The Knorr quinoline synthesis is an intramolecular organic reaction converting a β-ketoanilide to a 2-hydroxyquinoline using sulfuric acid. This reaction was first described by Ludwig Knorr (1859–1921) in 1886Synthetische Versuche mit dem Acetessigester Justus Liebig's Annalen der Chemie Volume 236, Issue 1–2, Date: 1886, Pages: 69–115 Ludwig Knorr
The reaction is a type of electrophilic aromatic substitution accompanied by elimination of water. A 1964 study found that with certain reaction conditions formation of a 4-hydroxyquinoline is a competing reaction.The Conversion of Benzoylacetanilides into 2- and 4-Hydroxyquinolines B. Staskun J. Org. Chem. 1964; 29(5); 1153–1157. For instance, the compound benzoylacetanilide (1) forms the 2-hydroxyquinoline (2) in a large excess of polyphosphoric acid (PPA) but 4-hydroxyquinoline 3 when the amount of PPA is small. A reaction mechanism identified a N,O-dicationic intermediate A with excess acid capable of ring-closing and a monocationic intermediate B which fragments to aniline and (ultimately to) acetophenone. Aniline reacts with another equivalent of benzoylacetanilide before forming the 4-hydroxyquinoline.
A 2007 studyKnorr Cyclizations and Distonic Superelectrophiles Kiran Kumar Solingapuram Sai, Thomas M. Gilbert, and Douglas A. Klumpp J. Org. Chem. 2007, 72, 9761–9764 revised the reaction mechanism showing that based on NMR spectroscopy and theoretical calculations an O,O-dicationic intermediate (a superelectrophile) is favored comparing to the N,O dicationic intermediate. For preparative purposes triflic acid is recommended:
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