Organic chemistry mainly studies the cleavage and formation of bonds in a practical and selective fashion, and the formation of carbon-carbon (C–C)[11] and C–Heteroatom (C–
Het)[12] bonds is the most important part, since it can serve as a valuable tool for scientists to design and synthesize different kinds of functional materials and bioactive molecules.
Original works in coupling reactions were realized by Glaser[13] in the late of 19th century and Ullmann[14] in the early of 20th century using stoichiometric or catalytic amounts of copper. Now highly efficient transition-metal catalyzed organic reactions have made a huge impact on organic transformations for C–C and C–Het bond formations. In the recent decades, significant progress have been further witnessed in this area by the invention of a variety of named cross-coupling reactions, such as the Kumada-Corriu-coupling,[15]
Mizoroki-Heck-coupling,[16] Negishi-coupling,[17] Stille-coupling,[18] Hiyama-coupling,[19]
Suzuki-Miyaura-coupling,[20] and Sonogashira-coupling[21] reactions. Thus, transition metal-catalyzed cross-coupling reactions performed as a powerful tool in organic synthesis, with applications ranging from the construction of natural product and useful materials to the modifications of biologically active chemicals,[11, 12] and their significance was further reflected by Heck, Negishi and Suzuki being collectively awarded with the Nobel Prize in chemistry in 2010.[23]
Based on transition-metal catalysis, this newly acquired ability to forge carbon–carbon bonds between or within functionalized and often sensitive substrates provided new opportunities, particularly in total synthesis but also in medicinal chemistry as well as in chemical biology and nanotechnology. Prominent among these processes are the palladium-catalyzed C–C bond-forming reactions. The historical, mechanistic, theoretical, and practical aspects of these processes have been amply discussed. Indeed, these protocols have revolutionized organic syntheses, albeit a few problems still exist. First, the use of pre-functionalized starting materials is needed, such as the organic (pseudo)halides.
And even for the widely used organic nucleophiles, multiple synthetic steps, difficulty in storing and handling make them user unfriendly, e.g. RMgX, R2Zn, and toxic R’3RSn.
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Therefore, the selective C–H functionalization can serve as an elegant tool to diminish these problems,[24] combining the broad practicability of cross-couplings with the nature of green chemistry—atom economy and environmentally friendly methods (Scheme 1.1).
Moreover, two-fold C–H dehydrogenative activation also contribute to the formation of C–C bonds while external oxidants are required in the dehydrative step.[25]
Scheme 1.1. Comparison of traditional cross-coupling vs. C–H activation.
The last thirty years have seen many examples of C–H activation at different metal centers, usually with good regio- and chemoselectivity and under mild conditions. The selective transformation of ubiquitous but inert C–H bonds to other functional groups has far-reaching practical implications, ranging from more efficient strategies for fine chemical synthesis to the replacement of current petrochemical feedstocks by less expensive and more readily available alkanes.[26] All the potential practical applications have inspired chemists to study how these organometallic reactions occur, and what their inherent advantages and limitations for practical alkane conversion and late-stage functionalization are. As the transition metal-facilitated cleavage of the C–H bonds is the common key step in the above-mentioned C–H functionalization strategies, it has been heavily examined.
Excluding outer-sphere mechanisms, such as carbene/nitrene insertions[27] or radical reactions[28], the bond dissociation proceeds generally via five different pathways, depending on the nature of the metal, the ligands and oxidation states.[29] These methods (Scheme 1.2) are oxidative addition, electrophilic substitution, -bond metathesis, 1,2-addition and base-assisted metalation. Electron-rich complexes of late transition metals
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are prone to cleave the inert C–H bonds by oxidative addition, while this mode of action is unfavorable for early transition metals.[29b] Most late transition metals in higher oxidation states often act as a Lewis acid to cleave C–H bond by an electrophilic substitution mode.
The -bond metathesis is observed for early transition metals which cannot undergo oxidative addition. Metals containing an unsaturated M=X bond tend to undergo C–H activation via 1,2-addition. This fashion can be found in early transition metals.
Scheme 1.2. Mechanistic pathways for the C–H activation.
Besides the mechanistic scenarios, many examples proceed via the base-assisted C–H metalation events (Scheme 1.3). Further research on this base-assisted C–H activation led to the proposal of several transition states. The base-assisted deprotonation takes place via a six- or five-membered transition state respectively in the presence of
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carboxylate or a secondary phosphine oxide.[29a, 30] This C–H cleavage mode was classified as Concerted Metalation-Deprotonation (CMD)[30b] and ambiphillic metal-ligand activation (AMLA).[31] An additional mechanism is the base assisted intramolecular electrophilic substitution (BIES), which is common for base assisted electrophilic transition metals.[32]
Scheme 1.3. Transition states for the C–H cleavage in base-assisted C–H metalation.
Although many modes have been proposed for the C–H cleavage, another big challenge about C–H activation is the regioselectivity due to the almost equal bond dissociation energies and acidities among several C‒H bonds.[33] This issue can be tackled through steric hindrance, electronic bias, or the incorporation of directing groups.[34] The lone pair of the directing groups can coordinate to the transition metal, thus bringing the catalyst in close proximity to the desired C–H bond (Scheme 1.4).[35] Remarkably, different templates[36] and strategies[37] have been developed for the para- and meta- C–H activation.
Even free amine and hydroxyl groups could be used as directing groups to control the selectivity.[38]
Scheme 1.4. Regioselective C–H activation using directing groups(DGs).
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Scheme 1.5. Common directing groups for proximity induced C–H activation.