Nitration of 2-tert-Butylaniline: Preparation of an Intermediate Used in the Development of the Cystic Fibrosis Drug Ivacaftor

TCE

The Chemical Educator

ISSN: 1430-4171 (electronic version)

Table of Contents

Abstract Volume 23 (2018) pp 124-128

Nitration of 2-tert-Butylaniline: Preparation of an Intermediate Used in the Development of the Cystic Fibrosis Drug Ivacaftor

Chelsea E. Prince and Mark Turlington*

Department of Chemistry and Biochemistry, Berry College, 2277 Martha Berry Hwy NW, Mount Berry, GA, 30149, mturlington@berry.edu
Received April 18, 2018. Accepted June 5, 2018.

Published: 26 June 2018

Abstract. Laboratory experiments connected to medicinal chemistry help students comprehend and appreciate the relevance of organic chemistry reactions learned in lecture and performed in the laboratory. This experiment describes the nitration of 2-tert-butylaniline, a reaction used in the development of the Cystic Fibrosis drug Ivacaftor and reported in over 20 drug discovery patents. Predicting the regiochemistry of the nitration reaction involves a conceptual discussion of electronic and steric directing effects in electrophilic aromatic substitution reactions. Confirming the predicted regiochemistry of the product provides an exercise in determining the identity and substitution pattern of the product using IR and NMR spectroscopy. The experiment also provides technical training in all the components of a typical organic chemistry reaction including reaction workup via extraction and silica gel column chromatography.

Key Words: Laboratories and Demonstrations; analytical chemistry; inorganic chemistry; atomic spectroscopy; zinc

(*) Corresponding author. (E-mail: mturlington@berry.edu )

Article in PDF format (141 KB) HTML format

Supporting Materials:

The supporting material includes the chemical list and hazards information, notes for instructors, notes for laboratory preppers, a prelab handout covering the electronic and steric directing effects in the nitration reaction and the accompanying prelab key, the student laboratory manual chapter and detailed experimental procedure, calculation of chemical shifts for substitution patterns i – iv, student handouts explaining extraction and flash silica gel column chromatography, and IR, ¹H NMR, and ¹³C NMR spectra of the starting material and product. (199 KB)