CHAPTER -1

SYNTHESIS OF SYMMETRICAL & UNSYMMETRICAL PORPHYRINS & MESO-SUBSTITUTED 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 . 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.

N NH N N N N N N N HN N N

PORPHYRIN

PORPHYRAZINE

PHTHALOCYANINE

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 metalloenzymes.

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 chemists 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 chlorophylls 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 1.1.4 Laboratory Synthesis of Porphyrins

structure of vitamin B12

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

) from ground state dioxygen ( 3O

),

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. (HIVPR) 16 . An analysis of nonpeptide compounds with useful

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

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 benet 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 efciency. 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 elds 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 Moores 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 polyuorene 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 .and as sensitizers for solar cells
26 2125

. This review will focus speci- 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 lms 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 * transition. Of these, the first set of two lines is x-component of Q while the second set is its ycomponent. 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 -* 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 -pyrrolic protons had been observed in proton NMR spectrum of 5, 10, 15,20-tetrakis-phenylporphyrin.
R3 R1 R2

CHO + R2 R3 R1 propionic acid N H reflux, 1.5h R3

R2

NH N

N HN

R1 R3

R1

R2

R1=R2=R3=H

R2 R3

R1

R1=R2=R3=H,

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 tertbutyl-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-tertbutyl-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 -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.
R3 R1 R2

CH3 NBS, DMSO R2 R3 4 R1=R2=C(CH3)3, R3=OH R1 120 C, 10 min. R2

CHO

N H propionic acid R3

R2

NH N

N HN

R1 R3

R1 reflux, 1.5h R3 5

R1

R2

R2 R3

R1

3b: R1 = R2 = C(CH3)3, R3 = OH

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

CHO

OH

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

Figure 1.2: UV-Visible spectrum of hydroxyphenyl)porphyrin (3b)

5,10,15,20

tetrakis-(3,5-di-tert-butyl-4-

OH

NH N HO N HN

OH

OH

Figure 1.3:

H NMR spectrum porphyrin (3b)

of

5,10,15,20-tetra-(3,5-di-tert-butyl-4-hydroxyphenyl)

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 NHs 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 -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-tertbutyl-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-ditert-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
1 1

in

NMR
9

spectrum formation

of 5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen was also confirmed. In

H 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 -pyrrolic protons and four pyrrolic NH proton respectively.
OH O

NH N HO N HN OH

DCM, rt alcoholic. KOH

NH HN O NH HN O

OH

3b

Scheme 1.3: Synthesis of oxoporphyrinogen

NH HN O NH HN O

Figure1.4:

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

Figure 1.5:

UV-Visible spectrum of 5, 10, 15, 20-tetrakis-3, 5-di-tert-butyl-4oxocyclohexadienylidene 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 -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 l 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 l 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 100107 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 Jobs 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 -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.
CHO + COOH CHO

+ N H

propionic acid reflux, 3h

NH N + N HN

NH N COOH N HN

3a

3c

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. triphenylporphyrin was prepared by 5-(4-carbomethylphenyl)-10,15,20the 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).

NH N

N COOH HN

DMF, K2CO3 CH3I, reflux

NH N

N COOCH3 HN

3c

3d

NH N

N COOCH3 HN

Zn(OAc)2

DMF, reflux

Zn
NH N

COOCH3

3d

3e

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

N Zn N N

COOCH3

Figure 1.9: 1H NMR spectrum of 5 -(4-carbomethylphenyl)-10,15,20-tris-(4-tert-butylphenyl)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 UVVisible 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 -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 max are expressed in cm-l. 1H NMR was recorded on Jeol-delta-400 spectrometer using tetramethylsilane (TMS) as an internal standard and chemical shifts () 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, nBu4NCl, 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: >300C, UV-Vis [max CDCl3, ( 10-4, cm-1, M-1)]: 420, 518, 550, 595, 645 nm.
1

H NMR (400MHz, CDCl3) = -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, -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 120C 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)
1

H NMR (400MHz, CDCl3) = 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 [max CDCl3, ( 10-4, cm-1, M-1)]: 425 (24), 522 (1.7), 559 (0.75), 593 (0.6), 651(0.4) nm.
1

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

OH), 8.03 (s, 8H, -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 (60-80C). 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: >300C UV-Vis [max CDCl3, ( 10-4, cm-1, M-1)]: 512 (23) nm.
1

H NMR (400MHz, CDCl3) = 1.23 (s, 72H, C(CH3)3), 8.01 (s, 8H, -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: >300C, (lit12 mp 300C) UV-Vis [max CDCl3, ( 10-4, cm-1, M-1)]: 420 (25), 518 (1.8), 550 (.80), 595 (0.7), 645 (0.58) nm.
1

H NMR (400MHz, CDCl3) = -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 pyrrolic-H), 8.41 (d, 2H, J = 8.04, 2H -pyrrolic-H), 8.75 (d, J = 8.04, 2H, Ar-H), 8.87 (s, 4H, -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-(4tert-butyl-phenyl)porphyrinatozinc(II) as purple solid. Physical state: purple solid Yield: 95% Rf : 0.35 (Hexane :CHCl3, 1:1, v/v) mp: >300C UV-Vis [max CDCl3, ( 10-4, cm-1, M-1)]: 424 (25), 554 (.76), 596 (0.57) nm.
1

H NMR (400MHz, CDCl3) = 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 -pyrrolic-H), 8.38 (d, 2H, J = 8.04, 2H -pyrrolic-H), 8.83 (d, J = 8.04, 2H, Ar-H), 8.96, (s, 4H, -pyrrolic-H) 8.97 (d, J = 4.6, 2H, Ar-H).

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