giovedì 5 novembre 2015

La mia cara, vecchia, lacrimatissima tesi di laurea...

One-pot synthesis of paracetamol via the catalytic reductive carbonylation of nitrobenzene in acetic acid-water as a solvent.

by
Andrea Vavasori[*]a, Marco CapponiaLucio Ronchina

                (a) Molecular Sciences and Nanosystems Department, Ca’ Foscari University of Venice
Paracetamol (N-(4-hydroxyphenyl)acetamide) is a major ingredient in numerous cold and flu medications due to its analgesic and antipyretic properties. 

A number of commercial methods of paracetamol manufacture are currently in use around the world.  Some commonly used processes start from chlorobenzene, phenol or nitrobenzene. 

All the industrial processes actually used, however, show several drawbacks. For instance, they are based on multistep routes which sometimes lead to poor overall yield, or show serious effluent problems. 

The increasingly stringent environmental legislation has generated a pressing need for cleaner methods of chemical production, for instance introducing technologies that reduce or, preferably, eliminate the generation of waste and avoid the use of toxic and/or hazardous reagents and solvents. 

According with this, we propose a new approach for the synthesis of paracetamol: by using Pd(II)-diphosphine catalyst precursors, in acetic acid-water as a solvent, we obtain paracetamol with high selectivity from nitrobenzene in one-pot. 

At 140 °C and under 45 atm of CO, nitrobenzene is completely converted to paracetamol and N-phenylacetamide. The latter is the major by-product of the reaction (ca. 15 molar %, under such reaction conditions) and also an interesting target for the pharmaceutical industry. 

The selectivity is influenced by several variables such as solvent composition (H2O-acetic acid ratio), temperature and batch time

The high temperature and the increase of reaction time favor the acetylation reaction, which occurs in-situ when p-aminophenol and aniline readily form from nitrobenzene/CO/H2O. Such reaction is proposed as a new sustainable alternative to the synthesis of paracetamol. 

The absence of chlorobenzene (chlorine-free chemistry), the use of efficient catalysts and the possibility to realize a single step process, make this reaction interesting to be evaluated as a possible alternative to the multi-steps industrial processes actually used.