In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better‐known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the author has been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy, the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.

In the intervening years since “The Chief” wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.

From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on even greater significance for the practice of chemical experimentation in the 21^st century.

Adams' description of the content of the intended chapters is still remarkably relevant today. The development of new chemical reactions over the past decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on the willingness of organic chemists to devote their time and efforts to the preparation of chapters. The fact that, at the dawn of the 21^st century, the series continues to thrive is fitting testimony to those chemists whose contributions serve as the foundation of this edifice. Chemists who are considering the preparation of a manuscript for submission to Organic Reactions are urged to contact the Editor‐in‐Chief.

The universe is asymmetric and I am persuaded that life, as it is known to us, is a direct result of the asymmetry of the universe or of its indirect consequences.

Louis Pasteur

The term chirality was originally coined by Lord Kelvin, and this concept now plays a central role in nearly every aspect of modern‐day life. This phenomenon's impact on biological systems is immense and arguably, the most vital force for sustaining life on the planet. Louis Pasteur appreciated the implications of chirality after he inadvertently discovered molecular chirality in the spontaneous resolution of an aqueous solution of racemic sodium ammonium tartrate tetrahydrate in 1848. Although enantiomers primarily differ in their ability to rotate plane‐polarized light, this definition is a gross oversimplification of the importance of homochirality. For example, Nature produces amino acids as single enantiomers, which provide the building blocks for proteins that recognize and differentiate between molecules with complementary shape and chirality. The origin of this preference for one‐handedness remains a subject of significant debate and speculation. Pasteur also described the first chiral resolution, which involved the addition of the chiral base, cinchonine, to rac‐tartaric acid to form diastereoisomers and thus established the basis for the classical chiral resolution process that is still widely employed today, particularly in the pharmaceutical industry. Based on these important discoveries, the idea that enantiomerically pure chiral molecules can only be formed in the presence of a chiral influence was formulated, which now forms the very basis of modern asymmetric catalysis. The following three chapters delineate the historical development of three entirely different transformations that, to varying degrees, incorporate the principles of chiral resolution and induction. Hence, the first chapter outlines non‐enzymatic resolution reactions, while the second two chapters provide examples of challenging enantioselective and desymmetrization reactions.

The first chapter by Aileen B. Frost, Mark D. Greenhalgh, Elizabeth S. Munday, Stefania F. Musolino, James E. Taylor, and Andrew D. Smith provides an outstanding treatise on the desymmetrization and kinetic resolution of alcohols and amines by non‐enzymatic enantioselective acylation reactions. The chapter aligns beautifully with the notion of efficiently separating enantiomers, which remains a stalwart approach in organic synthesis. Notably, the chapter describes the evolution of small molecules that emulate the efficiency and selectivity exhibited by enzymes. The discussion is organized in the context of stoichiometric and catalytic processes for the desymmetrization and kinetic resolution reactions of alcohols and amines in the context of mechanism, selectivity, scope and limitations, which illustrate the transition from the stoichiometric to the catalytic reaction manifold. The Mechanism and Stereochemistry section further subdivides the catalytic processes into the type of acylating agent and catalyst employed for a specific resolution. The Scope and Limitations component is categorized in the context of the substrate, namely, diols, alcohols, amines, diamines, amides, etc., which permits the reader to appreciate the expansive scope of this approach. The Applications to Synthesis illustrates how these methods have been implemented in the construction of some important pharmaceuticals and natural products, and the Comparison with Other Methods section provides a direct comparison with acylative and hydrolytic enzymatic kinetic resolution methods. The Tabular Survey summarizes the types of stoichiometric acylating agents and the various catalysts that have been employed to date, including oxidants and additives. The tables systematically provide examples of the types of substrates in the context of the associated approach and the organization mirrors the Scope and Limitations to permit the identification of suitable reaction conditions for a specific substrate. Overall, this is an excellent chapter on a particularly important and useful process, which will be an invaluable resource to anyone wishing to facilitate either a desymmetrization or kinetic resolution reaction of alcohol and amine derivatives.

The second chapter by Lucile Marin, Emmanuelle Schulz, David Lebœuf, and Vincent Gandon provides a scholarly account of the Piancatelli reaction or rearrangement, which is a useful process for the construction of 4‐hydroxy‐5‐substituted‐cyclopent‐2‐enones from 2‐furylcarbinols. Piancatelli and coworkers reported this process in the course of studying acid‐mediated reactions with heterocyclic steroid analogs in 1976. Notably, the rearrangement represents a rare example of a reaction that directly transforms a heterocycle into a carbocycle. The transformation is envisioned to proceed via an electrocyclic ring closure in a similar manner to the related Nazarov cyclization. Hence, while the preferred mechanism is a conrotatory 4π‐electrocyclization of a transient pentadienyl carbocation, the Mechanism and Stereochemistry section also outlines some other possibilities, namely, ionic stepwise and aldol‐type condensations. The Scope and Limitations portion is organized by the three variations of this process, namely, the oxa‐, aza‐, and carba‐Piancatelli reactions, which each include sections on cascade processes. Interestingly, the enantio‐determining step in this process, namely, a 4π‐electrocyclization of a transient pentadienyl carbocation, makes the asymmetric version challenging. Nevertheless, the ability to employ chiral phosphoric acids to generate enantiomerically enriched substituted cyclopentenones (albeit limited to the aza‐Piancatelli variant using anilines) represents a significant breakthrough for this process. The Applications to Synthesis describes the applications of this methodology to prostaglandin synthesis and some related natural products, and the Comparison with Other Methods section provides a relatively comprehensive assessment of other methods commonly deployed for the construction of this structural motif. The Tabular Survey incorporates reactions reported up to December 2019. The tables are uniquely organized based on the product framework with different substitutions to permit the identification of a suitable product. Overall, this is an important chapter on a remarkably useful reaction that has not been fully exploited in comparison with some of its related counterparts.

The third chapter by Constanze N. Neumann and Tobias Ritter outlines transition‐metal‐mediated and metal‐catalyzed carbon‐fluorine bond formation. The exponential growth in the development of methods that permit a late‐stage fluorination can be ascribed to the unique physical properties that fluorine bestows on functional organic molecules, such as pharmaceuticals, agrochemicals, and materials. For instance, fluorine forms the strongest bond to carbon, which results in a highly polarized bond that has significant ionic character. Hence the large dipole moment provides a weak hydrogen bond acceptor that infers unique conformational behavior. The Mechanism and Stereochemistry component of this chapter categorizes the fluorination process in the context of nucleophilic and electrophilic fluorine sources, which are subdivided into the type of catalyst employed. Notably, the authors have devised an excellent classification system highlighting the knowledge gaps in this important and rapidly developing area that should stimulate further work in this field. The mechanistic classifications are then used throughout the remainder of the chapter to make cross‐referencing a specific type of mechanism effortless for the reader. The Scope and Limitations part is organized by the substrate type, namely aryl, alkyl, and aliphatic substrates in the context of the aforementioned mechanistic variations, which permit one to identify the optimal approach for a particular substrate class. The substrates also address the critical challenges with site‐selectivity (aryl) and stereocontrol (alkenyl and aliphatic) that are encountered with these substrate classes. A key and striking feature is the realization that the C‐F bond can be introduced in a chemo‐, regio‐, and stereoselective manner. Consequently, several chiral catalysts have been developed that permit the asymmetric construction of carbon‐fluorine bonds through desymmetrization and enantioselective reactions, which have proven particularly important in medicinal chemistry. The Applications to Synthesis section delineates the incorporation of fluorine into unnatural functionalized molecules, given the relatively few natural products that contain this motif. Fluorine in natural molecules is rare because of the difficulties that a haloperoxidase has to oxidize fluorine anion compared with other halide ions. Hence, this section outlines several successful applications to fluorine‐18 positron‐emission tomography (¹⁸F‐PET) tracer synthesis, an important and challenging aspect of late‐stage fluorination given the relatively short half‐life of the ¹⁸F isotope. The Comparison with Other Methods portion describes some of the more classical fluorination methods, including nucleophilic aromatic substitution and displacement reactions with both nucleophilic and electrophilic fluorine sources. The Tabular Survey parallels the Scope and Limitations part in the context of aryl, alkenyl, and aliphatic fluorination reactions using both electrophilic and nucleophilic reaction conditions. Overall, this chapter provides the reader with an outstanding perspective on the recent developments of this important transformation, and represents a very important resource for the community.

I would be remiss if I did not acknowledge the entire Organic Reactions Editorial Board for their collective efforts in steering this chapter through the various stages of the editorial process. I would like particularly to thank Gary A. Molander (Chapter 1) and Steven M. Weinreb (Chapter 2), who each served as the Responsible Editor for the first two chapters and I was responsible for marshalling Chapter 3 through the various phases of development. I am also deeply indebted to Dr. Danielle Soenen for her heroic efforts as the Editorial Coordinator; her knowledge of Organic Reactions is critical to maintaining consistency in the series. Dr. Dena Lindsay (Secretary to the Editorial Board) is thanked for coordinating the contributions of the authors, editors, and publishers. In addition, the Organic Reactions enterprise could not maintain the quality of production without the efforts of Dr. Steven Weinreb (Executive Editor), Dr. Engelbert Ciganek (Editorial Advisor), Dr. Landy Blasdel (Processing Editor), and Dr. Debra Dolliver (Processing Editor). I would also like to acknowledge Dr. Barry Snider (Secretary) and Dr. Jeffery Press (Treasurer) for their efforts to keep everyone on task and make sure that we are fiscally solvent!

I am indebted to all the individuals that are dedicated to ensuring the quality of Organic Reactions. The unique format of the chapters, in conjunction with the collated tables of examples, make this series of reviews both unique and exceptionally valuable to the practicing synthetic organic chemist.