemistry, as it is now defined, is a young discipline dating
back to the late 1960s and early 1970s. However its concepts and roots and indeed
many simple (and not-so-simple) supramolecular chemical systems, may be traced
back almost to the beginning of modern chemistry [1]. Strictly speaking, a
supramolecule is beyond the normal concept of a molecule. As a large engineered
“molecule”, a supramolecule has many subunits, each designed to perform a specific
task. Therefore, while a supramolecule is still a single molecule, it is engineered to
function like a large complex compound. In a supramolecular system the components
are held reversibly by intermolecular forces, but not by covalent bonds. These
intermolecular forces include Van der waals molecular interaction, electrostatic
interaction and hydrogen bonding [2]. Recent research progress in supramolecular
science is so striking that it has attracted the attention of many scientists from both the
physical sciences and the biological sciences division. Supramolecular materials have
astonishing applications from quantum dots to biomedicine and bioinformatics, from
artificial intelligence to virtual reality. With such widespread application, scientists
have argued that supramolecules will be the chemical building blocks of the future
[3]. On the back cover of Nobel Laureate Lehn’s book, Supramolecular Chemistry:
Concepts and Perspectives, the following inspiration on supramoleuclar science is
offered [3].
“Supramolecular chemistry embodies the creative power of chemistry.
By its very essence, by its ability to create and through the beauty of
their object, chemistry is an art as well as a science. Indeed, it fashions
entire new world that do not exist before they are shaped by the hand
of the chemist, just as matter, shaped by the hand of the sculpture,
becomes a work of art.”
Introduction
Chapter 1 Page 5
The aim to amalgamate a variety of host molecules is a demanding task in the
field of molecular recognition chemistry because of the implausible qualities
manageable by forming supramolecular complexes from the host and guest molecules
[4]. In other form we can say, the advent of a new host compound is crucial for
development of highly advanced functional materials such as high performance
catalyst, extremely sensitive sensors, ultra fine separation materials etc. For a
compound to make a useful host it is necessary that the basic molecular scaffold
should have impending aptitude for molecular recognition with ready feasibility to the
varying chemical modifications for drawing out the best performances of the
molecule for a specific application. Thus a hopeful candidate, host compound should
be not only readily synthesized in large quantities but also easily modified for
maximizing molecular recognition power towards relevant guest molecules [5].
One such host molecule which perfectly matches above requirements is
calix[4]arenes, chemistry of which has been one of the most extensively developed in
the field of supramolecular chemistry during the span of last 20 years [6].
Calix[n]arene, a macrocyclic compound, composed of phenolic units is linked with
methylene groups at the o, o’ positions [6]. Calixarenes have been actively studied
and utilized as the third generation of host compounds in addition to the well known
crown ethers [7] and cyclodexrins (Figure 1) [8].
Introduction
Chapter 1 Page 6
Figure 1 Structure of cyclodextrin (I), crown ether (II), calix[4]arene (III),
calix[4]pyrrole (1) and porphyrin (2).
Calixarenes, a class of cyclic phenolic compounds, are called so due to their
shape and structure [6]. The term calixarene was given by C. D. Gutsche [1] in 1978.
The name “calixarene” is derived from Greek word, calix meaning vase or cone
shaped conformation. Calixarenes are often described as “macrocycles with almost
unlimited possibilities [9] due to their versatility and utility as host molecules, which
is seen from the ease in the synthesis of the basic platform and well set
functionalization at both the rims, so as to build a new modified three dimensional
structures [6], two different zones can be distinguished in calixarenes, viz. the region
O
OH
OH
OH O
O
O
OH
OHOH
O
O
OHOH
OH
O
O
OH
OH
OHO
O
O
OH
OHOH
O
OH OH
OH
n
n = 1 - Cyclodextrin; n = 2 - Cyclodextrin;
n = 3 - Cyclodextrin
(I)
O
O O
O
Crown ether
(II)
CH3
CH3
CH3
CH3
OHOH
OHOH
CH3CH3
CH3
CH3
CH3 CH3
CH3
CH3
p - tert butyl Calix[4]arene
(III)
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
Calix[4]pyrrole
1
N
NH
N
NH
Porphyrin
2
Introduction
Chapter 1 Page 7
of phenolic hydroxy groups and the para-position of the phenols, which are called the
‘lower rim’ and the ‘upper rim’ of the calixarene respectively (Figure 2).
Figure 2 Different zones of calix[4]arene.
Calixarenes may be modified by tuning its size, depth or conformation of π e-
rich cavity and functionalization at rim(s), provide receptors with targeted properties
[6]. The replacement of their phenolic unit(s) by heterocycle(s), constitute hetero-
calixarenes [11] classified according to the category of the subcycle(s). The nature of
subcycle(s) reveals electron rich or deficient cavity and varied transformation profile
for hetero-calixarene systems. Therefore, calixarenes may be further divided into
following two broad classes,
1] Hetero-calixarenes: When organic moiety is replaced by pyrrole, furan, pyridine
etc. they are known as herero-calixarenes.
2] Hetera-calixarenes: When methylene junctions occupy elements like S, O, N etc.
they are known as hetera-calixarenes.
Thus, a range of rational design of hetero-calixarene receptors, with
possibilities of wider range of non-covalent interactions and consequent recognition
events than calixarenes, can be predicted. These hetero-calixarenes possess unique
supramolecular characteristics and present interesting chemical and physicochemical
properties as well as wide applications [10].
RR
R
R
OHOH
OH
OH
Upper rim
Lower rim
Introduction
Chapter 1 Page 8
Calix[4]pyrrole belongs to the family of hetero-calixarene macrocycles, which
has four pyrrole units instead of phenolic units (Figure 1). Various reviews have
appeared on their synthetic methodologies and applications during last 10 years [11-
14]. Synthesis and applications can be viewed from these reviews published during
last decade.
2. THE CHEMISTRY OF CALIXPYRROLE
Calix[4]pyrrole 1, formally known as “pyrrole-acetone” are venerable class of
tetra-pyrrolic macrocycles. Originally coined meso-octasubstituted porphyrinogens.
Porphyrinogens [15] are naturally occurring colourless macrocycles consisting of four
pyrrole rings linked through α (i.e. pyrrolic 2 and 5) or meso like positions by sp3-
hybridized carbon atoms. The most common formulation of this system is a result of
the condensation of acetone and pyrrole, which leads to the formation of a tetra-
pyrrolic macrocycle structurally similar but electronically different than porphyrin in
such a way that 18π electron aromatic structure cannot be formed in calix[4]pyrrole.
This imparts drastically different properties to it (Scheme 1), where each pyrrole is
electronically independent and consequently, can donate one hydrogen bond.
Calix[4]pyrroles are easy to make class of neutral macrocycles and differ from
the porphyrin. Calix[4]pyrrole (non-aromatic system) and porphyrin (aromatic
system) are obtained from the condensation of pyrrole with an electrophile. In case of
calix[4]pyrrole, the electrophile is a ketone whereas in the case of porphyrin it is
generally aldehyde (Scheme 1). Calix[4]pyrrole macrocycles can not be oxidized to
their corresponding aromatic porphyrin.
Introduction
Chapter 1 Page 9
Scheme 1 Schematic representation showing the different behavior of calix[4]pyrrole
1 and porphyrin 2 with respect to oxidation.
.
2.1. Historical development
In 1886, a white crystalline material was synthesized by condensing pyrrole
with acetone in the presence of hydrochloric acid by Baeyer [16]. Later considering
the same work of Baeyer, Dennstedt and Zimmermann (1886) [17], also studied this
reaction, using “Chlorzink” as the acid catalyst. Thirty years later, Chelintzev and
Tronov repeated this reaction and proposed a cyclic tetrametric porphyrinogen
structure for the product, which later proved to be correct.
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
N
NH
N
NH
1 Calix[4]pyrrole
stable
2 Porphyrin
stable
oxidation oxidation
NH
NH
H
H
NH
NH
HH H
H
H
H
Porphyrinogen
unstable
NH
+H H
ONH
+CH3 CH3
O
Lewis acid or
protic acid
Lewis acid or
protic acid
Introduction
Chapter 1 Page 10
In 1955, Rothemund and Gage [18] improved this synthesis by using methane-
sulfonic acid as the acid catalyst. Other than these important findings, this class of
compounds were studied, most of which merely focused on the refined synthesis of
these macrocycles and their meso-substituted derivatives [19-20]. In early 1970s,
Brown et al. [19] modified the procedure of Chelintzev et al. [20] which resulted in
getting tetra-spirocyclohexylcalix[4]pyrrole 3 (Figure 3) in decent yield by
condensing cyclohexanone and pyrrole in the presence of acid.
Figure 3 Tetra-spirocyclohexylcalix[4]pyrrole 3
In 1990s interest in these macrocycles was renewed by the extensive work of
Floriani and co-workers [21] on the metallation and attendant synthetic chemistry of
deprotonated-calixpyrroles. Mid of 90s Sessler and co-workers [22] discovered that
the NH array present in these species can act as a binding site for anionic and neutral
guest species. These calix[4]pyrrole macrocycles which were known as
porphyrinogens because of their interesting conformational behaviour it drew
attention to the clear differences in analogy between them and the calix[4]arenes. This
analogy coupled with the fact that as these species carry alkyl or aryl groups in the
meso-positions and hence are not susceptible to oxidation (to produce either porphyrin
or less oxidized macrocyclic products), led them to propose that they should be re-
named as calix[4]pyrroles.
NH
NH
NH
NH
3
Introduction
Chapter 1 Page 11
Recently, Ballester and co-workers showed interest in current trend of
endowing supramolecular gels with stimuli responsive functionality that could be the
basis of smart materials useful in areas such as controlled drug release, sensing or
tissue engineering among others [22].
2.2. Mechanism
The mechanism for the formation of calix[4]pyrrole by the acid catalyzed
condensation reaction [23-24] has been studied in detail. Calix[4]pyrrole - a non-
conjugated macrocycle, is formed by electrophilic α-substitution of pyrrole by ketone,
acid-catalyzed oligomerization and spontaneous non-template cyclization wherein
four pyrrole units are combined (Scheme 2). The synthetic methodologies for
calix[4]pyrrole are generally simple, but the yield obtained is considerably less due to
the formation of linear by products and/or polymerization. The reaction conditions
and substituents at the ketone functionality also play a significant role in achieving
quantitative recovery of calix[4]pyrrole.
Scheme 2 Synthetic mechanism of calix[4]pyrrole macrocycle.
NH
CH3
CH3
O H+ -H+ NH
CH3
CH3
OH H+
NH
-H2O
NH
NHCH3CH3N
H
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
..
Introduction
Chapter 1 Page 12
2.3. Different conformers of calix[4]pyrroles
Calix[4]pyrrole adopts similar conformations same as to calix[4]arenes : 1,3-
alternate; 1,2-alternate; partial cone and cone (Figure 4). The most stable form
predicted and having experimentally lowest energetic is the 1,3-alternate
conformation where the pyrrole rings are found to be alternate in an up-down-up-
down setup [25].
NH
NH
CH3
CH3
NHCH3
CH3 NH
CH3
CH3
CH3
CH3
1,3-alternate
NH
NH
NH
CH3CH3NH
CH3
CH3 CH3
CH3CH3
CH3
1,2-alternate
NH
NH
NH
CH3
CH3
CH3
CH3
NH
CH3
CH3
CH3
CH3
CH4
patial cone
NH
NH
NH
NH
CH3
CH3
CH3
CH3CH3
CH3CH3
CH3
cone
Figure 4 Representation of the limiting possible conformations conceivable for
calix[4]pyrrole.
Jorgensen [25] investigated the complexation of compound 1 with anions by
carrying out energy minimizations in the gas phase and via Monte Carlo simulations
in a dichloromethane milieu using the OPLS force field. The gas phase calculations
revealed that 1,3-alternate conformation of compound 1 was most stable in the
absence of a halide anion, while in the presence of halide anions the cone
conformation was the most stable among all possible conformations (Figure 5).
Figure 5 Cone like halide complex of compound 1.
Introduction
Chapter 1 Page 13
Wu et al. [26] also studied the conformation features and anion binding
properties of compound 1 theoretically. Both, gas phase and solution phase (CH2Cl2)
studies revealed a predicted stability sequence for the various conformers; 1,3-
alternate > partial cone > 1,2-alternate > cone.
3. VARIOUS SYNTHETIC TECHNIQUES FOR
CALIX[4]PYRROLE MACROCYCLES
There are four major synthetic techniques for the synthesis of calix[4]pyrrole:
3. 1 One-pot [1+1+1+1] condensation
3. 2 [2+2] Condensation
3. 3 [3+1] Condensation
3. 4 Eco-friendly synthesis of calix[4]pyrroles using different catalysts
Where the numbers in the brackets refer to the number of pyrrolic subunits in
the precursors involved. Among these, one-pot approach is most popular for preparing
simple calix[4]pyrrole.
3.1. One-pot [1+1+1+1] condensation
The one-pot synthesis of calix[4]pyrroles involves the condensation of
pyrrole(s) and ketone(s) in 1:1 ratio in the presence of an acid catalyst e.g.
hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, and boron trifluoride
diethyl etherate. Solvents generally used for the reactions are methanol, ethanol,
acetonitrile, and dichloromethane, but in some reactions, ketones are used both as
reactant as well as solvent for condensation with pyrrole. Depending on how many
types of pyrroles or ketones are used in the reaction, one-pot condensation can be
categorized into:
- Homo-condensation
Introduction
Chapter 1 Page 14
- Mixed condensation
3.1.1. Homo-condensation
In this type of condensation (homo-condensation) a specific pyrrole reacts
with a specific ketone. According to the symmetry of the pyrrole or ketone
components, these homo-condensations can be further classified as symmetric homo-
condensations and asymmetric homo-condensations.
Symmetric homo-condensations
A symmetric homo-condensation represents a reaction involving a symmetric
pyrrole and a symmetric ketone. Generally such reactions produce an easy to separate
major product in good yield. One typical example of symmetric homo-condensation is
the synthesis of meso-octamethylcalix[4]pyrrole 1 via the condensation of pyrrole
with acetone in a 1:1 ratio in methanol using methanesulfonic acid as an acid catalyst
[22]. Column chromatography separation affords 1 in 60-80% yields by symmetric
homo-condensation (Scheme 1).
Asymmetric homo-condensations
An asymmetric homo-condensation normally involves the reaction of pyrrole
with an asymmetric ketone. For example, condensation of pyrrole with 4-hydroxy
acetophenone, 3-hydroxyacetophenone and 3, 5-dihydroxyacetophenone in methanol
in the presence of methanesulfonic acid resulting the desired calix[4]pyrrole [27-28]
4a, 4b and 4c respectively in good yield (Scheme 3). The product actually consists of
a mixture containing different configurational isomers; which are difficult to separate
and may require tedious separation procedures including careful column
chromatography.
Introduction
Chapter 1 Page 15
NH
NH
CH3
NH
NH
CH3
CH3
CH3R2
R2
R2
R2
R1
R3
R1
R3
R1
R3
R3
R1
NH
+
CH3
R2
O
R1 R3
MeSO3H
MeOH
4a R1, R3 = H ; R2 = OH, 4b R1 = OH ; R2 , R3 = H
4c R1, R3 = OH; R2 = H
Scheme 3 Synthesis of the tetra-phenolic calix[4]pyrroles by asymmetric homo-
condensation.
3.1.2. Mixed condensation
Mixed condensation involves the condensation of more than one kind of
pyrrole with a specific ketone or of a specific pyrrole with more than one kind of
ketone. In this type of condensation reactions, mixtures of products are formed, so the
reactant ratio must be carefully controlled in order to optimize the yield of the desired
products. However, once separated, the various calix[4]pyrroles can often find
application in a variety of areas, because mixed condensation product provides a good
platform for selective functionalized systems.
Calix[4]pyrrole with a carboxylate pendant arm (monoester) 5 [29] was
obtained by acid catalyst condensation of ethyl pyruvate and acetone with pyrrole, in
a 1:3:4 ratio. Column chromatography (silica gel; dichloromethane/hexane, eluent)
afforded 5 in 14% yield (Scheme 4).
Introduction
Chapter 1 Page 16
NH
+O
CH3CH3+
O
CH3O
O CH3 CH3SO3H
Methanol
5
NH
NH
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3
CH3O
O C2H5
Scheme 4 Mixed condensation of calix[4]pyrrole monoester.
Calix[4]pyrrole 6 containing monoester group on meso position was
synthesized by co-condenstation of methyl-4-acetyl benzoate pyrrole and acetone
(Scheme 5) in a ratio of 1 : 4 : 3 with methanesulfonic acid as an acid catalyst,
stirred in methanol [30]. Yield of the product obtained was about 12%
Scheme 5 Synthesis of mono ester substituted calix[4]pyrrole.
3.2. [2+2] Condensation
Acid-catalysed condensation of two dipyrromethane units with ketone units
comes under [2+2] condensation method. In this method dipyrromethane units are
synthesized by condensation of a pyrrole unit with a single ketone unit (normally
different from those used in the synthesis of the dipyrromethanes) to achieve the
predicted product. This [2+2] approach represents an important means of constructing
O CH3
+NH
+O
CH3CH3
MeOH
CH3SO3H
6
NH
NH
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
MeOOC
Introduction
Chapter 1 Page 17
a variety of calix[4]pyrrole macrocycles, which otherwise can not be obtained by one-
pot condensation.
Compounds 7-8 may be obtained readily using a [2+2] approach. These
particular products were synthesized from the dipyrromethane precursors (Scheme 6).
These precursors were in turn prepared from the condensation of pyrrole with aryl
ketones in presence of trifluoro acetic acid using boron trifluoride diethyletherate as
the catalyst. Once obtained, these precursors were condensed with acetone, acting
both as a reactant as well as a solvent. This gave cyclic products 7-8 in decent yield.
[31].
Scheme 6 Synthesis of compounds 7-8 via [2 + 2] condensation.
3.3. [3+1] Condensation
[3+1] Condensation involves the reaction of a tripyrrane or its derivative with
a pyrrole or its derivative in the presence of an acid catalyst. The reaction products are
generally obtained in low yield due to the poor stability of most tripyrranes in the
presence of acid. Infact, no true calix[4]pyrroles have been synthesized using this
method.
Jeppesen et al. [32] reported that a “pseudo” calix[4]pyrrole 11 was
synthesized using the [3+1] method (Scheme 7). Tripyrranedimethanol 9c was
R1
R2
OCH3
pyrrole
TFA NHNH
CH3
R1
R2acetone
BF3.OEt2
NH
NH
NH
NH
CH3 CH3
CH3
CH3
CH3
CH3
R1
R2
R1 R2
7 (R1 = OH, R2 = H)
8 (R1 = H , R2= OH)
Introduction
Chapter 1 Page 18
synthesized by reducing the corresponding tripyrranedialdehyde 9b, which was
synthesized by formylation of tripyrrane 9a [33] with sodium borohydride in a
mixture of tetrahydrofuran (THF) and methanol. Treatment of the resulting tripyrrane
diol with the tetrathiafulvalene-containing pyrrole 10 in dry acetonitrile using boron
trifluoride diethyl ether as an acid catalyst afforded the mono-
tetrathiafulvalenecalix[4]pyrrole 11 in 21% yield.
Scheme 7 Synthesis of a “pseudo” calix[4]pyrrole via [3+1] condensation
.
Jeppesen et al. [34] later synthesized the two mono-TTF calix[4]pyrroles 17
and 18 shown in (Scheme 8). Both derivatives were functionalized with an
alkanethiol anchor group (protected with an acetyl group). Mono pyrrole
tetrathiafulvalene MPTTF derivatives 12, 13 with approximately two equivalents of
the tripyrrane 14 synthesized by above literature procedure, in a mixture of Me2CO
NHNH
NH
CH3CH3
CH3
CH3
R R
9c R=CH2OH
NHNH
NH
CH3CH3
CH3
CH3
R R
9a R=H
9b R=CHO
NaBH4/LiBr
THF/MeOH
NH
SS
SS
S S
CH3 CH310
NH
NH
CH3
CH3
NH
NH
CH3
CH3
SS
SS
S S
CH3 CH3
11
BF3.Et2O
MeCN
+
Introduction
Chapter 1 Page 19
and CH2Cl2, in the presence of one equivalent of tetrabutylammonium chloride
(TBACl) and excess trifluoroacetic acid (TFA) resulted in the mono-TTF calix[4]-
pyrroles 15 or 16 in 23 and 22% yield, respectively. The precursors were heated under
reflux temperature in the presence of excess potassium thioacetate (KSAc) in
anhydrous THF which afforded the corresponding thioesters 17 or 18 in 88 and 69%
yield, respectively.
Scheme 8 Synthesis of a “pseudo” calix[4]pyrrole via [3+1] condensation
3.4. Eco-friendly synthesis of calix[4]pyrroles using different catalysts
To achieve calixpyrrole macrocycles in high yield by an environmentally
clean process is of topical interest so as to meet the increasing demand for reducing
the pollution hazards caused by the usage of homogeneous acid catalysts [35].
Heterogeneous catalytic synthesis is known to be one of the most effective ways to
the selectivity of calixpyrroles with high yield and it has the potential to be scaled up
at relatively low cost. Properly functionalized and structurally ordered mesoporous
molecular sieves such as MCM-41 was found to be the most effective heterogeneous
NH
SS
SS
S S
CH3
Brn
NHNH
NH
CH3CH3
CH3
CH3
TFA/ TBACl
Me2CO/ CH2Cl2/ RT
NH
NH
CH3
CH3
NH
NH
CH3
CH3
SS
SS
S S
CH3Br
n
KSAcTHF/reflux
NH
NH
CH3
CH3
NH
NH
CH3
CH3
SS
SS
S S
CH3SAc
n12 (n=6) 89%
13 (n=10) 85%
14
15 (n=6) 23 %
16 (n=10) 69 %
17 ( n=6) 88%
18 (n=10) 69 %
Introduction
Chapter 1 Page 20
catalyst for the synthesis of calix[4]pyrrole. Various metal ion substituted MCM-41
samples were synthesized and were used to improve the yields of calix[4]pyrrole. Co-
MCM-41 was found to give maximum yields. The effects of varying Si/Al ratio in
MCM-41, molar ratio of various reactants, and the role of solvent towards this
macrocyclization reaction have also been studied [35]. Calixpyrroles were also
synthesized using zeolite based molecular sieves as catalyst and sorbents in thin layer
chromatography(TLC) to achieve in single step by in situ synthesis from pyrrole with
and ketones under microwave irradiation [35]. Different zeolite catalysts such as
HZSM-5, HY and mesoporous Al-MCM-41 molecular sieves were used for above
same reactions.
A facile, highly efficient and eco-friendly protocol for the synthesis of
calix[4]pyrrole in excellent yield is reported by Sarkar et al. [36]. The binding of
methanol, ethanol and N,N-dimethylformamide to meso-tetra(methyl)
tetrakis(ethyl)calix[4]pyrrole in both solid and solution with the exhibition of multi-
fashion hydrogen bonding as shown by X-ray crystallography were also studied. The
thermodynamic stability of these host-guest inclusion complexes [36] ware
determined by exploiting thermal gravimetric analysis (TGA) and differential thermal
analysis (DTA). Recently, S. M. S. Chauhan et al. [37] have developed a facial and
efficient protocol for the synthesis of calix[4]pyrroles and N-confused
calix[4]pyrroles in moderate to excellent yield by reaction of dialkyl or cyclo
alkylketones with pyrrole, catalyzed by reusable AmberlystTM-15 under eco-friendly
conditions.
Introduction
Chapter 1 Page 21
4. MODIFICATION IN CALIX[4]PYRROLE BY
FUNCTIONALIZATION
Calix[4]pyrroles have been found to have good complexing affinity towards
anions and neutral guests through hydrogen of pyrrolic nitrogen atoms. Complexes of
calix[4]pyrroles with anions and neutral atoms were not very stable. To improve the
binding abilities, the three potential sites available with calix[4]pyrrole skeleton
namely, the β-position (C-rim), the meso-position (bridge-position) and N-rim which
can be used for the introduction of different functionality.
4.1. Modification at the N-rim
Modification at N-rim in calix[4]pyrroles has been reported by Takata et al.
[38] meso-octaethylcalix[4]pyrrole 19 on reaction with sodium hydride and methyl
iodide in the presence of 18-crown-6 in THF resulted in formation of variety of N-
methylated calixpyrroles 20-25 (Figure 6). The variation of product was dependent
on the concentration of methyl iodide. When one equivalent of methyl iodide was
used, the main product was the mono-N-methylated derivative 20. On the other hand,
use of 2 equivalent methyl iodide resulted in predominant formation of 22, 23, and 24,
where 22 was isolated predominantly. The authors have also studied the X-Ray
diffraction analysis of 22. The resulting structure revealed that the macrocycle adopts
a 1,3-alternate conformation in the solid state.
Alkylation with ethyl iodide resulted in the isolation of the mono-ethyl
derivative 25 only. Takata et al. considered that, in solution, reaction of
calix[4]pyrrole 19 with butyl lithium results in the formation of a tight ion pair
between the deprotonated calix[4]pyrrole nitrogen atoms and the lithium cations.
Under this reaction conditions, Takata et al. proposed that the 18-crown-6 serves to
break up this ion pair, thereby allowing N-alkylation to occur. While far from
Introduction
Chapter 1 Page 22
established, important support for this hypothesis comes from the solid state structural
analysis of Floriani [39].
Figure 6 N-methylated calixpyrroles.
4.2. Functionalization at the β-position (C-rim)
Functionalization at β–positions, also called C-rim functionalization, has been
extensively explored by Sessler at el. [40] and S.M.S Chauhan et al. [41] recently. The
most popular C-rim functionalization is β-mono functionalization and β-octa
functionalization, since they produce only one dominant product. β- functionalization
procedures in between these two extremes have not been extensively explored due to
the production of multiple products, poor reaction control and difficulties in achieving
product separation.
During the last two decades, studies have flourished on functionalized
calix[4]pyrroles to understand ,improve and tuning the binding affinity and selectivity
of different anions. Recently S.M.S. Chauhan and co-workers [41] reported synthesis
NH
NH
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
N
NH
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
MeN
N
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
Me
Me
N
NH
N
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
Me
Me
19 20 21 22
N
N
N
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
Me
MeMe
23
N
N
N
NMe
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
Me
MeMe
24
N
NH
NH
NH
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
Et
25
Introduction
Chapter 1 Page 23
of 2-arylazo-meso-octamethylcalix[4]pyrroles 28-33 functionalized at β–position and
their role in binding of different anions under different conditions (Scheme 9).
It is found that development of anion sensors and receptors is an important
area of supramolecular chemistry in chemical and biological processes. S.M.S.
Chauhan et al. [42] has developed two novel 3,12- and 3,7-bis(4’- nitrophenyl)-azo-
5,5,10,10,15,15,20,20-octamethyl calix[4]pyrroles 34,35, introducing the
chromogenic group at two different position and studied them as potential anion
binders due to their rich and unique complexation behaviour (Figure 7).
NH
+Amberlyst 15
26
CH3CH3
ONH
NHNH
NH
CH3CH3
CH3
CH3
CH3
CH3CH3
CH3NH
NHNH
NH
CH3CH3
CH3
CH3
CH3
CH3CH3
CH3
NaHCO3 , THF, -10oC
N+
N R
Cl-
NH
NHNH
NH
CH3CH3
CH3
CH3
CH3
CH3CH3
CH3
NN R
R= H
R=CH3
R=OH
R=OCH3
R=Cl
R=NO2
27
28
29
30
31
32
33
Scheme 9 Synthesis of 2-arylazo-meso-octamethylcalix[4]pyrroles functionalized at
β–position
Introduction
Chapter 1 Page 24
Figure 7 Two novel 3,12- and 3,7-bis(4’-nitrophenyl)-azo- 5,5,10,10,15,15,20,20-
octamethyl calix[4]pyrroles
β-Octabromocalix[4]pyrrole 36 [40] was synthesized by reacting 1 with eight
equivalents of NBS reagent in THF and reflux for five hours and yield obtained was
90%. The method adopted was an alternative method to the earlier method of one-pot
condenstation of 3,4-dibromopyrrole with acetone which proved to be unproductive
due to the instability of 3,4-dibromopyrrole under the occurring reaction conditions.
(Scheme 10)
Scheme 10 Synthesis of β-octabromocalix[4]pyrrole by C-rim functionalization.
The reaction of monopyrrolo-TTF with an excess of TFA and a mixture of
CH2Cl2 and Me2CO yielded 18% of tetrathiafulvalene calix[4]pyrrole 37 (Scheme 11)
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3 NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3Br
Br
Br Br
BrBr
Br
Br
1
NBS
THF, 650C
36 90%
NH NH
CH3CH3
NHNH
CH3 CH3
CH3
CH3CH3
CH3
R
R
NH NH
CH3CH3
NHNH
CH3 CH3
CH3
CH3CH3
CH3
R
R
NO 2NNCH3R =
3435
Introduction
Chapter 1 Page 25
[43]. This system can act as an effective receptor for neutral electron acceptors such
as 1,3,5-trinitrobenzene, tetrafluoro-p-benzoquinone, tetrachloro-p-benzoquinone, and
p-benzoquinone.
Scheme 11 Synthesis of tetra-TTF calix[4]pyrrole.
Miyaji et al. [44] synthesized a series of halogen bearing β-rim mono-
substituted calix[4]pyrroles 37-40 by adding an appropriate electrophilic halogen
source in a finely tuned manner to form mono-functionalized calix[4]pyrroles as
shown in Scheme 12. This study emphasized the importance of electron withdrawing
or donating groups on the β-rim periphery in terms of regulating the anion affinity of
calix[4]pyrroles.
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3S
S
S
S
S S
S S
SS
SS
S
S
S
SSPr
SPrPrS
SPrPrS
PrS
PrS
37 18%
NH
S S
S S
PrS SPr
(i)
Me2CO / TFA
CH2Cl2/21 hours SPr
Introduction
Chapter 1 Page 26
Scheme 12 Monohalogenation of calix[4]pyrrole.
Chupakhin et al. [45] reported the first example of direct heterylation of
calix[4]pyrroles in 2004. Heterylation of calix[4]pyrroles was obtained by reacting 1,
2, 4-triazines derivatives (belonging to the most electrophilic heterocycles) with
calix[4]pyrrole to give stable nucleophilic addition products 41 and 42. The
heterylation of calix[4]pyrrole was done keeping in mind to increase the complexing
ability of calix[4]pyrrole by introduction of heterocyclic fragments (Scheme 13).
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3N
N
N
R
+
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
N
N
NH
R H
1 41, 42
R= SMe (41a,42a)
NH2 (41b,42b)
H+ or BF3.OEt2
Scheme 13 Heterylation of calix[4]pyrroles
Augusto C. Tome et al. used 3-(octamethylcalix[4]pyrrol-2-yl)propenal 43
used as precursors of azomethine ylides which was trapped in situ with a range of
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3X +
X = F, Cl, Br, I
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
X
37 X = F
38 X = Cl
39 X = Br
40 X = I
Introduction
Chapter 1 Page 27
dipolarophiles, such as 1,4-benzoquinone, 1,4-naphthoquinone. Azomethine ylides
generated by reaction of 43 with N-methylglycine could be trapped with
dipolarophiles to afford new β- substituted octamethylcalix[4]pyrrole derivatives 44,
45 in moderate yields [46]. These cycloadducts showed high affinity constants for
fluoride anions and selectivity for acetate anions when compared with dihydrogen
phosphate anions.
43 44
45
Scheme 14 Synthesis of new β- substituted octamethylcalix[4]pyrrole
4.3. Functionalization at the meso-position (bridge position)
Functionalization at bridge position or meso position of calix[4]pyrrole by
introduction of aryl or other rigid groups influences the increase in binding capacity
NH
NH HN
HN NH
NH HN
HN
CHON
MeMeNHCH2COOH
Toluene / NEt3 Reflux
O
O
O O
NH
NH HN
HN NH
NH HN
HN
CHON
Me
O
O
O O
MeNHCH2COOH
Toluene / NEt3 Reflux
Introduction
Chapter 1 Page 28
for selectivity of cations, anions or neutral guest molecules. Modifying the
calix[4]pyrrole skeleton by different functional groups can also hold great potential to
act it as a ditopic receptor.
Calix[4]pyrrole with a carboxylate pendant arm (monoester) 46 [47] was
obtained by acid catalyst condensation of methyl 4-acetylbutyrate and cyclohexanone
with pyrrole, in a 1:1:2 ratio. Column chromatography (silica gel; dichloromethane,
eluent) afforded 46 in 12% yield (Scheme 15). A good example of meso-
modification was provided by the first type of carboxyl-functionalized calix[4]pyrrole
[44] When the proper ratios were used, taking into account the slow reactivity of the
δ-ketoester, the meso-“hooked” calixpyrrole (Scheme 15) was formed in reasonable
yield. Hydrolysis of the ester generated the free carboxylic acid functionalized
calix[4]pyrrole 47 (Figure 8), which could be used for further derivatisation.
Scheme 15 Calix[4]pyrrole with a carboxylate pendant arm
Figure 8 Carboxylic acid functionalized calix[4]pyrrole.
NH
NH
NH
NH
CH3
CO2H
3
47
NH
NH
NH
NH
CH3
CO2Me
NH
O
CH3
CO2Me
O
3+ +
MeSO3H
MeOH
46 12%
3
Introduction
Chapter 1 Page 29
Revising the approach for synthesis of Calixpyrrole, Sessler et al. [48]
produced amine functionalized calixpyrroles. Specifically, condensation of
benzyloxycarbonyl (Cbz) protected 3-aminoacetophenone, 3-pentanone and pyrrole in
the presence of BF3·Et2O was found to afford the mono-functionalized calix[4]pyrrole
48. Subsequent deprotection by Pd–C gave the mono-amine functionalized
calixpyrrole 49 in 23% yield (Scheme 16).
Scheme 16 Synthesis of mono-amine functionalized calix[4]pyrrole.
In an effort to further improve the selectivity of calixpyrrole derivatives for
particular anions and especially the chloride-over-phosphate selectivity,
calix[4]pyrrole systems bearing substituted aryl groups in the meso-positions were
prepared and their anion coordination properties had been examined [27]. As detailed
in reported paper, calix[4]pyrrole 50a consists of four isomers that can be separated
via column chromatography. According to the relative position of the bulky
substituted phenyl group, these isomers were identified as being the αβαβ, ααββ,
NH
NH
CH3
NH
NH
CH3
CH3
CH3
CH3 CH3
CH3
NH R
NH
CH3O
NH
CBz
CH3
CH3
O+BF3.Et2O
23%
48 R = CBz
49 R = H Pd-C 98%
+
Introduction
Chapter 1 Page 30
αααβ, and αααα configurational isomers, where the “α” and “β” nomenclature follows
the standard porphyrin convention (Scheme 17).
For instance, each of the isomers of 50a was found to display a considerably
higher affinity for anions than did the corresponding isomers of the methoxy
substituted system, 50b. Further, as a general rule the anion affinities of both species
were found to be less than those of parent calix[4]pyrrole 1. This was an unexpected
result that contradicts author’s expectation that the deep cavities of 50a and 50b
would serve to increase anion affinities in absolute terms.
Scheme 17 Isomers of “deep cavity” calix[4]pyrrole.
Further modification at meso-position was obtained by reaction of compound
50a with ethylbromoacetate in dry acetone in presence of K2CO3 with heating at
reflux for 5 days [49]. The tetraester derivative 51 was isolated as a white powder in
76.5% yield. Amide macrocycle 52 was synthesized by reaction of compound 50a
with 2-chloro-N,N-dimethylacetamide and potassium iodide in dry acetone with
NH
NH
Ar
Me
NH
NH
ArMe Ar
Me
Ar
Me NH
NH
Me
Ar
NH
NH
Ar
Me Ar
Me
Ar
Me
NH
NH
Ar
Me
NH
NH
ArMe Ar
Me
Ar
Me NH
NH
Ar
Me
NH
NH
Ar
Me Ar
Me
Ar
Me
50a Ar =
50b Ar =
MeI/K2CO3
CH3 OH
CH3 OMe
Introduction
Chapter 1 Page 31
stirring for 5 days and was isolated in 50% yield (Scheme 18). These extended cavity
ester and amide calix[4]pyrrole macrocycles have shown to bind fluoride exclusively
in DMSO-d6 solution.
Scheme 18 Synthesis of novel, super extended deep cavity calix[4]pyrrole.
The thermodynamics of anion complexation of several calix[4]pyrrole
derivative, namely, meso-octamethylcalix[4]pyrrole 1, calix[1]thieno[3]pyrrole 53a,
calix[2]thieno[2]pyrrole 53b, N,N-dimethyl-calix[2]thieno[2]pyrrole 53c, meso-tetra
Br-CH2CO2Et
K2CO3
ClCH2CONEt2
K I
50a
51 52
CH3
CH3
OH
NH
CH3
4
4CH3
CH3
O
NH
CH3
O
EtO
4CH3
CH3
O
NH
CH3
O
Et2N
Introduction
Chapter 1 Page 32
methyl-tetra[N-(2-phenoxyethyl)-N’-phenylurea]calix[4]pyrrole 53d, meso-tetra
methyl-tetrakis(thiophene)calix[4]pyrrole 53e, and meso-tetramethyl-tetrakis{4-[2-
(ethylthio) ethoxy]phenyl}calix[4]pyrrole 53f in non-aqueous media have been
discussed by Angela et al. (Figure 9) [50]. Given that these derivatives have potential
to interact with anion and cation (through the donor atoms of the pendant arms of the
di-substituted methylene bridges), their complexation with anions and cations have
been investigated through 1H NMR, conductance and calorimetric studies.
Figure 9 Calix[4]pyrrole derivatives.
Novel deep cavity calix[4]pyrroles 54 and 55 derived from steroidal ketones
were synthesized and studied for their ability to effect the selective recognition of
appropriate sized organic anions (Figure 10) [51]. One good receptor, the
polyhydroxylated αααβ configurational isomer of 55b, was found to bind both,
tartaric acid and mandelic acid selectively, while 54 and 55a were found to be far less
CH3
NH
CH3CH3
O
NH
NH
O
4
53d
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
1
S
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
53a
S
NH
CH3
CH3
S
NH
CH3CH3 CH3
CH3
CH3
CH3
53b
S
N
CH3
CH3
S
N
CH3CH3 CH3
CH3
CH3
CH3
CH3
CH3
53c
CH3
NH
CH3CH3
S4
53e
CH3
NH
CH3CH3
O
S
CH3
4
53f
Introduction
Chapter 1 Page 33
effective as receptors for these guests. These findings were rationalized in terms of a
combination of both, specific anion-pyrrole NH hydrogen bonding interactions and
less well-defined steroid-substrate interactions.
In 2003, Gale et al. [52] reported the synthesis of a new meso-modified
calix[4]pyrrole, namely the pentapyrrolic calix[4]pyrrole 57 (Scheme 19). The fifth
pyrrole unit, attached synthetically to a meso-position, was expected to act as an
ancillary hydrogen bonding donor, thereby enhancing the anion affinities of 57
relative to simple calix[4]pyrroles. Tripyrrolylmethane 56 was synthesized via
methanesulfonic acid catalyzed condensation of pyrrole with 2-acetyl-3,4,5-
tribromopyrrole. But, the [2+2] mixed condensation of 56 with dimethyl
dipyrromethane in acetone afforded 57 in 14% yield.
Figure 10 Structure of steroidal calix[4]pyrroles.
NH
NH
RCH3
NH
NH
RCH3 R
CH3
R
CH3
CH3
CH3
OAc
CH3
CH3
CH3
CH3
55a R'=H
55b R'=OH
R = CH3
CH3
HO
CH3
CH3
R'
R'
CH3
CH3
54
Introduction
Chapter 1 Page 34
Scheme 19 Synthesis of pentapyrrolic calix[4]pyrrole.
Ballaster et al. recently designed new calix[4]pyrroles having extended
aromatic cavities using 4 ureas in the para position of the meso phenyl positions. This
elaboration of the upper rim was completed in two synthetic steps starting from αααα
tetranitro isomer 58 of the calixpyyrole obtained by acid catalysed condensation of p-
nitro methyl ketone and pyrrole (Scheme 20). These derivatives 60, 61, 62 were
specially designed to form a capsule and encapsulate 4, 4-bipyridine bis N- oxide
[53].
NH
Br Br
BrCH3
O
MeSO3H
pyrroleNHNH
CH3NH
Br
Br
Br
56
NHNH
CH3 CH3
MeSO3H
acetone
NH
NH
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3 NH
Br
BrBr
57
Introduction
Chapter 1 Page 35
NH
NH
CH3
NH
NH
CH3
CH3
CH3
NO2
NO2
O2N
O2N
NH
NH
CH3
NH
NH
CH3
CH3
CH3
NH2
NH2
NH2
NH2
Pd/C
H2 10%
NH
NH
CH3
NH
NH
CH3
CH3
CH3
NH
NH
NH
NH
C
C
C
C
O
NH R
O
NH RO
NHR
O
NHR
C O
N
R
CH3 CH3
CH3
R =
CH3
Br
58
59
60 61 62
Scheme 20 Synthesis of calix[4]pyrrole with extended aromatic cavities
Novel admantane derivatives 63-67 of calix[4]pyrroles (Scheme 21) were
synthesized by Kate Mlinaric-Majerski and co-workers and characterized by X-ray
powder diffraction method. Calix[4]pyrrole derivative binds with Cl- ion in DMSO
solution and also in solid state. Kata Mlinaric-Majerski and co-workers were first to
report complexation with anion in solid state [54].
Introduction
Chapter 1 Page 36
TFA
NH
NH
TFA
CH3 CH3
ONH
NH
NH
NH
H CH3
CH3
CH3
CH3
H
NH NH
NHNH
H
H
H
H
NH
NH
NH
NH
CH3
CH3
CH3
CH3
NH NH
NHNH
NH NH
NHNH
HH
62 63 64
65 66 67
Scheme 21 Admantane derivatives of calix[4]pyrroles
Drasar et al. [55] synthesized two new steroidal spiroannulated
calix[4]pyrroles 69 and 71, derived from bile acids (lithocholate). These
calix[4]pyrroles were prepared by the acid catalyzed condensation of methyl-3,3-
bis(pyrrol-2-yl)-5β-cholan-24-oate with carbonyl compounds and with 2,2'-propane-
2,2-diylbis(1H-pyrrole), respectively (Scheme 22).
Pavel Drasar et al. [56] have prepared first calix[4]pyrrole 74 containing
unprotected carbohydrate moiety directly linked to meso-position of oligopyrrole by
stable “C-glycosidic” bond (Scheme 23).
Introduction
Chapter 1 Page 37
PDA/ AcetoneTFA, rt, 1.5 hr
CH3
H
CH3
H
CH3
O
OCH3
CH3
H
CH3
H
CH3
O
OCH3
NH
N
NH
N
FF
F
FF
CH3
H
CH3
H
CH3
O
OCH3
NH
NH
NH
NH
CH3
CH3
CH3
CH3CH3
CH3
CH3
H
CH3
H
CH3
O
OCH3
NH
NH
69
70
71
Scheme 22 Synthesis of two new steroidal spiroannulated calix[4]pyrroles
Introduction
Chapter 1 Page 38
Scheme 23 Calix[4]pyrrole containing unprotected carbohydrate
Ahmet Akar et al. synthesized novel meso-tetracarboxylic acid and meso-
tetraester functionalized calix[4]pyrroles by condensation of pyrrole with levulinic
acid and ethyl pyruvate in sufficient yields. In addition, mixed condensation products
were also be synthesized using this method [57].
75
NH
NH
CH3
CH3
NH
NH
CH3 CH3
CH3
CH3
CH3
O
OHOH OH
OH
O
OHOH OH
NH
NH
CH3
OH
NH
NH
CH3
CH3
O
OH
OH OH
O
CH3
OH
O
CH3CH3
+
+MeSO3H
MeOH
MeSO3H
MeOH
72
73
74
Introduction
Chapter 1 Page 39
76
77
Scheme 24 Novel meso-tetracarboxylic acid and meso-tetraester calixpyrrole,
5. FUCTIONALIZED CALIX[4]PYRROLE AND THEIR
APPLICATIONS Literature survey reveals that calixpyrroles have been used for various
applications e.g. as optical sensors, electrochemical sensors, HPLC supports, anion
transporting agents, chelating polymer and nonlinear optical materials etc.
Introduction
Chapter 1 Page 40
5.1. Calix[4]pyrrole-based optical sensors
Two main approaches (Scheme 25) have been used to get calix[4]pyrrole-based
optical anion sensors,
In Covalent attachment approach a colorimetric or fluorescent reporter group
is linked covalently to the calix[4]pyrrole skeleton. Perturbation of the electronic
properties of these reporter groups upon anion complexation then produces a response
detectable by visual or fluorescence-based means. Since 1999, numbers of covalently
linked calixpyrrole-based optical sensor systems have been synthesized. Sessler et al.
[58] reported a new library of covalently linked calixpyrrole derivatives, which
showed that they could find application as anion sensors.
Scheme 25 Two approaches for optical sensors.
Augusto C. Tomé et al. [47] synthesized new calix[4]pyrrole derivatives 44 and 45,
the azomethine yield generated from aldehyde 43 were successfully trapped in 1,3-
Calixpyrrole
XAddition of anion
a) Covalent attachment
Receptor group
(Fluourescent/colorimetric moiety)
X CH3 CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Change in optical properties
A-
b) Displacement assay
A1-
Calixpyrrole + anion A1
A2- + CH3 CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH3
CH3
CH3
CH3
CH3
A1-Addition of more strongly
Binding anion A2
Change in optical properties of anion A1
Introduction
Chapter 1 Page 41
dipolar cyclo-additions with fumaronitrile and quinones. The resulting cycloadducts
showed high affinity constants for fluoride anion and a significant selectivity for
acetate when compared with dihydrogen phosphate.
The synthesis of new calixpyrrole derivatives were obtained from (E)-3-
(meso-octamethylcalix[4]pyrrol-2-yl)propanol and its use in Knoevenagel reactions
are described (Scheme 26). The resulting compounds display sharp changes in colour
in the presence of fluoride, acetate, and dihydrogen phosphate anions. Compounds
78–81 showed quite different absorption spectra, displaying blue, orange, and yellow
colours. The addition of fluoride, chloride, and acetate anions to sensor 79 resulted in
an impressive change in colour while minor changes were observed for compounds 80
and 81. The addition of nitrate, nitrite and bromide anions caused almost no change in
the colour of the four sensor solutions, indicating a low affinity for these anions
[59].
Scheme 26 Calixpyrrole derivatives obtained from (E)-3-(meso-
octamethylcalix[4]pyrrol-2-yl)propenal
NH NH
CH3CH3
NHNH
CH3 CH3
CH3
CH3CH3
CH3
CHO
(a),(b)
(c),(d)
NH NH
CH3CH3
NHNH
CH3 CH3
CH3
CH3CH3
CH3
X
X
NH NH
CH3CH3
NHNH
CH3 CH3
CH3
CH3CH3
CH3
NC
X
(a) 1,3-bis(dicyanomethylidene)indane, AC2O, reflux, 30 min; (b) indane-1,3- dione, Et3N, THF, rt, 24 h; (c) malononitrile, Et3N, CH2Cl2, rt, 24 h; (d) ethyl cyanoacetate, Et3N, CH2Cl2, rt, 24 h.
78, X = C(CN)2 (41%)
79, X = O (65%)
80, X = CN (82%)81, X = CO2Et (73%)
Introduction
Chapter 1 Page 42
A comparative study of the halide and benzoate anion binding properties of a
series of phenyl, pyrrole and furan-strapped calix[4]pyrroles 82, 83 and 84 were
carried out by J. L. Sessler et al. [60]. They found straped calix[4]pyrrole derivatives
to bind bromide and benzoate anion (studied as the corresponding tetra butyl
ammonium salts) with near equal affinity in acetonitrile, although less well than
chloride, as determined from NMR spectroscopic titrations. Out of three anions for
which quantitative data were obtained (i.e. Cl-, Br-, PhCO2-), the pyrrole-strapped
system displayed the highest affinity, in the specific case of fluoride anion binding to
the pyrrole-strapped receptor, two modes of interaction are inferred, with the first
consisting of binding to the calix[4]pyrrole via NH-anion hydrogen bonds, followed
by a process that involves deprotonation of the strapped pyrrolic NH proton.
82 83
84
Figure 11 A series of phenyl, pyrrole, and furan-strapped calix[4]pyrroles
HN
NH
NH
HN
O O
OOO
HN
NH
NH
HN
O O
OONH
Introduction
Chapter 1 Page 43
A strapped calix[4]pyrrole bearing a 1,3-indanedione group at a β-pyrrolic
position 85 has been synthesized and studied as a ratiometric cyanide selective
chemosensor by C. H. Lee et al. [61]. A concentration-dependent bleaching of the
initial yellow colour was observed upon addition of the cyanide anion. The bleaching,
which was observed exclusively with the cyanide anion occurred even in the presence
of other anions. Spectroscopic studies provide support for a mechanistic interpretation
wherein the cyanide anion forms a complex with the receptor. A minimum inhibitory
effect from other anions was observed, a feature that could be beneficial in the
selective sensing of the cyanide anion.
85
Figure 12 A strapped calix[4]pyrrole bearing a 1,3-indanedione group
at a β-pyrrolic position
A new catechol derived strapped calix[4]pyrrole 86 (Figure 13) bearing
diether strap linked via alkyl chains have been synthesized and characterized for the
first time. The strap with 1,2-diether link provided a relatively constrained geometry
on its side of the calix[4]pyrrole moiety. This calix[4]pyrrole also exhibits enhanced
N H H N
H NN H
OO
O O
O
O
Introduction
Chapter 1 Page 44
binding towards halide anions compared to simple calix[4]pyrrole apart from showing
binding towards dihydrogenphosphate and acetate ions. The association constants
were found to be quite similar to that found for orcinol strapped calix[4]pyrrole
towards halide anions in general, but having a higher preference for chloride than
bromide ion in particular. Further it showed very strong preference towards fluoride
ion [62].
86 87
Figure 13 A new catechol derived strapped calix[4]pyrrole
Three new chromogenic calix[4]pyrrole sensors 88-90 [63] were synthesized
and characterized. Sensor 88 was prepared by an electrophilic aromatic substitution
reaction of octamethylcalix[4]pyrrole 1 with tetra-cyanoethylene. Sensors 89 and 90
were obtained by condensation of formyl-octamethylcalix[4]pyrrole with 1-
indanylidene-malononitrile and anthrone, respectively. The anion sensing ability of
sensors 88, 89 and 90 was studied on a qualitative level by visual examination of the
NH HN
HNNH
O O
NH HN
HNNH
O O
Introduction
Chapter 1 Page 45
anion-induced colour changes in the solution of the sensors 88-90. To demonstrate the
relevance of sensors 88-90 to health care applications [64] sensing experiments were
performed in blood plasma at a high electrolyte concentration. Furthermore, studies
with carboxylates of medical interest (salicylate, ibuprofen and naproxen) were
performed using newly developed assay with sensors 88-90 embedded in
polyurethane films (Figure 14).
Anzenbacher et al. [65] also synthesized, 1,3-indane-based chromogenic
calixpyrroles with push-pull chromophores. The Knoevenagel condensation of 2-
formyl-octamethylcalix[4]pyrrole with selected 1,3-indanedione derivatives gave
sensors 91-94. The push-pull feature results in augmented signal output as well as in
dramatic changes in anion selectivity exemplified by a 50 fold increase in acetate vs
chloride selectivity compared to the parent calix[4]pyrrole (Figure 14) .
Introduction
Chapter 1 Page 46
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3 NC
CN
CN
88
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
NC
CN
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3 O
89 90
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
Y
X 91 X=H2, Y=C(CN)2
92 X=Y=O
93 X=O, Y=C(CN)2
94 X=Y=C(CN)2
Figure 14 Calix[4]pyrrole based optical sensors.
The β-octaalkyl-substituted calix[4]pyrrole [66], the first to be prepared via a
direct condensation reaction, was obtained by reacting the 3,4-alkyl-functionalized
pyrrole with acetone in the presence of an acid catalyst. The synthesis and preliminary
solution phase ion binding properties of the N-tosylpyrrolidine calix[4]pyrrole 95 are
reported for first time. On the basis of 1H NMR spectroscopic analyses and isothermal
titration calorimetry, it was concluded that, compared with the parent, β-unsubstituted
calix[4]pyrrole 1, possesses significantly enhanced binding ability for halide anions in
chloroform. Furthermore, 95 proved capable of solubilizing in chloroform solution the
Introduction
Chapter 1 Page 47
insoluble salts like CsF and CsCl. These effects are ascribed to the interactions
between the four tosyl groups present in 2 and the counter cations of the halide anion
salts.
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3 NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
NS OO
CH3
N S
O
O
CH3NS
O
O
CH3
NSO O
CH3
1
95
Figure 15 The β-octaalkyl-substituted N-tosylpyrrolidine calix[4]pyrrole
Two novel 3,12- and 3,7-bis(4’-nitrophenyl)-azo- 5,5,10,10,15,15,20,20-
octamethyl calix[4]pyrroles 34 and 35 were prepared and studied as potential anion
binders for AcO- and H2PO4-; the isomeric pair not only allowed for the colourimetric
detection but also helped to discriminate these geometrically different anions from
other anions [43].
Calix[4]pyrroles bearing appended pyrenyl groups 96, 97 at the meso-
positions on one side of the calix[4]pyrrole have been synthesised and characterised
by C. H. Lee et al. [67]. The host calix[4]pyrrole derivatives exhibited a selective
increase in their fluorescence intensity upon the addition of Pb+2 or Cu+2 . When
excess chloride anion was added after subjecting the host to pre-complexation with
Introduction
Chapter 1 Page 48
Pb+2, the cation-induced enhancement in fluorescence was sustained. On the contrary,
no changes in fluorescence was observed when the calix[4]pyrrole host was first
treated with chloride anion, followed by the addition of Pb+2. These results were
found to be consistent with pre-complexation of Pb+2 not serving to inhibit the
binding of chloride anion, while, by contrast, the initial interaction between a chloride
anion and the calix[4]pyrrole cavity acts to inhibit the subsequent binding of Pb+2,
possibly due to anion-binding-based constraints on the conformational flexibility
(Figure 16).
NH NH
CH3CH3
NHNH
CH3 CH3
CH3CH3
O
O
O
O
( ) n
96, n = 0
97, n = 2
Figure 16 Calix[4]pyrroles bearing appended pyrenyl groups
at the meso-positions
C. H. Lee et al. [68] synthesized and fully characterized calix[4]pyrroles
bearing two fluorescent pyrenyl groups at the diametrical meso-positions on one side
of the calix[4]pyrrole 98, 99. The preliminary solution phase anion-binding studies
indicate that fluoride and chloride anion irreversibly binds to the pocket generated by
the two pyrene pickets and the affinity for other anions is far less than those of
fluoride anion resulting fast complexation/decomplexation kinetics. The observed
higher affinity of chloride anion other than fluoride anion may be associated with
stronger anion π interaction in the chloride complex with receptor (Figure 17).
Introduction
Chapter 1 Page 49
98 99
Figure 17 Calix[4]pyrroles bearing two fluorescent pyrenyl groups at the diametrical
meso-positions on one side of the calix[4]pyrrole
A series of second generation calix[4]pyrrole anion sensors 100, 101, and 102
[48] were synthesized by coupling meso-monoaminecalix[4]pyrrole 37 with
commercially available dyes as fluorescent tags (Figure 18). These adduct 100, 101,
and 102 are based on dansyl, lisamine-rhodamine B and fluorescein, respectively.
These were tested for their affinities towards the usual set of test anions via
fluorescence quenching using a 0.01% v/v acetonitrile/water mixture. The presence of
the second anion binding group alters the anion selectivity of the calix[4]pyrrole.
Specifically, selectivity is enhanced for dihydrogenphosphate and pyrophosphate
relative to chloride. The fluorescence of receptors 100, 101, and 102, were found to be
quenched in the presence of anions.
Introduction
Chapter 1 Page 50
Figure 18 Fluorescent receptors prepared by linking commercial dyes to the amino-
functionalized calix[4]pyrroles.
The second displacement assay approach has not been explored much than the
first approach. Still, it has been successfully exploited to produce different kind of
colorimetric anion sensors [69, 70] which do not require any functionalization of the
parent molecule. They discovered that when bound to meso-octamethyl
calix[4]pyrrole 1, the 4-nitrophenolate anion X loses its intense yellow colour and the
decrease in intensity was visible to the naked eye. Anions, such as fluoride, displaced
the 4-nitrophenolate anion from the complex thereby restoring the native absorbance
of the 4-nitrophenolate anion (Figure 19)
.
NH
NH
CH3
NH
NH
CH3
CH3
CH3
CH3 CH3
CH3
NH S
N
CH3
CH3
O
ONH
NH
CH3
NH
NH
CH3
CH3
CH3
CH3 CH3
CH3
NH S
O
O
CH3
O
N
EtEt
N+
Et
Et
SO3-
NH
NH
CH3
NH
NH
CH3
CH3
CH3
CH3 CH3
CH3
O
OH
O
NH
NHS
HOOC
100 101
102
Introduction
Chapter 1 Page 51
Figure 19 F- dependent equilibrium between the meso-octa(methyl)calixpyrrole-4-
nitrophenolate and meso-octa(methyl)calixpyrrole-fluoride.
An interesting example of a fluorogenic sensor based on displacement assays
was discovered by Machado et al. [71] The interaction of Brooker’s merocyanine
(BM), a merocyanine dye with calix[4]pyrrole 1 (CP) was studied in acetonitrile. BM
is violet in solution, but its interaction with CP changes the colour of the solution due
to the formation of CP–BM species associated through hydrogen bonding. A
displacement assay was then carried out in the presence of different anions (F-, Cl-,
Br-, I-, H2PO4-, HSO4
- and NO3-). It was verified that F- and to a lesser extent Cl- and
H2PO4-, displace BM through the formation of a complex with CP. Addition of HSO4
-
makes the solution almost colourless because it is sufficiently acidic to transfer a
proton to BM, removing it from the receptor site in CP and protonating the dye,
thereby allowing the visual detection of the anion in relation to the other anions
(Figure 20).
CH3
NH MeNHNH
CH3
CH3
NHCH3
CH3 CH3
CH3
CH3
CH3
NO2-
O-
1
X
CH3NO2
-
O-
yellow1-X
colorless
F CH3
NH MeNHNH
CH3
CH3
NHCH3
CH3 CH3
CH3
F_
+
O2N CH3O-
yellow
Introduction
Chapter 1 Page 52
Figure 20 The competition between the anion and merocyanine solvatochromic dye
for calix[4]pyrrole as a receptor site.
5.2. Calix[4]pyrrole-based electrochemical sensors
For the development of calixpyrrole-based electrochemical anion sensors,
different approaches include the incorporation of calixpyrroles in ion-selective
electrodes (ISEs), discrete redox active molecular receptors and chemically modified
electrodes.
5.2.1. Ion-selective electrodes (ISEs)
Kim et al. [72, 73] reported that electrode based on the meso-
tetracyclohexylcalix[4]pyrrole exhibit excellent electrochemical response
characteristics and selectivity for Ag(I) ion. They utilized the
calix[m]pyrrole[n]furans (m+n=4), such as trans-octamethylcalix[2]pyrroles[2]furans
103, cis-octamethylcalix[2]pyrroles[2]furans 104 and
octamethylcalix[1]pyrrole[3]furans 105 (Figure 13) as sensing materials in ion-
CH 3
NH MeNHNH
CH3
CH3
NHCH3
CH3 CH3
CH3
1 CH 3
NH MeNHNH
CH3
CH3
NHCH3
CH3 CH3
CH3
_
+O -
N+
CH3
BM
Violet
O -
N+CH3
BM
Violet
A_A
CP-A -
O -
N+
CH3
CP-BM
Change in color
Introduction
Chapter 1 Page 53
selective electrodes to investigate the relationship between Ag(I) ion selectivity and
the conformation of the porphyrinogen substituents.
Lee et al. [74] reported the potentiometric behavior of three types of newly
synthesized calix[2]furano[2]pyrrole derivatives towards Ag(I) ion (Figure 21). PVC
(polyvinyl chloride) membrane electrodes incorporating the ionophores 106, 107 and
108 exhibited the response to Ag(I) ion. The best results were obtained with the
membrane containing N and O atoms in the ligand (ionophore 106). These Ag(I) ion
electrodes displayed very good selectivity for Ag(I) ion in comparison to alkali and
alkaline earth metal ions, NH4+ and H+.
Figure 21 Various ionophores for ion-selective electrodes.
PVC based ISEs from meso-octamethylcalix[4]pyrrole 1 and analogue system
were also prepared [75,76] namely dichlorocalix[2]pyrrole[2]pyridine 109 and
teterachloro-calix[4]pyridine 110 (Figure 22).
NH
R2
CH3
CH3
NH
R1
CH3CH3 CH3
CH3
CH3
CH3
106: R1=R2=O
107: R1=R2=S
108: R1=S, R2=O
NH
O
CH3
CH3
NH
O
CH3CH3 CH3
CH3
CH3
CH3
103
O
NH
CH3
CH3
NH
O
CH3CH3 CH3
CH3
CH3
CH3
104
O
O
CH3
CH3
NH
O
CH3CH3 CH3
CH3
CH3
CH3
105
Introduction
Chapter 1 Page 54
ISEs derived from compound 1 showed strong anionic response for Br-, Cl-
and H2PO4- and to a much lesser extent for F-. ISEs derived from compound 109 and
compound 110 were investigated towards these anions and were found to be pH
dependent.
Figure 22 Dichlorocalix[2]pyrrole[2]pyridine and tetrachlorocalix[4] pyridine.
5.2.2. Discrete redox active molecular receptors
Novel calix[4]pyrrole bearing vic-dioxime ligand has been synthesized by the
reaction of anti-chlorophenylglyoxime with 3-aminophenylcalix[4]pyrrole at room
temperature. The mononuclear Cu(II), Ni(II) and Co(II)complexes of this vic-dioxime
ligand were prepared and their structures were confirmed by elemental analysis,
FTIR, TGA and magnetic susceptibility measurements; the HMBC, DEPT, 1H and
13C NMR spectra of the ligand were also reported. B. Taner et al. have investigated
redox behaviors of Ni(II), Co(II) and Cu(II) complexes of ligand by cyclic
voltammetry at glassy carbon electrode. Electrochemical data showed that nickel and
copper complexes exhibit almost similar electrochemical behavior, with the
irreversible reduction processes based on metal cations, while the Co(II) complex
displays quasi-reversible one-electron transfer reduction process in the cathodic
region based on metal [77].
NH
CH3
CH3
CH3
CH3
N
NH
CH3
CH3
CH3
CH3
N
Cl
Cl
N N
CH3
CH3
N
CH3CH3
Cl
CH3
CH3CH3
CH3
N
Cl
Cl
Cl
109 110
Introduction
Chapter 1 Page 55
The development of discrete redox active receptors [78] containing a guest
binding site coupled to a redox active reporter group is an area in supramolecular
chemistry that has attracted much attention. Beer and Gale [79] have synthesized a
redox active ferrocene group to the calix[4]pyrrole framework 111-113 but anion
binding properties of the resulting receptors are to be studied using electrochemical
means. As with the optical sensors described earlier, this was done via both meso
functionalization and modification of β-pyrrolic position (Figure 23) [80].
Figure 23 Ferrocene appended calix[4]pyrrole.
1H-NMR titrations have revealed that one CH proton of ferrocene participated
in hydrogen bonding interactions with calixpyrrole NH hydrogen bonding interaction
that are thought to stabilize the bound anion in complex (Figure 24). The crystal
structure of compound 113 revealed that it functions as electrochemical sensor and
binds F-, H2PO4- and Cl- anions [80].
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3NH
O
Fe
CH3
Fe
NH
NH
NH
NH
CH3
R
CH3 NH
O
3Fe
111
112 R =
113 R =
Introduction
Chapter 1 Page 56
Figure 24 Proposed CH-anion interaction in complex
5.2.3. Chemically modified electrodes
Gale et al. [81] prepared chemically modified electrode from calix[4]pyrrole
monomers containing α-unsubstituted pyrrolic species and compounds 114 and 115
(Figure 25), were synthesized using methods analogous to those used to prepare 111
and 112. Specifically, they were made by coupling the relevant calix[4]pyrrole mono-
acid species with 3-aminopropylpyrrole using the benzotriazolyloxy-
tris(dimethylamino) phosphonium (BOP) amide coupling agent.
They also investigated the use of these co-polymer films of 114-pyrrole and
115-pyrrole (Figure 26) as anion masks and any perturbation due to the formation of
calix[4]pyrrole-anion complexes on the cyclic voltammogram.
Figure 25 Chemically modified electrodes.
Fe
NH MeNHNH
CH3
CH3
NHCH3
CH3 CH3
H
CH3
A-
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
NH
N
O
114
NH
NH
NH
NH
CH3
NH
O
N115
Introduction
Chapter 1 Page 57
Figure 26 Polymerization of calix[4]pyrrole monomers.
5.3. Calix[4]pyrrole-based HPLC supports
Reports on calix[4]pyrrole modified stationary phase are relatively few. The
important one came from Sessler et al. [82] calix[4]pyrrole-modified silica gels (Gel
B and Gel M) could act as new solid-phase HPLC supports. Under different
conditions, they realized that this calix[4]pyrrole-modified silica gels were useful for
the separation of some inorganic and organic anions, such as fluoride, chloride, Cbz-
protected amino acids, phosphorylated derivatives of adenine, oligonucleotides, and
some small neutral substrates. A mechanism for HPLC-based separation was
proposed as resulting from the weak hydrogen bonding interactions between
calix[4]pyrrole moieties and the anionic substrates. These weak interactions, which
presumably differ in strength for each anionic substrate in question, lead to selective
retention of the anions under conditions of isocratic elution using a competitive
solvent system. For instance, HPLC separation of 5'-adenosine monophosphate
(AMP), 5'-adenosine diphosphate (ADP), and 5'-adenosine triphosphate (ATP) on Gel
M revealed that the more highly charged nucleotide is retained longer without the use
of ion-pairing agents (Figure 27).
NH
N
CH3
+Potential cycling or chronoamperometry
114 or 115NH
NH
N
NH
CH3
NH
NH
N
NH
CH3
NH
NH
Electrode
Calixpyrrole anion binding sites
Introduction
Chapter 1 Page 58
Figure 27 Calix[4]pyrrole-modified silica gels.
Recently, Jiang et al. [83] explored the separation ability and mechanism of
calix[4]pyrrole stationary phase, where two calix[4]pyrrole-modified silica gels (gel
BM and BC in Figure 27) were synthesized and successfully applied to separate
amino acids, phenols, benzene carboxylic acids, and some medicines.
Calix[4]pyrrole-modified HPLC columns have the potential to separate some
positional isomers and medicines, which would be helpful for further studies and
applications in the fields of analytical and supramolecular chemistry.
5.4. Polymer-bonded calix[4]pyrrole and their chelating properties
The synthesis and preliminary sorption properties of three types of chelating
resins containing calixpyrrole units (Figure 28) have been reported by Andrzej et al.
[84] obtained by :
(i) Immobilization of calix[4]pyrrole on a polymeric support (vinylbenzyl
chloride/divinylbenzene co-polymer),
NH
NH
NH
NH
CH3
NH CH3
O
Gel M
CH3
CH3
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3
O
NH CH3
CH3
CH3
Gel BC
NH
NH
NH
NHO
NH CH3
CH3
CH3
Gel B (Gel BM)
Introduction
Chapter 1 Page 59
(ii) Condensation of calix[4]pyrrole with formaldehyde to form insoluble
polymeric materials and
(iii) Radical co-polymerization of calixpyrrole monomer with methylacralyte
and divinylbenzene that led to cross-linked insoluble resin in the form of beads.
“Hetero” or “hybrid-calixpyrroles” are among the many new calixpyrrole
receptors found. These hybrid systems contain thiophene or furan other than pyrrole
heterocycles incorporated into macrocycles, presenting a new class of receptors with
interesting anion and cation-binding potential. Andrzej et al. [85] presented the
synthesis and batch-mode sorption characteristics of a novel chelating resin
containing macrocyclic ligands calix[4]pyrrole[2]thiophene immobilized on a cross-
linked vinyl benzyl chloride/divinylbenzene copolymer which played important role
in selectively complexing precious metal cations.
It was observed that all resins demonstrated a preference for fluoride anions
over other halides in static sorption studies. [86] Larger anions, like iodides, did not
form complex with the resin due to difference between the size of the anion and the
size of the binding site. Thus resins 1-3 (Figure 28) have been proved to be used as
sorbents of anions from non-aqueous media and are promising materials for
separation techniques.
A range of static sorption studies were performed on resin 4, (Figure 28) that
demonstrated strong affinity towards cations of the noble metals (Au, Ag, Pt, Pd)
over other transition metals. The sorption studies also revealed a considerable
preference of the chelating resin for gold over other precious metals in binary
mixtures, which might be useful in the removal of gold from scraps or ores containing
other noble metals.
Introduction
Chapter 1 Page 60
Figure 28 Calixpyrrole macrocycles-based chelating resins.
5.5. Miscellaneous Applications of Calix[4]pyrrole Macrocycles
F. L. Gu et al. [87] have investigated the structures and static
(hyper)polarizabilities of the [Li+[calix[4]pyrrole]Li-]n dimer and trimer with C4v
symmetry in details. The 2s electron of Li atom inside each calix[4]pyrrole unit were
ionized to form the diffuse excess electron under the action of the lone pairs of its four
N atoms. Compared to the corresponding [calix[4]pyrrole]n (n=5,2,3) without Li
NH
NH
R
Me
NH
NH
R
Me R
Me
R
Me
CH3 O CH2
CH2
R =
CH2
NH
NH
Me
NH
NH
MeMe
Me
OH
OH
O
OH
CH3
CH3
CH3
CH2
CH3
OCH3
O
CH3
CH3CH3
NH
NH
R
Me
NH
NH
R
Me R
Me
Me
O
CH3
CH3
CH3
CH3
CH3
X Y Z
CH3 O CH2
CH2
R =
CH3
CH3
CH3
CH3
CH3 CH3
resin-1
resin-2
resin-3
NH
NH
SCH3
CH3
CH3
OCH2CH3
NH
NH
CH3
CH3
CH3
O CH2 CH3
SCH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
resin-4
Introduction
Chapter 1 Page 61
atom, the first hyperpolarizablities of dimer and trimer sharply increased up to 30–40
times by inserting Li atoms, which demonstrated that the excess electrons play an
important role in these large static (hyper)polarizabilities. The detailed investigations
about dimer, trimer, and even polymer of [Li+[calix[4]pyrrole]Li-]n were useful and
helpful for designing new type of NLO materials.
The impact of anion receptor (1,1,3,3,5,5-meso-hexaphenyl-2,2,4,4,6,6-meso-
hexamethylcalix[6]pyrrole) on physicochemical and ion transport properties of
poly(ethylene oxide)-salt composites was studied by M. Siekierski et al. [88].
A DFT based methodology [89] was used to study the complexation of the
alkali metal cations (Li+, Na+, K+, Rb+ and Cs+) and alkaline-earth metal cations
(Be2+, Mg2+, Ca2+, Sr2+ and Ba2+) with calix[2]furano[2]pyrrole 116 (Figure 29). This
compound, which is a promising selective metal extracting agent, showed large
flexibility, with 4.4 kcal mol-1 for the maximum amplitude of conformational energy.
Except for the case of lithium, all the metal ions are held at the centre of the ligand
cavity, with the vertical position depending on the ion radius, small metal ions are
found in inner positions and bigger ones are shifted progressively to the upper rim of
the cavity. The coordination to the central ion is made by the oxygen atoms and the
delocalized electronic density of the pyrrole rings. The binding strength of the ions to
the calix[2]furano[2]pyrrole was found to increase with charge and decrease with
their size.
Figure 29 Calix[2]furano[2]pyrrole
O
NH
CH3
CH3
O
NH
CH3CH3 CH3
CH3
CH3
CH3
116
Introduction
Chapter 1 Page 62
Poly(ethylene oxide) based electrolytes comprising LiCF3SO3 and calix[2]-p-
benzo[4]pyrrole (CBP) as anion binder were prepared and subjected to DSC, ionic
conductivity, cationic transport number and FTIR analysis [90]. The calix[2]-p-
benzo[4]pyrrole (CBP) 117 prepared as an anion receptor in a PE was investigated for
possible application in lithium batteries. The incorporation of CBP in a PEO
environment considerably reduced the crystallinity of the polymer host. However, the
ionic conductivity of electrolytes with CBP was found to be lower than that of a CBP-
free electrolyte below the melting point of PEO. Interactions between the polymer
host, CBP and lithium salt were further inferred from FTIR results (Figure 30).
NH R
R
NHR
R
CH3CH3
NH
CH3
CH3
NH CH3
CH3
R R
117
Figure 30 Calix[2]-p-benzo[4]pyrrole
P. Ballester et al. [22] reported formation of gels, responsive to sodium cations
or pH changes, in aqueous media by an aryl extended calix[4]pyrrole 50a receptor
and the tetramethylammonium guest. It was observed that the addition of TMA
bromide to a solution of 50a in aqueous NaOH afforded with time a transparent
hydrogel.
Sessler et al. [91] examined cooperative relationship between
tetrathiafulvalene (TTF)-calix[4]pyrrole 119-121 and several nitroaromatic guests
and developed new allosteric systems that function as rudimentary colorimetric
Introduction
Chapter 1 Page 63
chemosensors for common nitro aromatic based explosives, and which are effective
even in the presence of potentially interfering anions (Figure 31).
Figure 31 New annulated TTF-calix[4]pyrrole receptors
6. SYNTHESIS OF HIGHER ORDER CALIXPYRROLES
Calix[4]pyrroles are promising anion receptors, but due to the small size of
their cavities, they bind only small anions, such as fluoride and chloride, effectively in
aprotic solvents. Way to improve, or at least adapt, the anion binding properties of
calix[4]pyrroles would be to expand them to produce so called higher order
calix[n]pyrrole (n>4). Such systems are expected to bind larger anions selectively due
to a change in the anion-receptor size or geometry match. However, these higher
order structures are likely to prove more flexible than calix[4]pyrroles, which could
also affect their anion binding properties.
Luis Chacón-García et al. [92] describe the first synthesis of the novel meso-
pentaspirocyclohexyl calix[5]pyrrole 122. Anion–guest properties of the new
NH
NH
CH3
CH3
NH
NH
CH3CH3 CH3
CH3
CH3
CH3S
S
S
S
S S
S S
SS
SS
S
S
S
S
NH
S S
S S
Me2CO / TFA
CH2Cl2
CH3
CH3
SPr
SPr
S==
18%
15 %
21%
118
119
120
121
Introduction
Chapter 1 Page 64
compound were evaluated with respect to fluoride, chloride, and bromide
tetrabutylammonium salts by 1H NMR titration techniques in deuterated
dichloromethane by following the induced shifts in the NH resonances upon
complexation (Figure 32).
Figure 32 meso-pentaspirocyclohexyl calix[5]pyrrole
The first example of a stand alone higher order calix[n]pyrrole was
calix[6]pyrrole. This synthesis was based on the use of the dipyrromethane building
blocks 123 and 124. In particular, reaction of 123 or 124 in a mixture of dry acetone
and ethanol (1:1 v/v) in the presence of trifluoroacetic acid gave rise to meso-
hexa(phenyl)calix[5]pyrrole 125 and meso-hexa(2-pyrridyl)calix[6]pyrrole 126,
respectively (Scheme 27).
NH
NHR
R
123 R= phenyl
124 R= 2-pyridyl
TFA
acetone-EtOH
NH
NH
R
R
NH
NH
R
R
CH3CH3
NHCH3
CH3
NH CH3
CH3
R R
125 R= phenyl
126 R= 2-pyridyl
NH
NH
NH
NH
NH
122
Introduction
Chapter 1 Page 65
Scheme 27 Synthesis of the calix[6]pyrroles
Investigating into the role of the acid catalyst in the synthesis of 125 revealed
that, in addition to acting as a catalyst for the reaction, the trihaloacid catalyst plays an
independent role as a template, promoting the formation of the calix[6]pyrrole product
[93]. 1H NMR-based anion binding studies in acetonitrile-chloroform (1:9) revealed
that compared to parent molecule calix[4]pyrrole 1, 125 binds larger anions such as I-,
BF4-, and CF3CO2
- quite effectively [94]. By contrast, this expanded system shows
relatively reduced affinities for smaller anions, such as F-, Cl-, Br-, and SCN-.
AIM AND SCOPE
Supramolecules derived from calix[4]pyrroles are synthesized by acid
catalyzed condensation of pyrrole with any aliphatic or aromatic ketone. As
conventional method suffers from large amount of solvent, longer reaction time and
low yield, therefore, microwave assisted organic synthesis has become an increasingly
popular technique in academic and industrial research laboratories, due to certain
advantages like (a) faster reaction time (b) higher yield (c) less quantity of solvent
volume (d) improved purity (e) ease of work up after the reactions and (f) eco-friendly
reaction conditions. Product obtained by the condensation of pyrrole with 3,5-
dihydroxyacetophenone is likely to exhibit the properties of resorcinarene as well as
calixpyrrole and its further functionalization with chelating group such as azo, may
further enhance its complexing ability with various metal ions.
Introduction
Chapter 1 Page 66
Aim of the work to be presented in thesis:
1. To develop a rapid, convenient, efficient and environment friendly method
using microwave irradiation technique for synthesis of meso-tetra(methyl) meso-
tetra(3, 5-dihydroxyphenyl) calix[4]pyrrole and its various azo derivatives.
2. To synthesize two new functionalized Amberlite XAD-2 polymeric
chelating resins, resin I and resin II, by covalently linking diazotized Amberlite
XAD-2 with meso-tetra(methyl) meso-tetra(3, 5-dihydroxyphenyl) calix[4]pyrrole
and meso-tetra(methyl) meso-tetra{(3, 5-dihydroxy phenyl-4-(2-diazenyl phenol)}
calixpyrrole respectively.
3. To study the complexation and selectivity behaviour of azo dyes of meso-
tetra(methyl) meso-tetra(3, 5-dihydroxyphenyl) calix[4]pyrrole with various rare earth
metal ions like U(VI), Th(IV), La(III), Ce(III) and develop method for liquid-liquid
extraction, preconcentration and transportation of selective metal ions.
4. To use resin I and resin II for the solid phase extraction, separation,
preconcentration and trace determination of Cu(II), Zn(II), Cd(II), Ni(II), La(III),
Ce(III), Th(IV) and U(VI) in synthetic as well as natural samples under optimum
conditions.
5. To examine antimicrobial activity of azo derivatives of meso-tetra(methyl)
meso-tetra(3, 5-dihydroxyphenyl) calix[4]pyrrole against E. coli, S. aureus and A.
niger, Rhizopus sp. To evaluate the dyeing performances of these dyes on fibers like
cotton, wool, silk, acrylic, nylon and paper study their fastness properties towards
water, sunlight, washing and perspiration.
Introduction
Chapter 1 Page 67
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