Synlett 2006(9): 1283-1294  
DOI: 10.1055/s-2006-939728
© Georg Thieme Verlag Stuttgart · New York

Discovery and Understanding of Transition-Metal-Catalyzed Aromatic Substitution Reactions

John F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8107, USA
Fax: +1(203)4326144; e-Mail:;
Further Information

Publication History

Received 5 January 2006
Publication Date:
22 May 2006 (online)


This article presents studies on the development of cross-coupling reactions of aryl halides and sulfonates with amines, alkoxides, and various enolates. Emphasis is placed on the process of developing new catalysts with mechanistic information gained in the author’s laboratory.

  • 1 Introduction

  • 2 Early Reaction Development

  • 3 New Catalyst Developments

  • 4 Mechanism of the Cross-Coupling Processes

  • 5 Mechanism of Oxidative Addition

  • 6 Reductive Elimination of Amines

  • 7 Stable Palladium Catalysts for Coupling of Primary Amines

  • 8 Guidelines for Catalyst Selection


For a review of our work on the reductive elimination to form carbon-nitrogen and carbon-oxygen bonds, see reference 10.


Our original work on the catalytic process led to the conclusion that the immediate product of the C-N bond-forming step [Pd(BINAP)(NArRR")], reacts with free ligand to regenerate [Pd(BINAP)2] faster than the amine dissociates to generate [Pd(BINAP)] and that [Pd(BINAP)2] lies directly on the catalytic cycle. We recently remeasured kinetic data on the order of the catalytic process in bromoarene and ligand and our corrected data imply that [Pd(BINAP)(NArRR")] dissociates the amine to form [Pd(BINAP)] faster than it reacts with the free ligand and that [Pd(BINAP)2] lies off the cycle as shown in Scheme [4] . These data are presented in reference 62.