FERDOUSI, FARHANA,KHANAM (2015) NOVEL APPROACHES FOR CATALYTIC
DIRECT AMIDE FORMATION. Doctoral thesis, Durham University.
The significance of amides as a component of biomolecules and synthetic products has triggered the development of catalytic direct amidation methods which involve reaction of a carboxylic acid and amine to form an amide with water as the only by-product. These methods evade the need for stoichiometric activation or coupling reagents and hence, are important green chemical processes.
Investigations into direct amide formation began with the development a mild reaction conditions for the direct amidation reaction with known arylboronic acid catalysts in two different model reactions and compared with both reported and potential organometallic catalysts (Zr and Fe based).
After a systematic evaluation of solvent, temperature and catalyst, ambient reaction conditions were applied in the direct amidation of amino-acid derivatives in order to exploit these more economical reagents for peptide synthesis which is both little used and little explored. Protected amino acid derivatives showed slow reactivity compared to simple amine-carboxylic acid combinations and hence high catalyst loadings were required, though did proceed at 65~68 °C generally avoiding racemisation.
However, an interesting synergistic catalytic effect was observed during dipeptide formation using mixture of two arylboronic acid catalysts (1:1) in the direct amidation reaction at lower temperatures, although the process was particularly slow.
This impressive result led to explore more about the effect of ‘Cooperative Catalysts’, particularly, on the less reactive acid-amine combination. As a consequence, some commercially important synthesis has been reviewed through this novel cooperative catalysis to ensure their real applicability in industries.
Acceptance of the practicability and general applicability of this new approach depends upon the understanding of the mechanism of the cooperative catalysis. In order to reveal the mechanism of the cooperative catalysis the direct amide formation reactions were followed by the real time monitoring technology (React-IR) and HPLC. However, further investigations are required to understand the mechanistic intricacies of this cooperative catalysis.
Further, the role of H-bonding in the amide bond formation with significantly inert acid (pivalic acid) towards the amine to form amide has been attempted. In order to accelerate the catalytic activity the use of a potential catalyst promoter, ‘ANB 209’ in the direct amidation reactions was also examined. Improvements in catalysts activity or alterations in catalyst would need further study so that the direct amide formation becomes a common tool for a wide range of carboxylic acid and amine partners.
The effect of different substituents on the α-position of carboxylic acid with various amine substrates was investigated to understand the exceptional direct amide formation of the synthesis of mandipropamid, a well known fungicide. Both uncatalysed and catalysed direct amidations of mandelic acid was done with different amine substrates at different temperatures, resulting different rate of amide formation.
Finally, the application of two novel borinic acid (R1RBOH) compounds in the direct amide formation reactions has been assessed for the first time, which displayed in some cases the potential to act as catalysts for direct amide formation. Further research will likely to accelerate the developments of this type of catalysts in direct amidations.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||16 Mar 2016 14:43|