Open access peer-reviewed chapter

Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation

Written By

Priyank Purohit, Gaurav Joshi and Meenu Aggarwal

Submitted: 20 April 2022 Reviewed: 25 May 2022 Published: 17 June 2022

DOI: 10.5772/intechopen.105544

From the Edited Volume

Exploring Chemistry with Pyridine Derivatives

Edited by Satyanarayan Pal

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Carbon-hydrogen (C–H) bond activation involves a methodology for the construction of carbon-X (C–X) bonds where X can be carbon (C), oxygen (O), or the nitrogen (N), allowing the formation of C–C, C–O, or C–N bonds. Among them, the construction of the C–C bond within the aromatic moiety has remained a bottleneck because the abundance of C–H bonds in aromatic molecules possesses almost similar bond dissociation energies comparable to the C–C bond allowing leading to the poor reactivity and selectivity. Secondly, C–H bonds possess low polarity and thus confer them inertness. Considering this, directing group strategy came into existence, where the coordination ability of the heteroatoms such as O and N atoms within the ring was utilized for the direction of the reaction. The use of the heteroatom for the regioselective C–H bond activation is quite advantageous that could be explored immensely for their functionalization. In this chapter, we have congregated the information and put forth the evidence of C–H activation leading to the C–C bond formation in pyridine and pyridine-containing entities.


  • C–H bond activation
  • meta directing C–H activation
  • regioselective C–H activation
  • pyridine template

1. Introduction

C–H activation or functionalization is a technique of activating and transforming the C–H bond into the C–X bond, allowing the C–C, C–N, or C–O bond construction [1]. Among these, the functionalization to form a C–C bond is widely used [2]. As the aromatic moieties consist of an array of C–C bonds with attached hydrogens ( C–H bond), the selective activation of C–H bond is troublesome owing to similar bond dissociation energies to C–C bonds and low polarity of C–H bond [1, 3, 4]. The C–H is a saturated bond possessing only sigma bond, which must be preactivated. Traditionally, coupling or cross-coupling reactions (Suzuki, Heck, etc.) were immensely utilized to form these C–C bonds. However, these reactions confer additional steps to synthetic methodologies, including oxidative addition, reductive elimination, conversion to organic halides, triflates, along with boron or metal-based compounds. The available methods (coupling) that allow preactivation of the C–H bond to facilitate the construction of the C–C bonds (Figure 1) [4, 5, 6].

Figure 1.

Classical metal-based C–C bond forming reaction.

Owing to the drawbacks, direct C–H activation is seen as an alternative method possessing a cost-effective and eco-friendly system. The direct C–H activation allows the utilization of numerous transition metals as a catalyst with advantages over the traditional C–H bond activation pathway(s). Metal such as Ru, [7] Pd, [8], and Cu, [9] is frequently used for an efficient C–H activation leading to the C–C functionalization [3, 10]. The stability of the oxidation states of these transition metals remains one of the prerequisites peculiar features in catalyzing the C–C bond formation. Briefly, these transition metals primarily allow the C–H bond cleavage by forming an organometallic complex upon their reaction with the hydrocarbon. The C–H activation is preceded by an initial step that includes sigma and agostic interactions (Figure 2a) [11]. These interactions activate a C–H bond primarily by stabilizing metal intermediates possessing high energy and inducing the polarity in the C–H bond, thereby allowing the cleavage to occur. These interactions allow the transfer of electron density from the sigma orbital of C–H bonds to transition metals empty d-orbital. The sigma interaction proceeds via an intermolecular approach while the C–H bond interacts with the metal through is involved in the intramolecular approach in agostic interaction. The agostic complex forms the coordination sphere complex via the interaction of C–H with the metal-ligand. Further, the sigma interactions are considered weak, and the transition state complexes are usually not trapped or isolable [1, 11, 12].

Figure 2.

The illustration depicts A. the preactivation of the C–H bond via sigma and agnostic interaction; B. electrophilic substitution (ES) mechanism; C. oxidative addition (OA); D. sigma bond metathesis (SBM); and E. 1,2-addition mechanism. The blue ball represents carbon; red represents hydrogen; green represents nitrogen or halide, whereas the hexagon represents the metal.

Considering this interaction for preactivation of the C–H bond, the C–H activation proceeds via four effective mechanisms, which are determined by numerous factors, including the nature of metal (early or late transition metal) involved in catalysis , change in oxidation state during bond cleavage of metal, and the type of ligand involved [1, 2, 10]. These central mechanisms for C–H activation include the electrophilic substitution (ES) mechanism (Figure 2b) that usually occurs at an electropositive late transition metal complex leading to the formation of a four-membered centered transition state with no change in the oxidation state of the metal involved in the catalysis [13]. ES further does not need the involve lone pair involvement. The recent advancement of ES mechanism advanced mechanism under ES that has been identified includes processes such as ambiphilic metal-ligand activation (AMLA), concerted metallation deprotonation (CMD), electrophilic concerted metallation deprotonation (eCMD), and ligand-to-ligand hydrogen transfer (LLHT). The second mechanism includes oxidative addition (OA) [14]. OA involves the breaking of C–H bond (Figure 2c) by low-valent electron-rich metal complexes having neutral ligands (L-type) association. These associated ligands strongly donate the electron, thus creating the charge disparity between C–H bond and thereby inducing the enough polarity in the C–H bond for undergoing the activation. The breakage of the C–H bond is associated with an increase in metal formal oxidation state and coordination number by a factor of 2. The third mechanism associated with C–H bond direct activation is sigma bond metathesis (SBM) [15, 16]. This methodology (Figure 2d) is limited to metals in early transition series devoid of d-orbital electrons for oxidative addition. This proceeds via the formation of a four-centered transition complex where an H atom ( C–H) is transferred to the metal-carbon bond (M-C). This allows the dissociation of the H-atom acceptor from the transition metal complex (M-C). The net change in oxidation state is usually restricted in this mechanism. The fourth mechanism is 1,2-addition [17]. This mechanism (Figure 2e) usually involves early transition metals but is associated with C–H activation across multiple bonds. The mechanism proceeds via the addition of H-atom from C–H fragment on a double or triple bond, allowing the reduction of atom or ligand bound to the metal, leading to a new M-C bond formation.

The transition metals in the C–H activation increase the atom economy by reducing the number of functional groups (FG) for making the required bonds. The other advantages include reducing reaction times, synthetic steps, and allowing more greener chemistry. However, the C–H activations offer various advantages, but at the same time, maintaining the regioselectivity due to uncontrolled and unspecific C–H bond activation is troublesome. This has now been omitted chiefly due to the use of the directing group strategy. Various functional-based (Figure 3) directing groups are used to activate the inert C–H bonds. Most functional groups have oxygen and nitrogen atoms within the core structure such as the amide, sulfonamide, phosphonamide, ester, acid, and other carbonyl-based groups [4]. The specific/coordinating functional group was a prerequisite in all those reported protocols, which was the demerit of those reaction design protocols. However, later the heterocycle-based aromatic ring was found suitable for the regioselective C–H activation. The heteroatoms such as N and, O inside the ring were used by various groups, with a detailed mechanistic investigation. It was utilized for the functionalization of the various medicinally important pharmacophores, such as indole, imidazole, pyridine, pyrimidine, etc., as depicted in Figure 4 [18].

Figure 3.

Functional group-based C–H bond activation.

Figure 4.

Heteroatom-based C–H bond activation with pyridine as directing group.

The chapter therefore is kept forth to discuss the mechanistic insight that includes the discussion on C–H activation in pyridine and pyridine-containing entities. The chapter will provide enough insights to the organic and medicinal chemists to further explore these privileged heterocyclesic for their use as pharmaceuticals or diagnostic agents.


2. Pyridine as a directing group

Pyridine, an aromatic compound, possesses uneven electronic distribution on the ring because of heteroatom, which results in the loss of the aromaticity. In comparison with the high aromatic benzene ring, it has less aromaticity because of the presence of the heteroatom, N. The nitrogen atom on the pyridine acts as a donor to bind with metal to form (pyridine)N-metal bond s many complexes, which is the critical factor of the ring to acts as directing group with the metal-based C–H activation. Pyridine provides regioselectivity (Figure 5) to the attached aryl group at ortho and meta positions. However, some of the reactions are reported where pyridine makes ortho selective metal complex on its own [19].

Figure 5.

Regioselectivity of pyridine nucleus.

The metal and coordinating groups form a cyclic intermediate to get the space between the C–H bond and result in the C–C bond with desired regioselectivity. The pyridine nucleus was also used to synthesize chiral catalyst, using the coordinating capability of nitrogen to and metal with the appropriate direction [20].

2.1 Ortho C–H bond activation through pyridine directing group

Various other reactions are reported with the 2-aryl pyridine as a directing group for the ortho functionalization. In these reactions, many organometallic catalysts were used. The pyridine nucleus was were a directing group for the functionalization of the 2-aryl group with different functional groups through the metalacyclic system, where the reduction of the metal was the key to the newly constructed bond, as it is depicted the below in Figure 6.

Figure 6.

Metal-based cyclic intermediate with 2-aryl pyridine.

Pyridine nucleus-based drugs are an essential class of the heterocycles that possess important medicinal values [21]. The hydrogen bonding capacity of nitrogen atoms because of their non-bonded electron makes them available to make a hydrogen bond with the target amino acids/protein/enzymes. US FDA has approved various pyridine-based nuclei with a very high success rate unlimited successful as the first pyridine-based drug was known as Omeprazole, a widely used drug since 1998 as proton pump inhibitor. Many drugs based on pyridine have been approved later as Netupitant (2014), Abemaciclib (2015), Lorlatinib (2018), Apalutamide (2018), and Ivosidenib (2019) [22, 23, 24].

Ortho arylation at the two positions with the metal gains momentum with the attachment of the sensitive functional group such as a halo, ester, cyano, etc. The ortho-substituted reaction protocol was extended with C–O, C–P, and C–S, which claims the directing group capability of the pyridine with various coupling partners. The scope of the pyridine directing group is depicted in the Figure 7 with limited and important ed examples [25].

Figure 7.

Metal-based ortho substitution ation of 2-aryl pyridine.

Pyridine undergoes substitution with allyl group under the influence of ruthenium catalyst (Figure 8) at the C2 position of the pyridine ring via metal-based C–H activation. However, in the absence of catalyst, electrophilic aromatic substitution was found to occur predominantly instead of C–H activation. The allylation chiefly take place at phenyl ring (C2) rather than C2 position of the pyridine ring in the absence of metal catalyst [9].

Figure 8.

C–H bond activation of pyridine or pyridine-linked ring.

In pursuit of the ortho arylation with the chlorobenzene counterpart, which is considered the least reactive part because of the weak leaving property, the research group Crabtree and group developed a biomass-derived ligand that portrayed significantly improved catalytic activity (Figure 9) of ruthenium catalyst for ortho C–H bond arylation of 2-phenyl pyridine [10].

Figure 9.

Arylation of 2-phenyl pyridine through Ru biomass ligand direct C–H activation.

The 2-aryl-based scaffold was employed to substitute with azide to develop further a multi-nitrogen-bearing ring. The method of ortho-azidation was developed using copper catalyst (CuI), an oxidant, and benzotriazole sulfonyl azide as the azidating agent (Figure 10). The oxidant, K2S2O8 was used to enhance the system's catalytic activity. The advantage of this protocol was claimed as a starting material for the many pharmaceutical products as apoptosis inducers and phosphate transport protein inhibitors [11].

Figure 10.

Azidation of 2-phenyl pyridine.

In the ortho functionalization, the C–P bond was formed through the palladium-based cyclo-metallic system, wherein the nitrogen atom of pyridine was acting as a directing group to get the substitution on the 2-aryl pyridine (Figure 11) [12].

Figure 11.

Phosphonation of 2-phenyl pyridine.

2.2 Meta C–H activation through pyridine directing group

Various reports for the meta-C–H activation were reported, with the help of the directing group assisting bridge, where the geometry played a pivotal role to activate the meta-C–H bonds. The assisting bridge was found suitable for the meta directing as depicted below in the Figure 12 [13]. Some of them arise from the pyridine bases, as one of the important examples is the use of the direct ruthenium-catalyzed meta-bromination of arenes, which was utilized for the synthesis of Vismodegib. However, the mechanistic approach was found in their free radical mechanism [14].

Figure 12.

Meta-directed C–H activation.

The palladium-catalyzed meta-selective C–H deuteration substrates with pyridine ring were used to develop a meta-directing protocol to functionalize a complex ring-based structure. The optimized protocol successfully activated (Figure 13) the pyridine-based template with acid and ester-based functional group. The ester linkage played a pivotal role in developing a bridge to activate the meta-C–H activation [14].

Figure 13.

Deuteration through pyridine template.

A scientific group reported using a pyridine template to get the meta-C–H activation of benzyl and phenyl ethyl alcohols through its stereo interference (Figure 14) on the metalacyclic intermediate. The claim over the Pd and its sigma coordination to the site of concern is proved with the help of the designed experiment and found success with this versatile catalytic system [26].

Figure 14.

Alkenylation through pyridine template.

2.3 Pyridine vs. pyridine N-oxide as directing group

Pyridine N-oxides show reactivity toward nucleophile and an electrophile, while pyridine shows the most negligible reactivity for both of them. The oxidized form of pyridine is also considered a directing group for the metal-based C–H activation, with high regioselectivity [27]. The research group of Keith Fagnou used pyridine N- oxide extensively (Figure 15) for C–H activation-based methodology. Their methodologies were able to show the precise role of the Pyridine N-oxide as a regioselective directing group [28].

Figure 15.

Pyridine N-oxide and pyridine.

This directing group is to show the advantage of the pyridine nucleus as its oxidized form. Given the regioselectivity, one of the research groups claims different selectivity of the pyridine and its oxidized form (pyridine N-oxide) to the alkene counterpart. It also justifies that the shifting of regioselective functionalization is possible in the pyridine and its oxidized form [27].


3. Conclusion

The opening of the new C–H activation era has unlocked opened a wide range of options to develop a successful scaffold without disturbing the core structure and sensitive functional group. The ease and the minimal waste without using prefunctionalization of the C–H bond are the merits of this organometallic reaction. The importance of the reaction is that it can be utilized for the functionalization of the various heteroatoms–based scaffolds. The various scaffolds have been utilized for functionalization so far. Moreover, important and active moleculess are is also reported with good biological activity by various esteemed groups. Herein we summarized the functionalization of the pyridine nucleus with the help of organometals. The nitrogen of the pyridine was taken as a standard for directing the C–H activation, which resolved the issue of the regioselectivity. The problem of regionselectivity was also discussed here in the example of directing-group-based C–H activation. The reduction of the step and regioselectivity through the C–H activation protocol will have a significant impact on the chemistry and the pharmaceutical field through the reduction of cost. The reduction of the prefunctionalization step will also exert a beneficial action on the environment.



The authors are thankful to Graphic Era Hill University, Dehradun, India, for providing the required infrastructure.


Conflict of interest

The authors declare no conflict of interest.



CuICopper (I) Iodide
Ortho1 and 2 substituted aromatic compound.
Meta1 and 3 substituted aromatic compound.
Para1 and 4 substituted aromatic compound.
MetallocycleA cyclic structure with metal.
K2S2O8Potassium persulfate
HalidesF, Cl, Br, I
N atomNitrogen
O atomOxygen
P atomPhosphorus
S atomSulfur
FGFunctional group


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Written By

Priyank Purohit, Gaurav Joshi and Meenu Aggarwal

Submitted: 20 April 2022 Reviewed: 25 May 2022 Published: 17 June 2022