C-H BOND ACTIVATION

IN COMPLEX
COMPOUNDS
Name : Jitendra Sahoo
226CY014
nd
M.Sc. 2 Year
 CONTENT
• Introduction
• Historical Overview
• Why C-H bond Activation is Difficult !
• C-H bond Activation v/s C-H Functionalization
• Sigma and Agostic Interaction
• Mechanism of C-H bond Activation
• Examples Of C-H Activation
• Application Of C-H Activation
• Limitations of C-H bond Activation
• Summary
• References
INTRODUCTION
• C-H activation, short for Carbon-Hydrogen activation, refers to a chemical process in which a carbon-hydrogen (C-
H) bond in an organic molecule is selectively broken and replaced with a new chemical group or functional group.

• This transformation allows for the modification of organic molecules at specific C-H bonds without requiring the use
of pre-functionalized starting materials or the introduction of additional functional groups.

• C-H activation has become a significant field in modern synthetic chemistry, as it provides a more efficient and
sustainable way to create complex molecules by directly modifying the typically inert C-H bonds present in organic
compounds.

• This approach can lead to the development of new drugs, materials, and other valuable compounds with improved
synthetic routes and reduced waste.
HISTORY
TRADITIONAL METHOD V/S C-H BOND
ACTIVATION
The cross coupling reaction requires extra procedures for preparing organic halides (or triflates) compounds, and
organic boron or metal compounds. On the other hand, the C-H bond activation can reduce these procedures, thus
making this reaction a cost-effective and eco-friendly system.
 WHY C-H BOND ACTIVATIONIS
DIFFICULT
• C-H bonds typically have high bond dissociation energies, which means that a significant amount of energy is
required to break these bonds. The high BD E results from the relatively small difference in electronegativity
between carbon and hydrogen, leading to a strong covalent bond w ith shared electrons.
• In a C-H bond, carbon and hydrogen have similar electronegativities, meaning they have a roughly equal attraction
for the shared electrons. This results in a nearly nonpolar covalent bond w ith low ionic character. Bonds w ith a
higher degree of ionic character are generally more reactive.

2 3
• Bon d St reng th of SP C-H > SP C-H >SP C-H
WHY C-H BOND ACTIVATIONIS
Kinetics Reason for low Reactivity:-
DIFFICULT
2 3

LUMO- Antibonding orbitals at high energy.

Even if you pump electron (Symmetry & Energy)
Pumping electron on C side of C-H antibonding is sterically inaccessible

HOMO- Bonding orbital is low lying compared to most hetero atoms

 C-H ACTIVATION VS C-H FUNCTIONALIZATION
C-H Activation
A specific mechanistic step involving the direct cleavage of a C-H bond that occurs due to an interaction with a transition metal, where the result is
a new carbon-metal bond.

C-H Functionalisation
A process involving the replacement of a C-H bond by another element or functional group but where the functionalisation is most often preceded
by a C-H activation event.

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Sigma and Agostic Interaction

Sigma and agostic interactions have been established as the principal step prior to C-H bond activation30. It must be recognised that in almost all cases these
interactions are crucial for activating a C-H bond by stabilising high energy metal intermediates and polarising the C-H bond to allow for cleavage to occur.
Both terms describe the same interaction: the donation of electron density from the σ-orbital of a C-H bond into an empty d-orbital on a transition metal.
The difference, however, is in the connectivity of the molecule undergoing the interaction. Sigma complexes are classified as C-H bonds undergoing this
interaction through an intermolecular approach.
An agostic complex is therefore classified as an intramolecular approach by a C-H bond that is held in the coordination sphere of the metal due to another
primary metal–ligand interaction.
 THE MECHANISM OF C-H BOND
ACTIVATION

1 2 3 4

Electro ph ilic Oxidative Sigma Bond 1,2- mechanism

mechanism addition Metathesis
mechanism
 ELECTROPHILIC
MECHANISM
• An electrophilic mechanism is the abstraction of a proton by
an available lone pair on the neighbouring heteroatom during
the transition state.
• In these systems, the oxidation state of the metal normally
doesn’t change and remains constant throughout the process.
• Generally, the formation of a ring that includes the metal, the
C-H fragment and the heteroatom is present.

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 OXIDATIVE ADDITION

• In this mechanism, the formal oxidation state and the

coordination number of the metal is increased by two units. It
has long been believed that oxidative addition reactions are
exclusive to electron-rich late transition metals.
• Oxidative addition is generally reserved for low valent
electron-rich metal complexes featuring strongly donating L-
type (L = neutral) ligands, such as those pften seen in
dehydrogenation chemistry

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 SIGMA BOND METATHESIS

• Sigma bond metathesis (SBM) generally involves the early

transition metals when d electrons are not available for
oxidative addition.
• A four-centred transition state is operative in which the H
atom from a C-H bond is transferred to an existing M-C
bond. The H atom acceptor normally dissociates from the
metal complex upon acceptance of the H atom.
• In sigma bond metathesis systems, the oxidation state does
not change throughout the reaction. The receiving ligand is
generally another hydrocarbyl or hydride fragment, but can
also be a main group substituent such a boryl or silyl.
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 1,2-ADDITION MECHANISM

• 1,2-Addition across a multiple bond is generally associated with

early transition metals.
• In this mechanism, the hydrogen atom from the C-H fragment adds
across a double or triple bond, thereby reducing the atom bound to
the metal and forming a new M-C bond in the process.
• These reactions are most often seen in metals such as Zr and Ti,
featuring multiply bonded carbon or heteroatoms.

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 Examples of C-H Activation
1,2-Bis(phenylsulfinyl)ethane palladium(II) diacetate is a palladium catalyst, which was
developed by M. C. White et al., and named “White catalyst” after the developer. For an
example of its characteristic reactivity differing from other homogeneous palladium
catalysts, the allylic C-H oxidation reaction has been reported, in which an acetoxy group
is introduced regioselectively into the allylic position.
In 1993, Murai et al. reported the direct addition of C-H bonds of aromatic ketones to olefins in the presence of a catalytic
amount of carbonyl(dihydrido)tris(triphenylphosphine)ruthenium(II). Since then, numerous examples of C-H bond
activation have been reported. The reaction above proceeds without using halogenated compounds and organic boron or
organic metal compounds. Thus, this system is cost-effective and eco-friendly.
 C-H activation using iron catalysts, Charette et al. have reported the direct coupling reaction of benzene with aryl
iodides using iron(II) acetate. This reaction is highly costeffective and environmentally friendly in the sense of using
an iron catalyst, which is less expensive, and therefore, further development and applications are expected from the
point of green chemistry.
In this reaction, a nitrogen atom of 7,8-benzoquinoline functions as a directing group to allow it to
selectively introduce arenes at the C-10 position. Moreover, arene compounds also react with 7,8-
benzoquinoline at the least sterically hindered positions. In this reaction system, 1,4-benzoquinone
functions as a reaction promoter, and silver(I) carbonate oxidizes the generated Pd(0) species, which
forms the Pd(II) / Pd(0) catalytic cycle.
Miyaura, Ishiyama and Hargwig et al. have reported the direct C-H borylation in 2002. This reaction is the most famous
and practical example of C-H bond activation using iridium catalysts. Aryl borates had been synthesized by the reaction of
aryl lithium or magnesium reagents with trialkyl borates so far, however, their method allowed a one-step preparation of
alkyl borates in a simple manner
 APPLICATIONS

Carbon-hydrogen (C-H) activation has a wide range of applications in synthetic chemistry and various industries. Here are some
notable applications of C-H activation:

• Pharmaceuticals: C-H activation is used extensively in the synthesis of pharmaceuticals. It enables the construction of
complex drug molecules more efficiently and with improved selectivity, ultimately contributing to drug discovery and
development.

2. Agrochemicals: C-H activation methods are applied in the production of agrochemicals, including herbicides, pesticides, and
fungicides, allowing for the efficient synthesis of these important compounds.

3. Materials Science: C-H activation is utilized in the design and synthesis of advanced materials, such as polymers, catalysts, and
functional materials used in electronics and optics.

4. Natural Product Synthesis: C-H activation methods facilitate the efficient synthesis of natural products, which are often
complex and contain numerous C-H bonds. This is valuable for both chemical research and the production of bioactive
compounds.
 APPLICATIONS
5. Fine Chemicals: C-H activation is employed in the synthesis of fine chemicals and specialty compounds used in various
industries, including flavors, fragrances, and dyes.

6. Sustainable Chemistry: C-H activation is considered a green and sustainable chemistry approach, as it reduces the need for
multiple synthetic steps, minimizes waste, and conserves energy.

7. Energy Conversion: C-H activation plays a role in energy-related processes, such as the production of biofuels, hydrogenation
reactions, and the development of fuel cells and energy storage materials.

8. Cross-Coupling Reactions: C-H activation is used in cross-coupling reactions to form carbon-carbon (C-C) or carbon-heteroatom
(C-X) bonds, enabling the synthesis of diverse chemical structures with broad applications.

9. Selective Functionalization: C-H activation allows for the selective functionalization of specific C-H bonds within a molecule,
providing control over the regioselectivity and site-selectivity of reactions.

10. Drug Modification: C-H activation is used to modify existing drug molecules, enhancing their pharmacological properties,
metabolic stability, and selectivity, which can lead to the development of improved medications.
 DISADVNTAGES
Selectivity: Achieving specificity for a particular C-H bond in complex molecules is challenging.

Functional Group Compatibility: Certain functional groups can hinder C-H activation reactions.

Reactivity Variation: C-H bonds have varying reactivity, making some harder to activate.

Catalyst Dependency: Many reactions rely on costly or toxic transition metal catalysts.

Regioselectivity and Stereoselectivity: Controlling which C-H bond is activated and stereoisomer formation can be complex.

Harsh Reaction Conditions: Some reactions require extreme conditions, unsuitable for sensitive molecules.

Limited Substrate Scope: Applicability may be restricted to specific compound types.

Catalyst Poisoning: Impurities can deactivate catalysts, impacting reaction efficiency.

Waste Generation: Some reactions generate significant byproducts or waste.

Complex Mechanisms: Understanding reaction mechanisms can be challenging due to intricate intermediates and pathways.
 SUMMARY

• C-H bond activation is a cutting-edge field with transformative potential in chemistry.

• Challenges include high C-H bond dissociation energies and nonpolar nature.
• Reactivity varies with hybridization: sp > sp² > sp³ C-H bonds.
• Alkane C-H bonds are particularly inert due to their saturated nature.
• Steric hindrance, thermodynamics, and kinetics can impede activation.
• Catalysts, often transition metals, are essential for C-H bond cleavage.
• Selective C-H activation finds applications in drug discovery and green chemistry.
• Ongoing research is pushing boundaries and driving sustainability in chemistry.
• C-H activation is a gateway to precise and efficient molecule modification.
• It offers endless possibilities for innovation in various scientific disciplines.
 REFERENCES

• https://www.nature.com/articles/s42004-021-00611-1#Abs1
• https://pubs.acs.org/doi/full/10.1021/cr9411886
• C-H Bond Activation Reaction
https://www.tcichemicals.com/assets/brochure-pdfs/Brochure_R5107_E.pdf
• The continuum of carbon–hydrogen (C–H) activation mechanisms and terminology by
Kristof M. Altus & Jennifer A. Love.
• Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex
Molecules
• https://pubs.acs.org/doi/10.1021/acs.joc.5b02818
• https://pubs.acs.org/doi/10.1021/acs.chemrev.2c00888
THANK YOU