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Historical Perspective and Mechanistic Aspects of C-H Bond Functionalization

Tariq M. Bhatti1, Eileen Yasmin2, Akshai Kumar2,3,4, and Alan S. Goldman1

1 Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, United States of America
2 Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, India
3 Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam, India
4 Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India

1.1 Introduction

The C-H bond is the most common linkage in organic chemistry and, surely not entirely by coincidence, is also one of the least reactive groups. The bonds of carbon to hydrogen are, of course, terminal bonds in any organic molecule. Therefore, they cannot contribute to the complexity of a molecule in the same way as C-O, C-N, or, most importantly, C-C bonds. This terminal nature is shared, for the most part, with bonds to halogens or alkali metals, but (with the exception of C-F bonds) those bonds are generally far more reactive; indeed, in contrast with C-H bonds, bonds of carbon to halogens, and even more so to alkali (and other) metals, are viewed by organic chemists as particularly desirable points of opportunity to create new bonds and increase molecular complexity.

The standard graphical depiction of organic molecules indicates C-H bonds by default, highlighting that the ubiquitous C-H bond is the singular "unfunctional group" of organic chemistry. Thus, the ability to effect transformations of C-H bonds is potentially the most powerful class of reactions in organic chemistry. Yet for most of the history of organic chemistry the selective functionalization of the most common C-H bonds (sp2 and especially sp3) was considered a largely unrealistic goal - however desirable it might be - and was the subject of very little active pursuit.

The challenge of functionalizing C-H bonds has been attributed most simplistically to their high bond strength, but this is certainly an incomplete explanation at best. The homolytic bond energy of H-F for example is far greater than that of typical C-H bonds yet no chemist would ever consider H-F to be unreactive. But a high homolytic bond strength combined with very low polarity and the absence of a lone pair of electrons begins to account for their general lack of reactivity. In comparing H-C bonds to other covalent H-element bonds, one observes that cleavage by polar reagents is generally uphill for C-H bonds.

Despite this general tendency to be unreactive, however, there are a fair number of reagents that will readily react with C-H bonds. O2 is certainly cheap, abundant, and effective in this respect. But this leads to the next great obstacle toward achieving useful C-H bond functionalization: selectivity. The ubiquitous nature of C-H bonds means that there are often multiple, and often very similar, possible sites of initial attack. And if that challenge is somehow addressed, one then faces the unpleasant fact that an initial C-H bond functionalization generally leads to a molecular product with C-H bonds that are both (a) weaker than those of the starting material, and therefore typically more reactive with respect to homolytic cleavage, (b) more polar, and therefore typically more reactive in a heterolytic sense. Thus, even if one successfully and selectively functionalizes a C-H bond, secondary reactions lie waiting to prey upon the initial product.

Thus it is not surprising that for most of the 20th century useful examples of C-H bond functionalization were quite limited. But in part thanks to the groundwork laid at the end of that century in the field of organotransition chemistry, the past few decades have seen an explosion of examples of transition metal chemistry exploited to yield highly valuable and elegant organic transformation. This volume highlights many of the most elegant of such examples. In this introductory chapter we discuss the fertile ground from which they emerged. Our perspective has of course been shaped by that of many others in the field, including those put forth in numerous excellent reviews [1]. The diversity of these and other reviews reflects the remarkably interdisciplinary range of approaches and perspectives that have been brought to bear on the inspiring challenge of functionalizing C-H bonds.

1.2 Electrophilic C-H Bond Activation and Concerted Metalation Deprotonation

1.2.1 The (Very) Early Years - from Mercury to the Palladium Era

In the modern historiography and taxonomy of C-H bond activation, electrophilic chemistry is often considered the earliest class of mechanisms discovered, whereas concerted metalation deprotonation (CMD) is perhaps the most recent important example. The distinction between these two classes of mechanisms, however, is less clear upon careful consideration. In that context we note that this lack of a clear boundary between various classes of C-H activation extends well beyond this particular example; indeed, blurry lines are more the rule than the exception [2].

Although CMD was first described independently in 2005-2006 by Davies and Macgregor [3], Daugulis [4], Maseras and Echavarren [5], its importance was first particularly recognized and exploited by Fagnou [6]. However, despite being recognized relatively recently, CMD is perhaps the operative pathway for the first selective C-H bond functionalizations ever identified. The term is used to refer to a mechanism in which a C-H bond is associated with a vacant site on an electrophilic metal center (typically an electrophilic, late transition metal) through an initial sigma complex (3-center-2-electron bond). This leads to an acidification of the C-H bond, which enables a basic ligand, most classically a carboxylate, to abstract the hydrogen as proton and often dissociate synchronously with carbon-metal bond formation.

Selective functionalization of "unactivated" C-H bonds by a transition metal can arguably be dated back to 1891 [7]. BASF used fuming sulfuric acid to oxidize naphthalene to phthalic anhydride, a key intermediate for production of synthetic indigo dye [8]. During one batch, Eugene Sapper, the technician on duty, decided to stir the hot mixture of acid and naphthalene with the nearest object available - a mercury thermometer. The thermometer broke and the mercury entered the reactor, where it was quickly taken into solution. However unplanned, this procedural deviation sharply increased the yield of phthalic anhydride and was quickly commercialized by BASF. It also appears to have initiated academic research into reactions of mercury with aromatic compounds.

Thus in 1892, Jacob Volhard, then at Friedrichs-Universität Halle, discovered that aqueous mixtures of mercuric chloride and sodium acetate could mercurate thiophene alpha to sulfur [9]. With a bit of heating, both alpha positions could be substituted. This reaction, however, only afforded modest conversions, and it led to complex mixtures.

During his habilitation at the University of Tubingen in 1898, Otto Dimroth observed that boiling benzene with mercury(II) acetate resulted in the formation of phenylmercuric acetate [10]. Acetic acid was formed as the byproduct, accounting for the proton displaced from benzene. Phenol displayed even faster kinetics. It reacts with mercuric acetate at ambient temperature in aqueous media with a bias toward ortho mercuration. Ortho and para mercuration of toluene was also observed [11]. Additionally, thiophene undergoes cleaner mercuration using Dimroth's conditions. Dimroth noted that this was a general electrophilic reaction for aromatic compounds, akin to sulfonation, nitration, and bromination [12].

But even at this early stage of investigation, there are hints that electrophilic aromatic substitution could not be the entire story. That would not account for the ortho-selectivity in the mercuration of nitrobenzene [12], which overrides the meta-directing tendency of the nitro group. Additionally, in 1907, Reissert reported [13] that the methyl group of nitrotoluene could be mercurated - an sp3 C-H bond functionalization.

These early examples remained curiosities for some time, and were seldom the preferred way to access organomercury compounds. Indeed, in 189 pages of preparations of organomercury compounds in Goddard and Goddard's 1928 textbook Organometallic Chemistry [14], only a handful of preparations involve direct reaction on C-H bonds [15]. And from a theoretical point of view, mechanistic understanding would await the development of physical organic chemistry methods.

Starting in the 1920s, significant research was done on the regiochemistry of mercuration of aromatic systems. In 1921, Dimroth studied the mercuration of nitrobenzene, anisole, and phenetole [16]. Burton, Hammond, and Kenner described the orientation of products obtained from mercuration of o-nitrotoluene [17]. Samuel Coffey conducted more detailed studies on the mercuration of nitrobenzene and nitrotoluene [18] and...