45
3.3 C(sp
2
)–H and Organometallic Reagents as Nucleophiles
Compared to terminal alkynes, the use of C(sp
2
)–H of arenes or alkenes as nucleophiles in the oxidative cross-coupling reactions is more challenging because of two
problems. First is the inert nature of most C(sp
2
)–H bonds. The two atoms are
bonded together by a strong covalent bond with a dissociation energy in the range
of 100–120 kcal mol
−1
. Meanwhile, the C–H bond is of low polarity and acidity;
pKa values often lie above 40, making it fairly unreactive (pKa of terminal alkyne
is about 25). Second is the requirement to control site selectivity in arenes that contain multiple C(sp
2
)–H bonds.
Although C(sp
2
)–H bonds are generally unreactive, there are still several different approaches for activating and functionalizing C–H bonds. In particular, since the
1960s, many studies have demonstrated that transition metals can react with C–H
bonds to produce C–M bonds (known as C–H activation), and the corresponding
organometallic intermediates open up opportunities to further C–M bond functionalization [23–33]. Owing to the presence of their d-orbitals, transition metals display the ability to break unactivated C–H bonds via “coordination” in a controlled
and predictable manner. Inspired by this fundamental discovery, during the past
several decades, organic chemists have begun to harness the power of transition
metals to conduct these activation processes [34–43]. Meanwhile, to address the
selectivity challenge of C–H functionalization, several strategies have been developed [44]:
1. Innate electronic properties strategy: utilizing the innate property of C–H bonds,
for example, usually electrophilic metalation is favored at the most nucleophilic
position, and concerted metalation deprotonation (CMD) pathway is favored on
the most acidic C–H bond.
2. Intramolecular reaction strategy: using tethered reacting sites to limit the degrees
of freedom in one molecule, thereby controlling the regioselectivity.
3. Directing group strategy: using auxiliary or coordinating groups usually containing Lewis basic heteroatoms, thereby binding to the metal center and selectively
delivering the catalyst to a proximal C–H bond.
4. Steric properties: depending on substrate structure, certain C–H bonds may be
more accessible to the metal center than others.
5. Ligand-controlled strategy: using ligand in the reaction to create a specific steric
and electronic environment, thereby controlling the diastereoselectivity and
enantioselectivity.
Based on the aforementioned development of C–H bond functionalization, the
oxidative cross-couplings between C(sp
2
)–H bond and another nucleophile are
becoming a powerful method for the construction of various aromatic motifs or
alkene derivatives (Scheme 3.5). The discussion of this section will be highlighted
3 Oxidative Coupling Reactions Between Hydrocarbons and Organometallic Reagents…
3.3 C(sp
2
)–H and Organometallic Reagents as Nucleophiles
Compared to terminal alkynes, the use of C(sp
2
)–H of arenes or alkenes as nucleophiles in the oxidative cross-coupling reactions is more challenging because of two
problems. First is the inert nature of most C(sp
2
)–H bonds. The two atoms are
bonded together by a strong covalent bond with a dissociation energy in the range
of 100–120 kcal mol
−1
. Meanwhile, the C–H bond is of low polarity and acidity;
pKa values often lie above 40, making it fairly unreactive (pKa of terminal alkyne
is about 25). Second is the requirement to control site selectivity in arenes that contain multiple C(sp
2
)–H bonds.
Although C(sp
2
)–H bonds are generally unreactive, there are still several different approaches for activating and functionalizing C–H bonds. In particular, since the
1960s, many studies have demonstrated that transition metals can react with C–H
bonds to produce C–M bonds (known as C–H activation), and the corresponding
organometallic intermediates open up opportunities to further C–M bond functionalization [23–33]. Owing to the presence of their d-orbitals, transition metals display the ability to break unactivated C–H bonds via “coordination” in a controlled
and predictable manner. Inspired by this fundamental discovery, during the past
several decades, organic chemists have begun to harness the power of transition
metals to conduct these activation processes [34–43]. Meanwhile, to address the
selectivity challenge of C–H functionalization, several strategies have been developed [44]:
1. Innate electronic properties strategy: utilizing the innate property of C–H bonds,
for example, usually electrophilic metalation is favored at the most nucleophilic
position, and concerted metalation deprotonation (CMD) pathway is favored on
the most acidic C–H bond.
2. Intramolecular reaction strategy: using tethered reacting sites to limit the degrees
of freedom in one molecule, thereby controlling the regioselectivity.
3. Directing group strategy: using auxiliary or coordinating groups usually containing Lewis basic heteroatoms, thereby binding to the metal center and selectively
delivering the catalyst to a proximal C–H bond.
4. Steric properties: depending on substrate structure, certain C–H bonds may be
more accessible to the metal center than others.
5. Ligand-controlled strategy: using ligand in the reaction to create a specific steric
and electronic environment, thereby controlling the diastereoselectivity and
enantioselectivity.
Based on the aforementioned development of C–H bond functionalization, the
oxidative cross-couplings between C(sp
2
)–H bond and another nucleophile are
becoming a powerful method for the construction of various aromatic motifs or
alkene derivatives (Scheme 3.5). The discussion of this section will be highlighted
3 Oxidative Coupling Reactions Between Hydrocarbons and Organometallic Reagents…