The past several decades have witnessed the development of more sustainable transformations with the aid of metal-catalyzed manifolds that have revolutionized the art of forming chemical bonds.[5] The importance of these methodologies was appreciated by a number of Nobel Prizes for Chemistry within the past few years, such as 2010 in recognition of palladium-catalyzed cross-coupling reactions to Heck, Negishi and Suzuki.[6]
Furthermore, the use of catalytic reactions is often advantageous for economic reasons, since mild reaction conditions, increased throughput and overall reduced waste formation lead to cost savings.[7]
Despite the tremendous influence of cross-coupling reactions for modern carbon–carbon (C–C) or carbon–heteroatom (C–Het) bond formations,[8] these approaches often fall short in addressing key green chemistry criteria,[4g] such as waste reduction, the minimization of pre-functionalization and the common requirement of precious metal catalyst (Scheme 1).[9]
In sharp contrast, the direct activation of omnipresent C–H bonds has emerged as an increasingly powerful tool to minimize waste products and at the same time significantly improve the atom economy[10] of coupling reactions.[11] In addition, the direct formation of the desired bond avoids laborious pre-functionalization of the synthetic building blocks
and thus enables excellent levels of step economy.[12]
Although isohypsic C–H activation obviates the manipulation of one substrate, additional reaction steps are required to synthesize the second preactivated coupling partner, such as organic (pseudo)halides.[13] In contrast, oxidative C–H/C–H or C–H/Het–H functionalizations are particularly desirable in terms of atom and step economy since
they are devoid of additional pre-functionalization steps, and in theory, only hydrogen is formed as the byproduct.[9, 14]
Scheme 1. Comparison of metal-catalyzed coupling reactions.
However, twofold C–H activations or cross-dehydrogenative couplings (CDC)[9, 14] inherently require stoichiometric amounts of often toxic and environmentally-harmful chemical oxidants and therefore result in poor levels of oxidant economy.
Moreover, dehydrogenative coupling reactions frequently suffer from harsh reaction conditions, strongly limiting their application to the synthesis of complex organic molecules.
Atom economy: maximizing the number of atoms of the raw materials that are incorporated non-renewable oxidants to affect oxidative transformations.[9]
In comparison to classical cross-coupling reactions, the direct functionalization of omnipresent C–H bonds with similar bond dissociation energies[15] also features additional challenges in terms of site-selectivity control.[16] To discriminate among different C–H bonds, chemists employ different approaches (Scheme 2a). First, activated arenes or heterocycles, such as indoles, exhibit distinct pKa-values[17] of the C(sp2)–H bonds and consequently C–H metalation via proton-transfer proceeds at the kinetically most acidic C–H bond.[18] Likewise, sterically demanding groups lead to a steric bias of the adjacent C–H bonds and hence C–H activation will occur in the most accessible position.[19] Since these two approaches are inherently substrate dependent, their range of application in organic synthesis is rather limited. In contrast, the most common way to achieve site-selective C–H metalation is the use of auxiliary groups that contain Lewis-basic heteroatoms which coordinate the metal complex and bring the catalytically active center in close proximity to a specific C–H bond (Scheme 2b). In recent years, the interest in chelation-assisted C–H activation has increased dramatically and notable efforts have been made to expand the approach to weakly coordinating,[20] removable[21] or transient[22]
directing groups.
Scheme 2. Site-selectivity control in C–H activation.
Although there are different definitions describing C–H transformations,[23] C–H activation in this thesis refers to an organometallic reaction step and the involvement of a resulting C–Met bond, whereas C–H functionalization is used in a broader context and can involve
the abstraction of an electron or proton via outer-sphere/radical-type mechanism, thus creating radical intermediates before a new functional group is introduced.[24]
One of the key challenges in developing novel C–H activations is to elucidate the underlying reaction mechanism. Over the past decades, different mechanistic pathways have been proposed for the key elementary step of the organometallic C–H activation event (Scheme 3).[23b, 25] In this context, oxidative addition was mainly described to occur for electron-rich late transition metals in low oxidation states, such as iridium(I) or rhodium(I) complexes (Scheme 3a).[26] In contrast, early transition metals of group 3 and 4 or actinides and lanthanides were prevalently reported to undergo isohypsic σ-bond metathesis (Scheme 3b).[27] Often, the catalytically active complex features alkyl or hydride ligands. A closely related mechanistic scenario was mainly suggested for electrophilic late transition metals such as Pd2+, Pt2+ or Pt4+ (Scheme 3c).[28] Here, the metal acts as a Lewis acid and undergoes electrophilic attack with the C–H containing substrate.[29]
Scheme 3. Established mechanistic pathways for organometallic C–H activation.
The concept was later extended by Periana and Goddard for internal electrophilic substitutions (IES) in where the deprotonation is facilitated by oxy-ligands in a concerted fashion.[30] Among these, a 1,2-addition was proposed for early transition metals or complexes which contain M=Y double bonds, with Y as π-donating ligands such as oxo, imido or alkylidines (Scheme 3d).[31] Within the last two decades, base-assisted C–H activation has received significant attention, which commonly proceeds via a five- or six-membered transition state (Scheme 3e). Here, bifunctional basic ligands such as carbonates,[32] secondary phosphine oxides[33] or carboxylate facilitate the hydrogen abstraction.[23b, 34] Indeed, detailed mechanistic studies have unravelled manifold mechanistic pathways for base-assisted C–H metalation (Figure 1).[35]
Figure 1. Proposed transition states for base-assisted C–H metalation.
After pioneering theoretical studies by Sakaki on undirected benzene activation,[34b]
detailed mechanistic work by Fagnou and Gorelsky have suggested that the C–H metalation proceeds via a simultaneous metalation and intramolecular deprotonation within a six-membered transition state.[36] Hence, they have termed the pathway concerted metalation deprotonation (CMD).[37] Important experimental observations included typically a preference of electron-deficient arenes for palladium-catalyzed C–H arylations[38] and the presence of large kinetic isotope effects (KIEs).[39] Subsequently, MacGregor and Davies have proposed a related scenario but, based on theoretical calculations, explicitly postulated an agostic interaction between the metal center and the C–H bond and summarized their findings as ambiphilic metal-ligand activation (AMLA).[40]
More recently, Ackermann has identified the pivotal role of bifunctional basic ligands within electrophilic substitution-type C–H activations. In contrast to CMD/AMLA, intermolecular competition reactions revealed a strong preference for electron-rich substrates and theoretical studies were suggestive of a six-membered transition state. Based
on their findings, the mechanistic pathway was termed base-assisted internal electrophilic substitution (BIES).[35, 41]
In spite of major progress, C–H activations and foremost cross-dehydrogenative couplings are largely dominated by cost-intensive and toxic precious metal catalysts. In addition, due to their low abundance, their extraction represents a serious environmental impact.[42] Also, among poor levels of oxidant economy, oxidative couplings usually demand toxic, halogenated solvents, which contradicts the inherently green nature of C–H activations.
Within recent years a remarkable progress has been made to address those limitations and to achieve ideal levels of resource economy in molecular syntheses.[9, 43] Notable efforts include the use of Earth-abundant catalyst,[23a, 44] the employment of biomass-derived solvents[45] and alternative concepts for the catalyst reoxidation to avoid sacrificial oxidants (vide infra).
Figure 2. Precious Metal versus Earth-abundant metal catalyst. Molar amount of transition metal per 100€.[46]
Resource economy: minimizing the in the overall footprint of chemical transformations as to the complete life cycle analysis, including, but not being limited to the use of naturally abundant or renewable feedstocks, solvents, metal catalysts, energy, and redox reagents.[9, 43]