Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, First Edition. Edited by Jacques Mortier. © 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc. 3.1 INTRODUCTION AND HISTORICAL BACKGROUND The Friedel–Crafts acylation reaction generates aromatic ketone products from the combination of an aromatic substrate with an acyl component typically in the presence of a catalyst [1]. Interest in this electrophilic process and the optimization of preparative methods is generated by the consider- able practical value of the aromatic ketone products. In fact, these compounds constitute fundamental intermediates or target products in the pharmaceutical, fragrance, flavor, dye, and agrochemical industries [2–4]. The Friedel–Crafts acylation reaction can be performed without any catalyst, but very harsh conditions are necessary [5]. Conventionally, and more efficiently, this electrophilic acylation using acyl chlorides or anhydrides is catalyzed by Lewis acids (such as ZnCl 2 , AlCl 3 , FeCl 3 , SnCl 4 , and TiCl 4 ); when carboxylic acids are directly utilized as acylating reagents, strong protic acid catalysts (such as H 2 SO 4 and HF) are needed. The simplified mechanism of the reaction involving an acyl chloride and AlCl 3 is depicted in Scheme 3.1. Depending on the strength of the Lewis acid and on the structure of the R 1 substituent, the actual acylating agent may be the acid–base complex 1 or the acyl cation 2. The active reagents 1 or 2 or even a mixture of both undergo the electrophilic aromatic substitution affording the final ketone product 3 [1]. Friedel–Crafts acylation follows the established “activation–orientation rules” of electro- philic aromatic substitution. However, the acylation of some highly activated aromatic compounds such as phenols and aromatic amines preferentially occurs at the substituent heteroatom, affording esters or amides instead of the more valuable aromatic ketones. These ortho‐hydroxy‐ or CATALYTIC FRIEDEL–CRAFTS ACYLATION REACTIONS Giovanni Sartori, Raimondo Maggi, and Veronica Santacroce “Clean Synthetic Methodology Group”, Dipartimento di Chimica dell’Università, Università degli Studi di Parma, Parma, Italy 3