Selected applications to organic synthesis of intramolecular C-H activation reactions by transition metals ref.Pure & Appl. Chem., 1992 64, 335-342.

1. Selected applications to organic synthesis of intramolecular
C-H activation reactions by transition metals
Michel Pfeffer
Pure & Appl. Chem., 1992, Vol. 64, No. 3,335-342.
NAME: SUMAN MONDAL.
REGISTRATION NO: 20CHMS55.
YEAR:2022. CY-552.
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2. Content :
oWhat is C-H activation?
oHistory?
oC-H Activation vs C-H functionalization.
oWhy now a days it’s a popular research topic?
oWhy only transition metal can do C-H activation?
oTypes of C-H activation.
oReactivity of isolated C-H bond.
oMechanism.
oDifferent types of additives and their role in C-H activation.
oReaction of cyclopalladated compounds.
oOpportunities and challenges.
oSummary.
oReference.
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3. WHAT IS C-H ACTIVATION?
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The term usually implies that a transition metal is involved in the C-H cleavage process. Reactions classified by
the term typically involve the hydrocarbon first to react with a metal catalyst to create an organometallic complex
in which the hydrocarbon is coordinated to the inner-sphere of a metal, either via an intermediate "alkane
or arene complex" or as a transition state leading to a "M−C" intermediate

4. Lets go back to history :
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A. W. Hofmann
1883
1892
1898
Otto Dimroth
Jacob
Volhard

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1965
1969
Alexander
Shilov
Joseph
Chatt

6. C-H activation vs functionalisation
• 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 functionalization :
• 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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7. Why now-a-days it’s a popular research topic?
• Notoriously stable carbon–hydrogen bonds are commonplace in
almost all organic compounds. Being able to home in on
individual bonds and replace a hydrogen with a group of one’s
choosing is no mean feat, but it would offer chemists huge
power to modify organic molecules at will.
• It’s not just substrate scope, but also it has broadened the
reaction type. We’re not doing just one reaction – we can do
cross coupling, we can do hydroxylation chemistry.
• In 1995 fewer than 100 papers on C–H activation were
published. In 2019 there were more than 12 times that number.
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8. Why only transition metal can do C-H
activation?
• Several researchers conducted studies to investigate C-H bond activation in transition
metal species from a computational perspective.
• It was demonstrated that homogeneous catalysis mediated by transition metal
complexes was one of the most efficient ways to achieve high activity and control of
the selectivity in C-H activation.
• Different strategies were designed to achieve selective activation, as the C-H bond
was a poor Lewis base. It was demonstrated that selectivity was induced by an
external partner, such as an added base as in the concerted metalation-deprotonation
(CMD) mechanism or the ambiphilic metal-ligand activation (AMLA).
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 The C-H activation reaction between an organic substrate and a transition
metal complex can occur either inter- or intra-molecularly as represented in
the following scheme:
Between this two intra molecular C-H activation is more common

10. • About the reactivity of the isolated C-H bond :
 An isolated, i.e. non acidic, C-H bond in a molecule has, in general, a very low reactivity. This is mainly due to the large
kinetic barrier associated with the C-H bond cleavage, which is in turn related to the apolar nature of this bond.
 The BDE decreases along the series C(sp)-H C(sp2)-H C(sp3)-H, and on passing from 1° 2° 3° allylic C(sp3)-
H bond.
 On the other hand, being acidity proportional to the stability of the corresponding deprotonated species, the pKa trend goes
roughly in the opposite direction
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11. Overview of metal-promoted mechanisms :
• Outer sphere mechanisms : In the field of alkane oxidation, enzymatic metal-oxo species, or
bioinspired versions of them,promote C-H activation through a metalloradical pathway
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• Inner sphere mechanisms :
(a) oxidative addition (OA) for low-valent electron-rich transition metal complexes .
(b) σ-bond metathesis (σ-BM), for electrophilic early transition metal complexes .
(c) electrophilic activation (EA), for late transition metals with electron withdrawing ligands. However,
nowadays these distinctions appear less clear-cut.

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Fig: Frontier orbital interactions for electrophilic (left) and nucleophilic
(right) mechanisms

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 Electrophilic substitution mechanism :
 Ambiphilic concerted mechanisms :

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 Oxidative addition mechanism :
 1,2-Addition mechanism:
1. Roudesly,F.; Oble,J.; Poli,G. Metal-catalyzed C-H activation/functionalization: The fundamentals,Journal of
Molecular Catalysis A: Chemical 2017,426,275-296.

15. Different types of additives and their roles in
C-H activation reaction:
• Oxidants : most often Cu salts ( commonly Cu(OAc)2 and Ag salts (AgOAc, AgOTf)
sometimes Mn salts, are used in stoichiometric or superstoichiometric amounts
in Oxidative reactions, other oxidants, used alone or in combination with Cu or Ag
are benzoquinones,peroxides,O2/air,K2S2O8 or hypervalent iodine compounds.
• Catalytic Ag salts : Catalytic amounts of Ag salts are often used in combination
with groups 8 or 9 metal halide dimers, commonly used as catalysts ( e.g-
[RhCp*Cl2]. In these cases the Ag acts as a halide scavenger, and the counterion (
usually OTf,NTf2 or SbF2) promotes the in situ formation of cationic metal
catalysts in solution.
• Carboxylates : Main role of carboxylates is to deprotonate the desired C-H bond ,
which is to be activated . It occurs via concerted metalation deprotonation (CMD)
mechanism e.g.- Cu, Ag , Zn , Na salts of acetates , benzoates, pivalates,
admantanecarboxylates, trifluoroacetates, etc.
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16. • Ligands: In C-H activation approach , DG itself act as ligand (internal ligand),
hence there is no need of external ligands . But sometimes carbenes,
phosphines, mono – protected amino acids (MPAA) etc. can be used as
ligands. The choice of ligand is dependend upon the particular mechanism of
C-H activation .
• Lewis acids : IT can be used to activate the coupling partner (like ketone,
aldehyde, etc) lewis acids can be used in catalytic or stoichiometric amount
e.g. Zn salts (ZnCl2), the applied Lewis acids span over a wide range of reagents
also including more exotic In/Gd salts or BPh3.
• Bases: bases are used to neutralize the acid formed in the reaction or to
deprotonate the starting material/additives used in the reaction . Mostly
carbonates are used , e.g. Ag2CO3, Na2CO3, K2CO3,Cs2CO3 etc Ag2CO3 is used as
base as well as oxidant.
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17.  The reactions of cyclopalladated compounds derived mainly
from the palladation of nitrogen containing ligands :
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 These cyclometallated compounds afford new organopalladium compounds in several instances when they
are reacted with internal alkynes. One or more equivalents of the alkyne may insert into the Pd-C bond.
 Both types of compounds obtained in this way show interesting synthetic potentiality upon removal of the
palladium centre.

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DISADVANTAGES OF PREVIOUS REACTION :
Originally these inserted compounds showed an unexpected thermal stability so that any reaction performed to
recover the modified palladium-free ligand did not lead to any clean products.
 MODIFIED REACTIONS :
It was found recently that the stability of these compounds is very much dependent upon the nature of the other
ligands on the Pd atom.

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No reaction takes place between the chloride bridged cycloruthenated compound of 2-phenylpyridine with either
hexafluorobut-2-yne or dimethylacetylenedicarboxylate, whereas these alkynes readily insert into the Ru-C bond
of the corresponding iodide derivative.
Insertion of alkynes into Ru-C bonds can also take place starting with cycloruthenated compounds.
Interestingly, here too, the organoruthenium complex needs to be activated as for its palladium analogue.

20. MECHANISTICCONSIDERATIONS :
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22. Summary :
 The past 25 years have seen tremendous strides made toward the goal of selective
catalytic functionalization of C-H bonds by organometallic systems.
 Studies of stoichiometric reactions have contributed greatly to this progress; it is
primarily through such studies that we learn about the actual process of C-H activation.
 Studies of catalytic systems have led directly to improved systems; such studies have
also elucidated the problems faced in the development of such systems, revealing many
issues that are quite distinct from the challenge of stoichiometric C-H activation.
 Systems of significant practical utility have only just begun to emerge from this field.
 Extrapolating the current rate of progress,however, leads us to believe that the next 25
years will see the appearance of a diverse array of valuable systems involving substrates
ranging from methane to the most complex targets of organic synthesis.
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23. Reference :
1. Dalton,T.; Faber,T.; Glorius,F. C–H Activation: Toward Sustainability and Applications , ACS Cent. Sci. 2021, 7, 2, 245–261.
2. HOLY GRAILS Seeking out selective C–H activation BY JAMIE DURRANI28 SEPTEMBER 2020.
3. Roudesly,F.; Oble,J.; Poli,G. Metal-catalyzed C-H activation/functionalization: The fundamentals,Journal of
Molecular Catalysis A: Chemical 2017,426,275-296.
4. Pfeffer,M. Selected applications to organic synthesis of intramolecular C-H activation reactions by
transition Metals, Pure & Appl. Chem.1992,64(3),335-342.
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