Recent advances in heterolytic nucleofugal leaving groups

Leaving groups have been defined as that part of a substrate that becomes cleaved by the action of a nucleophile.1 The IUPAC definition specifies a leaving group as a molecular fragment (charged or uncharged) that becomes “detached from an atom in what is considered to be the residual or main part of the substrate” in a given reaction.2 A leaving group that carries away an electron pair is called a nucleofuge.3 However, these terms are not synonymous since a nucleofuge may be a functional group that simply receives an electron pair during a nucleophilic attack without itself being cleaved away from the substrate. The term “leaving group” seems to have entered the chemical literature4 in the early 1950’s although its mechanistic role was certainly understood much earlier. For example, in a 1951 paper detailing the study of nucleophilic displacement reactions of neopentyl tosylates, the term “leaving group” does not appear anywhere in the abstract or discussion.5 In this 1951 paper, the leaving group concept was expressed by naming the actual departing group in each example under consideration (such as halide, tosylate, etc.). In the following year and in the same journal, a paper describing a study of solvolysis reactions of norbornyl halide and arylsulfonate systems uses the term “leaving group” in the paper’s abstract. However, in the body of the six-page paper the term is used only once along with “departing ionizing group”.6 In a short 1953 communication on the solvolysis of various alkyl halides (< 600 words), the term “leaving group” appears three times.7 By the following year, the term seems to have gained general acceptance, appearing for the first time in the title of a paper.8 By the mid 1960’s the term “leaving group” appeared in the titles of over 25 papers and was used in over a 125 abstracts. Some undergraduate textbooks of organic chemistry also adopted the term by this time period.9 Leaving groups are ubiquitous in organic chemistry, playing a key role in a wide range of reactions, including nucleophilic substitution (aliphatic and aromatic), electrophilic substitution, and elimination reactions. A survey of 135 named organic reactions widely utilized in modern preparative organic chemistry10 reveals that 38 reactions involve heterolytic nucleofugal leaving groups at some stage of their mechanism. If this selection of named reactions is representative, then it could be inferred that leaving groups play an important role in as many as 25% of all organic reactions. Despite the wide variety of available leaving groups, there is still a need to improve their performance in terms of selectivity, reaction rates, scalability, environmental compatibility, atom economy, and other parameters. Thus, research on leaving groups continues to be an area of fruitful endeavor. As described in the subsequent pages, variations on traditional leaving group motifs have been the principal means of developing groups with improved performance. This review therefore begins with a discussion of advances in sulfonate and carboxylate-based leaving groups. The use of chiral leaving groups in asymmetric synthesis is not a new area. However, an improved mechanistic understanding of asymmetric induction in a variety of reactions in recent years has inspired the design of new chiral leaving groups that are, in many cases, modifications of traditional groups such as sulfonates and carboxylates. These and other chiral leaving groups will be discussed in some detail. The field of organometallic chemistry has offered powerful new reagents and catalysts for small-molecule synthesis over the years. It is then no surprise that new organometallic leaving groups such as carboranes have recently emerged. Heterocyclic leaving groups have long been part of the synthesis chemist’s repertoire and new groups arise from this class of compounds with regularity. Many researchers look to biological systems for inspiration in the design of improved reagents. This trend is also seen in the development of nucleophile assisting leaving groups (NALGs) which stabilize a reaction transition state through chelating interaction with the incoming nucleophile. Several recent examples of this relatively new class of leaving group will be described in this review. To our knowledge, the present article is the first review of heterolytic nucleofugal leaving groups broadly defined. Given the ubiquity of leaving groups in organic chemistry, it would seem nearly impossible to review this topic exhaustively except as an extensive monograph. Indeed, reviews in this area have concentrated on specific leaving groups types such as sulfonates,11 pyridines,12 2-thiopyridylcarbonates,13 and carbanionic14 to name a few. Thus, the present review will extend to research findings primarily from the last 15 years, although a limited number of leaving group technologies from earlier periods that have not been covered in previous reviews will also be discussed. Also, some leaving groups that have been briefly reviewed as part of a larger work have been revisited here in greater detail. New reactions involving existing leaving groups will not be discussed here. Instead, the focus of this review will be on the mechanisms and performance characteristics of relatively new leaving groups. To further reduce the scope of this report to manageable proportions, heterolytic nucleofugal leaving groups involved in the vast field of acyl coupling chemistry has been excluded, especially since this area is reviewed on a routine basis.15 Also, reports describing the adaptation of existing leaving groups to the solid-phase will not be discussed here since this area has been reviewed in extensive surveys of solid phase organic synthesis techniques.16 Finally, new leaving groups in purely inorganic systems17 and in biological applications18 have been omitted here as these are somewhat tangential to the emphasis of this review on new leaving groups that facilitate the synthesis of organic small molecules.