Chapter II

Anion Templated Synthesis Anion Templated Synthesis Anion Templated Synthesis Anion Templated Synthesis oooof f f f Calix[4]Pyrroles Calix[4]Pyrroles Calix[4]Pyrroles Calix[4]Pyrroles aaaand nd nd nd NNNN----Confused Confused Confused Confused

Calix[4]PyrrolesCalix[4]PyrrolesCalix[4]PyrrolesCalix[4]Pyrroles

56

CHAPTER II

ANION TEMPLATED SYNTHESIS OF CALIX[4]PYRROLES

AND N-CONFUSED CALIX[4]PYRROLES

2.1. Introduction

Anions play essential roles in biological systems and are important environmental

pollution such as nuclear waste produced during the reprocessing of nuclear fuel.

Anions participate 70% of all enzymatic binding events, serving as either enzyme

substrates or cofactors. Further, excess phosphate and nitrate as the result of agricultural

run-off and urban use are responsible for eutrophication in water-ways.

Simmons and Park reported the first synthetic polyammonium-based anion receptors in

1968.1 Since then especially over the course of the last two decades numerous anion

receptors have been synthesized and studied. Over the past several decades a large

number of acyclic and macrocyclic compounds have been synthesized as cation

receptors and evaluated for their abilities to recognize cations.2 In recent years as the

importance of anions in biological and environmental systems has become increasingly

recognized and attention has been directed towards the design and construction of anion

receptors. As a consequence both cation and anion recognition are now well-established

branches of supramolecular chemistry.3,4 To effect anion recognition most ion pair

receptors take advantage of hydrogen bonding donors (urea, amide, imidazolium,

pyrrole, and hydroxyl group), Lewis acidic sites (boron, aluminum and uranyl) and

positively charged polyammonium groups.

Figure 2.1: Ion-pair interaction to receptor mediated ion-recognition

57

2.2. Calix[4]pyrrole as a anion receptor based on pyrroles

The tetrapyrrolic macrocycle calix[4]pyrrole was found in 1996 by Sessler et al. to be

able to bind certain anions in organic solvents.5 In 2005 Moyer, Sessler and Gale et al

reported that calix[4]pyrroles can act as an ion pair receptor for various cesium salts and

certain organic halide salts in the solid state.6 X-ray crystal structures of several cesium

and organic cation-containing anion complexes of calix[4]pyrroles were solved, Taken

in concert they revealed that the anions are bound to the pyrrolic NH protons via

hydrogen bonding. These interactions which were expected on the basis of prior studies

serve to fix the calix[4]pyrrole in the cone conformation. This conformational locking

in turn, provides an electron-rich bowl-shaped cavity into which, e.g., cesium cation is

bound via a combination of π-metal and dipole interactions. Further evidence that

calix[4]pyrrole is effective for ion pair recognition came from liquid-liquid extraction

studies carried out by Wintergerst et al.7 This study demonstrated that compound can

extract CsCl and CsBr, but not CsNO3, from an aqueous phase into nitrobenzene, a

relatively polar organic phase. The solvent extraction process was modeled in terms of

three thermochemical steps. The first of these steps involves a partitioning of the

cesium cations and the halide anions into the nitrobenzene phase from the water phase.

The second step involves a conformational change of the calix[4]pyrrole such that it

adopts the cone conformation, a geometry it maintain as the results of halide anions

binding. The third step involves the cesium cation binding within the bowl-shaped calix

cavity created as the result of the conformational change takes place in 2nd step. While

thermodynamically equivalent in terms of the final state it was appreciated that these

steps could be taking place concurrently. The key point is that under conditions of this

extraction calix[4]pyrrole binds both the cesium cation and a halide anions (Cl¯or Br¯).

2.3. History and structure of calix[4]pyrroles

The white crystalline material first synthesized by Baeyer in 1886, by the

cyclocondensation of pyrrole with acetone in the presence of hydrochloric acid.8 Later

Chelintzev and Tronov repeated the reaction and proposed the structure of the

compound which was named as α,β,γ,δ-octamethylporphinogen by Fischer.9 In 1955,

58

Rothemund and Gage improved this synthesis by using methanesulfonic acid as the

catalyst.10 Other than these important findings this class of compounds (e.g.,

octamethylcalix[4]pyrrole) were only studied sporadically in the 100 years following

their discovery, most of which merely focused on the refined synthesis of these

macrocycles and their meso-substituted derivatives but not their applications.11 This

situation changed in the early 1990s when Floriani and coworkers began exploring their

metal coordination chemistry extensively, thus reviving interest in these venerable

macrocycles after a long dormant period.12

Calix[4]pyrroles, originally named “pyrrole-acetone” and formally known as meso-

octaalkylporphyrinogens are macrocycles composed of four pyrrole units linked via

four di-substituted meso-carbons at the α positions. Figure 2.2 describe the basic

skeleton of calix[4]pyrrole where bracket number indicates the repeating pyrrolic units

linked to each other by sp3 hybridized carbon atoms. calix[4]pyrroles are not readily

oxidized to form porphyrin-like structures. As a consequence the four pyrrole units are

all in their neutral NH-bearing forms in calix[4]pyrroles and no electron delocalization

exists within the macrocyclic system as a whole.

´

NH

NH HN

HN

H3C

H3C

H3C CH3

CH3

CH3

H3C CH3

1

2

3

4

5

6

7

8910

1112

14

13

15

20

22

2124

23

1819

17

16

n

Figure 2.2: Structure of calix[4]pyrrole

Calix[4]pyrrole can adopt four different confirmations: 1,3-alternate, 1,2-alternate,

partial cone and cone, similar to calix[4]arene which has been observed experimentally

and noted theoretically.13

59

OROR

OROR

RO

OR OR

OR OR

OR

OR OROROR ROOR

1,3-alternate 1,2-alternate partial cone cone

HN H

NHN N

HN

NH

NH

HN

H

N

H

N

H

N

H

N

H

HN H

NHN

N

H

0.0 (0.0) 6.7 (4.4) 4.8(3.7) 16.0 (11.4)

Figure 2.3: Four possible conformations of calix[4]arenes (upper) and calix[4]

pyrrole (lower)

2.4. Synthesis of calix[4]pyrroles and related macrocycles

Calix[4]pyrroles or meso-substituted porphyrinogens are an important class of neutral

macrocycles receptor capable of binding anions, transition metals14 and neutral

molecules15 in both solution and solid states.16 The synthesis of calix[4]pyrroles bears

analogy to that of porphyrin in that they obtained from the electrophilic α-substitution

of pyrrole with ketones in the presence of acid catalyst.

There are three general method for the synthesis of calix[4]pyrroles:

(a) one-pot [1+1+1+1+1] condensation;

(b) [2+2] condensation and

(c) [3+1] condensation.

HN

R1

R2

O

+

HN

R1

R2

OH

HN

OH

R1

R2

HN

OH2

R1

R2

HN

R1

R2

HN

+3

R1

R2

O

+3

NH

NHHN

NH

R1

R2

R1

R2

R1 R2

R1 R2

NH

NH HN

HN

R1 R

2

R1

R2

R1

R2

R2

R1

[H+]

3

1 2

Scheme 2.1: Mechanistic presentation of the synthesis of calix[4]pyrrole

60

Although calix[4]pyrroles have been synthesized 100 years ago by the acid catalyzed

condensation of ketones and pyrrole, after that a number of strategies have been

employed to synthesized and characterized various functionalized calix[4]pyrroles by

using a wide varieties of catalyst including HCl,17,18 Lewis acids,19,20 chlorzinc,21 p-

toluenesulfonic acid or zeolites22 to improve the yield of specific calix[4]pyrroles.

Among which an alternate synthetic protocol using acidic zeolites catalyst gave a facile

and efficient method for the synthesis of variety of calix[4]pyrroles.23 The graphite

oxide and reduced graphene oxide has been used as solid acid catalysts in organic and

aqueous solutions for the preparation of 5,5-dimethyldipyrromethane and

octamethylcalix[4]pyrrole at room temperature.24

NH

R2R1

O

NH HN

R1 R2

NH

NH HN

HN

R2

R1

R1 R2

R1

R2

R2 R1

HNNH

NH HN

R1

R2

R2

R1

R1 R2

R2R1

GO

+

AI-MCM-41

+

1 2

3 4

3

Scheme 2.2: Selective synthesis of calix[4]pyrrole and dipyrromethane using

different catalyst

Interestingly, meso-octamethylcalix[4]pyrrole (OMCP) or acetonpyrrole was first

reported by Baeyer, and its structure is shown in Figure 2.2 and N-confused

calix[4]pyrrole (Figure 2.3) both macrocycles are position isomers. While in the regular

calix[4]pyrrole the meso-carbons are always connected to C2 and C5 position of the

pyrrole moieties, the N-confused isomer comprises at least one pyrrole moiety

connected to the rest of the macrocycle via C2, C4-connection.

61

NH

NH

HN

HN

H3C

H3C

H3C CH3

CH3

CH3

H3C CH3

5

Figure 2.4: Structure of N-confused calix[4]pyrrole

In the early 1990s, first reports emerged describing the identification of porphyrin

isomers, in which one or more of the four pyrrole moieties are inverted.25,26 The

inverted pyrrole in these N-confused porphyrins is connected to the rest of the

macrocycle via one α-carbon (C2-position) and one β-carbon (C4-position) as opposed

to α,α’-carbons (C2, C5-positions) in regular porphyrins.

Similarly to the formation of N-confused porphyrins, the condensation of ketones and

pyrrole also produces a certain number of C2, C4-pyrrole connections giving rise to N-

confused calix[4]pyrroles. The first N-confused calixpyrrole synthesis was reported in

1975 although the structural assignment may not have been correct, as the NMR spectra

were not recorded at the time. 27 Inspired by the earlier report and by further reports on

N-confused porphyrins, Dehaen and co-workers mounted the first systematic effort

aimed at the preparation of N-confused calix[4]pyrroles which provided the first

rational synthesis of this calix[4]pyrrole isomer.28

2.5. Conformations of calix[4]pyrrole and their relative energies

Calix[4]pyrrole shows geometrical resemblance to calix[4]arene and that it would be

expected to adopt four major conformations like calix[4]arene. Energies optimization

by BLYP/6-31G, and BLYP/6-31+G** methods reveals that the predicted orders of

stabilities for the gas phase and CH2Cl2 solution are namely 1,3-alternate > partial cone

> 1,2-alternate> cone. Molecular mechanics calculations indicate that the 1,3-alternate

conformation is most stable conformation in case of calix[4]pyrrole having torsional

interaction of about 1-2 kcal/mol smaller than that of the other conformations. Each set

of adjacent pyrrole rings in calix[4]pyrrole has an inherent propensity to exist in an anti

rather than syn orientation. In the 1,3-alternate conformation each adjacent pyrrole pair

62

is anti as a result this particular conformation benefits the most from this electrostatic

effect. On the other hand, the pyrroles in the cone conformation are point to the same

direction and as a result this conformation suffers the most from electrostatic repulsion.

2.6. Analysis of anion-binding modes of calix[4]pyrrole

Experimental results indicate that meso-alkyl substituted calix[4]pyrrole form 1:1

complexes with fluoride and chloride anions. In these anion complexes the

calix[4]pyrrole macrocycles are observed to adopt the cone conformation with the anion

sitting above the cone and forming four hydrogen bonds with the four pyrrole N-Hs.29

On the other hand neutral molecules such as alcohols and amides form 2:1 complexes

with calix[4]pyrroles. Optimization of all the putative anion-binding structures for all

the four limiting conformations of calix[4]pyrrole showed that 1,3-alternate structure is

unstable and is converted into the cone structure upon geometry optimization.30

HN H

NHN N

H

N

NHNH

HN

HX

NNN N

HH H H

X

Organic Solvent

Figure 2.5: Conversion of 1,3-alternate conformation into cone in the presence of

anion

In the case of cone structure it has four equivalent NH---F bonds of about 1.68 Å. Due

to the short NH---F hydrogen bonds, the calix[4]pyrrole become flattened. This is

indicated by the decrease of N1-C2-C3-C4 dihedral angles from -76° in F-free cone

structure 6 to -64.8° in cone-F- complex. In contrast to the cone complex, the partial

cone complex forms three NH- - -F- hydrogen bonds.

NNN N

HN

H

N

HN

H

N

H

NNN

N

H

X1.385

X

H H H

1.4621.534

X

HH H

1.627

1,2-alternate (Cs)22.0 (20.4)

partial cone (Cs)10.6 (9.4)

cone (C4v)0.0 (0.0)

Figure 2.6: Calculated structure of calix[4]pyrrole-F and their relative energies at

BLYP/6-31-G**level

63

Table 2.1: Binding energy (kcal/mol) of 1:1 fluoride anion binding modes of

calix[4]pyrrole calculated at the blyp/6-31+g** level

Entry 1,2-alternate

∆Ebinding

Partial cone

∆Ebinding

Cone

∆Ebinding

Gas phase -44.6 -56.0 -66.6

Solution -7.0 -17.5 -27.6

There is a considerable change in geometry observed upon fluoride anion binding, the

flat pyrrole in partial cone tilts upward while the other three pyrroles become relatively

flattened. The cone complex is calculated to be most stable whereas the partial cone

complex is predicted to be the second most stable. In the gas phase partial cone anion

complex is higher in energy by 10.6 kcal/mol than that of cone complex. When the

solvent effect by dichloromethane is accounted for the destabilization of partial cone as

compared to cone is decreased to9.3 kcal/mol. The 1,2-alternate complex is predicted

to be less stable than the cone structure by 25.4 and 20.4 kcal/mol in the gas phase and

in CH2Cl2 solution respectively. The relative stabilities reflect the number of hydrogen

bonds in these complexes indicating that the in ionic hydrogen bonds in these

complexes are very strong.

2.7. β-Substituent effects on anion-binding abilities of calix[4]pyrrole

One simple way to strengthen the anion-binding is to increase the binding force i.e.

hydrogen bond strength between the host and anion. Modification of the hydrogen bond

acceptor (host part) is apparently a possible approach to tune the binding ability of

calix[4]pyrroles. In the anion-free pyrroles the bond length of N-H is about 1.01-1.02 Å

at the BLYP/6-31+G** level. When fluoro anion is involved, the N-H bond is

elongated to1.24-1.46 Å varying in different substituted structures. The stronger

electron-withdrawing group normally elongates the N-H bond more while the H-F bond

is significantly shortened. This implies that the basicity of F- is stronger than those of

the pyrrole anions in the gas phase.

64

N

R1

R2

H N

R1

R2

H

R1=R2= CH3O, CH3, H, F, Cl, Br, CN

7 8 3 9 10 11 12= X

6

Scheme 2.3: β-Substitution effect on calix[4]pyrrole--anion binding

It appears that both σ and π effects of the substituents affect the anion binding energy.

Methoxy group is a strong π donor and a weak σ acceptor. While the π-donating factor

decreases the binding energy, the σ-accepting factor increases the binding energy. As a

result, the methoxy group has little effect on the binding energy. Fluoro, chloro, and

bromo groups are stronger σ-acceptors and behave as electron-acceptors. Therefore they

all increase the binding energy to similar extents. Cyano group is a strong electron-

acceptor and it can significantly increase the binding energy.31

Table 2.2: Calculated anion-binding energies in kcal/mol of different β-

disubstituted calix[4]pyrrole with fluoride ion

β-substitutedCP-X- BLYP 6-31+G** BLYP6-31+G**(sol.)

R1=R2= OCH3 -40.4 -13.3

R1=R2= CH3 -38.9 -13.1

R1=R2= H -38.6 -13.4

R1=R2= F -48.4 -18.7

R1=R2= Cl -51.6 -19.0

R1=R2= Br -52.9 -19.2

R1=R2= CN -68.3 -27.5

2.8. Synthesis of conformational isomer of calix[4]pyrrole

Introduction of aryl or other rigid groups into the meso-like positions of calix[4]pyrroles

could serve not only to change the intrinsic anion selectivity of the calix[4]pyrrole

skeleton but also in appropriate cases to introduce secondary binding sites that might

65

allow for selective recognition of cationic, anionic or neutral guests. The aryl ketone,

pyrrole and acid were dissolved in methanol and stirred at room temperature in inert

atmosphere to give four conformational isomers namely αααα, αααβ, ααββ and αβαβ.32

In the specific case of the αααα isomer of a deep cavity structure was observed in the

solid state, wherein the calixpyrrole core is in a so-called cone conformation.5

Structures of lower symmetry are seen in the case of the other isomers with

conformations other than pure cone (e.g., 1,3-alternate, partial cone) being observed in

certain instances (e.g., the αααβ isomer). Proton NMR spectroscopy was used to

confirm the configurational assignments and to analyze conformational effects in

solution. As a general rule it was found that free rotation around the pyrrole-bridging

meso-like carbons and ipso-aryl bonds pertains at room temperature in acetonitrile-d3-

D2O (99.5:0.5; v/v) in the absence of an added anionic substrate. Thus the symmetries

of the various isomers were reflected directly in their 1H NMR spectra particularly in

the number of pyrrole CH resonances. The αααα isomers have one type of CH group

represented by an “a” in Scheme 2.4 , while the ααββ isomer has two types of pyrrolic

CH group (represented by “a” and “b”), and the αααβ isomer possesses four different

CH groups (“a”,“b”, “c” and “d”) and in all cases the requisite number of signals were

observed.

NH

NH HN

HN

NH

COCH3

H3C

CH3

CH3

H3C

+

NH

NH HN

HN

H3C

CH3

CH3

H3C

NH

NH HN

HN

H3C

CH3

CH3

H3C

NH

NH HN

HN

H3C

CH3

CH3

H3C

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

αααααααααααααααα

a

a aa

a

aaa

a

a

aa

bb

bb

a

a

a

aa

a

aa

ααααββββααααββββ

ααααααααββββββββ

ααααααααααααββββ

ab

a

b

c

d

cd

CH3SO3H

Dry methanol

1 13

14 15

16 17

Scheme 2.4: Synthesis of conformational isomer of calix[4]pyrrole

66

2.9. Results and discussion

The discovery of octamethyl calix[4]pyrrole as an anion receptor has prompted the

synthesis of a variety of calix[4]pyrrole derivatives,33 expanded calixpyrroles,34

strapped calixpyrroles35 and N-confused calixpyrroles36 to understand the binding of

different anions with specific calix[4]pyrrole. From chemical viewpoint calix[4]pyrroles

are being explored as catalyst in organic synthesis37 as well as precursor of important

organic molecules such as calixpyridines and calixpyridinopyrrole.38 Beside these, they

have been found applications as fluorescent,39 colorimetric,40 electrochemical signaling

device41 and new solid supports capable of separating anion mixtures.42 This

macrocycles are also used as anion transporter across lipid bilayer membrane.43

Moreover, in contrast to the well-studied templating properties of cationic44 and neutral

species45 anion templates have been very little exploited in synthetic chemistry. This

relative lack of anion-templated processes is partially attributed to some of the intrinsic

properties of anions such as their diffuse nature, pH sensitivity, and their relative high

solvation free energies.46 However, as the increasing number of anion-directed

assemblies reported in the last few years, these limitations are not as critical as initially

thought. They act as template in the coordination, supramolecular and inorganic hybrid

structures.47,48 The use of anions templates to prepare cyclic structures is not exclusive

confined to metal-containing assemblies,49 but it is also found in organic systems. For

example Alcalde et al., have reported the halide-directed synthesis of a series of

[14]imidazoliophanes,50 trihalogenated-templates in the synthesis of calix[6]pyrroles51

and solution phase anion directed self-assembly of meso-functionalized

calix[4]pyrroles.52 Owing to their tremendous applications in the area of supramolecular

chemistry they have gained significant importance. The synthesis of calix[4]pyrroles

and N-confused calix[4]pyrroles in higher yields have been discussed in the following

subsection:

2.9.1. Synthesis of calix[4]pyrroles and N-confused calix[4]pyrroles

The reaction of equimolar quantity of pyrrole (1) with acetone (2a) in the presence of

tetrabutylammonium fluoride in dichloromethane at 25˚C afforded a isomeric mixture

67

of octamethylcalix[4]pyrrole (OMCP) (3a) and N-confused octamethylcalix[4]pyrrole

(NC-OMCP) (4a) in 81% and 18% yield respectively. (Scheme 2.5)

NH

NH HN

HN

R1

R2

R1 R2

R1

R2

R1 R2

NH

+ R1 R2

O

1 2 3 5

Bu4N+X-

NH

NH

HN

HN

R1

R2

R1 R2

R1

R2

R1 R2

2a. R1=R2 = CH3 3a. R1=R2 = CH3 5a. R1=R2 = CH3

2b. R1=R2 = C2H5 3b. R1=R2 = C2H5

2c. R1= CH3, R2 = C2H5 3c. R1= CH3, R2 = C2H5 5c. R1= CH3, R2 = C2H5

2d. R1-R2 = (CH2)4 3d. R1-R2 = (CH2)4 5d. R1-R2 = (CH5)4

2e. R1-R2 = (CH2)5 3e. R1-R2 = (CH2)5 5e. R1-R2 = (CH2)5

2f. R1-R2 = (CH2)6 3f. R1-R2 = (CH2)6 5f. R1-R2 = (CH2)6

X- = F, Cl, I, AcO

Scheme 2.5: Anion-templated synthesis of calix[4]pyrroles and N-confused calix[4]

pyrroles

Using the catalytic amount of anion along with .01 equivalent of methanesulfonic acid

fasten the reaction as well as improved the yield of the products. To analyze the role of

anions in the reaction the cyclocondensation reaction of the pyrrole and acetone was

performed using different solvent and acid catalyst with and without the use of anion

and the results obtained were summarized in table 2.2. It was observed that when the

reaction of equimolar quantity of pyrrole (1) and acetone (2) was performed using

ethanol as a solvent and methanesulfonic acid catalyst the reaction was completed in

four hours at refluxing temperature giving 65% of OMCP (3a) and 15% of NC-OMCP

(5a) along with some polymeric product. Whereas using ytterbium triflate in ionic

liquid for the cyclocondensation of pyrrole and acetone gave octamethylcalix[4]pyrrole

as the only product in excellent yield.53 Cyclocondensation reaction of pyrrole with

acetone without using anions gave acceptable results taking Amberlyst™-15 as a

catalyst in 8 hours at ambient temperature. 54

68

Table 2.2: Synthesis of meso-octamethylcalix[4]pyrrole (3a) and N-confused

octamethylcalix[4]pyrrole (5a) using different catalyst and solvent

S.No. Solvent Catalyst Anions Reaction

time

(mins)

Conversion

of pyrrole

%

yield

of 3a

%

yield

of 5a

1 Ethanol Conc. HCl - 300 62a 56 -

2 Ethanol CH3SO3H - 120 90a 68 15

3 Ethanol BF3OEt2 - 200 85a 65 12

4 Ethanol CF3COOH - 140 87a 60 10

5 CH2Cl2 CH3SO3H - 140 85a 80 3

6 CH2Cl2 BF3OEt2 - 260 80a 63 4

7 CH2Cl2 CF3COOH - 150 94a 56 8

8 [bmim][BF4] Yb(OTf)3 - 90 95b 92 -

9 CH2Cl2 Amberlyst™-15 - 480 99 b 83 14

10 CH2Cl2 CH3SO3H F - 5 100 b 81 17

11 Toluene CH3SO3H F - 10 87 b 75 8

12 CHCl3 CH3SO3H F - 7 98 b 80 15

(a) at refluxing temperature; (b) at 25˚C

The structure of 3a and 5a were confirmed by IR, 1H-NMR, 13C-NMR and ESI-MS

spectroscopic data. In fact 1H NMR-spectroscopy is particularly useful for the

differentiation of the OMCP (3a) and NC-OMCP (5a). The 1NMR-spectrum of

compound 3a, showed a sharp singlet at δ 1.52 ppm were assigned for the twenty four

methyl group protons at meso position, a doublet at δ 5.90 ppm for the eight β-pyrrolic

protons and a broad resonance at δ 7.08 ppm for the four pyrrolic N-H protons (Figure

2.7). The integration ratio of the three peaks areas were 6:2:1, in agreement with the

empirical formula and D4 symmetry of the compound 3a.

Figure 2.7: 1H NMR spectrum of 5,5,10,10,15,15,20,20-octamethylcalix[4]pyrrole

69

On the contrary, in the 1NMR-spectrum of 5a, multiplet appeared at δ 1.53-1.56 ppm

for the 24 methyl protons. Signals for the α-pyrrole hydrogen (1H) and β-pyrrole

hydrogen (1H) of the 2,4-disubstituted pyrrole appear at δ 6.51(doublet) and 5.09,

respectively, which was well apart from those of the β-hydrogens atoms (6H) of the 2,5-

disubstituted pyrrole (δ. 5.82-5.97). The coupling constant between the band α-

hydrogen atoms of the confused pyrrole in 5a has a typical value of 2.0 Hz. Four

distinct broad resonances at δ 7.00 (1H), 7.15 (1H), 7.54 (1H) and 7.78 (1H) ppm is due

to four pyrrolic N-H protons indicates the reduction of symmetry in case of N-

confused-octamethylcalix[4]pyrrole (5a) as compared to octamethylcalix[4]pyrrole.

The higher polarity and non-zero dipole moment of the compound 4a have been

attributed to their lower symmetry. The highly unsymmetrical nature of the compound

5a is also seen in its carbon spectrum which gives total of twenty four peaks. The four

peaks at δ 28.94, 29.34, 29.67 and 30.30 ppm is due to CH3 carbons, at δ 31.40, 31.90,

34.59 and 35.32 ppm for four meso carbons, at δ 101.55, 101.77, 102.13, 102.75,

103.33, 103.89 and 104.21 ppm for β-pyrrolic carbon, at δ 111.61 ppm for the α-carbon

of inverted pyrrole ring and at δ 133.19, 137.59, 137.82, 138.28, 138.45, 138.77,

138.89, 139.48 and 141.13 ppm for α-pyrrolic carbon atoms.

Figure 2.8: 1H NMR spectrum of N-confused 5,5,10,10,15,15,20,20-octamethyl

calix[4]pyrrole in CDCl3

70

Figure 2.9: 13

C NMR spectrum of N-confused 5,5,10,10,20,20-octamethyl calix[4]

pyrrole in CDCl3

The reaction of equimolar quantity of pyrroles (1) with acetone (2a) in the presence of

tetrabutylammonium fluoride in dichloromethane was also monitored by the high

pressure liquid chromatography (HPLC). The reaction was monitored at different

intervals and the chromatograms obtained were identified by comparison with authentic

samples prepared. After the completion of the reaction two peaks were obtained having

retention time of 3.45 and 3.96 respectively (Figure2.10), which was assigned for the N-

confused octamethyl calix[4]pyrrole and octamethyl calix[4]pyrrole respectively by

comparing with authentic samples. Whereas the examination of reaction mixture after

two minutes of the shows three peaks having the retention time of 3.02, 3.39 and 3.97

were assigned for dipyrromethane, calixpyrrole and N-confused calixpyrrole

respectively. The peak at 3.02 was appeared due to the dipyrromethane formation in the

reaction, which was confirmed by comparison with authentic samples.

71

Figure 2.10: High pressure liquid chromatogram of (A) dipyrromethane, (B)

5,5,10,10,15,15,20,20-octamethyl calix[4]pyrrole

Figure 2.11: High pressure liquid chromatogram of reaction mixture

Figure 2.12: High pressure liquid chromatogram of N-confused 5,5,10,10,15,

15,20,20-octamethyl calix[4]pyrrole

72

Owing to our curiosity and high yields of compound 3a and 5a in the presence of

anions prompted us to examine the role of anions in the cyclization of other ketones 2b-

2h with pyrrole (Table 2.5). The reaction of cyclohexanone with pyrrole in the

presence of tetrabutylammonium fluoride in dichloromethane gave solid precipitate

within minutes indicates formation of two products on TLC with Rf values 0.85 and

0.42 respectively. Crystal of the compound was grown by the slow evaporation of the

CHCl3 solution of the crude mixture without any further purification. Examination of

the crystalline product shows the association of the fluoride ion with the NH proton of

the calix[4]pyrrole (3e). The crystal structure of the complex between calix[4]pyrrole

and tetrabutylammonium fluoride reveals the role of tetrabutylammonium fluoride as

the template. The fluoride atom of the guest is anchored to the cavity of the

calix[4]pyrrole through the hydrogen bonds between the fluoride atom of the guest and

hydrogen atom of the NH of four pyrrole rings. The crystal of N-confused-cyclohexyl

calix[4]pyrrole with anion cloud not be obtained from the mixture this could be

attributed to the lower percentage of N-confused-cyclohexyl calix[4]pyrrole in the

reaction mixture as compared to the percentage of cyclohexyl calix[4]pyrrole. In 1H

NMR spectrum of 5,5,10,10,15,15,20,20-tetraspiro-cyclohexylcalix [4]pyrrole (3e) two

multiplets at 1.46 and 1.89 ppm were assigned for the cyclohexyl methylene group

protons, and a doublet at 5.88 ppm with coupling constant J = 2.7 Hz was assigned for

the eight β-pyrrolic protons and a broad singlet at 7.04 ppm was assigned for four

pyrrolic NH protons. 13C NMR spectrum confirmed the symmetry of the molecule in

13C NMR spectrum of compound 3e showed three peaks at 22.69, 25.96, and 37.13

ppm for cyclohexyl carbon, peak at 39.55 ppm for the meso-carbon, and two peaks

appeared at 103.41 and 136.39 ppm for β-pyrrolic carbon and α-pyrrolic carbon

respectively, confirmed the formation of compound 3e. A band appeared at 3445 cm-1

in IR spectrum of compound 3e which indicates the presence of NH group in the

molecule.

In a given templated reaction the size and shape of the directing anions are the main

factors that determine the reaction. It was seen that when the reaction was performed in

the presence of anions other than fluoride the yield of the reaction decreases as

73

compared to that in the presence of fluoride ion as well as reaction time also increases

table 2.3. This could be attributed to the stronger binding affinity of fluoride ion

towards the compound 3a and 5a. Apart from its strong affinity towards calix[4]pyrrole

and N-confused calix[4]pyrrole, fluoride ion also favors the reaction as a template due

to its smaller size.

Figure 2.13: ESI-MS spectrum of crude reaction mixture of 1 and 2 after completion

of reaction

Table 2.3: Anion catalyzed condensation of pyrroles and acetone in dichloromethane

Entry Anions % Yield of 3a % Yield of 5a Reaction time

(mins)

1 F- 81 17 5

2 Cl- 80 15 7

3 I- 71 10 20

4 AcO- 70 9 30

Further the reaction of pyrrole and acetone was also examined in different solvent. A

subsequent solvent screening revealed that low-polarity solvents led to higher yield,

with CH2Cl2 providing the best results (Table 2.4). Reaction carried out in toluene and

benzene gave comparatively low yield with prolonged reaction time.

74

Table 2.4: Anion templated synthesis of octamethylcalix[4]pyrrole and N-confused

octamethylcalix[4]pyrrole in the presence of fluoride ion in different

solvents

Entry Solvents % Yield of 3a % Yield of 5a Anions

1 MeOH (EtOH) 65 10 -

2 CHCl3 80 15 F-

3 CH2Cl2 81 17 F-

4 CH3CN 78 14 F-

The reactions of different ketones with pyrrole were performed in the presence of

fluoride ion and the results were summarized in table 2.5. The reaction of

cycloheptanone with pyrrole in the presence of fluoride ion gave the corresponding

calix[4]pyrrole and N-confused calix[4]pyrrole in thirty minutes at room temperature

and the isolated yields were 70% and 10% respectively, but the time required for the

conversion was relatively long. This could be attributed to the bulkiness of

corresponding ketone. The 1NMR-spectrum of compound 5f shows two multiplets

appeared at δ 1.46-1.63 ppm and2.00-2.08 ppm for the methylene protons. Signals for

the α-pyrrole hydrogen (1H) and β-pyrrole hydrogen (1H) of the 2,4-disubstituted

pyrrole appear at δ 6.41(doublet, J=2 Hz) and 5.74, respectively. Whereas multiplet

appears for β-hydrogens atoms (6H) of the 2,5-disubstituted pyrroles at δ. 5.82-5.97).

Four distinct broad resonances at δ 6.82 (1H), 6.97 (1H), 7.43 (1H) and 7.65 (1H) ppm

is due to four pyrrolic N-H protons.

Table 2.5: Anion templated synthesis of different calix[4]pyrroles and N-confused

calix[4]pyrroles in the presence of fluoride ion

Entry 3, 5 % Yields Time (min)

1 3a, 5a 81, 17 5

2 3b 61 30

3 3c, 5c 78, 13 15

4 3d, 5d 86, 12 20

5 3e, 5e 79, 20 3

6 3f, 5f 70, 10 30

75

Figure 2.14: 1H NMR spectrum of 5,5,10,10,15,15,20,20-tetraspiro-N-confused

cycloheptylcalix [4]pyrrole

2.9.2. Synthesis of meso-unsubstituted porphyrinogens and N-confused

porphyrinogens in the presence of anions

One equivalent of sodium borohydride was added portion wise to the solution of

pyrrole-2-carboxaldehyde in 20 ml of THF under nitrogen atmosphere. The mixture

was stirred for 2-3 hours under nitrogen atmosphere. After completion of the reaction,

reaction mixture was treated with water for complete dissolution of the suspension of

NaBH4 and the mixture was extracted with dichloromethane. The combined organic

phase was further washed with water and dried over anhydrous sodium sulfate.

Triethylamine (2-3 drops) was added and solvent was evaporated under reduced

pressure to give yellow oil. Further 1-2 drop of triethylamine was added and the pure

compound was distilled off under reduced pressure as colorless liquid. The pure

compound was stored in the refrigerator to avoid polymerization. The structure of

compound was confirmed by IR and 1H-NMR spectroscopic data.

76

NH

CHONH

OH

NaBH4/THF

N

N N

N

Bu4N+X-

CDCl3, [H+]F

H H

HH

N

N

HN

N

FH H

HH

18 19 20 21

Scheme 2.6: Synthesis of porphyrinogen and N-confused porphyrinogen

Figure 2.15: 1H NMR spectrum of 2-Hydroxymethylpyrrole

Further acidic cyclocondensation reaction of the 2-hydroxymethylpyrrole (19a) was

performed in the presence of tetrabutylammonium fluoride (TBAF) in deuterated

chloroform under nitrogen atmosphere and completion of the reaction was

monitored by TLC. After the completion of reaction the mixture was examined by

1H NMR spectroscopy. In 1H NMR spectrum of the reaction mixture showed four

broad resonances at δ 8.60, 8.76, 8.96 and 9.22 which can be assigned for the N-

confused porphyrinogen and porphyrinogen respectively. Downfield shift in the

peak of NH proton can be attributed to the fluoride ion binding to the NH-proton of

the porphyrinogen. Appearance of the three broad peaks in the reaction mixture can

be assigned as the presence of N-confused porphyrinogen in the mixture. The peak

appeared at 4.45 ppm was assigned for the meso-methylene protons of

porphyrinogen.

77

Figure 2.16: 1H NMR spectrum of the mixture of porphyrinogen and N-confused

porphyrinogen

Figure 2.17: 1H NMR spectrum of the mixture of porphyrinogen and N-confused

porphyrinogen (expanded aryl region)

2.10. Conclusion

Acid catalyzed condensation of different aliphatic ketones and pyrrole using

tetrabutylammonium anions (F-, Cl-, I-, AcO-) as a template in dichloromethane at room

temperature gave octamethylcalix[4]pyrroles and N-confused octamethylcalix[4]pyrroles

in different reaction conditions. Anions templated synthesis of calixpyrroles and N-

confused calixpyrroles were less time consuming with high yields of desired products.

The reaction of pyrrole with different ketones were performed in presence of methane

78

sulfonic acid in dichloromethane using different anions as template and best results were

obtained when F anion was used as a template due to the smaller size and greater affinity

to bind with calixpyrrole and N-confused calixpyrrole. The reaction of bulky alkyl and

cycloalkyl ketones with pyrrole gave the calix[4]pyrroles in good yields whereas N-

confused calix]4[pyrroles in low yields but in case of cyclohexanone the yield of

calixpyrrole and N-confused calixpyrrole is equal to like acetone this is due to the greater

reactivity of cyclohexanone than other cyclic ketones.

The meso-unsubstituted porphyrinogen or calixpyrrole and N-confused calixpyrroles

are highly unstable and readily oxidized to corresponding stable porphyrins due to this

effect

The meso-unsubstituted porphyrinogen or calixpyrrole and N-confused calixpyrrole

were also formed in situ by the acid catalyzed tetramerization of 2-hydroxymethyl

pyrrole which was synthesized by the reaction of pyrrole-2-carboxyldehyde with

sodium borohydride, in presence of F anion in deuterated chloroform at room

temperature and formation of the products were confirmed by 1H NMR spectroscopy.

2.11. Experimental

All melting points are uncorrected and expressed in degree centigrade and were

recorded on Thomas Hoover Unimelt capillary melting point apparatus. The infrared

spectra were recorded on Perkin-Elmer FT-2000 spectrometer and νmax are expressed in

cm-l. 1H NMR was recorded on Jeol-delta-400 spectrometer using tetramethylsilane

(TMS) as an internal standard and chemical shifts (δ) are expressed in ppm. ESI-MS

were recorded by LC-TOF (KC-455) mass spectrometer of Waters. The starting

materials such as pyrrole, acetone, diethyl ketone, ethylmethyl ketone, cyclopentanone,

cyclohexanone and methane sulphonic acid were purchased from Spectrochem

Chemicals India. The quaternary ammonium salts; normal tetrabutylammonium halides

(n-Bu4NF, n-Bu4NCl, n-Bu4NBr, n-Bu4NI), and normal tetrabutylammonium acetate

(n-Bu4NAcO) were purchased from Aldrich. The pyrrole was distilled prior to use and

the solvents used were of analytical reagent grade. The compounds synthesized were

separated by column chromatography using neutral alumina and characterized by

melting points, 1H NMR, 13C NMR, IR and ESI-MS techniques.

79

2.11.1. 5,5,10,10,15,15,20,20-Octamethyl calix[4]pyrrole (3a)

Equimolar amount of pyrrole (1 ml, 14 mmol) and acetone (1.04 ml, 14 mmol) were

taken up in dry dichloromethane (10 mL). Tetrabutylammonium fluoride (0.95 mg,

0.003mmol) was added to the reaction mixture, which was stirred at 25˚C for a minute

and then methanesulfonic acid (0.1 mmol) was added. The progress of reaction was

monitored by thin layer chromatography (TLC). After the completion of reaction, the

reaction mixture was extracted by dichloromethane and washed several time with water.

Organic phase was separated and dried over sodium sulfate. The filtrate was

concentrated at vacuum to gave the crude product, which was subjected to column

chromatography over neutral alumina eluting with petroleum ether-chloroform (9:1,

v/v) to afford pure meso octamethylcalix[4]pyrrole (3a).

5,10,15,20-Octamethyl-calix[4]pyrrole (3a)

Physical state: White solid

Yield: 2.05 g (81%)

mp: 295 ºC (Lit. mp. 296 ºC)

Rf = 0.8 (SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1

): 3444(br, pyrrole NH), 2973, 2932, 2870, 1578, 1448, 1414,

1279, 1233, 1044, 759

1H NMR (400 MHz, CDCl3): δ = 1.52 (s, 24H, CH3), 5.90 (d, J = 2.92 Hz, 8H, β-

pyrrole CH), 7.08 (brs, 4H, Pyrrole NH)

13C NMR (100 MHz, CDCl3) δ = 29.08 (CH3), 35.15 (meso C), 102.67 (β-pyrrole

CH), 138.55 (α-pyrrole C)

HRMS (ESI-MS) for C28H36N4 [M+H]+ : calcd, 429.2862; found, 429.2860.

2.11.2. 5,5,10,10,15,15,20,20-Octamethyl-N-confused calix[4]pyrrole (5a)

Further elution of the column with petroleum ether-chloroform (3:2, v/v) gave the N-

confused isomer of octamethylcalix[4]pyrrole (5a).

Physical state: white solid

Yield: 250 mg (17%)

80

mp 184 ºC

Rf = 0.45 (SiO2, 1:1 petroleum ether/chloroform);

IR (KBr pellet, cm-1): 3430, 2910, 2845, 1521, 1616, 1179, 749.

1H NMR (400 MHz, CDCl3) δ = 1.48-1.54 (m, 24H, CH3), 5.07 (brs, 1H, β-pyrrole

CH), 5.87 (m, 2H, β-pyrrole CH), 5.89 (brs, 2H, β-pyrrole CH), 5.90 (brs, 2H, β-pyrrole

CH), 6.51 (s, 1H, α-pyrrole CH), 6.97 (brs, 1H, pyrrole NH), 7.13 (brs, 1H, pyrroles,

NH), 7.48 (brs, 1H, pyrrole NH),7.76 (brs, 1H, pyrrole NH);

13C NMR (100 MHz, CDCl3) δ = 29.0, 29.4, 29.6, 30.3 (4x CH3), 34.6, 35.3, 35.8,

35.9 (4x meso C), 101.6, 101.8, 102.1, 102.8, 103.3, 103.9, 104.2 (7x β-pyrrole CH),

111.6 (α-pyrrole CH), 133.2 (β-pyrrole C), 137.5, 137.8, 138.2, 138.7, 138.8, 139.4,

141.1 (7x α-pyrrole C)

ESI-MS for C28H36N4 [M+H]: calcd, 429.2862; found, 429.2860.

2.11.3. Synthesis of 5,5,10,10,15,15,20,20-octaethyl calix[4]pyrrole (3b)

Similar procedure was used for the synthesis of the compound as used above for the 3a

Physical state: white solid

Yield: 1.97 g (61%)

Mp: 224 °C

Rf = 0.76 SiO2, 1:1 petroleum ether/chloroform)

1H NMR (400 MHz, CDCl3) δ = 0.64-0.68 (t, 24 H, CH3-), 1.79-1.57 (q, 16H, -CH2-),

5.89 (d, J =2.80 Hz, 8H, β-pyrrole CH), 7.09 (brs, 4H, NH)

13C NMR (100 MHz, CDCl3) δ = 8.04 (CH3), 29.18 (-CH2-), 42.63 (meso-C), 104.98

(β-pyrrolic C), 135.78 (α-pyrrolic C)

ESI-MS for C36H52N4 [M+H]-: calcd, 539.4113; found, 539.4120.

2.11.4. Synthesis of 5,10,15,20-tetraethyl-5,10,15,20-tetramethyl-calix[4]pyrrole (3c)

Similar procedure was used for the synthesis of the compound as used above for the 3a

Physical state: white solid

Yield: 1.86 g (78%)

81

mp 144 ºC

Rf = 0.76 SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1): 3435 (br, pyrrole NH), 2968, 2931, 2876, 1413, 1297, 1211,

1040, 761, 706

1H NMR (400 MHz, CDCl3) δ = 0.68-0.71 (t, 12H, CH3-), 1.36-1.40 (q, 8H, -CH2-),

1.85 (brs, 12H, CH3), 5.88 (d, J = 1.44 Hz, 8H, β-pyrrole), 7.08 (brs, 4H, NH)

13

C NMR (100 MHz, CDCl3, TMS): δ = 8.6 (-CH3), 29.9 (CH3-), 33.1(-CH2),

39.1(meso-C), 103.7(β-pyrrole CH), 137.2(α-pyrrole C)

ESI-MS for C32H44N4 [M+H]: calcd, 484.1162; found, 483.2840.

2.11.5. 5,10,15,20-tetraethyl-5,10,15,20-tetramethyl N-confused-calix[4]pyrrole (5c)

Physical state: yellow solid

Yield: 180 mg (13%)

mp 120 ºC

Rf = 0.4 SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1): 3435 (br, pyrrole NH), 2968, 2931, 2876, 1413, 1297, 1211,

1040, 761, 706

1H NMR (400 MHz, CDCl3) δ= 1.83-1.12 (m, 29H, - CH2CH3), 1.92 (3H, s, CH3),

5.53 (1H, br), 5.78 (m, 2H), 5.88 (brs, 2H,), 6.03 (br, 2H, β-pyrrole), 6.40 (d, J = 2 Hz,

1H, α-pyrrole CH), NH: 7.35 (br, 2H), 7.53 (br, 1H), 7.63 (br, 1H)

ESI-MS for C32H44N4 [M+H]: calcd, 484.1162; found, 483.3482.

2.11.6. 5,5,10,10,15,15,20,20-Tetrakis spirocyclopentyl calix[4]pyrrole (3d)

Physical state:

Yield: 2.26 g (76%)

mp 235 ºC;

Rf = 0.63( SiO2, 1:1 petroleum ether/chloroform);

IR (KBr pellet, cm-1

): 3496 (brs, pyrrole NH), 2959, 2870, 1630, 1580, 1414, 1254,

1042, 765;

82

1H NMR (400 MHz, CDCl3) δ= 1.71-1.69 (m, 16H, CH2), 2.03-2.00 (m, 16H, CH2),

5.86 (d, J = 2.8 Hz, 8H, β-pyrrole), 7.10 (brs, 4H, NH);

13C NMR (100 MHz, CDCl3, TMS): δ = 23.76, 38.89 (cyclopentyl C), 46.79 (meso

C), 102.89 (pyrrole β-CH), 137.14 (pyrroles α-CH);

ESI-MS for C32H44N4 [M+H]: calcd: 531.3488; found: 531.3486.

2.11.7. 5,5,10,10,15,15,20,20-Tetrakis spirocyclopentyl N-confused calix[4]pyrrole (5d)

Physical state: white solid

Yield: 350 mg (12%)

mp 199 ºC

Rf = 0.42 SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1

): 3496 (br, pyrrole NH), 2959, 2870, 1630, 1580, 1414, 1254,

1042, 765

1H NMR (400 MHz, CDCl3) δ= 1.50-1.20 (m, 16H, CH2). 2.25-1.98 (m, 16H, CH2),

5.58 (br, 1H, β-pyrrole -CH), 5.88 (m, 2H, β-pyrrole -CH), 5.90 (br, 2H, β-pyrrole -

CH), 6.00 (br, 2H, β-pyrrole -CH), 6.42 (d, J =1.97 Hz, 1H, α-pyrrole), 7.00 (brs, 2H,

NH), 7.29 (brs, 1H, NH), 7.48 (brs, 1H, NH).

2.11.8. 5,5,10,10,15,15,20,20-Tetrakis spirocyclohexyl calix[4]pyrrole (3e)

Physical state: white solid

Yield: 2.79 g (80%)

mp 273 °C (lit28-271-272 ºC)

Rf = 0.85 SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1

): 3445 (br, pyrrole NH), 2924, 2849, 1577, 1413, 1184, 752

1H NMR (400 MHz, CDCl3) δ= 1.40-1.47 (m, 24H, CH2), 1.89-1.92 (m, 16H, CH2),

5.88 (d, J = 2.7 Hz, 8H, β-pyrrole), 7.04 (brs, 4H, NH)

13C NMR (100 MHz, CDCl3, TMS): δ = 22.69, 25.96, 37.13, 39.55 (hexyl C), 103.41

(pyrrole β-CH), 136.39 (pyrroles α-CH)

(ESI-MS) for C40H52N4 [M+H]- : calcd, 587.4114; found, 587.3860.

83

2.11.9. 5,5,10,10,15,15,20,20-Tetrakis spirocyclohexyl N-confused calix[4]pyrrole (5e)

Physical state: white solid

Yield: 600 mg (20%)

mp 223 ºC (lit28-223.2-223.6 ºC)

Rf = 0.42 SiO2, 1:1 petroleum ether/chloroform)

IR (KBr pellet, cm-1

): 3468 (br, pyrrole NH), 1423, 1280

1H NMR (400 MHz, CDCl3) δ=1.20-1.60 (m, 24H, cyclohexyl, CH), 1.70-2.10 (m,

16H, cyclohexyl, CH), 5.50 (br, 1H; pyrrole β-H), 5.82 (m, 2H; pyrrole β-H), 5.97 (br,

2H; pyrrole β-H), 6.03 (br, 2H; pyrrole β-H), 6.42 (d, J =1.97 Hz, 1H; pyrrole α-H),

7.10 (br, 2H; pyrrole NH), 7.44 (brs, 1H; pyrrole NH), 7.63 (brs, 1H, pyrrole NH)

13

C NMR (100 MHz, CDCl3, TMS): δ = 22.77, 25.91, 25.99, 26.36, 36.51, 37.0, 37.4,

37.67, 38.36, 39.31, 39.70, 39.72, (hexyl C), 101.3, 102.2, 103.9 (pyrrole β-CH), 112.8

(pyrrole α-CH), 130.1 (pyrrole β-C), 133.7, 134.6, 136.5, 137.8, 139.1, 140.3 (pyrrole

α-C)

(ESI-MS) for C40H52N4 [M+H]- : calcd, 587.4114; found, 587.3860.

2.11.10. Synthesis of 5,10,15,20-tetrakis spirocycloheptyl calix[4]pyrrole

Physical state: white solid

Yield: 2.5 g (76%)

Mp: 163 ˚C

Rf: .67 (SiO2, 1:1 petroleum ether/chloroform))

1H NMR (400 MHz, CDCl3, TMS): δ 1.52-167 (m, 32H, cyclo-heptyl, CH); 1.92-2.02

(m, 16H, cyclo-heptyl, CH), 5.84 (d, 8H, β-pyrrolic), 6.87 (brs, 4H, NH);

13C NMR (100 MHz, CDCl3, TMS): δ 23.12, 29.77, 39.33 (cycloheptyl); 42.69 (meso

C); 102.88 (β-pyrrolic CH); 138.35 (α-pyrrolic CH)

(ESI-MS) for C44H60N4 [M+H]- = calcd, 644.4818; found, 645.4824.

84

2.11.11. Synthesis of 5,10,15,20-tetrakis spirocycloheptyl N-confused calix[4]pyrrole

Physical state: white solid

Yield: 382 mg 10%

Rf: 0.49 (SiO2, 1:1 petroleum ether/chloroform))

1H NMR (400 MHz, CDCl3, TMS): δ 1.46-1.67 (m, 32H, cyclo-heptyl, CH); 2.00-

2.07 (m, 24H, cyclo-heptyl, CH); 5.18 (brs, 1H; pyrrole β-H), 5.74-5.95 (m, 6H; pyrrole

β-H), 6.41 (d, J =1.97 Hz, 1H; pyrrole α-H), 6.82 (br, 1H; pyrrole NH), 6.96 (brs, 1H;

pyrrole NH), 7.52 (brs, 1H, pyrrole NH); 7.65 (brs, 1H, pyrrole NH)

13C NMR (100 MHz, CDCl3, TMS): δ = 23.04, 23.30, 29.68, 29.87, 30.01, 38.64, 40.78,

42.19, 42.46, (heptyl C), 100.11, 101.69, 102.27, 104.48 (pyrrole β-CH), 114.63 (pyrrole

α-CH), 137.09 (pyrrole β-C), 138.43, 139.29, 139.60, 141.06, 143.05 (pyrrole α-C)

(ESI-MS) for C44H60N4 [M+H]- = calcd, 644.4819; found, 645.4820.

2.11.12. Synthesis of 2-hydroxymethylpyrrole

A three-necked flask equipped with magnetic stirrer pyrrole-2-carbaldehyde (500mg,

5.25mmol) was dissolved in THF (15mL) under nitrogen atmosphere. Sodium

borohydride (208mg, 5.5 mmol) was added to the solution in 2-3 fractions resulting in

warming of the reaction flask and gas evolution. The mixture was stirred for 4h until the

reaction was complete. Completion of the reaction was monitored by TLC (n-

hexane/ethyl acetate 1:1) and after completion of the reaction the mixture was treated

with water (25 mL). After the NaBH4 in suspension was completely dissolved, the

mixture was extracted with dichloromethane (4×50 mL). The combined organic extracts

were washed with water and dried over Na2SO4. Triethylamine (2 drops) was added and

the solution was concentrated with a rotary evaporator to yield light-yellow oil. The

yellow oil was further purified by vacuum distillation (90 ˚C) to give a final product as

a colorless liquid and requires storage in the refrigerator to avoid polymerization.

Yield: 80 (400µl).

Rf = 0.32 (SiO2, 1:1 n-Hexane: ethylacetate);

1H NMR (400 MHz, CDCl3) δ= 7.98 (brs, 1H, NH), 7.68 (m, 2H, α-pyrrole), 7.25 (m,

2H, β-pyrrole), 6.95 (d, 2H, β-pyrrole), 4.93 (s, 2H, -CH2OH), 2.43 (s, 1H, OH).

85

2.11.13. Synthesis of meso-unsubstituted porphyrinogen and N-confused

porphyrinogen

Tetrabutylammonium fluoride (.03mmol) was dissolved in the solution of 2-

hydroxymethylpyrrole (195 mg, 2mmol) in deuterated chloroform 2ml. Reaction

mixture was stirred for 2 minutes under nitrogen atmosphere and then methanesulfonic

acid (10µl, 0.1mmol) was added to the mixture. Reaction was stirred at room

temperature for further 2 minutes and completion of reaction was monitored by TLC

(1:1, n-hexane:chloroform). After completion of the reaction the mixture was directly

given for the 1H NMR analysis.

1H NMR (400 MHz, CDCl3) δ= 9.22 (brs, 4H, NH), 8.96 (brs, 1H, NH), 8.77 (brs, 1H,

NH), 8.60 (brs, 1H, NH), 6.64 (d, 2H, J= 1.64 Hz, β-pyrrole), 6.03 (m, β-pyrrole), 5.22

(s, 1H, α-pyrrolic) 4.45 (s, meso-CH2).

86

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