A Bicentennial Perspective on Quinolines: The Application of the Skraup Reaction in the Synthesis of Heterocycles

Abstract:

In 1820, P. J. Pelletier and J. B. Caventou isolated quinine, a naturally occurring alkaloid with pronounced antimalarial activity, from the bark of Cinchona spp.; at that time, its molecular structure remained undetermined. Fourteen years later, in 1834, F. F. Runge identified quinoline during the fractional distillation of coal tar, thereby introducing a heteroaromatic scaffold of considerable chemical and pharmacological relevance. The first formal synthesis of quinoline was reported in 1880 by Z. H. Skraup, who described the cyclocondensation of aniline with glycerol in the presence of concentrated H2SO4 and nitrobenzene - a transformation that subsequently became a fundamental methodology in heterocyclic chemistry. The total synthesis of quinine and elucidation of its molecular structure were achieved much later, in 1944, by R. B. Woodward and W. E. Doering. Over subsequent decades, extensive research has focused on developing alternative synthetic routes and optimizing reaction conditions to enhance yield, selectivity, and reproducibility, reflecting the enduring importance of quinoline and its derivatives. Quantum chemical studies based on density functional theory have provided valuable mechanistic insight into the Skraup-Doebner-Miller reaction. Analyses of natural charges and frontier molecular orbitals indicate that regioselectivity is governed by electronic asymmetry between competing electrophilic sites. This review summarizes recent advances in the synthesis of quinoline derivatives via the Skraup-Doebner-Miller reaction, with particular emphasis on mechanistic understanding, regioselectivity, and methodological developments, covering the literature up to 2025.