CHAPTER -1

SYNTHESIS OF SYMMETRICAL & UNSYMMETRICAL

MESO-SUBSTITUTED PORPHYRINS &

METALLOPORPHYRINS

1.1 INTRODUCTION

1.1.1 Perphyrin

The porphyrins are a class of naturally occurring macrocyclic compounds, which play a

very important role in the metabolism of living organisms. The porphyrin molecule contains

four pyrrole rings linked via methine bridges. The porphyrin nucleus is a tetradentate ligand

in which the space available for a coordinated metal has a maximum diameter of

approximately 3.7 Å. When coordination occurs, two protons are removed from the pyrrole

nitrogen atoms, leaving two negative charges. The porphyrin ring system is very stable and

exhibits aromatic character. The porphyrin complexes with transition metal ions are very

stable, e.g. the stability constant for ZnTPP (tetraphenylporphyrin) is 1029.

Porphyrin metal complexes play an important role in biological activities as for

instance iron complex in the haemoproteins, magnesium complexes in the chlorophylls, and a

cobalt complex in Vitamin B12. Complexes of many metals with various porphyrins have

been extensively studied in order to understand the biosynthetic formation and biological

activity of natural compounds. Porphyrin derivatives play a key role in essential biological

processes such as photosynthesis, dioxygen transport and storage. From the perspective of

coordination chemistry, the porphyrin ligand has turned out to be very versatile, and almost

all metals have been combined with porphyrins. Such complexes have been used in a variety

of applications as models for biological electron transport, oxygen transport and metallo-

enzymes.

1.1.2 Metalloporphyrins

Almost all metals form complexes 1:1, although Na, K, Li complexes are 2:1 in

which the metal atoms are incorporated slightly below and above the porphyrin macrocycle

plane. When divalent metal ions (e.g. Co(II), Ni(II), Cu(II)) are chelated, the resulting

tetracoordinate chelate has no residual charge. While Cu(II) and Ni(II) in their porphyrin

complexes have generally low affinity for additional ligands, the chelates with Mg(II), Cd(II)

and Zn(II) readily combine with one more ligand to form pentacoordinated complexes with

square-pyramidal structure. Some metalloporphyrins (Fe(II), Co(II), Mn(II)) are able to form

distorted octahedral with two extra ligand molecules.

Owing to its well known photochemical and redox activity, the porphyrin

macrocycle is an attractive building block on which to append additional recognition sites for

anion binding. The combination with Lewis acid, such as zinc, complexed in the porphyrin

macrocycle cavity, may produce new selective redox active reagents for anions. Indeed

various metalloporphyrins have shown a potentiometric response to anions with selectivity

sequences solely dependent on the centrally bonded metal. The metalloporphyrins have rich

redox chemistry since they have the advantage of including coordination of additional ligands

above and below the porphyrin plane.

Due to strong complexing properties and catalytic behaviour of metalloporphyrins,

these compounds have found numerous applications in chemical analysis. This review

presents applications of porphyrin compounds in spectroscopy, electroanalytical chemistry,

flow injection analysis, and chromatography.

1.1.3 Porphyrin in biological activities

Porphyrins the bioinorganic component of an important class of cyclic tetra pyrrole

pigments are essential constituents of a number of important biological systems. The

Porphyrin-type nucleuses along with metal ions are found in cytochromes, peroxides and

catalases. Other biologically important porphyrins that occur in nature and in the human body

are hemin, an iron porphyrin- the prosthetic group of hemoglobin and myoglobin;

chlorophyll- magnesium porphyrin- like compound involved in plant

photosynthesis; and Vitamin B12 - cobalt porphyrin-like compound commonly known as

cobalamine. As a result of their vital role in life processes, metallo-porphyrins have always

warranted chemist’s attention.

Porphyrins are a component of hemoglobin, which in turn is a component of red blood cells.

Hemoglobin is what carries oxygen in the blood. When porphyrins are not used as a

component of hemoglobin, they can absorb energy from photons (particles of light) and

transfer this energy to surrounding oxygen molecules. Toxic oxygen species such as singlet

oxygen and free radicals are thus formed. Singlet oxygen, the predominant cytotoxic agent

produced during PDT is a highly reactive form of oxygen that is produced by inverting the

spin of one of the outermost electrons. These chemicals are very reactive and can damage

proteins, lipids, nucleic acids and other cellular components.

These porphyrins belong to a class of compounds that form vital constituents of several

important and diverse biological functions. All forms of life depend on the ability of

porphyrins to undergo oxidation-reduction and electron transfer reactions. This process in

chlorophyll’s and iron-porphyrin heme containing cytochromes converts light to chemical

energy . In addition to their biological implications, the cyclic tetra dentate framework of the

four central nitrogen atoms makes porphyrins unique chelating agents, almost every metal on

the periodic table is capable of forming a metalloporphyrin complex . More than eighty

different natural and synthetic metalloporphyrins are known. The fact that porphyrins can be

used in combination with almost any metal produces a Vast ranges of electronic, spectral are

structural properties, and this has caught the interest of many inorganic, organic, physical and

biochemists.

Structure of haemoglobin structure of vitamin B12

1.1.4 Laboratory Synthesis of Porphyrins

Cyclocondensation of pyrrole with benzaldehyde is one of the important methods for the

synthesis of 5,10,15,20-tetraarylporphyrins. Similarly the condensation of pyrrole with a

mixture of two aldehydes gives the mixture of six isomeric porphyrins which can be

separated by repeated column chromatography. Based on the basic principles of synthesis of

porphyrins, the synthesis, isolation and characterization by spectroscopic methods have been

discussed in this section.

It is well known that porphyrin is also a high sensitive chromogenic reagent. Porphyrins and

their metal chelates generally exhibit characteristic sharp and intensive absorption bands in

the visible region. The region from 400 to 500 nm, which is called the Soret band, shows the

most intensive absorption and molar absorptivities of the order of 105 are often found. The

Soret band is widely used for spectrophotometric determination of metalloporphyrins.

1.1.5 Properties of Porphyrin

Porphyrins are “a large class of deeply coloured red or purple, fluorescent crystalline

pigments, with natural or synthetic origin, having in common a substituted aromatic

macrocyclic ring consisting of four pyrrole-type residues, linked together by four methine

bridging groups”. All porphyrin-like compounds have a strong absorption band around 400

nm called soret band. Unfortunately this band is not useful for PDT since blue light does not

penetrate very deeply into tissue; thus the weaker satellite absorption bands (Q bands)

between 600 nm and 800 nm are used for treatment. Porphyrin exhibits weak absorption

maxima around 630nm while chlorins and bacterochlorins have strong absorption maxima

around 650nm and 710 nm respectively.

Porphyrins evinces as an ideal photosensitizers since they are non-toxic, selectively

retained in tumor tissue in high concentrations, water soluble to a certain level, cleared in a

reasonable time from the body and rapidly from the skin which avoid  photosensitive

reaction. Porphyrins have got competent amphiphilicity. Amphiphilicity is analogous to

zwitterionicity. It has been reported that amphiphilic photosensitizers are generally more

photodynamically active than symmetrically hydrophobic or hydrophilic molecules.

1.1.6 Porphyrins and Photodynamic Therapy

Several unique properties of these complexes have been reported in the literatures.

Porphyrins have applications in a variety of novel chemical and medicinal procedures

including the use of water-soluble porphyrins in PDT as photosensitizers for detection and

treatment of cancer and also an effective modality against antibiotic resistant bacteria and cell

free viruses.           

1.1.6.i. Photodynamic Therapy

Photodynamic therapy (also called PDT, photo radiation therapy, phototherapy, or

photochemotherapy) is a revolutionary treatment aimed at detecting cancers and treating

them without surgery or chemotherapy.  It is based on the discovery that certain chemicals

known as photosensitizing agents can kill one-celled organism when the

organisms are exposed to a particular type of light. PDT is the destruction of cancer cells

through the use of a fixed-frequency laser light in combination with a photosensitizing agent

like Porphyrins, Phthalocyanins, etc. Depending on the part of the body being treated, the

drug is either injected into the bloodstream or applied to the skin. Apart from cancer, PDT is

also promised for its efficiency in other complications associated with Cardiovascular (e.g.,

alternative to angioplasty), Chronic skin diseases [e.g. Psoriasis (in development)],

Autoimmune (e.g. Rheumatoid arthritis), Macular degeneration, Antibacterial (wound

healing, oral cavity), Endometriosis, Precancerous conditions.

1.1.6.ii Mechanism of Porphyrin sensitization

The figure below (Fig.1) shows a simplified Jablonski diagram (with vibrational levels

omitted). Provided that the porphyrin possesses an absorption maximum at a wavelength

corresponding with that of the incident laser light, shining light on a highly colored porphyrin

causes excitation to the singlet excited state ( 1P*). The singlet excited porphyrin can decay

back to the ground state with release of energy in the form of fluorescence - enabling

identification of tumor tissue. If the singlet state lifetime is suitable (and this is true for many

porphyrins) it is possible for the singlet to be converted into the triplet excited state ( 3P*)

which is able to transfer energy to another triplet. One of the very few molecules with a

triplet ground state is dioxygen, which is found in most cells. Energy transfer therefore takes

place to afford highly toxic singlet oxygen ( 1 O 2 ) from ground state dioxygen ( 3O 2 ),

provided the energy of the 3 P* molecule is higher than that of the product 1O 2 .

Fig.1. Photo physics of PDT sensitization (vibrational levels omitted). (Simplified Jablonski

diagram)

Type-I and Type-II photoreactions in the PDT.

Here the 1P is the photo sensitizer in a singlet ground state, 3P* is a photosensitizer in a triplet

excited state, S is a substrate molecule, P - is reduced photosensitizer molecule, S+ is an oxidized

substrate molecule O2 is molecular oxygen (triplet ground state), O2 – is the superoxide anion

O2 is the superoxide radical, P + is the oxidized photosensitizers, 3O 2 is triplet ground-state

oxygen , 1O2 in a singlet excited   state, and S(O) is an oxygen adduct of a substrate 1 .

In PDT, the photosensitizing agent is injected into the bloodstream and absorbed by cells all

over the body. The agent remains in cancer cells for longer times than it does in normal cells.

When the treated cancer cells are exposed to laser light (usually 16minutes), the

photosensitizing agent absorbs the light and produces an active form of oxygen that destroys

the treated cancer cells. Porphyrins have been determined to be ligands for the mitochondrial

peripheral benzodiazepine receptor (PBR) and correlation between the photodynamic

activities of several porphyrin photosensitizers and their binding affinities for the PBR.

1.1.7 Antibacterial and antiviral activity of porphyrin photosensitization

The development of photodynamic therapy (PDT) has also provided an effective modality

against antibiotic-resistant bacteria and cell free viruses. The antibacterial activity of

porphyrin induced photodynamic therapy shows unique properties. Porphyrins possess a high

binding-affinity to cellular components, membranes, proteins and DNA. Living cells as well

as dead cells are stained rapidly by different porphyrins. Appropriate illumination generates

an emission of red fluorescence and generates toxic oxygen species. Cancer cells stemming

from solid tumors cells and bacterial infected tissues show preferential retention of

porphyrins. In vivo administration of various sensitizers to tumor bearing animals and

humans resulted in retention of the porphyrins in the tumors, while the normal surrounding

tissues had a low comparable porphyrin contents. Photodynamic therapy of solid tumors was

found highly efficient in eradication of the inflicted tissues and the damage, -initiating

necrosis or apoptosis of Photodynamic therapy, occurred within a very small time frame.

Photodynamic interactions were described to take place wherever sensitizer, light and oxygen

are simultaneously present. Inflammatory tissue was described to manifest similarities in

porphyrin retention and therefore bacterial and viral infected tissues may become targets for

photodynamic treatment. It is independent of the antibiotic sensitivity spectrum of the treated

pathogen and it has an efficient and non-recovering anti-microbial killing effect upon

illumination of Gram positive bacteria. Bacterial PDT is affected by the use of various

sensitizers, as a general rule non-charged or positively charged.

molecules are effective in photoinactivation of Staphylococcus sp. In order to photosensitive

Gram (-) bacteria such as  Pseudomonas aeruginosa, it is necessary to introduce a small

peptide polymyxin-B nona-peptide (PBNP) which stimulate the translocation of  porphyrin

through the outer membrane of these bacteria and makes PDT possible. Gram negative cell

killing by the use of PBNP and DP broadens the antibacterial spectrum of photodynamic

inactivation and opens new horizons for this modality as a wide spectrum drug when

antibiotic resistance is the main concern.

1.1.8 Porphyrin against AIDS

The rapid spread of human immunodeficiency virus (HIV), the Causative agent of acquired

immunodeficiency syndrome (AIDS), throughout the world has promoted an intense search

for antiretroviral therapeutics.  An analysis of nonpeptide compounds with useful

pharmacological properties has led to test the ability of porphyrins to inhibit HIV protease

(HIVPR) 16 .

1.1.9 Porphryins and FDA

In December 1995, the U.S.Food and Drug Administration (FDA) approved a

photosensitizing agent called porfimer sodium, or photofrin, to relieve symptoms of

esophageal cancer that is causing an obstruction and for esophageal cancer that cannot be

satisfactorily treated with laser alone, In January 1998, the FDA approved porfimer sodium

for the treatment of early non-small cell lung cancer in patients for whom the usual

treatments for lung cancer are not appropriate. Recently the FDA has recommended that

BPDMA, given the trade name Visudyne (injection), be approved for use in Visudyne

therapy, which is essentially PDT to destroy the neo-vasculature on the retina . The National

cancer institute and other institutions are supporting clinical trials to evaluate the use of PDT

for the several types of cancers. Tin etiopurpurin (purlytin) is photosensitizer being

investigated for use in PDT a chlorin

The most commonly used and studied photosensitizer to date is photofrin, the only

commercially available photosensitizer. At the time of photofrin review in this innovative

PDT it has been used on nearly 10000 patients in the United States, Canada, Netherlands,

Japan, France, and Italy (and is pending approval for use in eight other countries).

Many new compounds have been synthesized in an attempt to create a better photosensitizer

than photofrin. Often, researchers examine new chromophores week absorption maxima at

wavelengths longer than 630nm, citing that photofrin really weak absorption band at 630nm

does not allow optimal penetration. Researchers are also looking at different laser types,

Photosensitizers that can be applied to the skin to treat superficial skin cancers, and new

photosensitizing agents that may increases the potency of PDT against cancers that are

located further below the skin or inside an organ.

1.1.10 Application of porphyrins in Molecular electronics

Porphyrin-based compounds are of interest in molecular electronics and supramolecular

building blocks. Phthalocyanines, which are structurally related to porphyrins, are used in

commerce as dyes and catalysts. Synthetic porphyrin dyes that are incorporated in the design

of solar cells are the subject of ongoing research. Recent applications of porphyrin dyes for

dye-sensitized solar cells have shown solar conversion efficiencies approaching silicon based

photovoltaic devices.

The proposal that molecules can perform electronic functions in devices such as diodes,

rectifiers, wires and capacitors, or serve as functional materials for electronic or magnetic

memory, has stimulated intense research across physics, chemistry, and engineering for over

35 years. Because biology uses porphyrins and metalloporphyrins as catalysts, small

molecule transporters, electrical conduits, and energy transducers in photosynthesis,

porphyrins are an obvious class of molecules to investigate for molecular electronic

functions. Of the numerous kinds of molecules under investigation for molecular electronics

applications, porphyrins and their related macrocycles are of particular interest because they

are robust and their electronic properties can be tuned by chelation of a metal ion and

substitution on the macrocycle. The other porphyrinoids have equally variable and adjustable

photophysical properties, thus photonic applications are potentiated. At least in the near term,

realistic architectures for molecular electronics will require self-organization or nanoprinting

on surfaces. This review concentrates on self-organized porphyrinoids as components of

working electronic devices on electronically active substrates with particular emphasis on the

effect of surface, molecular design, molecular orientation and matrix on the detailed

electronic properties of single molecules.

A great motivation towards the development of molecular electronics is part of efforts to

increase performance while at the same time diminishing component size, reduce production

costs, and minimize the environmental impacts of production and operation11 .Flexible

display and electronics technologies, and ink-jet printing of circuitry will also benefit from

molecule based electronics.

Molecules or collections of molecules functioning as electronic components have ample

precedent in nature. Voltage, ligand, antibiotic, and other ion conducting channels are digital

electronics self-assembled into biological membranes in that they have only ‘on’ or ‘off’

positions with unit conductance that are unique to a given channel12. Photosynthetic reaction

centers transport electrons over about eight nm with remarkable efficiency. Ion pumps can

also be gated. The photo-driven purple membrane pumps containing bacteriorhodopsin have

been studied for many decades in terms of their potential as molecular electronic and

photonic materials because they are very robust, can cycle many thousands of times, and the

distinctive color changes upon oxidation and/or reduction impart a second functionality to

these materials13,14. However, the rate of conducting ions in channels and bacteriorhodopsin

proteins, and the stability of the former, limit the usefulness of these constructs as

components of complex electronic devices. The various photosynthetic systems can provide

much inspiration, but are too fragile for real-world applications. Research on molecular

electronics focuses on the molecule, but melds concepts from diverse fields such as physics,

chemistry, biophysics, and electrical engineering. See several recent reviews that focus on

different aspects of molecular electronics ranging from surface chemistry to molecular design

to theory, including a beautiful discussion of mechanical bonds with molecular electronics

applications by Stoddart15-19. Electronics fabricated from organic materials are potentially

much less toxic, easier to recycle, and scalable. In addition, molecular electronics have the

potential to contribute to the continuation of Moore’s law in the miniaturization of electronic

components, pending the further development of bottom up nanofabrication techniques

suitable for mass production. In general, classic Coulombic charging, the relative spacing of

the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital

(LUMO), the spin, and the vibrational modes will determine single electron currents through

molecules connected to electrodes with tunneling barriers. Thus, the reversibility of

accessible redox states of molecules is important, e.g. in single molecule transistors19. In the

case of conducting polymers, the conductance is dependent on the structure, conjugation of

the molecular system, and the length. A recent study shows that the mechanical

characteristics and topology of a polyfluorene are also important. Pulling this polymer from a

gold surface with an STM tip allows about a 20 nm change in length whereupon the

conductance curves show an exponential decay with increasing length and oscillations that

correspond to a monomer unit detaching from the surface20. The molecular electronic

properties are also dependent on the matrix surrounding the molecule and the domain size

(number of copies of a molecule in a discrete domain). Many of the physical properties of

ceramic semiconductor devices have analogies in hybrid molecular electronics. For example,

image charges generated in the source and the drain can result in the localization of charges

in molecules such as conjugated phenyls 19, or in ensembled domains, until a critical charge

density is reached whereupon the transistor switches (see below). There are several reviews

of the potential applications of porphyrins and phthalocyanines in molecular electronics 21–

25 .and as sensitizers for solar cells 26. This review will focus specifi- cally on applications of

porphyrin and porphyrinoid molecules as components of working molecular electronic

devices on electronically active substrates fromca. the past decade. Particular emphasis will

be placed on how the detailed molecular architecture dictates the electronic properties and

how the performance of these molecules is affected by surface chemistry, attachment,

orientation, and matrix around the electroactive species. Though there is excellent work on

materials composed of porphyrin and phthalocyanine films and aggregates, for example as

components of solar energy harvesting, electroluminescent and electronic devices.

1.1.11 Potential of porphyrins and its derivatives in other fields

A large variety of synthetic porphyrins and their metalloderivatives were made over the years

to study the porphyrin based natural systems. The search for anti-cancer drugs, useful

catalysts, semiconductors and superconductors, electronic materials with novel properties has

also made this synthetic porphyrin chemistry a very actively probed one by chemists,

biologists and physicists alike. The synthetic meso-substituted porphyrins offer a great

advantage to study the physical and chemical properties of the porphyrin nucleus

quantitatively by a judicious choice of the substituents that may be attached on the periphery.

Metalloporphyrins are widely and intensely investigated in the area of catalysis and also as

models and mimics of enzymes lie catalase, peroxidases, P450 cytochromes or as

transmembrane electron transport agents27-29. They have also been used as NMR image

enhancement agents30, Nonlinear optical materials31 and DNA-binding or cleavage agent32-33.

1.1.12 Explanation of characteristic optical absorption spectra of porphyrin and

metalloporphyrin

The Q bands of free-base porphyrins are a set of four absorptions arising from HOMO to π*

transition. Of these, the first set of two lines is x-component of Q while the second set is its y-

component. Both these Qx and Qy components are composed of two types of vibrational

excitations too, the lower energy one being Q(0,0) and the higher energy one Q(1,0). Thus

the four lines in the set are Q,(0,0), Q,(1,0), Qy(0,0) and Qy(1,0) in the increasing order of

energy.

On metallation, the spectrum shows an intense B (Soret) band at 420 nm and two weaker Q

bands at 550-600 nm [2,3]. These spectral absorptions arise from π-π* transitions of the

aromatic porphyrin ligand.

1.2. RESULTS AND DISCUSSION

1.2.1. SYNTHESIS OF PORPHYRINS

Cyclocondensation of pyrrole with benzaldehyde is one of the important methods for the

synthesis of 5,10,15,20-tetraarylporphyrins. Similarly the condensation of pyrrole with a

mixture of two aldehydes gives the mixture of six isomeric porphyrins which can be

separated by repeated column chromatography. Based on the basic principles of synthesis of

porphyrins, the synthesis, isolation and characterization by spectroscopic methods have been

discussed in this section.

Synthesis of 5,10,15,20 tetrakis-phenylporphyrin

The reaction of equimolar quantity of benzaldehyde with pyrrole in refluxing propionic acid for

3h, after completion of reaction, reaction mixture was cooled to room temperature and water

was added into the reaction mixture and precipitate was filtered, the crude product was purified

by column chromatography to afforded 5,10,15,20-tetrakis-phenyl porphyrin as purple solid1,2.

The appearance of Soret at 416 nm and the four Q-bands at 516, 553, 595 and 649 nm

respectively had been observed in the UV-Visible spectrum of 5,10,15,20-tetrakis-phenyl

porphyrin . The most upfield singlet at -2.89 ppm for internal pyrrolic NH protons, two doublet

at 7.18 and 7.98 ppm (for eight protons) with coupling constant 8.08 Hz for aryl protons, one

singlet at 8.80 ppm for eight β-pyrrolic protons had been observed in proton NMR spectrum of

5, 10, 15,20-tetrakis-phenylporphyrin.

Scheme 1.1 Synthesis of meso-substituted porphyrins

Figure 1.1: 1H NMR spectrum of 5,10,15,20 tetrakis-phenylporphyrin

1.2.2 Synthesis of 5,10,15,20-tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrins(3b)

The 3,5-di-tert-butyl-4-hydroxybenzaldehyde was synthesized by the reaction of 2,6-di tert-

butyl-4-methylphenol with N-bromosuccinimide in DMSO at refluxing temperature for 10 min.

After completion of reaction the product was purified by column chromatography over silica

gel (60-120 mess) with hexane-ethyl acetate (9:1) afforded the product which was confirmed

by 2,4-DNP test primarily and other spectroscopic data. In 1H NMR spectrum of 3,5-di-tert-

butyl-4-hydroxybenzaldehyde showed four singlet at 1.45, 5.87, 7.71 and 9.83 ppm for

eighteen tert-butylmethyl protons, one phenolic proton, two aryl protons and one aldehyde

group proton respectively. Further 3,5-di-tert-butyl-4-hydroxybenzaldehyde react with

equimolar quantity of pyrrole in refluxing propionic acid for 1.5h gave 5, 10, 15, 20-tetrakis-

(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin. Appearance of a soret band at 425.5 nm and four

Q band at 522, 559, 598 and 651 nm In UV-Vis spectrum of 5, 10, 15, 20-tetrakis-(3,5-di-tert-

butyl-4-hydroxyphenyl)porphyrin indicate the formation of porphyrin moiety. In 1H NMR

spectrum of 5,10,15,20 tetra-(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin the pyrrolic N-H

protons appear at -2.65 ppm high field due to diamagnetic shielding. The β-pyrrolic protons

appear as a singlet at 8.03 ppm. The aryl proton adjacent to the t-butyl groups appear as singlet

at 8.92 ppm. The phenolic OH protons appear at 5.52 ppm and tert-butyl protons appear as a

singlet at 1.62 ppm for 96 protons.

Scheme 1.2: Synthesis of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 5,10,15, 20-tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin (3C)

Figure 1.4: 1H NMR spectrum of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5)

Figure 1.2: UV-Visible spectrum of 5,10,15,20 tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin (3b)

Figure 1.3: 1H NMR spectrum of 5,10,15,20-tetra-(3,5-di-tert-butyl-4-hydroxyphenyl) porphyrin (3b)

1.2.3 Synthesis of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene

porphyrinogen (7)

OxP belongs to the calixpyrrole family3,4,5 and contains a cyclic tetrapyrrole conjugated with

quinonoid moieties at its meso-positions. OxP binds a variety of guest molecules at its pyrrolic

NH’s as well as at the quinonoid C=O groups. In contrast to typical calixpyrroles, OxPs have a

strong absorption in the visible light region due to π-conjugation between tetrapyrrole and

quinonoid substituents. This conjugation is sensitive to binding of guests to OxPs and these

compounds have been reported to behave as probes for anions.6,7

In particular, 5,10,15,20-tetrakis(3,5-di-t-butyl-4-hydroxyphenyl) porphyrin,

TDtBHPP, undergoes a 2-electron oxidation to a stable quinonoid form 5,10,15,20-tetrakis(3,5-

di-tert-butyl-4-oxocyclohexadien-2,5-ylidene)-porphyrinogen, the oxoporphyrinogen OxP

possesses different reactivities, especially of the central cavity of the molecule which is much

more accessible to an incoming reagent than is the porphyrin. Ox[TDtBHPP], abbreviated to

OxP The OxP chromophore is electron-defi cient, which suggests its use as a mediator in

electron transfer processes, and also contains site(s) for binding of guests through hydrogen

bonding.

The 5,10,15,20-tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl) porphyrin undergoes rapid,

non-photosensitized, aerial oxidation in basic solutions8. Solution of 5,10,15,20-tetrakis-(3,5-di-

tert-butyl-4-hydroxyphenyl) porphyrin in dichloromethane, was stirred with 10% (w/v)

methanolic KOH, for 24 hours at room temperature gave dark green microcrystals were filtered

and washed with ether and dried. Disappearance of the regular characteristic porphyrins pattern

of four Q band in UV-Visible spectrum of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-

oxocyclohexadienylidene porphyrinogen and appearance of strong broad absorbance at 512.76

nm was confirmed the porphyrin moiety was disrupted and disappearing of two singlet at -2.65

and 5.52 ppm in 1H NMR spectrum

of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen9 formation

was also confirmed. In 1H NMR spectrum of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-

oxocyclohexadienylidene porphyrinogen showed four singlet at 1.23, 8.01, 8.90 and 9.01 ppm

for 72 tert-butyl methyl proton, eight aryl proton, eight β-pyrrolic protons and four pyrrolic NH

proton respectively.

Scheme 1.3: Synthesis of oxoporphyrinogen

Figure1.4: 1H NMR spectrum of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen (7)

Figure 1.5: UV-Visible spectrum of 5, 10, 15, 20-tetrakis-3, 5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen (7)

1.2.4 UV-visible spectroscopy

Anion-binding properties of the calix[4]pyrroles depend on hydrogen-bonding interactions

between the pyrrole NH groups and the analyte anion with the inherent flexibility of their

porphyrinogen skeleton allowing the calix[4]pyrroles to exist in many conformations. A species

related to the calix[4]pyrroles is the 4-oxocyclohexadienylidene- substituted porphyrinogen

which, although bearing essential similarities in its structure with the calix[4]pyrroles, can be

distinguished from them by an increased macrocyclic rigidity as a result of its conjugated

electronic system. Another novel feature of the extended π-electronic system is an intense color

in all of its derivatives.

The anion binding studies of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-

oxocyclohexadienylidene porphyrinogen were carried out with the help of UV-visible

spectroscopy in DMSO at room temperature similar to porphyrinogens. All of the anions

showed the significant bathochromically shift with oxoporphyrinogen. Titrations were

performed by adding aliquots of 20 µl of stock solutions (5 ´ 10-7M) of anionic guests (F-, Cl-,

Br-, I-, CH3COO-, HSO4-, and H2PO4

-) to the DMSO solutions oxoporphyrinogen (5 ´ 10-7M).

In all the cases 1:1 stoichiometry of receptors and anionic guests was determined by Jobs

method. The change in absorption spectra upon addition of tetrabutyl ammonium fluoride

(TBAF) to the DMSO solution of oxoporphyrinogen is shown in (Figure 1.6) UV-visible

spectra of oxoporphyrinogen showed the strong absorption at 512 nm in the absence of anion.

With the addition of different anions, the characteristic absorption peaks at 512 nm decrease

and a new peak appear at 617 nm.

OxP-5 / Cl- OxP-5 / CH3COO-

OxP-5 / PO43- OxP-5 / Br-

OxP-5 / HSO4- OxP-5 / F-

Figure 1.6: The absorption spectrum of porphyrinogen (5 × 10-6 M) in DMSO solution upon the addition of 20 µl stock solution (5 × 10-6M) of different anions

The anion binding studies were examined by UV-Visible spectroscopic titrations in

DMSO and CH2Cl2. The UV-visible spectra of oxoporphyrinogen (5 ´ 10-7M) gave two peak at

426 and 517 nm. On the addition of the solution of tetrabutylammonium fluoride (5 ´ 10-7M to

4 ´ 10-7M), the absorption peak of oxoporphyrinogen was bathochromatically shifted by 100-

107 nm with decrease in relative intensity. The large red sifts have been attributed to a partially

charge transfer resulting from the anion being bounded to the –NH protons of the pyrrole

constituting the chromophore. The bathochromically shift was also observed with significant

broadening. The two isobestic points were observed at 558 nm and 759 nm which indicate the

complex had been formed between host and guest. The cases, binding stoichiometries were 1:1

as determined by Job’s method. The binding constant calculated by UV-Visible titrations were

in the range of 106- 107 for oxaporphyrinogen.

1.2.5 Synthesis of 5 -(4-carbomethylphenyl)-10,15,20-tris-(4-tert-butylphenyl) porphyrin

and 5,10,15,20-tetrakis-(4-tertt-butylphenyl) porphyrin

The reaction of 4-tert-butylbenzaldehyde, 4-formylbenzoic acid with pyrrole in refluxing

propionic acid gave the mixture of porphyrins which were separated by chromatography

eluting with Chloroform/petroleum ether, 3:2 gave the second desire product 5 -(4-

carbomethylphenyl)-10,15,20-tris-(4-tert-butyl-phenyl)porphyrin as purple solid. The 1H-NMR

spectra of compound, integrated to two protons each gave two clear doublets at 8.88 ppm and

8.75 ppm with coupling constant 8.04 Hz respectively which were assigned for aryl protons

having carboxylic functionality. A singlet at 8.87 ppm was assigned for four β-pyrrolic protons.

In addition, the remaining aryl protons, substituted with tert-butyl group appeared as four

distinct doublets at 8.41, 8.29, 8.11 and 7.73 ppm with coupling constant 8.04 Hz respectively.

Further the upfield region of the 1H-NMR spectra showed two sharp peaks at 1.59 and -2.78

ppm, which were assigned for twenty seven tert-butylmethyl protons and two internal pyrrolic

NH protons.

Scheme 1.4: Synthesis of symmetrical and unsymmetrical porphyrins

Fig:1.7:1HNMR spectrum of 5,10,15,20-tetrakis[(4-tertbutyl)phenyl]porhyrin(3a)

Figure 1.8:1H NMR spectrum of 5-(4-carboxyphenyl-10,15,20-triphenyl porphyrin (3c)

1.2.6 Synthesis of 5 -(4-carbomethylphenyl)-10,15,20-triphenylporphyrinatozinc(II) (3e)

5-(4-carbomethylphenyl)-10,15,20-triphenylporphyrinatozinc(II) was prepared by in two step

from the corresponding 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin and metallation of

5-(4-carbomethylphenyl)-10,15,20-triphenylporphyrin. 5-(4-carbomethylphenyl)-10,15,20-

triphenylporphyrin was prepared by the reaction of

5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin with methyl iodide in presence of

anhydrous potassium carbonate in dry dimethyl formamide. In 1H NMR spectrum of

5-(4-carbomethylphenyl)-10, 15, 20-triphenylporphyrin a new singlet at 4.09 ppm was

assigned for three corboxymethyl protons confirmed the formation of desired product.

The meso-5 -(4-carbomethylphenyl)-10,15,20-triphenylporphyrinatozinc(II) was

prepared by the reaction of 5 -(4-carbomethylphenyl)-10,15,20-triphenylporphyrin and zinc

acetate dehydrate in refluxing DMF. The reaction mixture was reflux for 2h. after completion

of the reaction, reaction mixture was cool to room temperature and poured in ice cooled water

and precipitate was collected by filtration and dried under reduced pressure at 100 °C for 4h

gave desire compound 5 -(4-carbomethylphenyl)-10,15,20-triphenylporphyrinatozinc(II) as

purple solid. Disappearance a peak at -2.74 ppm was confirmed the formation of metallated

porphyrin in proton NMR spectrum of 5 -(4-carbomethylphenyl)-10,15,20-

triphenylporphyrinatozinc(II)(3e).

Scheme 1.5: Synthesis of 5-(4-carbomethylphenyl)-10,15,20-triphenylporphyrinatozinc (II) (3e)

Figure 1.9: 1H NMR spectrum of 5 -(4-carbomethylphenyl)-10,15,20-tris-(4-tert-butyl-phenyl)porphyrin (3e)

1.3 Conclusions

The meso-5,10,15,20-tetraaryl porphyrins were synthesized by usual 1+1 condensation of

pyrrole and different substituted aldehydes in refluxing propionic acid in different reaction

conditions. Oxoporphyrinogens were synthesized by simple oxidation of hydroxy porphyrins

with base in different solvent in various reaction conditions.

The anion binding properties of synthesized oxoporphyrinogens were studied by UV-

Visible spectroscopic techniques. Binding constants calculated by absorption spectroscopic

titrations, indicate that oxoporphyrinogen bearing C=O group at meso-position favour the

binding with all the tetrabutyl ammonium anions and strong binding was observed with

fluoride.

OxPs have a strong absorption in the visible light region due to π-conjugation between

tetrapyrrole and quinonoid substituents. This conjugation is sensitive to binding of guests to

oxoporphyrinogen and these compounds have been reported to behave as probes for anions. In

general, meso-tetrakis-5,10,15,20-(3,5-di-tert-butyl-4-oxocyclohexa-2,5-dienylene)-

porphyrinogen shows higher K values for a given anion.

1.4 Experimental

1.4.1 Materials and Method

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, 2,6-di-tert-butyl-4-methylphenol, benzaldehyde,

4-Hydroxybenzaldehyde, 4-tert-butylbenzaldehyde, 4-formylbenzaldehyde and tolualdehyde

potassium hydroxide, benzylbromide, 4-nitrobenzyl bromide, N-bromosuccinimide, methyl

tosylate, propionic acid and potassium carbonate 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 or silica gel and characterized by melting points, 1H NMR, 13C NMR, IR

and ESI-MS techniques. The multiplicity of signals were given abbreviations s (singlet), d

(doublet), t (triplet), q (quartet), quint (quintet), dt (doublet of triplet), br (broad) and m

(multiplet).

1.4.2 Synthesis of 5, 10, 15, 20-tetrakis-(4-tert-butyl-phenyl)porphyrin (3a) and Synthesis

of 5-(4-carboxyphenyl) 10, 15, 20-tris-(4-tert-butyl-phenyl) porphyrin (3c)

Pyrrole (5.36g, 80 mmol) was charged in the refluxing solution of 4-tert-butyl-benzaldehyde

(6.4g, 40 mmol) and 4-formylbenzoic acid (6.0g, 40 mmol) in propionic acid in two neck

500ml round bottom flask equipped with an efficient water condenser and magnetic stirrer.

After 3h reaction mixtures was cooled to room temperature and allow to stand overnight.

Filtration under suction pump on Buchner funnel and water washing afforded a purple product

in quantitative yield. The tlc analysis showed the six porphyrin isomers which were separated

by column chromatography on silica gel (60-120 mess). The elution of column with petroleum

ether/ chloroform (3:1, v/v,) gave 5, 10, 15, 20-tetrakis-(4-tert-butyl-

phenyl)porphyrin(3a).Finally elution of the column with chloroform gave 5-(4-carboxyphenyl)

10,15,20-tri-(4-tert-butyl-phenyl)porphyrin(3c)

Physical state: purple solid

Yield: 3 gm 9% (w.r.t. 4-tert-butyl-benzaldehyde)

Rf : 0.43 (Hexane :CHCl3, 1:1, v/v)

mp: >300˚C,

UV-Vis [λmax CDCl3, (ε× 10-4, cm-1, M-1)]: 420, 518, 550, 595, 645 nm.1H NMR δ (400MHz, CDCl3) δ = -2.75 (s, 2H, NH), 1.59 (s, 27H, C(CH3)3), 7.73 (d,

J = 8.04, 8H, Ar-H), 8.12 (d, J = 8.8, 8H, Ar-H), 8.85 (s, 8H, β-pyrrolic-H)

1.4.3 Synthesis of 3,5 di-tert-butyl-4-hydroxybenzaldehyde (5)

NBS (2.1 gm, 0.011 mol) was added to a solution of 2,6-di-tert-butyl-4-methylphenol (2.2 gm

0.010 mol) in 90 ml DMSO. The reaction mixture was heated at 120˚C for 10 minutes. After

completion of the reaction, reaction mixture was cooled to room temperature, brine solution

and DCM were poured into the flask. The separated organic layer was washed with water and

dried over sodium sulphate. The solvent was removed under reduced pressure and the residue

was purified by column chromatography over silica gel (60-120 mess) with hexane-ethyl

acetate (9:1) to give the product.(5)

Physical state: white Solid.

Yield: 2.1 gm (89 %)

mp: 178-180 °C (lit.10 mp 179-181 °C)

Rf : .45 (1:1 Ethyl acetate: petroleum. Ether, v/v)1H NMR δ (400MHz, CDCl3) δ = 1.45 (s, 18H, -C(CH3)3), 5.87 (s, 1H, -OH), 7.71 (s, 2H, Ar-

H), 9.83 (s, 1H, CHO)

1.4.4 Synthesis of 5,10,15,20-tetrakis(3,5-di-tert-butyl-4-

hydroxyphenyl)porphyrin (3b)

Pyrrole (1.45ml, 0.02 mol) was added in the solution of 3,5-di-tert-butyl-4-hydroxy

benzaldehyde, (5g, 0.021 mol) in propionic acid under stirring at refluxing temperature. After

1.5h, the mixture was concentrated to one-fifth its volume and cooled to room temperature. The

solid was filtered and crude product was purified by column chromatograph over neutral

alumina, eluting with chloroform. The elutant was concentrated and crytallised with light

peteroleum ether to afford the porphyrin as purple microcrystals (1.2 gm, 10%).

Physical state: purple solid

Yield: 1.20 gm (10 %)

Rf : 0.65 (Hexane :CHCl3, 1:1, v/v)

m.p.: >300 ˚C (lit11mp >300 ˚C)

UV-Vis [λmax CDCl3, (ε× 10-4, cm-1, M-1)]: 425 (24), 522 (1.7), 559 (0.75), 593 (0.6), 651(0.4)

nm.1H NMR δ (400MHz, CDCl3) δ = -2.65 (brs, 2H, NH), 1.62 (s, 72H, C(CH3)3), 5.52 (s, 4H, Ar-

OH), 8.03 (s, 8H, β-pyrrolic), 8.92 (s, 8H, Ar-H).

1.4.5 Synthesis of 5,10,15,20-Tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene

porphyrinogen (7)

To a solution of 5,10,15,20-tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl) porphyrin (2gm, 0.002

mmol) in dichloromethane200ml, was stirred with 10% (w/v) methanolic KOH, for 24 hours at

room temperature. The solution was then neutralized with a few drops of triflouroacetic acid

and then washed with water in separating funnel. The lower dichloromethane layer was run off,

dried over Na2SO4 (anhydrous) then filtered, evaporated to dryness and recrystallized from

DCM and light petroleum (60-80˚C). The intense dark green microcrystals were filtered and

washed with ether and dried.

Physical state: green solid

Yield: 1.2 gm. 61% (w.r.t. meso-(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin)

Rf : 0.43 (CHCl3)

mp: >300˚C

UV-Vis [λmax CDCl3, (ε× 10-4, cm-1, M-1)]: 512 (23) nm.1H NMR δ (400MHz, CDCl3) δ = 1.23 (s, 72H, C(CH3)3), 8.01 (s, 8H, β-pyrrolic-H), 8.90 (s,

8H, aryl-H), 9.01 (s, 4H, NH)

1.4.6 Synthesis of 5-(4-carboxymethylphenyl) 10, 15, 20-tris-(4-tert-butyl-phenyl)

porphyrin (3d)

The reaction of 5-(4-carboxyphenyl) 10,15,20-tris-(4-tert-butyl-phenyl)porphyrin (200mg, .242

mmol) with 10 equivalent methyliodide in dimethylformamide in presence of potassium

carbonate at refluxing temperature. Progress of the reaction was monitored by tlc after

completion of reaction, reaction mixture was poured into the ice-cooled water and precipitate

was filtered to gave crude product which was purified by column chromatography over silica

gel (60-120 mess) eluting with chloroform.

Physical state: purple solid

Yield: 95%

Rf : 0.57 (Hexane :CHCl3, 1:1, v/v)

mp: >300˚C, (lit12 mp 300˚C)

UV-Vis [λmax CDCl3, (ε× 10-4, cm-1, M-1)]: 420 (25), 518 (1.8), 550 (.80), 595 (0.7), 645 (0.58)

nm.1H NMR δ (400MHz, CDCl3) δ = -2.75 (s, 2H, NH), 1.59 (s, 27H, C(CH3)3), 4.09 (s, 3H,

OCH3), 7.73 (d, J = 8.04, 6H, Ar-H), 8.11 (d, J = 8.8, 6H, Ar-H), 8.29 (d, 2H, J = 8.04, 2H β-

pyrrolic-H), 8.41 (d, 2H, J = 8.04, 2H β-pyrrolic-H), 8.75 (d, J = 8.04, 2H, Ar-H), 8.87 (s, 4H,

β-pyrrolic-H), 8.88 (d, J = 8.04, 2H, Ar-H).

1.4.7 Synthesis of 5-(4-carboxymethylphenyl) 10,15,20-tris-(4-tert-butyl-phenyl)

porphyrinatozinc(II) (3e)

To a solution of 27 (1 g, 1.1 mmol) in 100 mL of DMF was added 2.6 g of ZnCl2 (10 mmol),

and the mixture was heated to reflux over a period of 15 h. The complete insertion of the zinc

was observed with TLC. The reaction was nearly quantitative. The solvent was removed on a

rotary evaporator. The residue was purified over column chromatography with a mixture of

dichloromethane / ethyl acetate (4:1) afforded 5-(4-carboxymethylphenyl) 10, 15, 20-tris-(4-

tert-butyl-phenyl)porphyrinatozinc(II) as purple solid.

Physical state: purple solid

Yield: 95%

Rf : 0.35 (Hexane :CHCl3, 1:1, v/v)

mp: >300˚C

UV-Vis [λmax CDCl3, (ε× 10-4, cm-1, M-1)]: 424 (25), 554 (.76), 596 (0.57) nm.1H NMR δ (400MHz, CDCl3) δ = 1.59 (s, 27H, C(CH3)3), 4.07 (s, 3H, OCH3), 7.72 (d, J =

8.04, 6H, Ar-H), 8.10 (d, J = 8.8, 6H, Ar-H), 8.28 (d, 2H, J = 8.04, 2H β-pyrrolic-H), 8.38 (d,

2H, J = 8.04, 2H β-pyrrolic-H), 8.83 (d, J = 8.04, 2H, Ar-H), 8.96, (s, 4H, β-pyrrolic-H) 8.97

(d, J = 4.6, 2H, Ar-H).

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