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Winner of the IUPAC Prize
for Young Chemists - 2002

 

Simi Pushpan wins one of the first 4 IUPAC Prize for Young Chemists, for her Ph.D. thesis work entitled "Core Modified N-confused and Expanded Porphyrinoids: Syntheses, Characterization and Photodynamic Activity."

Current address (at the time of application)

Indian Institute of Technology
Department of Chemistry, Kanpur, 208 016, India.

E-mail: simi_pushpan@lycos.com or simi_pushpan@rediffmail.com

Academic degrees

  • Ph.D. I.I.T - Kanpur, Bio-inorganic Chemistry, Sept. 2001
  • M.Sc. Chemical Sciences, Pondichery University, May 1996
  • B.Sc. Chemistry, Mahatma Gandhi University, Kerala, June 1994
Ph.D. Thesis

Title Core Modified N-confused and Expanded Porphyrinoids: Syntheses, Characterization and Photodynamic Activity
Adviser Prof. T. K. Chandrashekar
Thesis Committee Prof. M. J. Therien, Department of Chemistry, University of Pennsylvania, Philadelphia, USA; Prof. Martin Bröring, Institute of Inorganic Chemistry, University of Würzburg, Würzburg, Germany; Prof. S. Mazumdar, Department of Chemical Sciences, Tata Institute of Fundamental Research, India; Prof. A. J. Elias, Department of Chemistry, IIT-Kanpur, India; Prof. A.Sharma, Department of Chemical Engineering, IIT-Kanpur, India.

Essay

Porphyrins are the most widespread of all prosthetic groups found in nature. These highly colored tetrapyrrolic macrocyclic pigments play a diverse and critical role in biology ranging from electron transfer, oxygen transport and storage, photosynthetic processes and catalytic substrate oxidation which has inspired researchers around the globe to and focus on these "pigments of life". Nature’s choice of the porphyrin ring as the key structural backbone owes mainly to its inherent conformational and redox flexibility, which provides suitable coordination environment for many transition metals. The interdisciplinary interest generated by the porphyrins resulted in the syntheses of modified porphyrins, especially contracted, expanded and isomeric porphyrinoids. The major objective of my doctoral research was to formulate easy and efficient methodology to synthesize exotic porphyrinoid macrocycles and study their electochemical, structural and in a few cases their anion binding and photodynamic therapeutic efficacy.

My dissertation was mainly devoted to the syntheses and characterization of core modified N-confused and expanded porphyrins (see fig. 1) as there were only few reports on such porphyrinoid macrocycles bearing meso- aryl substituents. N-confused porphyrin is an isomer of porphyrin, which has 18 p electrons in its aromatic pathway but is associated with an inversion of one of the pyrrolic unit in the macrocycle.

I have chosen expanded porphyrins, which results from the expansion of the p electron conjugation by increasing the number of heterocyclic rings as the objective mainly due to the synthetic challenges encountered in previous attempts to make related macrocycles in high yields. The resulting chromophores show strong absorptions in the red region compared to normal 18p porphyrins. Core modification of these expanded porphyrins changes the electronic structure of the parent porphyrinoid, which in turn leads to interesting electrochemical, magnetic and photochemical properties. Its inherent stability, photophysical, electrochemical and biomedical applications have made it the cynosure of attention in recent times. This motivated me to take up the challenge of synthesizing fore mentioned porphyrinoids in high yields and evaluating the structural diversity and bio-medical utility in detail.

After the serendipitous discovery of N-confused porphyrin as a side product of meso-aryl porphyrin in 1994, attempts were on for an improved synthetic methodology that will yield exclusive formation of the desired isomer. My interest in exclusive syntheses of the core-modified porphyrinoids encouraged me to introduce chalcogens into the existing the N-confused porphyrin framework. Employing modified 3+1 MacDonald condensation I successfully obtained products containing thiophene/furan/selenophene units situated trans to the N-confused pyrrollic unit in high yields. Detailed NMR studies at variable temperatures were done on these macrocycles to establish the presence of three tautomers prevailing in solution. The crystal structure for the thia derivative revealed a ruffled conformation and a cyclophane like dimer formation in the unit cell due to the presence of inter and intramolecular hydrogen bonds (fig.2). The electrochemical and spectroscopic characteristics exhibited were interesting. The syntheses of expanded porphyrin bearing an N-confused moiety can be considered as a step forward in understanding the various interesting properties exhibited by the expanded porphyrin initiated by alteration of cavity size and electronic structure which can offer larger cavities for the formation of 4d and 5d metal-carbon bonds. A perusal of literature revealed that there are no reports on expanded porphyrin bearing N-confused pyrrole. My experience with N-confused porphyrins prompted me to extend the methodology used, to generate first examples of N-confused sapphyrins through an easy and efficient 3+2 MacDonald condensation methodology. In addition to synthesis, a detailed characterization of these modified stable aromatic expanded porphyrins were done using 1 H and 2D NMR, UV- visible spectroscopic techniques and single crystal X-ray structure (refer fig. 2) determination to establish the inversion of the N-confused ring in liquid and solid state. The formation of intra and intermolecular hydrogen bonding in crystal packing, its ability to act as anion binding agents in its diprotonated state were some of the interesting insights.

The simplest possible methodology till date to synthesize core modified expanded porphyrins namely diheteroatom substituted sapphyrins and rubyrins by condensation methodology involving heteroatom containing diol with excess pyrrole in presence of protic acid catalyst was also formulated during the course of reinvestigation of Ulman methodology for the synthesis of core modified porphyrins. Moreover, effect of natureand concentration acid catalyst used on the yields of the resultant product distribution was followed carefully. 4+3 oxidative coupling reaction led to the syntheses of a range of hitherto unknown expanded porphyrins, namely triheteroatom substituted [26]hexaphyrin(1.1.1.0.1.0), which are isomers of rubyrin and [30]heptaphyrin(1.0.1.1.0.1.0) which are the first aromatic meso-aryl heptaphyrins to be reported in the literature. All the hexaphyrins and heptaphyrins reported possess an inverted heterocyclic ring in their freebase and protonated state and thus reveals structural diversity with respect to other reported related macrocycles. Detailed studies on these conformational effects were followed by geometry optimisation computational programmes, which helped in establishing unequivocally the inverted geometry for the heterocyclic ring opposite to the bithiophene/biselenophene moiety in heptaphyrins and hexaphyrins. These differences highlight the presence of subtle conformational effects in meso-aryl expanded porphyrinoids.

After constructive modifications of existing methodologies and formulation of novel synthetic routes to arrive at these porphyrinoids, my priority shifted further explore their efficiency as photosensitizer in photodynamic therapy. Afore mentioned macrocycles absorb in the red region compared to Photofrin, a hematoporphyrin derivative currently used in the treatment of cancer. Preliminary studies of negligibly dark toxic trithiasapphyrin based photosensitizer (fig.3) revealed their efficiency to bind to human erythrocytes, which is a semi-model system. The relative efficiency of the sensitizer calculated in terms LC50 and LD50 based on time of incubation prior to exposure of light, drug uptake studies and photohemolytic studies were found promising.

The simplicity of the high yielding reaction conditions involving stable and variety of precursors containing heteroatoms highlights the versatality of the synthetic methodology adopted. Thus it is hoped that the availability of new methodology for high yield syntheses of these new core modified expanded porphyrins will allow further exploitation of their rich chemistry in terms of their coordination behavior towards transition metals and their use as catalysts for organic transformations and biomedical applications.


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