טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAmar Michal
SubjectDesign and Synthesis of Novel Stable Alfa Hydrogen
Nitroxides
DepartmentDepartment of Chemistry
Supervisor Professor Alex.m Szpilman
Full Thesis textFull thesis text - English Version


Abstract

Nitroxides are stable free NO radicals. They are important catalysts and reagents for synthesis - in redox reactions, in mechanistic studies - as radical traps and EPR spin labels, and in polymerization - as catalysts for living polymerization processes. Additionally, they have shown promising activity in various therapeutic applications such as, cancer prevention, cancer treatment, control of hypertension and more.

Nitroxides constitute powerful and environmentally friendly alternatives to transition metal catalysts. The nitroxide TEMPO-(2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl, is one of the most efficient and widely used  organocatalysts in industry and in academics for oxidation reactions.

TEMPO possesses limited reactivity towards bulky substrates due to its highly hindered structure, which contains two tertiary alkyl groups α to the reactive nitroxide N-O locus. A logical way to diminish the steric congestion is to replace an a-alkyl substituent with hydrogen. However, most nitroxides bearing a-hydrogens are highly unstable as they undergo fast disproportionation, in which two radicals react to give one molecule of nitrone and one of hydroxylamine. Prior to this work only two types of stable α-hydrogen nitroxides had been disclosed.

The first design involves bicyclic structures. The formation of a C-N double bond in the bridgehead of nitrone disproportionation product would lead to high ring tension and is forbidden according Bredt's rule. Several nitroxides have been synthesized based on this design including ABNO, of Iwabuchi, which exhibited increased reactivity compared to TEMPO. 

The second design concept relies on subtle conformational effects. Accordingly, the preferred conformation for hydrogen abstraction, during disproportionation reaction, is high in energy due to steric hindrance between the substituents surrounding the nitroxide. This group of nitroxides mainly performs as catalysts in polymerization processes.

This research discloses a unique and novel concept for the design of α-hydrogen substituted radicals, and present proof of principle demonstrated by two families of structures; isoindoline and isoazaphenalene.

The stability of the structures is accounted for by several effects resulting from steric hindrance between the R1 and R2 substituents and is explained in details in this thesis. Some of the synthesized nitroxides are stable for months with a compared stability towards TEMPO. Part of the isoazaphenalene nitroxides possess high catalytic activity in the aerobic oxidation of alcohols compared to TEMPO. Both families of nitroxides are prepared by short and flexible synthetic routes from available and commercial starting materials. Through the development of the synthesis of isoazaphenalene nitroxides a new method for the cyclization of isoazaphenalene was developed in a simple manner starting from simple commercial starting materials.

A computational study has been undertaken to evaluate the factors determining stability of representative synthesized nitroxides during disproportionation reaction. This study ruled out the mechanism of SET regarding our nitroxides.