Chapter 1 An Overview on the Synthesis of β-

Functionalized 5,10,15,20-Tetraarylporphyrins and their Diporphyrin Analogues

1

1.1 INTRODUCTION

Porphyrins are π-conjugated macrocycles, which have been found to be of great interest in diverse areas such as artificial photosynthesis,1 catalysis,2 molecular sensing,3 electrooptics,4 and medicine.5-7 They are capable to bind with variety of metal ions and play a number of critical biological functions including oxygen transport, light harvesting, energy and electron transfer etc. Thus porphyrins are often referred as “pigments of life”.8 They have also been proved as promising candidates to be used in the development of new molecular materials with improved electro- and photochemical properties. These chromophores display interesting photophysical, photochemical and electrochemical properties due to their unusual electronic structure and play vital roles in photosynthesis, cellular respiration, and act as a component of metalloenzymes.9 The basic tetrapyrrolic skeleton of porphyrin is present in many natural pigments such as heme, chlorophyll, bacteriochlorophyll, vitamin B12 and cytochromes etc (Figure 1.1).

N

N N

N

O H HH

H

OH

H3COOC

H

HO

RO

R = CH2

Bacteriochlorophyll- a

Mg

N

N N

N

O Me H Me H Me MeMe

O

HMe

H HO OCH3

O

Chlorophyll-a

MgN

N N

N

COOH COOHHeme

Fe

Figure 1.1: Structures of chlorophyll-a, heme and bacteriochlorophyll-a These macrocyclic molecules are proven to be efficient catalysts in a number of biological and chemical reactions. For example, heme can catalyze the biological oxidation using hydrogen peroxide in peroxidases, and catalyze the cleavage of hydrogen peroxide to water and oxygen in catalases. Moreover, a variant porphyrin derivative with Mg in the core such as chlorophyll plays a key role in photosynthesis.

2

1.2 GENERAL STRUCTURAL PROPERTIES OF PORPHYRIN MACROCYCLE

Porphyrins are the derivatives of a tetrapyrrolic macrocycle, porphin (Figure 1.2) where four pyrrole rings are joined by four interpyrrolic methine bridges to afford a highly conjugated structure. The structure of porphin was first suggested by Kuster in 1912,10 which was confirmed later by Fischer. In fact, the word porphyrin is derived from the Greek word porphura, meaning the purple colour.

N

NH N

HN

Figure 1.2: Structure of Porphin Two nomenclature systems are generally used for giving a particular name to porphyrin analogues. The older one is known as “Fischer system” in which Greek letters are used to label meso-positions, and four pyrrole subunits are labelled with the capital alphabets A, B, C and D. However, this system does not identify all the carbon atoms on the porphyrin skeleton. In contrast, the most recent and widely accepted “IUPAC” system identifies every carbon in the macrocyclic ring (Figure 1.3). In IUPAC nomenclature, carbons 5, 10, 15 and 20 are generally referred to as the meso-postions, carbon 2, 3, 7, 8, 12, 13, 17 and 18 as β-positions and carbons 1, 4, 6, 9, 11, 14, 16 and 19 as α-positions.

N

NH

NHN

N

NH

NHN

A

B

C

D

1 2

3

4

56

7

8

α

βγ

δ 12 3

4 56

78

910

111213

141516

1718

1920

Figure 1.3: Fischer (left) and IUPAC (right) nomenclature systems for porphyrins

3

Porphyrin macrocycle is found to be highly aromatic. Although, a porphyrin ring has a total of 22-π electrons, only 18 of them participate in any one of the several delocalization pathways (A-F) as shown in figure 1.4. Porphyrin macrocycles obey Huckel’s (4n+2) rule for aromaticity,9 where n = 4. Because of extensive conjugation, porphyrins absorbs in the visible region and thus, are vibrantly colored compounds.

N

NH N

HNN

NH N

HN N

NH N

HN

N

NH N

HN N

NH N

HN N

NH N

HN

E

A B C

D F Figure 1.4: Six possible 18 π-electron delocalization pathways of porphyrins

Initially, these aromatic super structures were assumed to be the planar on the basis of X-ray analysis of simple porphyrin molecules but later studies11,12 have revealed that factors such as metallation, peripheral substitutions, alkylation of the pyrrolenine nitrogen atoms and even protonation are responsible for the distortion of the planarity. Consequently, the tremendous number of porphyrins were found to exhibit nonplanar, ruffle, saddle, wave and dome conformations. Nonplanar porphyrins have intriguing physical, chemical and biological properties due to the distortion of porphyrin ring. The anisotropic effect due to the porphyrin ring current, the shielded N-H protons appear at very high field (between -2 to -4 ppm) in the 1H-NMR spectrum, whereas the peripheral protons show up at low field ( between 7-10 ppm) due to the presence of the deshielding environment as a result of the aromatic ring current.13 In the Infrared spectra14 of the free-base porphyrins, the weak N-H stretching vibrations appear at around 3300 cm-1, whereas the same peak disappears in the case of metalloporphyrins as two acidic hydrogens are replaced by the metal ion. The band near 700-

4

800 cm-1 and 980-1000 cm-1 appears due to the out of plane bending C-H vibrations and the in-plane C-H vibrations of pyrrole rings, respectively. Porphyrins are amphoteric compounds having two pyrrolenine nitrogen atoms and two internal NH groups. The porphyrin ring is generally stable under strong acidic and basic conditions. Strong bases, such as alkoxides can remove the two protons (pKa ~16) on the inner nitrogen atoms of porphyrin to form a dianion. On the other hand, the two free pyrrolenine nitrogen atoms (pKb ~9) can be easily protonated with acids such as trifluoroacetic acid, to form a dication. The inner protons can also be replaced by various metal ions including Zn, Cu, Ni, Fe etc. to produce chelate complexes known as metalloporphyrins. Metallated porphyrins acquire a fourfold symmetry axis and the metal ion in the core is linked to the four nitrogen atoms via equivalent chemical bonds. Demetallation of metalloporphyrins can be usually achieved by the treatment with various acids. Metalloporphyrins are not amphoteric because the nitrogens are chelated to the metal ions with both covalent and dative bonds.

1.3 PHOTOPHYSICAL PROPERTIES OF PORPHYRINS

Porphyrins and their metal complexes are well known for their intense colour which is a consequence of extensive macrocyclic conjugation. The UV-Vis absorption spectrum of porphyrin consists of two distinct regions namely, violet and visible region. In the violet region, extremely intense absorption band known as soret band is present at around 400 nm. The number of absorptions known as the Q bands are present in visible region around 500-650.nm Soret band has a typical extinction coefficient of approximately 1 x 105 M-1cm-1 whereas Q bands possess typical extinction coefficient of approximately 1 x 104 M-1cm-1. The characteristic intense soret band in the region of ~400 nm was discovered in hemoglobin by Soret15 and this was later observed in porphyrins by Gamgee.16 The inner 16-membered ring of the porphyrin is responsible for maintaining the 18-π electrons conjugated pathways, that generate typical porphyrin-type optical spectrum (Figure 1.5).

5

N

NH N

HN N

NH N

HN N

NH N

HN

A B Figure 1.5: The inner 16 membered ring (A) responsible for maintaining the

conjugation for 18-π electrons pathways (B) that generate the porphyrin optical spectrum

Further, the ring is susceptible to perturbation through various chemical modifications to the basic structure of porphyrin. The absorption spectra of free-base porphyrins display four lower intensity Q bands between 500-650 nm due to D2h symmetry, whereas metallo porphyrins show only two Q-bands due to D4h symmetry. The Soret and the Q bands both arise from π–π* transitions and can be explained by considering the four frontier orbitals of the Gouterman four orbital model.17 Typical absorption spectra of meso-tetraphenylporphyrin (TPP) and zinc(II) meso-tetraphenylporphyrin (Zn-TPP) are shown in figure 1.6.

Figure 1.6: Electronic absorption spectra of TPP and Zn-TPP 1.3.1 GOUTERMAN FOUR-ORBITAL MODEL

Gouterman developed the four orbital model which has been used extensively to explain the absorption and emission spectra of metalloporphyrins.18 For the metalloporphyrin with D4h

QY(1,0)

QY(0,0)

QX(0,0) QX(1,0)

Q bands

Q(1,0)

Q(0,0)

Q bands

TPP Zn-TPP

Soret band Soret band

6

symmetry, a 16 membered cyclic polyene model is applied. The highest filled orbitals are singly degenerate and denoted by a1u and a2u, while the lowest empty orbitals to which electron can be promoted are doubly degenerate and denoted by eg

The excitation of electron from a1u or a2u to eg results in the transitions seen in the absorption spectra of porphyrins (Figure 1.7 and 1.8). The four-orbital model has been confirmed satisfactorily by the results of numerous spectroscopic studies. The modifications at the periphery of the porphyrin ring normally result in the change of intensity and wavelength of the absorption bands. Moreover, a disrupted porphyrin macrocycle results in the disappearance of the Soret band.19

egy (LUMO) egx (LUMO)

a2u (HOMO)a1u (HOMO) Figure 1.7: Gouterman four-orbital model

a2u

a1u

eg x,y

S2

S1

S0

B

Q

Figure 1.8: Orbital diagram showing possible transitions for porphyrin macrocycle

7

1.4 APPLICATIONS OF PORPHYRINS

Porphyrins are organic chromophores which have unique and excellent photophysical properties as they absorb light in visible region and show luminescence with high efficiency. They have also been proved to be promising candidates for various applications such as optical applications (data storage, non linear optics and electrochromism), photosensitized solar cells, organic-light emitting devices, artificial photosynthesis and many more.20,21 Porphyrins have several desirable properties such as greater thermal stability, extended π-conjugation and larger non linear optical (NLO) effects, which make them useful in optoelectronics. Thus, the synthesis of porphyrin-based NLO materials is of great interest. The free-base porphyrins can be used in analytical chemistry for spectrophotometric determination of cations, as they have the potential to bind selectively with a variety of metal ions.22 The stable transition metal complexes of porphyrins are used as components of membranes of ion selective electrode (ISE) in potentiometry and in voltammetry, as these complexes have the ability to coordinate with extra ligands. The increasing importance of these applications has provided the impetus for intensive research towards the synthesis of artificial porphyrin systems that may be able to model or mimic their natural counterparts.

On the basis of their photophysical properties and selective localization in the tumor cells, these naturally occurring and several other synthetic porphyrins have demonstrated specific biomedical applications, particularly in the field of photodynamic therapy (PDT),23 Boron neutron capture therapy (BNCT),24 and more recently for the treatment of age related macular degeneration.25 PDT and BNCT are both binary cancer therapies and their side effects are limited. PDT involves the irradiation of a photosensitizer with light of a specific wavelength, subsequently causes the excitation of the photosensitizer to excited singlet state (1P*) and ultimately, it reaches to excited triplet state (3P*) through intersystem crossing. The resulting excitation energy is finally absorbed by the triplet ground state of molecular oxygen (3O2, found in all living cells) to generate highly toxic singlet oxygen (1O2*), which kills the tumor cells (Figure 1.9).

8

0P

1P*

3P*

1O2*

3O2

E

Porphyrin sensitizer Oxygen

Intersystemcrossing (ISC)

Fluorescence

Phosphorescence

Figure 1.9: Simplified Jablonski diagram showing singlet and triplet states of porphyrin

and oxygen. P = Porphyrin; * = electronically excited state; 0 = ground state; 1 = singlet state; 3 = triplet state

In contrast, BNCT involves the capture of thermal neutrons by boron-10 nuclei, which have been selectively delivered to tumor cells. The captured neutron releases 7Li and 4He nuclei, which are extremely cytotoxic but can only travel a distance of about one cell diameter in tissue and thus, it can selectively kill the tumor cells.26,27 Porphyrin derivatives and their metal complexes are known to be highly efficient triplet state photosensitizers,28,29 capable of producing copious yield of singlet oxygen, when illuminated with the light of correct wavelength. The singlet molecular oxygen is highly reactive and can be used for therapeutic or deleterious purposes (Figure 1.10).30,31

9

Figure 1.10: Treatment of cancer by photodynamic therapy (PDT)

In clinical practice, the photosensitizers arise from three families: a) porphyrins, b) chlorophylls, and c) dyes. The photosensitizers developed from each family have unique properties, and their ability to fluoresce and visualize the lesion is always advantageous. Furthermore, the delivery of photosensitizer to the tumor site has also been considered. Creams containing photosensitizers may be used in case of topical applications, where as systematic administration (oral or intravenous) would be expected in case of internal tumor or leukaemia. Delivery vehicles such as liposomes or antibodies can also be used in other areas of drug administration.32

1.4.1 PORPHYRIN-BASED PHOTOSENSITIZERS IN PDT

The number of different aromatic dyes such as methylene blue,33 rose bengal,34 and acridine35 etc (Figure 1.11), are known to be efficient singlet oxygen generators. Thus, they can be used as potential photodynamic agents, but the porphyrin derivatives are most

Phototoxic drug is administered and accumulated in tumor tissue

Patient is diagnosed with cancer

Drug is activated by illumination with laser

Highly toxic radicals Generated Kill tumor cells

10

promising photosensitizers because of their ability to accumulate in tissue very efficiently and low dark toxicity.

O

I

NaOI I

O

I

ClCl

O2C Cl

Cl

Na

Rose bengal

S

N

NN

Methylene blue

N

AcridineFigure 1.11: Structures of non-porphyrin photosensitizers

Porphyrin based materials possess a number of interesting photochemical, photophysical and biological properties that make them highly desirable for medical applications. They are found to be fluorescent, absorb strongly in visible region of optical spectrum, have high chemical stability, and have affinity with serum proteins. For these reasons, several porphyrin-type compounds are currently in various stages of preclinical and clinical trials as phototherapeutic agents in PDT applications. The derivatives of naturally occurring hemato porphyrin are known as first generation photosensitizers. Photofrin® is the most commonly used and commercially available photosensitizer (Figure 1.12). It can be easily obtained from hematoporphyrin-IX by the treatment with acids followed by alkaline hydrolysis.

N

NH N

HN

O

O

NaO2C CO2Na

n

Photofrin, n = 1-9

N

NH

N

HN

H3CHO

CH3

CH3

CH3

HO

CH3

H3C

CO

CO

HO

OH

Hematoporphyrin Figure 1.12: Structures of naturally occurring hematoporphyrin and first generation

photosensitizer photofrin

11

The resulting crude mixture commonly referred as hematoporphyrin derivative (HpD).36,37 After chromatographic purification, it yields sufficiently pure material which was found to be optimally active against tumor cells. Photofrin® has been successfully used over the last three decades for the treatment of early and advance stages of cancer of lung, digestive track and genitourinary track. Though, Photofrin fulfills certain criterian to be an ideal photosensitizer, but it suffers from several drawbacks. Photofrin® constitutes a complex and inseparable mixture of monomers, dimers, trimers and large oligomers upto eight or nine porphyrin units and its efficacy against tumor cells varies from batch to batch. Furthermore, Photofrin® absorbs weakly at about 620 nm, thus it is not very effective for the treatment of deep-seated tumors. Its prolonged cutaneous photosensitivity as a result of long retention time makes it less attractive for clinical use. Photofrin’s inherent problems have resulted in large amount of work devoted to the synthesis of pure porphyrin compounds, which absorbs at long-wavelength and have well established structures.

1.4.2 SECOND GENERATION PHOTOSENSITIZERS

In view of the disadvantages associated with the first generation photosensitizers, researchers around the world are devoted to the development of more effective photosensitizers which must be localized at the site of photodynamic action, efficiently absorbs light of appropriate wavelengths and produce the desired biological response with minimal side effects. For PDT applications, the ideal photosensitizer should meet the following requirements: (i) it should be chemically pure and can be synthesized from easily available precursors, (ii) it should possess minimal dark toxicity and only be cytotoxic if exposed to the light, (iii) be preferentially retained by the target, (iv) should have strong absorbance with a high extinction coefficient in the 600-800 nm range where tissue penetration of light is maximum and where the wavelength of light are still energetic enough to produce singlet oxygen, (v) should have excellent photochemical reactivity, with long triplet state life times (τ1) and have high quantum yields (Фf) for the generation of singlet oxygen (1O2) or super oxide (O2-) for effective destruction of tumor cells, (vi) be rapidly excreted from the body to provide low systemic toxicity, (vii) have simple and stable drug formulation. These requirements led to the development of chemically pure synthetic compounds so-called “second generation

12

photosensitizers” which have absorption maxima in the red region of the absorption spectrum and induce significantly less skin photosensitivity.

Figure 1.13: Optical spectra of porphyrins, chlorins, bacteriochlorins and their metal

complexes

The second generation photosensitizers include mainly porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and other extended porphyrin derivatives. Chlorins (2,3-dihydroporphyrins) are distinguished from their parent porphyrins by the presence of one reduced peripheral double bond, and this change in symmetry leads to a strong absorption in

N

NN

NM

N

NN

NM

H

HH H

N

NN

NM

H

H

H

H

H H

H

H

Broken line = Porphyrin, (M = 2H) Solid line = Metalloporphyrin, (M = metal)

Broken line = Chlorin, (M = 2H) Solid line = Metallochlorin, (M = metal)

Broken line = Bacteriochlorin, (M = 2H) Solid line = Metallobacteriochlorin, (M = metal)

Wavelength/ (nm)

13

the long wavelength portion of the visible spectrum (Figure 1.13). The tetrahydro system with two opposite reduced pyrrolic units is called a bacteriochlorin and the regioisomer with two adjacent reduced pyrrolic units is called isobacteriochlorin. The optical spectrum of bacteriochlorin lies within the 'ideal' region for PDT. Many new compounds have been synthesized in an attempt to create a better photosensitizer than Photofrin. Among all, porphyrin-related chromophores have been emerged in large numbers due to their ability to produce singlet oxygen very efficiently, which makes them additionally attractive as photosensitizers.

N

NH N

HN

OCH3H3CO O O

O

OH

OOCH3

Verteporphin(Visudyne)

N

NH N

HN

Tetra(m-hydroxyphenyl) chlorin(Foscan or Temoporfin)

N

N N

N

OCH2CH3O

Cl2Sn

(Purlytin)Tin-etiopurpurin

N

NN

NN

OH

OH

O

O

OCH3

OCH3

3

3Lu

Lutetium texaphyrin(Lutex or Lutrin)

NH2

OH

O

O5-Aminolaevulinic acid

(ALA), Levulan

NH

N HN

N

COOH COOHProtoporphyrin IX

HO

OH

OH

HO

N

NHN

HN

O

n-HexO

HCO2MeH

HPPH

N

NN

N

N

NN N

M

M = Si(OH)OSi(CH3)2CH2CH2CH2NMe2PC-4

N

HNN

NH

Me

Et

Me

H H

H

HMe

CO2HCO2HHO2C

Me

OMe

Bacteriochlorin-a

N

HNN

NH

Me

Et

MeH

HMe

CO2HCO2H

Me

ONHCH(CO2H)CH2CO2HMonoaspartyl chlorin e6

(MACE)

Figure 1.14: Names and structures of some selected second generation photosensitizers.

ALA is a metabolic precursor of protoporphyrin-IX

14

The efficacy of a porphyrin based drug is dependent upon its ability to absorb light in the red or near infra-red region of the optical spectrum. Some selected photosensitizer candidates used in PDT are shown in figure 1.14. 5-Aminolaevulinic acid (ALA) is a naturally occurring amino-acid, which is used to treat a number of superficial cancers and tumors. ALA is not a photosensitizer but a metabolic precursor of protoporphyrin IX, an effective photodynamic agent.38,39

A methyl ester of ALA (Metvix) is now being marketed by Photocure ASA (Oslo, Norway) as a potential photosensitizer for basal cell carcinoma and other skin lesions.40-42 Chlorin derivatives were found to be effective not only as good therapeutic agents but also useful in cancer prevention.43 Among polyamide derivatives of chlorin e6 obtained from chlorophyll-a, monoaspartyl chlorin e6 (MACE) is found to be more effective than hematoporphyrin derivative (HpD) in in-vitro and in-vivo testing.44

Foscan, also known as temoporfin, has been evaluated as a phototherapeutic agent against head and neck cancers. Foscan is approximately 100 times more photoactive than Photofrin, and thus emerged as one of the most potent second generation photosensitizers currently under investigation.45-49 The second generation photosensitizer, visudyne, in collaboration with Ciba Vision Corporation, has undergone Phase III clinical trials in USA for the photodynamic treatment of age-related macular degeneration (AMD) and cutaneous nonmelanoma skin cancer.50 Lutetium texaphyrin (Lutex or Motexafin Lutetium) is registered for the treatment of cervical, prostate, and brain tumors. It shows long wavelength absorption maximum of 732 nm, and is an efficient generator of 1O2.51-55 Tin etiopurpurin, a chlorin photosensitizer, is marketed under the trade name purlytin by Miravant Medical Technologies. Purlytin has also undergone Phase II clinical trials in USA for the treatment of cutaneous metastatic breast cancer and Kaposi’s sarcoma in patients with AIDS.56 Purlytin has been used successfully to treat the non-malignant conditions psoriasis and restenosis. In addition, various phthalocyanines (Pc) are also emerging as promising candidates for the second-generation PDT photosensitizers. The phthalocyanine (Pc-4) has shown encouraging results from in-vitro and in-vivo studies of animal and human cancer cells. The silicon phthalocyanine, Pc-4 (λmax = 670 nm) is in various stages of clinical evaluation for cutaneous and subcutaneous lesions from diverse solid tumor origins.57,58 Limited solubility and poor selectivity of second generation photosensitizers has led to the development of more effective third generation photosensitizers with better selectivity and good solubility.

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1.4.3 THIRD GENERATION PHOTOSENSITIZERS

The poor solubility of many photosensitizers in aqueous media, particularly at physiological pH, prevents their intravenous delivery directly into the bloodstream. Thus, it would be advantageous if a delivery model could allow the transportation of these photosensitizers to the site of diseased tissue.

Recently, work has been focused on designing systems to affect greater selectivity and specificity of the photosensitizer to enhance the cellular uptake.59,60 A number of possible delivery strategies have been suggested, ranging from the use of oil-in-water (o/w) emulsions to liposomes and nanoparticles as potential carrier vehicles.61-64 However, the use of these systems may increase the therapeutic effect, observed as a result of photodynamic therapy. The singlet oxygen generated by the photosensitizer should be diffused out of the carrier system to reach the target but, it has a narrow radius of action and therefore, it may elicit the desired effect.65 If the size of the carrier system is not sufficiently small or does not fully dissolve in physiological media, the incidence light may not be sufficiently absorbed and thus, significant light scattering may inadvertently reduce the yield of singlet oxygen. An alternative delivery method which would solve this problem is the use of targeting moieties. Typical targeting strategies have included the investigation of photosensitizers directly attached to biologically active molecules such as antibodies.66,67 These third generation photosensitizers have shown in-vitro activity against colorectal tumor cells.68 The third-generation porphyrin dendrimers (DPs) containing either 32 quaternary ammonium groups or 32 carboxylic groups were evaluated as a novel supramolecular class of photosensitizers for PDT and showed a different cell-association profile depending on the positive or negative charge on the periphery of the ring with low dark toxicity.69 Additionally, new photosensitizers (A and B) having potential to bioconjugate with antibody fragments have also been synthesized in the past (Figure 1.15). The photosensitizers (A and B) are the derivatives of pyropheophorbide-a, absorb in red spectral regions and exhibit efficient cellular uptake with significant low dark toxicity.70

16

N

NH N

HN

OOO O

OO

OCH3O

OO

OCH3O

OO

OCH3

O

HO

N

NH N

HN

OOOH

NOOH3CO

Cl

A B Figure 1.15: Chemical structures of third generation photosensitizers (A and B)

1.4.4 PHOTOSENSITIZERS BASED ON ISOMERIC PORPHYRINS

Isomeric porphyrins such as porphycene, corrphycene, isoporphycene, hemiporphycene, N-confused porphyrins, and doubly N-confused porphyrins are called modified porphyrins. Some of these compounds have similar molecular formula and are obtained by the scrambling of four pyrrolic subunits and the four bridging carbon atoms.71-77 Among the isomeric porphyrins, porphycene and their derivatives are found to be very promising candidates for PDT applications78,79 because of their tumor specificity, in-vivo transport, optical absorption at longer wavelengths and singlet oxygen generating efficiency. Among the porphycene derivatives, carboxybenzoporphycene is an attractive candidate for the PDT applications owing to its extremely high efficacy.80 GlaxoWellcome (Research Triangle Park, NC, USA) and Cytopharm (Menlo Park, CA, USA) have jointly undertaken the extensive preclinical trials of porphycene and 9-acetoxy-2,7,12,17–tetrakis-(β-methoxyethyl)porphycene (ATMPn) for superficial non-melanoma skin cancer.81 The hydrophilicity and solubility due to the acetoxy group and β-methoxyethyl side chains82 resulted in fast uptake of these photosensitizers into the skin cells (Figure 1.16). In addition, N-confused porphyrins, corrphycene and hemiporphycenes are stable molecules and their absorption in red region coupled with their high singlet oxygen generating efficiency make them potential photosensitizing candidates for PDT applications.

17

N

NH N

HN

Porphycene

N

NH N

HN

Corrphycene

N

NH N

HN

Hemiporphycene

N

NH N

HN

Isoporphycene

NH

N

CH HN

N

N-confused porphycene

NH

N

CH

HN

HC

N

Doubly N-confused porphycene

N

NH N

HN

OCH3

O OCH3

O

OCH3H3CO

H3CO

ATMPn

Figure 1.16: Structures of isomeric porphyrins

1.5 SYNTHESIS OF meso-TETRAARYLPORPHYRINS

Since, the landmark synthesis of protohemin (iron protoporphyrin IX) by Hans Fischer in 1929 (which earned him the Nobel Prize), porphyrin chemistry has undergone a renaissance due to potential applications of these compounds in various areas including photodynamic therapy, solar energy conversion and catalysis. The variety of synthetic methods have been developed for the synthesis of various non natural porphyrins, especially the meso- tetrasubstituted porphyrins, in order to exploit their chemistry. meso-Tetrasubstituted porphyrins are the key starting materials for making a variety of the β- and meso-substituted porphyrin analogues. A brief overview on the various synthetic strategies used in the past decades for the synthesis of meso-tetraarylporphyrins are discussed below.

1.5.1 ONE-POT PYRROLE-ALDEHYDE CONDENSATION

(A) ROTHEMUND SYNTHESIS: For the first time, synthesis of tetraphenylporphyrin (3) was reported by Rothemund in 1936 using pyrrole (1) and benzaldehyde (2) in pyridine. The reaction was carried out in a sealed tube at 150˚C for 24 hours.83,84 He treated a variety of aldehydes such as acetaldehyde, propionaldehyde and benzaldehyde with pyrrole in methanol at various temperatures in a sealed tube to prevent the loss of volatile aldehydes and obtained

18

crystalline porphyrin products. The yields of porphyrins were quite low, but main drawback was the harsh reaction conditions, in which only few aldehydes may able to survive. Hence, practically this method is not very useful. Porphyrin research was therefore directed towards the development of milder reaction conditions, enabling the production of a variety of meso-substituted porphyrins with more reasonable reaction yields.

(B) ADLER AND LONGO SYNTHESIS: Adler and Longo modified the Rothemund process by allowing pyrrole (1) and benzaldehyde (2) to react for 30 minutes in refluxing propionic acid under aerobic conditions (Scheme 1.1).85

N +CHO

H N

NH N

HN1

3

∆2

CH3CH2COOH

O2,

Scheme 1.1

These are comparatively milder conditions which allow a wider selection of substituted benzaldehydes to be converted to the corresponding porphyrins in approximately 16-20% yields. By using these conditions, a greater variety of substituted benzaldehydes were reacted with pyrrole to afford the corresponding 5,10,15,20-tetraarylporphyrins and reactions could also be scaled up to produce multi-gram quantities of these compounds. Differentially functionalized porphyrins can also be prepared by using two different aldehydes and pyrrole under the same reaction conditions. Only the obvious problem is the separation of the mixture of products. However, the yields of the desired product can be maximized by varying the stoichiometry of the reagents. A variety of aromatic aldehydes have been condensed with pyrrole under the Adler Longo or slightly modified conditions, which involve the use of various protic acid, or acidic catalysts and aerial oxidation to yield the corresponding porphyrins slightly contaminated with tetraarylporphyrinogen (about 2-10%).

19

Tetraarylporphyrinogen can be easily removed by the treatment of the crude product with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in refluxing toluene.86,87 This method is used widely when large quantities of porphyrins are needed and where the aldehydes are capable of withstanding with acidic conditions.88-94 The recent synthesis porphyrin (6) by Czuchajowski and co-workers could be an elegant example of this type (Scheme 1.2).

NOCH3

CHO CHO

N

HNN

NH

N

N

N

OCH3propionic acid

1

4 5

6

HNheat, O2, DDQ

Scheme 1.2

CN CHO

Br Br

CHO

NO

O

N

NH N

HN

H2N

NH2

NH2

H2N

DIBAL-H, CH2Cl20-45 oC

potassium phthalamideDMF, reflux

i) pyrrole, propionic acidii)NaOH, 70% H2SO4, heat

7 8 9

10 Scheme 1.3

20

These compounds can be easily prepared by condensing 4-methoxybenzaldehyde (4) and 4-pyridinecarboxaldehyde (5) with pyrrole under Adler–Longo conditions.95 Lavalle et al. have synthesized cationic porphyrins by reacting a protected amino aldehyde (9) with pyrrole in propionic acid followed by deprotection of amino group to furnish tetraaminomethylporphyrin (10) as shown in scheme 1.3. The protonated porphyrin (10) have shown an efficient binding with DNA binding.96

Further, mechanistic studies were carried out to evaluate the role of molecular oxygen in the formation of a porphyrin analogues, a model reaction of benzaldehyde and pyrrole was performed in propionic acid at different pressures and concentrations of oxygen. All the reactions were monitored by UV-Vis spectroscopy. It was observed that the atmospheric oxygen is essential for the oxidation process to generate desired porphyrin derivative. A mechanistic pathway for the formation of meso-tetraphenylporphyrin is shown in figure 1.17.

NH

CHO NH

HO

NHHN

NH

HNH

NH

HN

HHO

H

NH HN

HNNH

H

H

H

H

N

NH N

HN

Porphyrinogen (12)

Oxidation

-H2O -H+

3

Step-12

Step-2

H

CHO

H H ,

Carbinol (11)1

Figure 1.17: Possible mechanistic pathway for synthesis of meso-tetraphenylporphyrin

The mechanism consists of two important steps. Step-1 involves the acid catalyzed condensation of pyrrole (1) and benzaldehyde (2) to form a key intermediate cabinol (11). This carbinol (11) intermediate losses a water molecule to form a resonance stabilized cation which on reaction with another pyrrole unit affords a meso-substituted dipyrromethane. The

21

dipyrromethane then condensed with another molecule of benzaldehyde and this chain building reaction repeats to yield a linear tetrapyrrolic moiety. Further, this linear tetrapyrrolic moiety forms porphyrinogen (12) by ring closure under acidic conditions. In step-2, porphyrinogen (12) is finally oxidized to the tetraphenylporphyrin in the presence of air.

(C) LINDSEY SYNTHESIS: In the late 1980s Lindsey et al. reported a milder one pot method for the synthesis of tetraarylporphyrins in which a pyrrole and an aromatic aldehyde are allowed to react at room temperature in dry CH2Cl2 under nitrogen atmosphere in the presence of acidic catalysts (BF3.Et2O or TFA). The reaction was reversible under these conditions and reaches to equilibrium in about 1hour to produce porphyrinogen (14) (Step-I, Scheme 1.4). Stoichiometric amount of DDQ (16) was then added in the same pot, which irreversibly oxidize the porphyrinogen to the corresponding meso-substitutedporphyrin (15)97, 98 (Step –II, Scheme 1.4).

Ar CHO4 + N H acid

NH

NH HN

HN

HAr

HAr

Ar H

ArH

4

13 1

14 STEP - II

NH

NH HN

HN

HAr

HAr

Ar H

ArH

O

O

CN

CN

Cl

Cl

OHCN

CN

Cl

ClOH

N

NH N

HNAr

Ar

Ar

Ar

3 3

14 15

16 17 Scheme 1.4

22

Lindsey and co-workers also investigated the synthesis of meso-tetraarylporphyrins in better yields, under high concentration conditions of starting materials.99 Further, one step synthesis had also been developed by this group where aldehyde, pyrrole, acid catalyst and oxidant were added simultaneously in the same step (Scheme 1.5).

Ar CHO4 + N Hacid

4

O

O

Cl

Cl

Cl

Cl

OHCl

Cl

Cl

ClOH

N

NH N

HNAr

Ar

Ar

Ar

3 3

13 1

15

18 19 Scheme 1.5

NH

NH HN

HN

HAr

HAr

Ar H

ArH

O

O

Cl

Cl

Cl

Cl

OHCl

Cl

Cl

ClOH

N

NH N

HNAr

Ar

Ar

Ar

TCQ TCQH2

FePc FePc(O)

1/2 O2

H2O

14 15

18 19

Scheme 1.6

23

Among various quinone oxidant examined, p-chloranil (18) provided successful oxidation of porphyrinogen (14). Later, an electron transport chain method using chloranil and Fe(II) phthalocyanine (FePc) in catalytic amounts and O2 as the terminal electron acceptor was also adopted by the Lindsey group (Scheme 1.6) for the synthesis of various aryl porphyrins.94 They postulated that FePc activates O2 and recycles the reduced p-chloranil at room temperature. This electron transport chain provided mild aerobic oxidation, which found to be cleaner than the oxidation with stoichiometric amounts of TCQ.

Lindsey and co-workers further extended this procedure by using a wide variety of protic and Lewis acid catalysts such as p-TSA, CH3SO3H, montmorrillonite K-10, SbF5, GeBr4, PBr5, MgBr2.Et2O, CuCl2, TiCl4, TiBr4, FeCl3, GaCl3 and SnCl4. Some of the catalysts like MgBr2.Et2O and CuCl2 have been found very effective but produced corresponding metal complexes (Mg and Cu TPP) during the synthesis of porphyrins.100 Moreover, a variety of porphyrins with sensitive functional groups have been prepared by this procedure in better yields (upto 58%) after chromatographic purification. In a recent review, Rowan et al. reported that the Lindsey synthesis provides a good example of the concept of Dynamic Covalent Chemistry (DCC).101,102 The first anaerobic phase of this procedure is reversible,103-

106 in which linear polypyrromethanes, porphyrinogens and expanded porphyrinogens are formed. As DCC based synthesis generally takes place under equilibrium control conditions, the Lindsey conditions were modified to allow the formation of o-substituted tetraphenylporphyrins which are difficult to prepare due to their sterically hindered nature.107 Sterically hindered porphyrins are useful as crowding around the macrocycle can lead to a non-planar conformation, which in turn can lead to modify optical properties.108 Lindsey method was further extended for the preparation of meso-tetraalkylporphyrins and a hybrid porphyrin containing both aryl and alkyl substituents.109 Furthermore, this synthetic method has also been used to furnish hangman porphyrins (23) in good yields from easily available starting materials (Scheme 1.7).110

24

N

NH N

HN

Ar1

Ar1

Ar1

HNO

CO2Me

CHO

O

CO2MeAr1CHO

F

FF

F F

N

NH N

HN

Ar1

Ar1

Ar1

O

COOH

Ar1 =1) 6N NaOH, THFmicrowave irradiation

2) 20% HCl

1 20

21

22

23

BF3.OEt2CHCl3, DDQ, 25 oC

Scheme 1.7 The mild reaction conditions and convenience of this method permits to design other synthetic strategies for preparation of the complex porphyrin analogues.

(D) ONE-POT SYNTHESIS IN IONIC LIQUIDS: Ishikawa et al.111 has described a phase separated ionic liquid catalysed synthesis of tetraarylporphyrins (3 or 25) by the reaction of arylaldehydes (2 or 24) and pyrrole in dichloromethane as solvent (Scheme 1.8).

ArCHOHN

N

NH N

HN

Ar

Ar

Ar

ArN

NHN

HN

Ar

Ar

Ar

Arionic liquid, CH3SO3H

ionic liquid = N N SO3HCF3SO3

2, Ar = C6H524, Ar = 4-CH3C6H4

3, Ar = C6H525, Ar = 4-CH3C6H4

26, Ar = C6H527, Ar = 4-CH3C6H4

28

DDQ, CH2Cl2, 25 oC

Scheme 1.8

25

The yields of the prepared porphyrins are found to be comparable with the Lindsey method. The reaction of arylaldehyde (2 or 24) and pyrrole in ionic liquid (28), in the presence of methanesulfonic acid at 25 oC, followed by the oxidation with DDQ provides tetraarylporphyrins (3 or 25) in 41% yield along with N-confused tetraarylporphyrins (26 or 27) as a side product in 7% yield. The advantage of this methodology is the reusability of ionic liquid atleast 10 times without loss of catalytical activity.

(E) IODINE CATALYSED ONE-POT SYNTHESIS: An efficient, rapid and easy one-pot procedure has been developed by Zerrouki and co-workers,112 for the synthesis of meso-tetraphenylporphyrins (3) using iodine as a catalyst under microwave conditions (Scheme 1.9). This method presents several interesting advantages such as reasonably good yields (35–47%), the use of undistilled reagents and solvents, and short reaction times. A catalytical amount of iodine (0.2 equivalent) is sufficient to ensure the production of desired tetraphenylporphyrin (3). However, the use of high concentration of iodine resulted in the formation of biopolymers as a black residue.

HN

N

NH N

HN

CHO

2 1

I2, CH2Cl2p-chloranil (0.75 eq)

MW

3 Scheme 1.9

(F) MICROWAVE ASSISTED SYNTHESIS: Chauhan et al.113 has reported a microwave assisted cyclocondensation of different aryl aldehydes (29) with pyrrole to synthesize 5,10,15,20-tetraarylporphyrins (30) by using very low amount of propionic acid. The reported protocol demonstrated the high yields of 5,10,15,20-tetraarylporphyrins, as

26

compared to other previously reported dilution methods (Scheme 1.10). Additionally, this methodology prevents, the use of large quantity of propionic acid and affords the products in short reaction times.

HN

N

NH N

HN

CHO

1

R1R2

R3

R2R1

R3

R1

R2

R3

R1R2

R3

R2

R3

R1

R1, R2, R3 = H, Me, NO2, Cl29

30

MW, O2

Scheme 1.10

(G) HIGH VALENT TRANSITION METAL SALTS CATALYZED SYNTHESIS: Recently, Llama et al. has reported, the one-pot synthesis of tetraarylporphyrins by using high valent transition metal salts as shown in scheme 1.11.114 In this process, the transition metal salts such as VOCl3, TiCl4, Mn(OAc)3 were act as an oxidant, in the transformation of porphyrinogen (32) to porphyrin (34) via a radical mechanism (Scheme 1.11). 5,10,15,20-Tetraarylporphyrins (34) can be prepared in excellent yields by using this protocol and better results were obtained without the addition of Lewis acids such as BF3·Et2O or TFA. Further, the development of new synthetic methodologies to obtain high yields and purity of the target meso-tetraarylporphyrins is still represent a challenging task for the porphyrin chemists.

27

HN

N

NH N

HN1

XMn = TiCl4, VOCl3, Mn(OAc)3Ar = C6H5, 4-CH3C6H4, 4-OCH3C6H4

31

32

Ar H

ArH

H Ar

HAr

ArCHON

NH N

HN

Ar H

ArH

H Ar

HAr

N

NH N

HN

Ar

Ar

Ar

Ar

XMnXMn-1

H

34

33

Scheme 1.11

1.5.2 SYNTHESIS VIA 2+2 ADDITION

A series of symmetrical and unsymmetrical porphyrins have been synthesized using 2+2 methodology via condensation of two dipyrromethane fragments. A large variety of β- and meso-functionalized porphyrins were synthesized by using this method. This pioneering work was done by Macdonald and co-workers115 and this method is commonly known as the 2+2 Macdonald synthesis.

Similarly, the strapped porphyrins which are bridged between opposing meso-positions, have been prepared by Baldwin et al. using a bis-dipyrromethane and trimethylorthoformate as the one carbon unit.116 Smith et al. has synthesized meso-tetraarylporphyrins (36 and 37) containing two fold rotational symmetry (Scheme 1.12).117 The porphyrins (36 and 37) were obtained in 30% yield, comparable with those of the tetraarylporphyrins synthesized by adler methodology.

28

HN

HOR1

R3R2

NH

CH3CH2CO2H

N

NH N

HNR1

R3

R2

R1

R2

R3

2

36, R1 = H, R2 = Me, R3 = H37, R1 = OMe, R2 = F, R3 = Me

35

Scheme 1.12

Trans-substituted porphyrins were successfully synthesized by Lindsey et al. by treating meso-substituted dipyrromethane with an aldehyde using two step one-pot porphyrin synthesis.118 Porphyrin (40) bearing different meso-substituents were also synthesized by Lindsey and co-workers (Scheme 1.13).119 Moreover, Maruyama and co-workers120 have synthesized some unsymmetrical porphyrin dimers by taking 5,15-bis(hydroxymethyl)dipyrromethanes as a starting compounds. Using similar methodology Anderson121 has synthesized porphyrin dimers using substituted dipyrromethane and trimethylsilylpropynal as the one carbon fragment.

NH

NH N

HN

CH3

CH3

Cl

Br

HOOH

(i) TFA(ii) DDQ

N

NH N

HNCH3

CH3

Cl

Br

39 40

38

Scheme 1.13

29

In addition, various Diphenylporphyrins such as 5,15-di(2-nitrophenyl)porphyrin and other analogues have also been synthesized in 45% yield by reacting 3,3’-diethyl-4,4’-dimethyl-2,2’-dipyrromethane with substituted benzaldehydes.122

The substituent pattern of the porphyrins formed from 2+2 reactions can be broadly classified into four categories: (a) all β- and all meso-substituted, (b) all β- and two meso-substituted, (c) no β-substituted and two meso-substituted, (d) no β-substituted and four meso-substituted. Due to the versatile use of this method, (2+2) synthesis has been very popular in recent years for making a large variety of substituted tetraarylporphyrins.123-134

1.5.3 SYNTHESIS VIA 3+1 ADDITION

This synthetic route involves the condensation of a tripyrrane with a diformyl pyrrole. Tripyrrane molecule consists of three pyrrole groups, linked alpha to the ring nitrogens by two saturated carbons. By using this procedure, a porphyrin containing acrylic acid units on the same pyrrole was synthesized by Momentau et al.135,136 Similarly, octaalkylporphyrins were also synthesized by Lash et al., by the reaction of dialdehyde and tripyrrane.137 Several other porphyrins such as acenapthoporphyrins138 and phenanthrolinoporphyrins,139 containing fused 1,10-phenanthroline subunits have also been synthesized by Lash and co-workers. A variety of porphyrins such as monofunctionalized alkylporphyrins,140 oxybenzaporphyrins141 and carbachlorins were also synthesized by using 3+1 route.

1.5.4 SYNTHESIS VIA CYCLIZATION OF LINEAR TETRAPYRROLES

Cyclization of linear tetrapyrroles and bilanes has been found as a useful method to produce unsymmetrical porphyrins and to incorporate a variety of substituent at the β-positions. The most common tetrapyrroles used for porphyrin synthesis are a,c-biladienes. Dolphin et al.142 used 1-bromo-19-a,c-methylbiladienes as porphyrin precursors to synthesize vinylporphyrins. Biladienes can also be used for making dinaphthoporphyrins143 and many other porphyrin based phototherapeutic agents.144

30

1.6 PERIPHERAL FUNCTIONALIZATION OF meso-TETRAARYL PORPHYRINS: SYNTHESIS OF β-FUNCTIONALIZED PORPHYRIN ANALOGUES

Porphyrin and their metal complexes exhibit several unique physico-chemical properties which are mainly determined by the functional groups present over the porphyrin ring. Therefore, the development of efficient methods for functionalizing the porphyrin periphery has always been an area of interest for chemists. Functionalization of the porphyrin periphery can mainly achieved via two routes, first being the multistep synthesis from the monopyrrole subunits, while the second route involves, the reaction on preformed monofunctionalized porphyrins. Synthetic processes for the preparation of β-functionalized meso-tetraarylporphyrins mainly involves the electrophilic substitution reaction on the porphyrin ring involving β-positions. These reactions include nitration, halogenation, formylation etc. to prepare easily available precursors for further reactions to generate highly conjugated porphyrin analogues. A brief account on peripheral functionalization of meso-tetraarylporphyrins involving β-positions is dicussed below.

1.6.1 REACTIONS ON MONO-FUNCTIONALIZED meso-TETRAARYL PORPHYRINS INVOLVING β-POSITIONS

The classical reactions on the β-position of meso-tetraarylporphyrins mainly involve electrophilic substitution such as halogenation, formylation, nitration and the subsequent transformations with mono-functionalized porphyrins by using these functional groups to afford a variety of porphyrin systems. Moreover, β-positions of a porphyrin molecule offer additional potential due to the isolated double bond character, as four of the eight β-positions are not involved in the conjugated aromatic π-system. Thus, individual β-substituents can exert a directing effect on subsequent reactions. For the example the electrophilic addition and cycloaddition reactions on porphyrin periphery allow the preparation of a variety of porphyrin precursors for further reactions and several other modified porphyrin molecules.

31

(A) FUNCTIONALIZATION THROUGH β-NITRO TETRAARYLPORPHYRINS

In the past, researchers have been successful for introducing a variety of functionalities onto the porphyrin periphery. For example, the nitration at β-positions was performed by the reaction of meso-tetraphenylporphyrins with nitronium ion which is generated in situ either from Cu(NO3)2 or N2O4. This reaction is found to be dependent on the metal, coordinated to the porphyrin core. Copper(II), nickel(II) and palladium(II) porphyrins were found to undergo mono β-nitration exclusively. These are stable towards demetallation and can be prepared in high yields by using chromatography free procedures.145 2-Nitro-tetraarylporphyrins behave similar to the simpler nitroalkanes and hence, undergo Michael additions with a wide range of nucleophiles such as hydride, alkoxides, active methylene compounds, Grignard reagent etc. to afford a variety of β-substituted tetraarylporphyrins. Smith et al.146 have reported the selective formation of cyclopropylchlorins and functionalized trans-chlorins by the reaction of 2-nitro-5,10,15,20-tetraphenylporphyrin (41) with active methylene compounds, such as malononitrile and alkylcyanoacetates. Malononitrile reacts with 2-nitrotetraphenylporphyrin (41) in the presence of base at room temperature to afford cyclopropylchlorins (42), but the same reaction at 65 °C afforded trans-chlorin (43) (Scheme 1.14).

N

N N

N

NO2

N

N N

N

N

N N

N

CNCN

H

H

CNCN

NC CN

NCCH2CN ,K2CO3, 65 °C

°

M M

M

a, M = 2Hb, M = Znc, M = Cud, M = Ni

41 42

43

K2CO3, 65 CNCCH2CN

K2CO3, 25 °C

NCCH2CN

Scheme 1.14

32

Similarly, the β-fused pyrroloporphyrins (44) have been successfully synthesized by Smith et al. (Scheme 1.15) by reacting nickel(II) 2-nitro-5,10,15,20-tetraphenylporphyrin (41d), and α-isocyanoacetic esters in the presence of DBU.147

N

N N

N

NO2

NCCH2COOR

DBU, THFNiN

N N

NNi

NHCOOR

41d 44 Scheme 1.15

N

NN

N

ArAr

Ar Ar

NO2

Me MeO O

K2CO3, DMSON

N

NN

ArAr

Ar Ar

O

Me

OMe

H

Cu Cu

N

N

NN

ArAr

Ar Ar

Cu

XN

NH2XHAcOH, 60 0C

MeMe

46, X = NH47, X = NPh48, X = O

41c 45

Scheme 1.16

33

Porphyrins bearing 1,3-dicarbonyl compound (45) synthesized by Cavaleiro et al.,148 have been further functionalized to obtain the corresponding porphyrin derivatives containing a heterocyclic ring (46-48) (Scheme 1.16) at the β-position. In addition, the β-nitro group can also be displaced with softer nucleophiles, such as thiolates and sodium salt of benzaldoxime without the assistance of any other electron withdrawing functionality in nucleophilic aromatic substitution reaction.149,150

A regioselective synthesis of 2,3-dibromo-tetraphenylporphyrins (51 and 52) and 2,3-dicyano-tetraphenylporphyrins (53 and 54) have been achieved from the corresponding free base β-NO2-porphyrin (41a) by Smith et al.,151 which later on used as precursors for making (Scheme 1.17) fused porphyrinophthalocyanines and fused porphyrinotetrathiafulvalenes. They also reported the synthesis of hexabromoderivative by the exhaustive bromination followed by denitration of copper(II) β-nitro-tetraphenylporphryin.

NNH

NHN

NO2

NNH

NHN

NO2

NN

NN

BrN

NN

N

CN

Br

Br

CN Br

NNH

NHN

Br

Br

NO2

HHHNBS, CHCl3 NaBH4

THF

C u C N, q u i n

o l i n e

200 °c

SiO2, CHCl3,∆

Ni(Acac)2, toluene,∆or

M MCuCN, quinoline∆

53, M = Cu54, M = Ni

51, M = 2H52, M = Ni

41a 49 50

∆

Scheme 1.17

34

Recently, Sebestian and co-workers has designed a three step strategy for the synthesis of β, β-fused imidazolo porphyrin (56) from β-nitro porphyrin (41d) (Scheme 1.18).152 According to the literature, the protocol consists of three steps: (i) amination of β-pyrrolic position adjacent to nitro group, (ii) reduction of the nitro group to afford corresponding 2,3-diaminoporphyrin, and (iii) reaction with CH(OMe)3 followed by cyclization to furnish the desired porphyrin (56).

N

N N

N

NO2

NiN

N N

NNi

NO2

NH2

NaOH, toluene, reflux

NN N NH2

N

N N

NNi

NHN

i) NaBH4, Pd/ C 10%CH2Cl2, MeOH, 25 oC

ii) CH(OMe)3, HCl, toluene90 oC

41d

55

56Scheme 1.18

Porphyrins bearing chelating peripheral groups fully conjugated with the macrocyclic π-system were also prepared from 2-nitroporphyrins. Callot and coworkers153 have synthesized porphyrins bearing enaminoaldehyde and enaminoketone ligands at the porphyrin periphery. These porphyrins were later thionated by Lawesson’s reagent for making porphyrin dimers. Furthermore, the electron withdrawing ability of the nitro group has shown to activate the

35

porphyrin ring as a dienophile in 4+2 cycloadditions to form various chlorins, bacteriochlorins and isobacteriochlorin derivatives.154

(B) FUNCTIONALIZATION THROUGH β-AMINO TETRAARYLPORPHYRINS

β-Amino-tetraarylporphyrins are useful precursors for the preparation of a variety of functionalized porphyrins. Their easy accessibility from β-nitro-tetraarylporphyrins by reduction under standard SnCl2/HCl conditions made them interesting for modulating the physico-chemical properties of the porphyrin ring. Cavaleiro et al. has successfully incorporated various alkyloxy groups to the β-position by diazotization (Scheme 1.19) of the copper(II) β-aminotetraphenylporphyrin (57) followed by reaction with different alcohols155 in the presence of sodium alkoxide. After demetallation of these compounds to the corresponding free-base porphyrins (58-63) under acidic conditions, their ruffling behaviour has also been studied by cyclic voltametry calculations.

N

N N

N

NH2

CuN

NH N

HN

57

ORi) NaNO2, H+

ii) ROH, RONaiii) H2SO4, CH2Cl2

58-63

Compds R

585960616263

-CH3-CH2CH3-CH2CH2CH3-CH(CH3)2-C6H11-CH2C(CH3)3

Scheme 1.19 Chen et al. synthesized nickel(II) β-azido-tetraphenylporphyrin (65) from nickel(II) β-amino-tetraphenylporphyrin (64) and used as a precursor for the synthesis of β-triazoloporphyrin (66) as shown in the scheme 1.20.156

36

N

N N

NNi

NH2

1) NaNO2/ H2SO4THF/ H2O, rt

2) NaN3, rt N

N N

NNi

N3

R

CuSO4.5H2Oascorbic acidDMF, 50 oC

N

N N

NNi

N

HNN R

64 65

66 Scheme 1.20

In addition, fused pyridinoporphyrin (67) was synthesized from nickel(II) β-amino-porphyrins (64) by the treatment with α, β-unsaturated aldehyde (Scheme 1.21).157

N

N N

N

NH2

NiN

N N

NNi

64 67

NPropenal, H2SO4, THF

Pd(OAc)2

Scheme 1.21

37

Porphyrin quinone dyads and π-extended heterocyclic fused porphyrin derivatives were also synthesized from the aminoporphyrins.158 Porphyrin dione and tetraone derivatives can also be obtained from the mono and diamino porphyrin derivatives as reported by Crossley et al., and serve as a building block for the synthesis of various porphyrin arrays.159

β-Amino-tetraarylporphyrins (68-70) were allowed to react with cyclic enol ethers to yield pyrido[2,3-b]porphyrins (71-76) bearing two vicinal hydroxyalkyl groups (Scheme 1.22).160 These reactions are catalyzed by lanthanum triflate and occur under mild conditions. The two vicinal hydroxyalkyl groups present in the new porphyrin derivatives are potential sites for further modifications. They can also used for the introduction of hydrophobic/hydrophilic groups or carrier molecules (for medicinal applications), or to link the porphyrins with polymers.

NN

NN

ArArNH2

Ni NN

NN

Ar

Ar

Ar

NiN

OH

OHn

n

O n

i) CHCl3, La(OTf)3, ref luxii) p-TsOH, MeOH, rtAr Ar Ar

68, Ar = 3-(OCH3)C6H469, Ar = 4-BrC6H470, Ar = 4-(COOCH3)C6H4

71; Ar = 3-(OCH3)C6H4, n = 172; Ar = 4-BrC6H4, n = 173; Ar = 4-(COOCH3)C6H4, n = 174; Ar = 3-(OCH3)C6H4, n = 275; Ar = 4-BrC6H4, n = 276; Ar = 4-(COOCH3)C6H4, n = 2

68-70 71-76

Scheme 1.22

(C) FUNCTIONALIZATION THROUGH β- FORMYL TETRAARYLPORPHYRINS

Quite accessible β-formylporphyrins are often used as a basic unit for molecular design in the field of porphyrin chemistry. Therefore, their chemical transformations are the subject of extensive studies.161,162 The Wittig reaction of formylporphyrins and their metal complexes with different ylides is one of the most successful and accessible methods for the modification of β-formyl tetraarylporphyrins.163-165 Pizzotti et al. has carried out a series of

38

reactions for the synthesis of porphyrin (81) having π-conjugated group with an electron-withdrawing 4-nitrophenyl functionality at β-position as shown in the scheme 1.23.166

N

NH N

HN

Ph

Ph

Ph

Ph

CHO

N

NH N

HN

Ph

Ph

Ph

Ph

CH2OH

N

NH N

HN

Ph

Ph

Ph

Ph

CH2Cl

N

N N

N

Ph

Ph

Ph

PhN

NH N

HN

Ph

Ph

Ph

Ph

CH2PPh3Cl

NO2

NaBH4,EtOH SOCl2

Pyridine, Et2Oref lux

Ph3P, CHCl3ref lux

i) 4-Nitrocinnamaldehyde,DBU, 25 °C

ii) Zn(OAc)2.2H2O,CHCl3, MeOH, reflux

Zn

77 78 79

8081 Scheme 1.23

β-Formyl-tetraphenylporphyrin (77), on reduction with sodium borohydride in ethanol gives the corresponding alcohol (78). This compound, on reaction with thionylchloride in pyridine followed by reaction with triphenylphosphine in chloroform at reflux, yielded porphyrinyl phosphonium chloride (80), which then reacts with 4-nitrocinnamaldehyde at 25 °C in the presence of DBU followed by zinc insertion afforded zinc(II) porphyrin (81) with extended π-system. By carrying out this experiment, Pizzoti and co-workers for the first time, showed clear evidence for a significant perturbation of the energy from the porphyrin macrocycle due to conjugation between the porphyrinic π-system and the π-delocalized linker with electron withdrawing substituent. The Knoevenagel reaction is another promising reaction for the modification of β-formylporphyrins into the corresponding porphyrin acrylic acid conjugates.

39

This reaction was generally used for the preparation of vinyl and acrylic acid porphyrin derivatives.

N

N N

NNi

CHO

82

i) RNH2, AcOH, toluene, THF,ii) NaBH3CN, MeOH

∆

N

N N

NNi

HN

83, R = Ph84, R = 4-(EtOOC)C6H4

NO2

OOMe

NO2

OOH

85

86

R

Scheme 1.24

N

N N

NM

ROR'

H

87, R' = H, R = CH3, M = 2H88, R' = H, R = CH3, M = Cu89, R' = H, R = 4-CH3COC6H4, M = 2H90, R' = H, R = 4-CH3COC6H4, M = Cu91, R' = CH3CO, R = CH3, M = 2H92, R' = CH3CO, R = CH3, M = Cu93, R' = H, R = Ph, M = 2H94, R' = R' = H, R = Ph, M = Cu

Figure 1.18

40

Recently, a diverse range of the substituents have been introduced to the β-position of the porphyrins (83-86) by Boyle et al. (Scheme 1.24), through reductive amination of the nickel(II) 2-formyl-5,10,15,20-tetraphenylporphyrin (82).167 In order to achieve the condensation of β-formylporphyrins with various diketones, β-formylporphyrin iminium salts were generated in situ, which efficiently reacts with acetone, 1,4-diacetylbezene, 2-acetyl thiophene, acetylacetone and acetophenone (Figure 1.18) to afford a variety of β-substituted tetraphenylporphyrins (87-94).168

A large number of free-base and metallated porphyrins with π-conjugated functionalities such as vinyl and p-phenylene vinyl substituents have also been synthesized from β-formylporphyrin by several groups,169-172 to develop potential sensitizers for the dye sensitized solar cells. In the search of better photosensitizers, Lingamallu et al. has synthesized 2-carboxy-5,10,15,20-tetraphenylporphyrin (95) from 2-formyl-5,10,15,20-tetraphenylporphyrin (77) by using hydroxylamine hydrochloride and phthalic anhydride in the presence of triethylamine (Scheme 1.25).173 The absorption maxima and emission maxima of the newly synthesized compound (95) was found to be red shifted by 5-7 nm.

N

NH N

HN N

NH N

HN

COOHCHO

NH2OH.HCl, N(C2H5)3Phthalic anhydride

77 95 Scheme 1.25

Officer et al. synthesized a series of novel intense green porphyrins containing carboxylate anchoring groups, which have potential to be used as light sensitizers in TiO2 solar cells. β-formyl-TPP (77) has been used for the synthesis of β-ethynyl carboxylic acid porphyrins (96 and 101) and β-styryl carboxylic acid porphyrins (100) using both Knoevenagel condensation and Wittig reactions (Scheme 1.26).174

41

N

NH N

HN

Ph

Ph

Ph

Ph

CHO

N

N N

N

Ph

Ph

Ph

Ph

N

NH N

HN

Ph

Ph

Ph

PhN

N N

N

Ph

Ph

Ph

PhN

NH N

HN

Ph

Ph

Ph

Ph

i) Zn(OAc)2.2H2O, CHCl3, MeOH, 25 °C

Zn

CN

COOH

NC COOH Piperidine, CH3CN, ∆ii)iii) H3PO4

Zn

PPh3CO2Et

i) Wittig reaction (approx. 40% cis)ii) Isomerization

CO2Et

i) Zn(OAc)2.2H2O,CHCl3, MeOH, 25 °Cii) NaOH, THF/H2O/EtOH (5:1:5),reflux

N

N N

N

Ph

Ph

Ph

Ph Zn

CH2OH CHO

N

N N

N

Ph

Ph

Ph

Ph Z n

NCCOOH

NC COOHPiperidine, CH3CNreflux

i)ii) H3PO4

i) MnO2, CH2Cl2DIBAL

ii) Zn(OAc)2.2H2O,CHCl3, MeOH,25 °C

COOH

77 96

97 98 99

100101

25 °C

Scheme 1.26

Recently, Nath et al. has reported the synthesis of nickel(II) 2-benzazolo-5,10,15,20-tetraphenylporphyrins (102-109) by refluxing nickel(II) 2-formyl-5,10,15,20-tetraphenylporphyrin (82) and o-arylenediamines, o-aminophenols or o-aminothiophenol in 1,2-dichlorobenzene, in order to develop potential candidates for various applications ranging from medicine to molecular devices (Scheme 1.27).175

42

NN

NN

CHONi N

NN

NNi N

XY

102-109

RY

HX

H2N R

1,2-dichlorobenzene,160 °C

Compd.

NH N H

102103104105106107108109

NH CH HNH CH ClNH CH CO(C6H5)NH CH CNO CH HO CH CH3S CH H

82

X Y R

Scheme 1.27

1.6.2 CYCLIZATION REACTIONS INVOLVING β-POSITION

Cyclization reactions of the porphyrins can be divided into two categories, namely intramolecular cyclization reactions and intermolecular cyclization reactions. Generally, cyclization reactions yield the fused ring porphyrins. The formation of these fused rings affects the electronic structure of porphyrins by altering their optical properties, coordination chemistry and redox behaviour, and attracted many scientists around the globe to work in this area.

1.6.2.1 INTRAMOLECULAR CYCLIZATION REACTIONS

(A) METAL-MEDIATED CYCLIZATIONS

In the 1980s, Smith et al. described a palladium-catalyzed method to attach a number of unsaturated substituents directly to the periphery of mercurated porphyrins.176,177 During the synthesis of bis-chloromercurated porphyrin by mercuration of zinc(II) deuteroporphyrin IX

43

dimethyl ester, an unexpected tris-mercurated by-product, was obtained in which mercuration was occurred at the 5 or 10-position. These isomers were subjected to palladium catalyzed coupling reaction to form two porphyrin products bearing fused five-membered exocyclic rings.178 This synthetic method was then used to synthesize deoxyerythroetioporphyrin and deoxophylloerythrin methyl ester.

Recently, Fox and Boyle179 has reported a method for palladium-catalysed intramolecular cyclization of meso-(2-iodophenyl)porphyrins (110), which affords a variety of porphyrin derivatives (111-114), in which the meso-phenyl ring are fused to adjacent β-positions (Scheme 1.28).

N

N

NM RR

I

R2 R2R1

N

N

NM RR

R2 R2R1

Pd(PPh3)4, K3PO4

110111, R = H, R1 = COOMe, R2 = H, M = Ni112, R = H, R1 = H, R2 = OMe, M = Ni113, R = H, R1 = H, R2 = OMe, M = Cu114, R = 4-(COOMe)Ph, R1 = COOMe, R2 = H, M = Ni

Scheme 1.28

N

N N

N

BrBr

BrBr

N

N N

N

N

N N

NZn

Zn, DMSO

85 °C

115 116

117

Zn Zn

Scheme 1.29

44

Similarly, Chen et al.180 discovered that the treatment of zinc(II) 2-bromo-5,10,15,20-tetraphenylporphyrin with activated zinc metal resulted in the formation of a fused five-membered ring. This method has also been efficiently applied for the cyclization of tetrabromo-5,10,15,20-tetraphenylporphyrin derivative (115) to generate β-fused porphyrins (116 and 117) as shown in scheme 1.29.

(B) ACID CATALYZED CYCLIZATIONS

Cavaleiro et al.181 has reported an intramolecular cyclization of the nickel(II) β-vinyl-5,10,15,20-tetraarylporphyrins (118 or 119) under acidic conditions to form the corresponding naphthochlorins (120 and 121) as the major products in 60% yields. However, the formation of expected demetallated products, was not observed (Scheme 1.30).

N

N N

N N

N N

N

Dil. H2SO4Ni Ni

CH3H H

R

R

R

R R

R R

R

120, R = H121, R = OMe118, R = H

119, R = OMe Scheme 1.30

N

N N

N

CHO

N

N N

N

O

TFACu Cu

122 123 Scheme 1.31

45

Callot has used copper(II) 2-formyl-5,10,15,20-tetraphenylporphyrin (122) as a starting material intermediate in an acid-catalyzed condensation to yield oxonaphthoporphyrin (123).182 In this reaction, the carbonyl carbon of the aldehyde group was fused to the ortho-position of the adjacent meso-phenyl group, producing an exocyclic six-membered ring containing a keto group in a low yield (Scheme 1.31).

The success in the formation of mono oxonaphthoporphyrin (123) prompted Callot and co-workers to introduce two exocyclic six-membered rings with keto groups for producing bis-(oxonaphtho)porphyrin systems (129 and 130) as shown in scheme 1.32.

N

N N

N

Ph

PhPh

Ph

CN

CuN

NH N

HN

Ph

PhPh

Ph

COOH

N

N N

NPhPh

Ph

Ni

O

HBr-AcOH

(i) Ni(acac)2(ii) (COCl)2(iii) SnCl4

N

N N

N

Ph

Ph

Ph

Ph Cu

CN

R1

RN

N N

NPh

Ph

Ni

O

O

N

N N

NPhNi

O

Ph

O127, R = CN, R1 = H128, R = H. R1 = CN

(i) HBr-AcOH(ii) Ni(acac)2

124 125 126

129130

(iii) (COCl)2(iv) SnCl4

Scheme 1.32

Making such compounds by classical approach of acid catalyzed condensation of 2-formyl groups onto the meso-aryl ring is difficult as the formylation of TPP produces di or polyaldehydes which on subsequent cyclization could lead a complex mixture of oxonaphthoporphyrins along with numerous reduced species. Thus, Callot and co-workers183 developed a new synthetic approach for the preparation of mono-oxonaphthoporphyrin (126) and bis-(oxonaphtho)porphyrins (129 and 130). The carboxy group at the β-position of porphyrin is formed by the oxidation of cyano group using HBr-AcOH mixture. The addition

46

of two unsaturated rings in the plane of the porphyrin (129 and 130) and the corresponding extension of the conjugation induce interesting optical properties.

Recently, Cao et al.184 has synthesized, a pentasulfonated porphyrin bearing an internal cyclic sulfone ring as shown in scheme 1.33. The 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (131) on treatment with fuming H2SO4 gave a pentasulfonated porphyrin (132) with sulfone bridge between an ortho-position of one of the meso-phenyl groups and a β-pyrrolic position on the porphyrin ring.

N

NH N

HN N

NH N

HN

Fuming H2SO4

SO3H

SO3H

SO3H

HO3S

SO3H

SO3H

SO3H

HO3S

SO

O

25 °C, 2h

131 132 Scheme 1.33

(C) REDUCTIVE AND OXIDATIVE CYCLIZATION

The reaction of 2-nitroporphyrin with triethyl phosphite is found to be a very efficient route to form nitrogen heterocycles on porphyrin periphery. Callot and co-workers have been successful for synthesizing, N-containing six-membered ring, fused to the meso-phenyl and β-position of a meso-tetraarylporphyrin macrocycle by reacting β-nitroporphyrin (41d) with excess of triethyl phosphite at 155 °C in 1,2-dichlorobenzene. A green enamine porphyrin (133) was obtained as the major product (Scheme 1.34).153 Cavaleiro et al. has described a new methodology for making various N-arylquinolino[2,3,4-at]porphyrins (138-141) through thermal oxidative cyclization of β-arylaminoporphyrins (134-137), using nitrobenzene as a solvent (Scheme 1.35).185

47

N

N N

N

NO2

N

N N

N

NH

P(OEt)3Ni Ni

41d 133

1,2-dichlorobenzene

Scheme 1.34

N

NH N

HN

HNR

N

NH N

HN

N

R

PhNO2

ref lux

136, R = H137, R = Cl

134, R = Me135, R = Br

138, R = Me139, R = Br

140, R = H141, R = Cl

Scheme 1.35

N

N N

NNi

N3

142

N

N N

NNi

133

NH

Toluene, reflux

Scheme 1.36

Recently, Chen et al.156. has synthesized interesting green colored N-containing fused six membered porphyrin (133) by refluxing nickel(II) 2-azidotetraphenylporphyrins (142) in toluene within two hours (Scheme 1.36).

48

(D) BERGMAN CYCLIZATION

There are several reports available in the literature involving the intramolecular cyclization onto the porphyrin periphery to produce highly conjugated porphyrin analogues. Among these, Bergman aromatization of vicinal dialkynylporphrins (143 and 144) has been reported recently to produce a new class of highly π-extended porphyrins (145 and 146). 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (143 and 144) were prepared by Pd0-catalyzed cross-coupling reactions186 of 2,3-dibromo-5,10,15,20-tetraphenylporphyrins (51 and 52) with the corresponding alkynyl trimethylstannanes in good to excellent yields (Scheme 1.37). Refluxing (143) in chlorobenzene containing 5% 1,4-cyclohexadiene as a hydrogen donor at 190 °C afforded nickel(II) 10,15-diphenyl-piceno[20,1,2,3,4,5-fghij]-porphyrin (145) as a green colored material.187

NN

NN

Ph

Ph Ph

Ph

MBr

Br NN

NN

Ph

Ph Ph

Ph

M

NN

NN

Ph

Ph

M

TMSMe3SnPd(PPh3)4, THF, RefluxK2CO3, MeOH, THF

orTBAF, THF

H

H

H

H

CHCl3/MeOHDDQ, 25°C, 30 min51, M = 2H

52, M = Ni

145, M = Ni146, M = 2H

143, M = Ni144, M = 2H

1.

2.

Scheme 1.37

49

N

N

NN

NiN

N

N

N

Ni

PtCl2, toluene, 125 oC

toluene, 115 oC

R

R

N

N

N

N

NiTMS

N

N

N

N

NiR

RN

N

N

N

NiR

R

R = TMS

R = Ph, Pr, iPr

147 148 149

150 151

148 N

N

NN

Ni

152

PhPh

Ph Ph

Cl

R = HP t C l2 , toluene85-90 o C

Scheme 1.38

In addition, Zaleski et al.188 discovered that this cascade tandem radical cyclization can be performed at room temperature in chloroform in the presence of DDQ as an oxidant.

Recently, Zaleski et al. has reported the cyclization of the Ni(II) 2,3-dialkynylporphyins in the presence of stoichiometric to catalytic quantities of PtCl2 to form fused phenanthroporphyrins (148-150) along with picenoporphyrin (151) and benzoporphyrin scaffold (152) at moderate temperatures as shown in scheme 1.38.189

Furthermore, Zaleski et al.190 has extended this methodology to synthesize Ni(II) bisphenanthroporphyrins (154 and 155) and Ni(II) picenophenanthroporphyrin (157) through a PtCl2-mediated 6-endo-dig cyclization pathway (Scheme 1.39). The reaction products are generated in good yields and at modest reaction temperatures. These novel π-extended porphyrins may find utility in optoelectronic, photovoltaic or imaging applications.

50

N

N

N

N

N

N

NN

Ni

Ni

N

N

NN

Ni N

N

NN

Ni

N

N

NN

Ni

PtCl2, toluene

90 oC, 8 hours

toluene, 115 oC, 1.5 hours

PtCl2, toluene

90 oC, 8 hours

153154 155

156157

Scheme 1.39

1.6.2.2 INTERMOLECULAR CYCLIZATION REACTIONS

Adequately substituted tetraarylporphyrins can act as heterodienes, dienophiles, dipolarophiles, and 1,3-dipoles, hence, these can undergo intermolecular cyclization through pericyclic reactions.191 All these reactions performed by the porphyrins have been used as an effective tool to synthesize new biologically active porphyrinic based architectures.

(A) PORPHYRINS AS A DIENE: The Diels–Alder reaction of vinylporphyrins with electron-deficient dienophiles192 can be utilized to synthesize variety of bacteriochlorins and isobacteriochlorins.193 Recently, Cavaleiro and co-workers has successfully used the β-iminoporphyrins (158) as heterodiene in Diels-Alder reactions for the synthesis of pyridoporphyrin derivative (159) as shown in scheme 1.40. The N-protected pyrroles have also been successfully used in a variety of [4+2] cycloaddition reactions with activated dienophiles as described by Zhang and Trudell.194

51

N

NH N

HN

Ph

PhPh

Ph

N

H

O

La(OTf)3 N

NH N

HN

Ph

PhPh

Ph

N

H

O

H

158 159 Scheme 1.40

N

NH N

HN

Ar

Ar

ArArN

NH N

HN

Ar

Ar

ArArN

NH N

HN

Ar

Ar

ArAr

CNCNNC CN

CNCNCN

CN

TCNE

160, Ar = Ph161, Ar = 4-MeOC6H4

162 163

N

NH N

HN

Ph

Ph

PhPh

MeO2C CO2Me

N

NH N

HN

Ph

Ph

PhPh

MeO2C CO2Me

164 165

DMAD

Scheme 1.41

Smith et al.195 synthesized β-fused pyrroloporphyrins from the Barton–Zard condensation196 of 2-nitro-5,10,15,20-tetraphenylporphyrins with isocyanoacetates. The possibility of β-vinyl-tetraarylporphyrins (160 or 161) to act as dienes in Diels-Alder reaction was investigated197 with tetracyanoethylene (TCNE), both the [4+2] and [2+2] adducts 162 and

52

163 were obtained respectively. NMR studies showed that the [2+2] adduct 163 was obtained by the rearrangement of the chlorin product 162. The vinyl-porphyrin 160 also reacts with dimethylacetylene dicarboxylate (DMAD) to yield chlorin 164 and the benzoporphyrin 165. Further compound 165 can be obtained in quantitative yield by oxidation of 164 with DDQ (Scheme 1.41).

(B) PORPHYRIN AS DIENOPHILE: Cavaleiro et al.198 investigated [4+2] cycloadditions using the porphyrin exocyclic double bonds as the 2π-electron component. On heating 5,10,15,20-tetraphenylporphyrin (3) reacted with an aromatic sulfone (166) in trichloro benzene for 7 hours, to produce a chlorine (168) with a fused tetrahydronaphthalene ring as the major product (Scheme 1.42).

N

NH N

HN

Ph

Ph

PhPh +

SO2

N

NH N

HN

Ph

Ph

PhPhH

HH

H

H

H

3

166

167

168

∆-SO2

Scheme 1.42

N

NH

NHN

Ar

Ar Ar

Ar

N

NH

NHN

Ar

ArAr

Ar

172, Ar = C6H5173, Ar = C6F5174, Ar = 4-MeOC6H4

171

3, Ar = C6H5169, Ar = C6F5170, Ar = 4-MeOC6H4

Scheme 1.43

53

Novel chlorins fused with barrelene moieties (172-174) were also prepared by Cavaleiro and co-workers199 in moderate to good yields from the Diels–Alder reaction of meso-tetraarylporphyrins (3, 169 and 170) with pentacene (171) in 1,2,4-trichlorobenzene at 200 °C (Scheme 1.43).

(C) PORPHYRINS AS DIPOLAROPHILE: Porphyrin can also undergo 1,3-dipolar cycloaddition reaction and can act as a dipolarophiles with a variety of 1,3-dipoles. Azomethine ylides can be generated in situ by reacting paraformaldehyde with N-methylglycine and undergo 1,3-dipolar cycloaddition reaction with meso-tetraarylporphyrins to yield chlorins (monoadducts; 179-183) along with isomeric isobacteriochlorins (bisadducts) as shown in scheme 1.44200

N

NH N

HN

Ar

Ar

Ar

Ar

X H CH

O HNCOOH

H3C

HC

HN CH2CH3 N

NH N

HN

Ar

Ar

Ar

Ar

NCH3X

Isobacteriochlorins(bisadducts)

3, 179: Ar = C6H5, X = H41a, 180: Ar = C6H5, X = NO2169, 181: Ar = C6F5, X = H170, 182: Ar = 4-(OCH3)C6H4, X = H178, 183: Ar = 2,6-Cl2C6H3, X = H

3, 41a, 169, 170, 178

175 176

177

179-183

toluene,reflux

Scheme 1.44

Isobacteriochlorins can be obtained as main products if a large excess of azomethine ylide is used in the reaction. Porphyrins with electron-withdrawing groups at the meso-position such as (pentafluorophenyl and 2,6-dichlorophenyl groups) were found to be the most reactive. The reactivity of porphyrin macrocycle can be increased by the introduction of a nitro group at the β-pyrrolic position which makes the reaction site selective to provide mainly the chlorin derivative (180) resulting from the attack of the azomethine ylide to the double bond bearing the nitro group.

54

The synthesis of mixed cycloadducts (186 and 187) using the chlorins 184 and 185 as starting materials is shown in scheme 1.45. The starting materials 184 and 185 were synthesized from the Diels-Alder reaction of meso tetrakis(pentafluorophenyl)porphyrin with pentacene or orthobenzoquino-dimethane,201 respectively. The reaction of chlorins 184 and 185 with azomethine ylide 177 gave mainly the isobacteriochlorins (186 and 187), respectively.

N

NH

NHN

Ar

ArAr

Ar

=

NH

N

NHN

Ar

ArAr

Ar

NCH3

HC

HN CH2CH3

Ar = C6F5

177

184

186 187

=185

NH

N

NHN

Ar

ArAr

Ar

NCH3

Scheme 1.45

These results describe that the second addition of azomethine yilde to the macrocycle occurs preferentially at the β-pyrrolic double bond adjacent to the ring already fused to the porphyrin periphery. Other aminoacids have also been successfully used as precursors to generate various azomethine ylides which behaves as 1,3-dipoles and yielded the corresponding desired chlorins202 on the reaction with meso-tetraarylporphyrins. 1,3-Dipolar [3+2] cycloaddition reactions are very effective protocols for the incorporation of five-

55

membered heterocycles203 to the porphyrin periphery. Cavaleiro et al. have used diazoalkanes204 and nitrones205,206 as 1,3-dipoles in Diels-Alder reaction with porphyrins. It has been observed that electron-deficient carbonyl ylides react with many dipolarophiles including aromatic systems.207 Moreover, non-stabilized carbonyl ylides have been shown to react with both electron-rich and electron-poor dipolarophiles.208 Fleming and Dolphin209 exploited these findings to devise a convenient route to chlorin derivatives via carbonyl ylides. On heating, the reaction of TPP (3) with tetracyanoethylene oxide (TCNEO, 188) provides the corresponding cycloadduct (190) in moderate yield (Scheme 1.46). The tetracyanoethylene oxide (188) undergoes first-order thermal electrocyclic ring opening to form the carbonyl ylide (189) in refluxing toluene. This ylide then reacts via a 1,3-dipolar cycloaddition with the dipolarophile (3) to yield a [3+2] adduct (190).

N

NH N

HN

Ph

Ph

Ph

Ph

O

NCNC

CNCN

O

NCNC

CNCN

N

NH N

HN

Ph

Ph

Ph

Ph

ONC CN

CNCN

∆188

189

3 190

Scheme 1.46

Recently, Cavaleiro and co-workers210 have successfully shown that the meso-tetrakis(pentafluorophenyl)porphyrin (169) undergoes 1,3-dipolar addition with N-aryl-C-ethoxycarbonylnitrile imines (192; generated in situ by base-induced dehydrobromination of ethyl hydrazono-α-bromoglyoxylates (191) to afford novel pyrazolochlorins (193-196) in moderate yields (Scheme 1.47). The photophysical properties of new chlorins (193-196) suggest that compounds (193 and 195) have potential to be used as photosensitizer in photodynamic therapy.

56

N

NH

NHN

C6F5

C6F5C6F5

C6F5

HNR N

CO2Et

Br

NR N CO2Et

N

NH

NHN

C6F5

C6F5C6F5

C6F5

NN

R

CO2Et

base

193, R = CH3194, R = OCH3195, R = Cl196, R = NO2

191

192

169 193-196

Scheme 1.47

(D) PORPHYRIN AS 1,3-DIPOLE: Porphyrins can act as an 1,3-dipole via porphyrinic azomethine ylide, which can be generated by the reaction of 2-formyl-5,10,15,20-tetraphenylporphyrin with N-methylglycine (176). It reacts with a range of dipolarophiles to yield the corresponding porpyrin adducts. Cavaleiro et al have synthesized new β-substituted meso-tetraphenylporphyrins (198) by reacting nickel(II) β-formyl-meso-tetraphenylporphyrin (82) with N-methylglycine (176) to generate porphyrinic azomethine ylide (197)211 in situ. The porphyrinic azomethine ylide (197), then undergo reaction with several dipolarophiles such as dimethylfumarate, trans-β-nitrostyrene, and N-phenylmaleimide etc., to yield new class of β-substituted porphyrin derivatives (198) (Scheme 1.48).212

N

N N

N

Ph

Ph

PhPh

CHO HNCOOH

Me

N

N N

N

Ph

Ph

PhPh

HC N CH2Me

N

N N

N

Ph

Ph

PhPh

NMe

Z

Z

NiNi NiToluene,reflux

Z

Z

82

178

197 198 Scheme 1.48

57

E) ELECTROCYCLIZATION REACTIONS: For the first time, it was found that in the absence of dienophiles, β-butadienylporphyrin (199) can undergo electrocyclization reaction followed by oxidation to give monobenzoporphyrin (202) in good yield (Scheme 1.49).

N

N N

N

Ph

Ph

Ph

PhN

N N

N

Ph

Ph

Ph

PhN

N N

N

Ph

Ph

Ph

Ph

N

N N

N

Ph

Ph

Ph

PhN

N N

N

Ph

Ph

Ph

PhN

N N

N

Ph

Ph

Ph

Ph

Ni Ni Ni

Ni Ni Ni

∆ ∆ ∆

199 200 201

202 203 204 Scheme 1.49

Similarly, adjacent and opposite dibenzoporphyrins (203 and 204) were successfully synthesized from adjacent and opposite β, β’-dibutadienylporphyrins (200 and 201), respectively.213

N

N N

N

Ph

Ph

Ph

Ph

CHO

NiN

N N

N

Ph

Ph

Ph

Ph

HC

NiN

N N

N

Ph

Ph

Ph

Ph Ni

NR

CH2 NR

RNHCH2CO2H

206, R = Me207, R = Bu

82 197, R = Me205, R = Bu

Scheme 1.50

58

In the absence of dipolarophiles the porphyrin azomethine ylides (197 and 205) undergo 1,5-electrocyclization reaction to afford pyrrolo[3,4-b]porphyrins (206 and 207) in the absence of dipolarophiles (Scheme 1.50).214 Porphyrin azomethine ylide (197 and 205) were obtained by the reaction of nickel (II) 2-formyl-5,10,15,20-tetraphenylporphyrin (82) with glycine derivatives. Dipyrrolofused porphyrins were also synthesized by the similar electrocyclization of diformylporphyrin derivatives.

1.6.3 MISCELLANEOUS REACTIONS INVOLVING β-POSITIONS

1.6.3.1 RING CONTRACTION REACTIONS

Recently, Zaleski and co-coworkers has synthesized diazo-oxochlorins (209) by the reaction of the corresponding metallated dioxochlorin precursors (208) and tosylhydrazine in the presence of Zn(OAc)2 in dichloromethane.215 The diazo-oxochlorins, (209) then undergo photolysis,216 in chloroform/methanol mixture to produce two major and two minor porphyrin products. The two major products were identified as unusual pyrrole ring-contracted azeteoporphyrin compound (213; 16%), derived from the Wolff rearrangement followed by quenching with MeOH and 2,2-dimethoxy-3-oxo-5,10,15,20-tetraphenylchlorin (211) in 32% yield. The two minor products were also identified as 2-methoxy-3-oxo-5,10,15,20-tetraphenylchlorins (212) and 2-hydroxy-5,10,15,20-tetraphenylporphyrins (210) (Scheme 1.51). A porphyrin dimer was also formed in low yield during the photolysis of of nickel complex of diazo-oxochlorin (209).

59

NN

NN

O

ON

NN

N O

N2TsNHNH2M M

NN

NNM H

OOMeN

NN

NM

OHN

NN

NM

hνCH2Cl2, MeOH

213

208 209

210 211, R = OMe212, R = H

OMeR

O

Zn(OAc)2, CH2Cl2

M = Ni, Cu, Zn

Scheme 1.51

1.6.3.2 CLEAVAGE OF β, β’-BONDS

Chlorophins and bacteriophins are porphyrin derivatives in which one or two sets of β,β′-pyrrolic carbon atoms have been removed. Their photophysical properties are similar to the chlorins and bacteriochlorins and they also have close relationship to various structural models of the porphyrin π-system.217 A novel and convenient approach to chlorophins (216-218) and bacteriophins (219) has been developed through a degradation of nickel(II) 2,3,12,13-tetrabromo-5,10,15,20-tetraphenylporphyrin (214) by sodium salt of E-benzaldoxime (215) on heating in DMSO containing CuBr under inert atmosphere (Scheme 1.52). The mechanism of the reaction is not yet clear. However, the degradation of two pyrrole units is unusual and rare in the field of porphyrin chemistry.

60

N

N N

N

Ph

Ph

Ph

Ph

BrBr

BrBr

NiN

N N

N

Ph

Ph

Ph

Ph

XY

NiN

N N

N

Ph

Ph

Ph

Ph Ni

216, X = Y = Br217, X = Br, Y = H218, X = Y = H

N ONa

CuBr, DMSON2, ∆

214 216-218 219

215

Scheme 1.52

1.7 SYNTHESIS OF DIPORPHYRIN ANALOGUES

Di-porphyrins are found to be very useful for energy and electron-transfer processes. Notably, these have been employed as catalysts and molecular hosts for the selective encapsulation of guest molecules. Researchers have reported a wide variety of porphyrin dimers with varying degree of fluxionality between two porphyrin units. Direct conjugation between the porphyrin units in these systems showed interesting physico-chemical properties. In the past several years meso-meso, meso-β and β-β-linked porphyrin dimers have been synthesized and they have shown potential applications in number of areas ranging from medicine to optoelectronics.

1.7.1 meso, meso-LINKED DIPORPHYRIN ANALOGUES

In the last few years, effort have been made to synthesize meso,meso-linked di-porphyrins due to their unique photophysical properties. For making meso, meso-linked diporphyrins, a sonogashira coupling reaction was performed between iodo- and alkyne-functionalized tetraarylporphyrins in presence of Pd(0) catalyst to generate diporphyrin (222). Lindsey’s group has synthesized diporphyrin (222) through Pd-catalyzed cross-coupling reaction between zinc(II) 5-(4-ethynylphenyl)-10,15,20-triarylporphyrin (220) and 5-(4-iodophenyl)-10,15,20-triarylporphyrin (221) (Scheme 1.53).218,219 They have also been successful to obtain a linear porphyrin trimer using same methodology.220-222 The coupling between zinc(II) 5-(4-azidophenyl)-10,15,20-triarylporphyrin (223) and zinc(II) 5-(4-ethynylphenyl)-

61

10,15,20-tri(4-tert-butylphenyl)porphyrin (224) in THF-water mixture, containing copper carbene complex with SIMes ligand (SIMes = N,N’-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene) afforded 1,2,3-triazole-bridge porphyrin dimer (225) (Scheme 1.54).223

N

N N

N

Ar

Ar

ArN

HNN

NH

Ar

Ar

ArI

N

N N

N

Ar

Ar

ArN

HNN

NH

Ar

Ar

Ar

Pd(PPh3)4, toluene

Ar =

Me

Me

Me

Zn

Zn

220 221

222

Et3N

Scheme 1.53

N

N N

N

Ar

Ar

Ar

N3

N

N N

N

Ar

ArN NN

(SIMes)CuBr,THF/Water (3:1),45 °C

Ar =

Zn

Zn

N

N N

N

Ar

Ar

Ar Zn

N

N N

N

Ar

Ar

Ar Zn

223 224

225

Ar

Scheme 1.54

62

N

NH N

HNCHO

NH

CHO

CH3CH2COOHreflux

N

NH N

HN N

NH N

HN

226

21

227 Scheme 1.55

Furthermore, the Adler method was employed to make meso-meso arene-linked porphyrin dyad (227) via the condensation of porphyrin (226) with excess of pyrrole and benzaldehyde in refluxing propionic acid (Scheme 1.55).224 A covalently linked bis-porphyrin (230) have also been synthesized by Bhyrappa et al.225 by coupling of a octobromo porphyrin (229) with Zinc(II) 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (228) in the presence of K2CO3 as base at 60 oC (Scheme 1.56).

N

N N

NZn

N

N N

NZnOH

BrBr

BrBrBr

Br

BrBr

OOBr

N

N N

NZn O

N

N N

NZn

BrBr

BrBrBr

Br

BrBr

OO

DMF, K2CO3, 60 oC

228 229

230

Scheme 1.56

63

N

N N

NZn

N

N N

NZn NH2

Toluene, pyridine232231

F

FF

F

F

F F

F

FF

F

FF

F

F

ClOC

C HNO

233

N

NN

NZ n

F

FF

F

F

FF

F

F F

F

FF

F

F

N

N N

NZn

N(CH3)2

(H3C)2N

N(CH3)2

N(CH3)2

N(CH3)2

N(CH3)2

Scheme 1.57

Further, steady-state fluorescence studies of diporphyrin (230) indicated, dramatic decrease in fluorescence quantum yields of the TPP moiety. Electrochemical redox and fluorescence data have suggested the possible existence of intramolecular interactions in the diporphyrin analogue (230).

Gust et al.226 has successfully synthesized amide linked bis-porphyrin (233) by reacting acid chloride of zinc(II) 5-(4-carboxyphenyl)-10,15,20-tris(pentafluoropheny1)porphyrin (231) and zinc(II) 5-(4-aminopheny1)-10,15,20-tris(4-N,N-dimethylaminophenyl)porphyrin (232) in the presence of pyridine in toluene (Scheme 1.57). The meso,meso-linked piperazine bridged porphyrin dimer, N,N’-di(5,10,15,20-tetraphenylporphinato)piperazine (235) has been synthesized (Scheme 1.58) by direct condensation of benzaldehyde (2), hetrocycle substituted benzaldehyde (234), with pyrrole (1) using Lindsey method.227

64

N

NH N

HNN

NN

NH N

HN

235

NN CHOOHC

HNCHO

BF3Et2O, CH2Cl2

234 1 2

Scheme 1.58

This porphyrin (235) was tested against liver cancer cells, stomach tumor cells and nasopharyngeal carcinoma cancer cells by the MTT assay. In comparision to cis-platinum (cis-Pt) and 5-Fluorouracil (5-Fu), porphyrin (235) have demonstrated better anticancer activity and thus, might have potential to be used in PDT applications.

1.7.2 β, meso-LINKED DIPORPHYRIN ANALOGUES

Although, very few reports are available on the synthesis of β, meso-phenyl linked diporphyrins, the Suzuki coupling protocol has been successfully employed to link various porphyrins and metalloporphyrins to generate desired β, meso-linked diporphyrins. Chan and Zhou228 provided the first synthesis of the formation of a heterodimer (238) in which β and meso-phenyl of porphyrins are directly linked by Suzuki coupling of a meso-tetraarylporphyrin-boronate (236) with zinc(II) 2-bromo-5,10,15,20-tetraphenylporphyrin (237) (Scheme 1.59).

65

N

NH N

HN

Ph

Ph

Ph BO

O

NN

NN

Ph Ph

PhPhBr

N

NH N

HN

Ph

Ph

PhN

NN

N

Ph

PhPh

Ph

Zn

Zn

Pd(PPh3)4, K2CO3,toluene, 100 °C

236237

238

Scheme 1.59 Similarly Gotz et al.229 has synthesized β, meso-linked dimeric porphyrin derivative (241) using Suzuki coupling of 5-bromo-10,15,20-triphenylporphyrin (240) with β-borylated 5,10,15,20-tetraphenylporphyrin (239) as shown in scheme 1.60.

N

NH N

HN

Ph

Ph

Ph

PhN

NH N

HN

Ph

Br

Ph

Ph

BO

O

Ba(OH)2.8H2OPd(PPh3)4, tolueneH2O, reflux

NNH

NHN

Ph Ph

Ph

N

NH N

HNPh

Ph

Ph

Ph

239 240

241 Scheme 1.60

66

N

NH N

HN NO

N

NN

N

N

NH N

HN NH2

OHN

N N

N

OHC

M

La(OTf)31,2-Dichlorobenzene

1 6 0 ° C M = 2HM = Ni

M

243, M = 2H244, M = Ni

242

77

82

Scheme 1.61

Nath and co-workers has synthesized230 β, meso-benzoxazole-linked diporphyrins (243 and 244), through La(OTf)3 catalyzed reaction of newly prepared 5-(3-amino-4-hydroxyphenyl)-10,15,20-triphenylporphyrin (242) with 2-formyl-TPP (77 and 82) in 1,2-dichlorobenzene (Scheme 1.61). The fluorescence studies of these molecules showed efficient intramolecular energy transfer between two porphyrin units. The fluorescence quenching was also observed in β, meso-benzoxazolyl- bridged porphyrin dyads and it was attributed to the possible nonplanarity of the diporphyrins.

67

N

NH N

HN

NN

NN

O

ONH2

NH2

M

N

HNN

NH

N

NN

N

NNM

1,2-Dichlorobenzene,100°c, 3 hours

246, M = 2H,247, M = Zn

248, M = 2H,249, M = Zn

245

Scheme 1.62

Furthermore, a simple and efficient synthetic protocol for the construction of novel meso-substituted quinoxalinoporphyrins has been also developed by Nath and co-workers. This methodology was explored to obtain β, meso-fused quinoxalinodiporphyrins (248 and 249)231 for the first time from the reaction of diaminoporphyrin (245) and porphyrin-2,3-diones (246 or 247) in 65–70% yields (Scheme 1.62). The preliminary photophysical studies showed a significant intramolecular energy transfer between two porphyrin units of these synthesized quinoxalinoporphyrin dyads (248 and 249).

68

1.7.3 β, β-LINKED DIPORPHYRIN ANALOGUES

In recent years, synthesis of bridged bis-porphyrins and oligomeric porphyrins has became a focus of many researchers because of their unique chemical and physical properties. The variety of porphyrin dimers and oligomers have been synthesized and studied widely as chemical sensors, and phototherapeutic drugs etc. Several β, β-linked porphyrin dyads have been synthesized in order to carry out the energy transfer studies. According to the literature Glaser coupling reactions are useful for the formation of carbon-carbon bond via dimerization of terminal alkynes in the presence of Cu(OAc)2 in pyridine/MeOH mixture.232 Thus Arnold et al.233 examined similar reactions with Nickel(II) 2-ethynyl-5,10,15,20-tetraphenylporphyrin (250) and demonstrated the formation of β,β-butadinyl bridged porphyrin dimer (251) (Scheme 1.63).

NN

NN

Ph

PhPh

Ph

Ni NN

NN

Ph

PhPh

Ph

Ni NN

NN

Ph

Ph Ph

Ph

Ni

250 251

Pyridine/MeOH

Cu(OAc)2

Scheme 1.63

Chan et al234 have shown a facile synthetic protocol for the preparation of various β-aryl substituted tetraarylporphyrins through Suzuki cross coupling reaction235 of 2-bromoporphyrins with the corresponding aryl boronic acid in the presence of Pd0 catalyst. This methodology has been successfully extended to synthesize various β, β-linked tetraarylporphyrins.

The β, β-linked bis-porphyrins (254) have been synthesized by using an optimized Suzuki-Miyaura coupling procedure236 (Scheme 1.64), from β-borylated tetraarylporphyrins (252) and β-monobromo tetraarylporphyrins (253).

69

N

N N

N

Ar

Ar

Ar

Ar

BO

O Me

Me

Me

MeN

N N

N

Ar

Ar

Ar

ArM M1

Br

NN

NN

Ar

ArAr

Ar

M1NN

NN

Ar

ArAr

Ar

M

Pd(PPh3)4,Ba(OH)2 .8H2Otoluene/H2O, reflux

252 253

254 Scheme 1.64

Quite accessible β-formylporphyrins are often used as a basic unit for molecular design in the field of porphyrin chemistry. The Wittig reaction of formylporphyrins and their metal complexes with different ylides, is one of the most successful and accessible procedures for the synthesis of β, β’-linked porphyrins.164

N

NH N

HN

Ph

Ph

Ph

Ph

PPh3Cl

NN

NN

Ph

Ph Ph

Ph

MO

H

NNH

NHN

Ph

PhPh

Ph

N

N N

N

Ph

Ph

Ph

Ph M

25-40% aq.NaOH,CH2Cl2, 25 °C255

256

257

Scheme 1.65

70

Bonfantini and Officer, subsequently employed porphyrinyl phosphonium salt (255) in a two-phase Wittig reaction with porphyrin aldehyde (256) to give butadiene-linked diporphyrin (257) in 62% yield (Scheme 1.65).237

NNH

NHN

Ph

PhPh

PhCHO

NN

NN

Ph

PhPh

Ph Br

Br NN

NN

Ph

PhPh

PhH

NN

NN

Ph

PhPh

Ph

NN

NN

Ph

PhPh

Ph

Zn

Zn Zn

ZnCBr4, PPh3, ZnCH2Cl2

BuLi, THF,-78 oC

I

IPd(PPh3)4, CuI, Et3N, toluene

77 258 259

260

Scheme 1.66

Konig et al238 has synthesized photoactive bis-porphyrin array (260) by using palladium catalyzed coupling reaction of zinc(II ) 2-ethynyl-5,10,15,20-tetraphenylporphyrin (259) with 1,2-diiodobenzene, in the presence of Pd(PPh3)4, CuI and Et3N in toluene (Scheme 1.66).

β, β-linked azoloporphyrin dyads (261 and 262) have been synthesized by Nath and co-workers from the reaction of readily available nickel(II) 2-formyl-5,10,15,20-tetraphenylporphyrin (82) and o-arylenediamines in 1,2-dichlorobenzene, to develop potential candidates for various applications ranging from medicine to molecular devices (Scheme 1.67).175

71

N

N

NNNi

CHO

N

N

NNNi N

NN

NNi

N

NN

NNi N

N

NN

N

HNN

NH

NNHN

NH

H2N

H2N

NH2

NH2.4HCl

H2N

H2N

NH2NH2

1,2-Dichlorobenzene,160 °C

1,2-Dichlorobenzene,160 °C

82

261

262

Ni

Scheme 1.67

1.8 CONCLUSIONS

This review gives an overall view on the synthesis and peripheral functionalization of meso-tetraarylporphyrins. A large number of porphyrin architectures have been designed and synthesized since the pioneering work of Hans Fischer in the late 1920’s for various applications ranging from material sciences to medicine. The field of synthetic porphyrin chemistry is a vibrant and rapidly changing area of research as these molecules play vital roles in human life and have the potential to be used as phototherapeutic agents in photodynamic therapy for the treatment of cancer. Reactions leading to porphyrins bearing fused ring systems have provided a wide range of novel macrocyclic molecules for diverse applications. Since most of the photosensitizers currently in human clinical trials are porphyrin based, therefore, we can anticipate a continued and high interest in this area apart from the development of porphyrinic aromatic superstructures for other potential applications.

72

1.9 REFERENCES

1. Straight, S. D.; Kodis, G.; Terazono, Y.; Hambourger, M.; Moore, T. A.; Moore, A. L.; Gust, D. Nat. Nanotechnol. 2008, 3, 280.

2. Zakavi, S.; Pour, G. R. K.; Gharab, N. G. Catalysis Comm. 2009, 10, 388. 3. Starnes, S. D.; Arungundram, S.; Saunders, C. H. Tetrahedron Lett. 2002, 43, 7785. 4. Lin, V. S. Y.; Dimagno, S. G.; Therien, M. J. Science. 1994, 264, 1105. 5. Kralova, J.; Kejik, Z.; Brija, T.; Pouckova, P.; Kral, A.; Martasek, P.; Kral, V. J. Med.

Chem. 2010, 53, 128. 6. Jori, G.; Fabris, C.; Soncin, M.; Ferro, S.; Coppellotti, O.; Dei, D.; Fantetti, L.; Chiti,

G.; Roncucc, G. Lasers Surg. Med. 2006, 38, 468. 7. Ozawa, T.; Santos, R. A.; Lamborn, K. R.; Bauer, W. F.; Koo, M-S; Kahl, S. B.; Deen,

D. F. Mol. Pharmaceutics. 2004, 1, 368. 8. Milgrom, L. R. The Colors of Life. An introduction to the chemistry of porphyrins and

related compounds; Oxford University Press: Oxford, ed.; 1997, 1-249. 9. Dolphin, D. The porphyrins Academic press, New York. 1978, vol 1-6. 10. Kuster, W. Z. Physiol. Chem. 1912, 82, 463. 11. Song, Y.; Haddad, R. E.; Jia, S. L. J. Am. Chem. Soc. 2005, 127, 1179. 12. Retsek, J. L.; Drain, C. M.; Kirmaier, C. J. Am. Chem. Soc. 2003, 125, 9787. 13. Becker, D. C.; Bradely, B. R.; Waston, C. J. J. Am. Chem. Soc. 1961, 83, 3743. 14. Thomas, D. W.; Martell, A. E. J. Am. Chem. Soc. 1959, 81, 5111. 15. Soret, J. L. Compt. Rend. 1883, 97, 1267. 16. Gamgee, A. Z. Biol. Munich 1897, 34, 505. 17. Gouterman, M. J. Chem. Phys. 1959, 30, 1139. 18. Gouterman, M.; Wagniere, G.; Synder, L. C. J. Mol. Spectrosc. 1963, 11, 108. 19. Weiss, C. Jr. J. Mol. Spectrosc. 1972, 44, 37. 20. Ao, R.; Kummerl, L.; Haarer, D. Adv. Mater. 1995, 7, 495. 21. Mortimer, R. J. Chem. Soc. Rev. 1997, 26, 147. 22. Biesaga, M.; Pyrzynska, K.; Trojanowicz, M. Talanta 2000, 51, 209. 23. Macdonald, I. J.; Dougherty, T. J.; J. Porphyrins and Phthalocyanines. 2001, 5, 105. 24. Song, Y.; Haddad, R. E.; Jia, S.L. J. Am. Chem. Soc. 2005, 127, 1179.

73

25. Keam, S. T.; Scott, L. J.; Curran, M. P. Drugs 2003, 63, 2521. 26. Barth, R. F.; Soloway, A. H.; Fairchild, R. G.; Brugger, R. M. Cancer, 1992, 70, 2995. 27. Barth, R. F.; Soloway, A. H.; Goodman, J. H.; Gahbauer, R. A.; Gupta, N.; Blue, T. E.;

Yang, W.; Tjarks, W. Neurosurg. 1999, 44, 433. 28. Sinclair, R. S.; Tait, D.; Truscott, T. J. J. Chem. Soc. 1980, 76, 417. 29. Hurley, J. K.; Sinai, N.; Linnschitz, H.; J. Photochem. Photobiol.1983, 38, 9. 30. Dougherty, T. J. J. Photochem. Photobiol. 1987, 45, 879. 31. Moan, J. J. Photochem. Photobiol. 1986, 43, 681. 32. Brown, S. B.; Brown, E. A.; Walker, I. Lancet. Oncol. 2004, 24, 497. 33. Wainwright, M. Chem. Soc. Rev. 2002, 31, 128. 34. Fischer, B. B; Krieger-Liszkay, A.; Eggen, R. I. L. Environ. Sci. Technol. 2004, 38, 6307. 35. Decuyper, J.; Houba-Hein, N.; Calberg-Bacq, C. M.; Van De Vorst, A. Photochem.

Photobiol. 1984, 40, 149. 36. Lipson, R. L.; Baldes, E. J. Arch Dermatatol. 1960, 82, 509. 37. Dougherty, T. J. J Clin Laser Med. 1996, 14, 219. 38. Kennedy, J. C.; Pottier, R. H. J. Photochem. Photobiol. B. 1992, 14, 275. 39. Peng, Q.; Warloe, T.; Berg, K.; Moan J.; Kongshaug, M.; Giercksky, K.-E.; Nesland, J.

M. Cancer 1997, 79, 2282. 40. Wang I.; Bendsoe N.; Klinteberg C. A.; Enejder, A. M. K.; Andersson-Engels, S.;

Svanberg, S.; Svanberg, K. Br. J. Dermatol. 2001, 144, 832. 41. Morton C. A.; Whitehurst C.; McColl, J. H.; Moore, J. V.; MacKie, R. M. Arch.

Dermatol. 2001, 137, 319. 42. Fan, K. F.; Hopper, C.; Speight, P. M.; Buonaccorsi, G.; MacRober, A. J.; Bown, S. G.

Cancer 1996, 78, 1374. 43. Dashwood, R. H. Int. J. Oncol. 1997, 10, 721. 44. Nelson, J.S.; Roberts, W.G.; Berns, M. W. Cancer Res. 1987, 47, 4681. (b) Roberts,

W.G.; Shiau, F. Y.; Nelson, J.S.; Smith, K. M.; Berns, M. W. J. Natl. Cancer. Inst. 1988, 80, 330. (c) Gomer, C. J.; Ferrario, A. Cancer Res. 1990, 50, 3985.

45. Bonnett, R.; White R. D.; Winfeild, U. J.; Berenbaum, M. C. Biochem. J. 1989, 261.

74

46. Berenbaum, M. C.; Bonnett, R.; Chevretton, E. B.; Akande-Adebakin, S. L.; Ruston,

M. Lasers Med. Sci. 1993, 8, 235. 47. Glanzmann, T.; Hadjur, C.; Zellweger, M.; Grosjean, P.; Forrer, M.; Ballini, J.-P.;

Monnier, P.; Bergh, H. V. D.; Lim, C. K.; Wagnieres, G. Photochem. Photobiol. 1998, 67, 596.

48. Baas, P.; Saarnak, A. E.; Oppelaar, H.; Neering, H.; Stewart, F. A. Br. J. Dermatol. 2001, 145, 75.

49. Savary, J. F.; Monnier, P.; Fontolliet, C.; Arch. Otolaryngol. Head Neck Surg. 1997, 123, 162.

50. Richter, A. M.; Kelly, B.; Chow, J.; Liu, D. J; Towers, G. H.; Dolphin, D.; Levy, J. G. J. Natl. Cancer Inst., 1987, 79, 1327.

51. Sessler, J. L.; Hemmi, G.; Mody, T. D.; Murai, T.; Burrell, A.; Young, S. W. Acc. Chem. Res. 1994, 27, 43.

52. Sessler, J. L.; Miller, R. A. Biochem. Pharmacol. 2000, 59, 733. 53. Dimofte, A.; Zhu, T. C.; Hahn, S. M; Lustig, R. A. Lasers Surg. Med. 2002, 31, 305. 54. Chou, T. M.; Woodburn, K. W.; Cheong, W. F.; Lacy, S. A.; Sudhir, K.; Adelman, D.

C.; Wahr, D. Catheter Cardiovasc. Interv. 2002, 57, 387. 55. Kereiakes, D. J.; Szyniszewski, A. M.; Wahr, D.; Herrmann, H. C.; Simon, D. I.;

Rogers, C.; Kramer, P.; Shear, W.; Yeung, A. C.; Shunk, K. A.; Chou, T. M.; Popm, J.; Fitzgerald, P.; Carroll, T. E.; Forer, D.; Adelman, D. C. Circulation. 2003, 108, 1310.

56. Mang, T. S.; Allison, R.; Hewson, G.; Snider, W.; Moskowitz, R. Cancer J. Sci. Am. 1998, 4, 378.

57. Dennis, E. J.; Dolmans, G. C.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer. 2003, 3, 380. 58. Miller, J. D.; Baron, E. D.; Scull, H.; Hsia, A.; Berlin, J. C.; McCormick, T.; Colussi,

V.; Kenney, M. E.; Cooper, K. D.; Oleinick, N. L. Toxicol Appl Pharmacol. 2007, 224, 290.

59. Dougherty, T. J.; Gomer, C. J.; Henderson, B. W. J. Natl. Cancer Inst. 1998, 90, 889. 60. Wilkinson, F.; Helman, W. P.; Ross, A. B. J. Phys. Chem. Ref. Data. 1993, 22, 113. 61. Bonnett, R.; Martinez, G. Tetrahedron, 2001, 57, 9513. 62. Lang, K.; Mosinger, J.; Wagnerov´a, D. M. Coord. Chem. Rev. 2004, 248, 321.

75

63. Alvarez, M. G.; Vittar, N. B. R.; Principe, F. Photodiagn Photodyn. 2004, 1, 335. 64. Collins-Gold, L.; Feichtinger, N.; Warnheim, T. Modern Drug Discovery. 2000, 3, 44. 65. Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol. B, 2004, 73, 1. 66. Hudson, R.; Carcenac, M.; Smith, K. Br. J. Cancer. 2005, 92, 1442. 67. Staneloudi, C.; Smith, K, A.; Hudson, R. Immunology. 2007, 120, 512. 68. Malatesti, N.; Smith, K.; Savoie, H.; Greenman, J.; Boyle, R. W. Int. J. Oncol. 2006,

28, 1561. 69. Nishiyama, N.; Stapert, H. R.; Zhang, G.; Takasu, D.; Jiang, D.; Nagano, T.; Aida, T.;

Kataoka, K. Bioconjugate Chem. 2003, 14, 58. 70. Stamati, I.; Kuimova, M. K.; Lion, M.; Yahioglu, G.; Phillips, D.; Deonarain, M. P.

Photochem. Photobiol. Sci. 2010, 9, 1033. 71. Sessler, J. I.; Weghorn, S. J. Elsevier: Oxford, 1997. 72. Vogel, E.; Köchner, M.; Schmickler, H.; Lex, J. Angew. Chem. Int. Ed. Engl. 1986, 25, 257. 73. Sessler, J. L.; Brucker, E. A.; Weghorn, S. J.; Kisters, M.; Schäfer, M.; Lex, J.; Vogel,

E. Angew. Chem. Int. Ed. Engl. 1994, 33, 2308; (b) Aukauloo, M. A.; Guilard, R. New. J. Chem. 1994, 18, 1205.

74. Callot, H, J.; Rohrer, A.; Tschamber, T. New. J. Chem. 1995, 19, 155; (b) Vogel, E.; Bröring, M.; Scholz, P.; Deponte, R.; Lex, J.; Schmickler, H.; Schaffner, K.; Braslavsky, S. E.; Müller, M.; Pörting, S.; Weghorn, S. J.; Fowler, C. J.; Sessler, J. L. Angew. Chem. Int. Ed. Engl. 1997, 36, 1651.

75. Chemielewski, P. J.; Latos-Grazynski, L.; Rachlewicz, K.; Glowiak, T. Angew. Chem. Int. Ed. Engl. 1994, 33, 779; (b) Furuta, H.; Asano, T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 767.

76. Vogel, E. J. Heterocycl. Chem. 1996, 33, 1461.; (b) Vogel, E.; Bröring, M.; Erben, C.; Demuth, R.; Lex, J.; Nendel, M.; Houk, K. N. Angew. Chem. Int. Ed. Engl. 1997, 36, 353.

77. Furuta, H.; Maeda, H.; Osuka, A. J. Am. Chem. Soc. 2000, 122, 803. 78. Richert, C.; Wessels, J. M.; Muller, M.; Kisters, M.; Benninghaus, T. M.; Goetz, A. E.

J. Med. Chem. 1994, 37, 2797.; (b) Canete, M.; Lapena, M.; Juarranz, A.; Venfrell, F.; Borrell, J. I.; Teixido, J.; Nonell, S.; Villanueva, A. Anticancer Drug Des. 1997, 12, 543.; (c) Luo, Y.; Chang, C. K.; Kessel, D. J. Photochem. Photobiol. 1996, 63, 528.

76

79. Segalla, A.; Fedeli, F.; Reddi, E.; Jori, G.; Gross, A. Int. J. Cancer. 1997, 72, 329.; (b)

Toledano, H.; Edrei, R.; Kimel, S. J. Photochem. Photobiol. B. 1998, 42, 20. 80. Dellian, M.; Richert, C.; Gmarra, F.; Goetz, A. E. Int. J. Cancer. 1996, 65, 246. 81. Szeimie, R. M. J. Photochem. Photobiol. B. 1996, 34, 67. 82. Levy, J. G. Trends Biotechnol. 1995, 13, 14. 83. Rothemund, P. J. Am. Chem. Soc. 1935, 57, 2010. 84. Rothemund, P. J. Am. Chem. Soc. 1936, 58, 625. 85. Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmacher, J.; Assour, J.; Korsakoff, L. J.

Org. Chem. 1967, 32, 476. 86. Barnett, G. H.; Hudson, M. F.; Smith, K. M. J. Chem. Soc. Perkin Trans. 1. 1975, 1401. 87. Rousseau, K.; Dolphin, D. Tetrahedron Lett. 1974, 48, 4251. 88. Dattagupta, N.; Jones, E.; Thomas, L. K.; Malakar, D. J. Indian Chem. Soc. 1981, 58,

1171. 89. Datta Gupta, N.; Malakar, D.; Jenkins, C.; Strange, C. Bull. Chem. Soc. Jpn. 1988, 61,

2274. 90. Kamogawa, H.; Koga, K. Bull. Chem. Soc. Jpn. 1992, 65, 301. 91. Tamiaki, H.; Suzuki, S.; Maruyama, K. Bull. Chem. Soc. Jpn. 1993, 66, 2633. 92. Hombrecher, H. K.; Ohm, S. Tetrahedron 1993, 49, 2447. 93. Matile, S.; Berova, N.; Nakanishi, K.; Novkova, S.; Philipova, I.; Blagoev, B. J. Am.

Chem. Soc. 1995, 117, 7021. 94. Neya, S.; Funasaki, N. J. Heterocycl. Chem. 1997, 34, 689. 95. Czuchajowski, L.; Habdas, J.; Niedbala, H.; Wandrekar, V. Tetrahedron Lett. 1991, 32,

7511. 96. Lavallee, D. K.; Xu, Z.; Pina, R. J. Org. Chem. 1993, 58, 6000. 97. Lindsey, J. S.; Hsu, H. C.; Schreiman, I. C. Tetrahedron Lett. 1986, 27, 4969. 98. Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C. P.; Kearney, C. A.; Marguettaz, M. J. Org.

Chem. 1987, 52, 827. 99. Lindsey, J. S.; Maccrum, K. A.; Tyhonas, J. S.; Chuang, Y. Y. J. Org. Chem. 1994, 59,

579. 100. Geier III, G. R.; Lindsey, J. S. J. Porphyrins Phthalocyanines. 2002, 6, 159.

77

101. Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew.

Chem. 2002, 114, 938. 102. Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew.

Chem. 2002, 41, 898. 103. Geier III, G. R.; Lindsey, J. S. J. Chem. Soc. Perkin Trans. 2. 2001, 677. 104. Geier III, G. R.; Lindsey, J. S. J. Chem. Soc. Perkin Trans. 2. 2001, 687. 105. Geier III, G. R.; Littler, B. J.; Lindsey, J. S. J. Chem. Soc. Perkin Trans. 2. 2001, 701. 106. Geier III, G. R.; Littler, B. J.; Lindsey, J. S. J. Chem. Soc. Perkin Trans. 2. 2001, 712. 107. Lindsey, J. S.; Wagner, R. W. J. Org. Chem. 1989, 54, 828. 108. Barkigia, K. M.; Chantranupong, L.; Smith, K. M.; Fajer, J. J. Am. Chem. Soc. 1988

110, 7566. 109. Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney Patrick C.; Marguerettaz, A. M. J.

Org. Chem. 1987, 52, 827. 110. Dogutan, D. K.; Bediako, D. K.; Teets, T. S.; Schwalbe, M.; Nocera, D. G. Org. Lett.

2010, 12, 1036. 111. Kitaoka, S.; Nobuoka, K.; Ishikawa, Y. Chem. Commun. 2004, 1902. 112. Lucas, R.; Vergnaud, J.; Teste, K.; Zirrouki, R.; Sol, V.; Krausz, P. Tetrahedron Lett.

2008, 49, 5537. 113. Chauhan, S. M. S.; Sahoo. B. B.; Srinivas, K. A. Synth. Commun. 2001, 31, 33 114. Gradillas, A.; Campo, C. D.; Sinistera, J. V.; Llama, E. F. J. Chem. Soc. Perkin Trans

1. 1995, 2611. 115. Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chem.Soc. 1960, 82, 4384. 116. Baldwin, J. E.; Crossley, M. J.; Klose, T.; O’Rear III, E. A.; Peters, M. K. Tetrahedron.

1982, 38, 27. 117. Wallace, D. M.; Smith, K. M. Tetrahedron Lett. 1990, 31, 7265. 118. Lee, C. -H.; Lindsey, J. S. Tetrahedron. 1994, 50, 11427. 119. Lee, C. -H.; Li, F.; Iwamoto, K.; Dadok, J.; Bothner-By, A. A.; Lindsey, J. S.

Tetrahedron. 1995, 51, 11645. 120. Maruyama, K.; Nagata, T.; Ono, N.; Osuka, A. Bull. Chem. Soc. Jpn. 1989, 62, 3167. 121. Anderson, H. J. Inorg. Chem. 1994, 33, 972.

78

122. Lecas-Nawrocka, A.; Boitrel, B.; Rose, E. Tetrahedron Lett. 1992, 33, 481. 123. Hombrecher, H. K.; Horter, G.; Arp, C. Tetrahedron. 1992, 48, 9451. 124. Wang, Q. M.; Bruce, D. W. Tetrahedron Lett. 1996, 37, 7641. 125. Wilson, G. S.; Anderson, H. L. Synlett 1996, 1039. 126. Ravikanth, M.; Strachan, J.-P.; Li, F.; Lindsey, J. S. Tetrahedron. 1998, 54, 7721. 127. Lecas, A.; Levisalles, J.; Renko, Z.; Rose, E. Tetrahedron Lett. 1984, 25, 1563. 128. Maruyama, K.; Nagata, T.; Osuka, A. J. Phys. Org. Chem. 1988, 1, 63. 129. Sessler, J. L.; Capuano, V. L. Angew. Chem. Int. Ed. 1990, 29, 1134. 130. Benson, D. R.; Valentekovich, R.; Diederich, F. Angew.Chem. Int. Ed. 1990, 29, 191. 131. Chang, C. K.; Abdalmuhdi, I. J. Org. Chem. 1983, 48, 5388. 132. Pandey, R. K.; Forsyth, T. P.; Gerzevske, K. R.; Lin, J. J.; Smith, K. M. Tetrahedron

Lett. 1992, 33, 5315. 133. Wasielewski, M. R.; Niemczyk, M. P.; Svec, W. A.; Pewitt, E. B. J. Am. Chem. Soc.

1985, 107, 5562. 134. Osuka, A.; Kobayashi, F.; Nagata, T.; Maruyama, K. Chem. Lett. 1990, 287. 135. Boudif, A.; Momenteau, M. Chem. Commun. 1994, 2069. 136. Boudif, A.; Momenteau, M. J. Chem. Soc. Perkin Trans. 1. 1996, 1235. 137. Lash, T. D. J. Porphyrins Phthalocyanines. 1997, 1, 29. 138. Chandrasekar, P.; Lash, T. D. Tetrahedron Lett. 1996, 37, 4873. 139. Lin, Y.; Lash, T. D. Tetrahedron Lett. 1995, 36, 9441. 140. Sessler, J. L.; Genge, J. W.; Urbach, A.; Sanson, P. Synlett. 1996, 187. 141. Lash, T. D.; Chaney, S. T.; Richter, D. T. J. Org. Chem. 1998, 63, 9076. 142. Wijesekera, T. P.; Dolphin, D. Synlett. 1990, 235. 143. Lash, T. D.; Roper, T. J. Tetrahedron Lett. 1994, 35, 7715. 144. Pandey, R. K.; Shiau, F.-Y.; Ramachandran, K.; Dougherty, T. J.; Smith, K. M. J.

Chem. Soc. Perkin Trans. 1. 1992, 1377. 145. Catalano, M. M.; Crossley, M. J.; Harding, M. M.; King, L. G.; Chem. Commun. 1984,

1535. 146. Shea, K. M.; Jaquinod, L.; Smith, K. M. J. Org. Chem. 1998, 63, 7013.

79

147. Gros, C. P.; Jaquinod, L.; Khoury, R. G.; Olmstead, M. M.; Smith, K. M. J. porphyrins

Phthalocyanines. 1997, 1, 201 148. Giuntini, F.; Faustino, M. A. F.; Neves, M.G. P. M. S.; Tome´, A. C.; Silva, A. M. S.;

Cavaleiro, J. A. S. Tetrahedron. 2005, 61, 10454. 149. Crossley, M. J.; king, L. G.; Simpson, J. L. J. Chem. Soc. Perkin Trans. 1. 1997, 3087. 150. Crossley, M. J.; King, L. G.; Pyke, S. M. Tetrahedron. 1987, 43, 4569. 151. Jaquinod, L.; Khoury, R. G.; Shea, K. M.; Smith, K. M. Tetrahedron. 1999, 55, 13151. 152. Lo, M.; Lefebvre, J. F.; Leclercq, D.; Lee, A. V.; Richeter, S. Org. lett. 2011, 13, 3110. 153. Richeter, S.; Jeandon, C.; Gisselbrecht, J-P.; Graph, R.; Ruppert, R.; Callot, H. J. Inorg.

Chem. 2004, 43, 251. 154. Ostrowski, S.; Wyrebek, P. Tetrahedron lett. 2006, 8437. 155. Hombrecher, H. K.; Gherdan, V. M.; Ohm, S.; Cavaleiro, J. A. S.; Graca, M. D.; Neves,

P. M. S.; Condesso, M. D. F. Tetrahedron. 1993, 49, 8569. 156. Shen, D-M.; Liu, C.; Chen, Q-Y. Eur. J. Org. Chem. 2007, 1419. 157. Alonso, C. M. A.; Neves, P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.; Hombrecher, H.

K. Tetrahedron lett. 1997, 38, 2757. 158. Alonso, C. M. A.; Neves, M.G. P. M. S.; Tome´, A. C.; Silva, A.M. S.; Cavaleiro, J. A.

S. Tetrahedron. 2005, 61, 11866. 159. Crossley, M. J.; Govenlock, L. J.; Prasher, J. K. Chem.Commun. 1995, 2379. 160. Alonso, C. M. A.; Serra, V. I. V.; Neves, M. G. P. M. S.; Tome, A. C.; Silva, A. M. S.;

Paz, F. A. A.; Cavaleiro, J. A. S. Org. Lett. 2007, 9, 2305. 161. Ishkov, Y. V. Russ. J. Org. Chem. 2001, 37, 288. 162. Ishkov, Y. V.; Zhilina, Z. I. Russ. J. Org. Chem. 1995, 31, 123. 163. Callot, H. Bull. Soc. Chim. France. 1973, 3413. 164. Arnold, D. P.; Gaete-Homes, R.; Johnson, A. W.; Smith, A. R. P.; Williams, G. A. J.

Chem. Soc. Perkin Trans. I. 1978, 12, 1660. 165. Morgan, A. R.; Rampersaud, A.; Garbo, G. M.; Keck, R. W.; Selman, S. H.; J. Med.

Chem. 1989, 32, 904. 166. Annoni, E.; Pizzotti, M.; Ugo, R.; Quici, S.; Morotti, T.; Bruschi, M.; Mussini, P. Eur.

J. Inorg. Chem. 2005, 19, 3857.

80

167. Welch, C.; Archibald, C. H. A.; Boyle, R. W. Synthesis. 2009, 4, 551. 168. Ishkov, Y. V.; Zhilina, Z. I.; Bardai, L. P.; Vodzinskii, S.V.; Russ. J. Org. Chem. 2004,

40, 434. 169. Ventura, B.; Flamigni, L.; Marconi, G.; Lodato, F.; Officer, D. L. New. J. Chem. 2008,

32, 166. 170. Anderson, H. L. Chem. Commun. 1999, 2323. 171. Susumu, K.; Duncun, T. V.; Therian, M. J. J. Am. Chem. Soc. 2005, 127, 5186. 172. Bonfantini, E. E.; Burrell, A.K.; Officer, D.L.; Reid, C. W. Inorg. Chem. 1997, 36,

6270. 173. Reeta, P. S.; Kandhadi, J.;Lingamallu, G. Tetrahedron lett. 2010, 51, 2865. 174. Wang, Q.; Campbell, W. M.; Bonfantani, E. E.; Jolley, K. W.; Officer, D. L.; Walsh, P.

J.; Gordon, K.; Baker, R. H.; Nazeeruddin, M. K.; Gratzel, M. J. Phys. Chem. B. 2005, 109, 15397.

175. Sharma, S.; Nath, M. J. Heterocycl. Chem., 2012, 49, 88. 176. Smith, K. M.; Langry, K. C. J. Org. Chem. 1983, 48, 500. 177. Smith, K. M.; Langry, K. C.; Minnetian, O. M. J. Org. Chem. 1984, 49, 4602. 178. Vicente, M. G.; Smith, K. M. J. Porphyrins Phthalocyanines 2004, 8, 26. 179. Fox, S.; Boyle, R. W. Chem. Commun. 2004, 1322. 180. Shen, D.-M.; Liu, C.; Chen, Q.-Y. Chem. Commun. 2005, 4982. 181. Faustino, M. A.; Neves, P. M. S.; Vicente, M. G. H.; Silva, A. M. S.; Cavaleiro, J. A. S.

Tetrahedron Lett. 1995, 36, 5977. 182. Callot, H. J.; Schaeffer, E.; Cromer, R.; Metz, F. Tetrahedron. 1990, 46, 5253. 183. Richeter, S.; Jeandon, C.; Kyritsakas, N.; Ruppert, R.; Callot, H. J. J. Org. Chem. 2003,

68, 9200. 184. Cao, Y.; Gill, A. F.; Dixon, D. W. Tetrahedron Lett. 2009, 50, 4358. 185. Pereira, A. M. V. M.; Alonso, C. M. A.; Neves, M. G. P. M. S.; Tome´, A. C.; Silva,

A.M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. J. Org. Chem. 2008, 73, 7353. 186. Dimagno, S. G.; Lin, V. S.-Y.; Therien, M. J. J. Org. Chem. 1993, 58, 5983. 187. Aihara, H.; Jaquinod, L.; Nurco, D. J.; Smith, K. M. Angew. Chem. Int. Ed. 2001, 40,

3439.

81

188. Nath, M.; Huffman, J. C.; Zaleski, J. M. Chem. Commun. 2003, 858. 189. Nath, M.; Pink, M.; Zalesky, J. M. J. Organomet. Chem. 2011, 696, 4152. 190. Boerner, L. J. K.; Nath, M.; Pink, M.; Zalesky, J. M. Chem. Eur. J. 2011, 17, 9311. 191. Cavaleiro, J. A. S.; Neves, M.G. P. M. S.; Tome, A. C. Arkivoc. 2003, 14, 107. 192. Callot, H. J.; Johnson, A. W.; Sweeney, A. J. Chem. Soc. Perkin Trans. 1. 1973, 1424. 193. DiNello, R. K.; Dolphin, D. J. Org. Chem. 1980, 45, 5196. 194. Zhang, C.; Trudell, M. L. J. Org. Chem. 1996, 61, 7189. 195. Gros, C. P.; Jaquinod, L.; Khong, R. G.; Olmstead, M. M.; Smith, K. M. J. Porphyrins

Phthalocyanines. 1997, 1, 201. 196. Barton, D. H. R.; Kervagoret, R. G.; Zard, S. Z. Tetrahedron. 1990, 46, 7587. 197. Faustino, M. A. F.; Neves, M. G. P. M. S.; Vicente, M. G. H.; Silva, A. M. S.;

Cavaleiro, J. A. S. Tetrahedron Lett. 1996, 37, 3569. 198. Vicente, M. G. H.; Tome, A. C.; Walter, A.; Cavaleiro, J. A. S. Tetrahedron Lett. 1997,

38, 3639. 199. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro J. A. S. Tetrahedron

Lett. 2000, 41, 3065. 200. Silva, A. M. G.; Tome, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.

J. Org. Chem. 2005, 70, 2306. 201. Tome´, A. C.; Lacerda, P. S. S.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Chem.

Commun. 1997, 1199. 202. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Perrone, D.;

Dondoni, A. Synlett. 2005, 857. 203. Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley Interscience:

New York, NY, 1984. 204. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Synlett. 2002,

1155. 205. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A.

S.; Perrone, D.; Dondoni, A. Tetrahedron Lett. 2002, 43, 603. 206. Jiménez-Osés, G.; García, J. I.; Silva, A. M. G.; Santos, A. R. N.; Tomé, A. C.; Neves,

M. G. P. M. S.; Cavaleiro, J. A. S. Tetrahedron. 2008, 64, 7937.

82

207. Linn, N. J.; Benson, R. E. J. Am. Chem. Soc. 1965, 87, 3657. 208. Hojo, M.; Aihara, H.; Sakata, K.; Hosomi, A. J. Org. Chem. 1997, 62, 8610. 209. Fleming, J.; Dolphin, D. Tetrahedron Lett. 2002, 43, 7281. 210. Moura, N. M. M.; Giuntini, F.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tomé, A. C.;

Silva, A. M. S.; Rakib, E. M.; Hannioui, A.; Abouricha, S.; Röder, B.; Cavaleiro J. A. S. Arkivoc. 2010, 5, 24.

211. Drovetskaya, T.; Reed, C. A.; Boyd, P. Tetrahedron Lett. 1995, 36, 7971. 212. Silva, A.M. G.; Tome, A. C.; Neves, M.G. P. M. S.; Silva, A.M. S.; Cavaleiro, J. A. S.

J. Org. Chem. 2002, 67, 726. 213. Silva, A. M. G.; De Oliveira, K. T.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tomé,

A. C.; Silva, A. M. S.; Cavaleiro, J. A. S.; Brandão, P.; Felix, V. Eur. J. Org. Chem. 2008, 704.

214. Silva, A. M. G.; Faustino, M. A. F.; Tomé, A. C.; Neves, P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S. J. Chem. Soc. Perkin Trans. 1. 2001, 2752.

215. Kopke, T.; Pink, M.; Zaleski, J. M. Synlett. 2006, 2183. 216. Kopke, T.; Pink, M.; Zaleski, J. M. Org. Biomol. Chem. 2006, 4, 4059. 217. Bruckner, C.; Sternberg, E. D.; MacAlpine, J. K.; Rettig, S. J.; Dolphin, D. J. Am.

Chem. Soc. 1999, 121, 2609. 218. Lindsey, J. S.; Prathapan, S.; Johnson, T. E.; Wagner, R. W. Tetrahedron. 1994, 50,

89041. 219. Nishino, N.; Wagner, R. W.; Lindsey, J. S. J. Org. Chem. 1996, 61, 7534. 220. Wagner, R. W.; Johnson, T. E.; Li, F.; Lindsey, J. S. J. Org. Chem. 1995, 60, 5266. 221. Wagner, R. W.; Johnson, T. E.; Lindsey, J. S. J. Am. Chem. Soc. 1996, 118, 11166. 222. Loewe, R. S.; Tomizaki, K.; Youngblood, W. J.; Bo, Z. S.; Lindsey, J. S. J. Mater.

Chem. 2002, 12, 3438. 223. Diez-Gonzalez, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem. Eur. J. 2006, 12, 7558. 224. Wennerstrom, O.; Ericsson, H.; Raston, I.; Svensson, S.; Pimlott, W. Tetrahedron Lett.

1989, 30, 1129. 225. Bhyrappa, P.; Krishnan, V. J. Chem. Sci. 2004, 116, 71

83

226. Gust, D.; Moore, T. A.; Moore, A.; Leggett, L.; Lin, S.; Degraziano, J. M.; Hermant, R.

M.; Nicodem, D.; Craig, P.; Seely, G. R.; Nieman, R. A. J. Phys. Chem. 1993, 97, 7926.

227. Guo, C.; Li, H.; Zhang, X. B. Bioorg. Med. Chem. 2003, 11, 1745. 228. Zhou, X.; Chan K. S. J. Org. Chem. 1998, 63, 99. 229. Gotz, D. C. G.; Bruhn, T.; Senge, M. O.; Bringmann, G. J. Org. Chem. 2009, 74,8005. 230. Sharma, S.; Nath, M. Dyes and Pigments. 2012, 92, 1241 231. Sharma, S.; Nath, M. New J. Chem. 2011, 35, 1630. 232. Schlogl, K.; Steyrer, W. J. Organomet. Chem. 1966, 6, 399. 233. Arnold, D. P.; Nitschinsk, L. J. Tetrahedron. 1992, 48, 8781. 234. Chan, K. S.; Zhou, X.; Lou, B. -S.; Mak, T. C. W. Chem. Commun. 1994, 271. 235. Suzuki, A. Pure Appl. Chem. 1994, 68, 213. 236. Bringmann, G.; Gotz, D. C. G.; Gulder, T. A.; Gehrke, T. H.; Bruhn, T.; Kupfer, T.;

Radacki, K.; Braunschweig, H.; Heckmann, A.; Lambert, C. J. Am. Chem. Soc. 2008, 130, 17812.

237. Bonfantini, E. E.; Officer, D. L. Tetrahedron Lett. 1993, 34, 8531. 238. Konig, B.; Zieg, H. Synthesis., 1998, 2, 171.