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CHAPTER 1

INTRODUCTION

Introduction

Chapter 1

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

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

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

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

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

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

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

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

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

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

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

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

- 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

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

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

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

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

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

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

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

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

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

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

[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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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

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