Chemistry of Pyridine Derivatives

#### **Chapter 1**

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

*Priyank Purohit, Gaurav Joshi and Meenu Aggarwal*

#### **Abstract**

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 pyridinecontaining entities.

**Keywords:** 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**) [4–6].

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].

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

**Figure 1.** *Classical metal-based C–C bond forming reaction.*

*DOI: http://dx.doi.org/10.5772/intechopen.105544 Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation*

#### **Figure 2.**

*The illustration depicts* **A.** *the preactivation of the C–H bond via sigma and ag***n***ostic 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.*

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

#### **Figure 4.** *Heteroatom-based C–H bond activation* **with** *pyridine as directing group.*

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].

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 **heterocycles** ic 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].

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].

*DOI: http://dx.doi.org/10.5772/intechopen.105544 Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation*

**Figure 5.**

*Regioselectivity of pyridine nucleus.*

#### **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**.

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) [22–24].

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].

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

**Figure 6.** *Metal-based cyclic intermediate with 2-aryl pyridine.*

**Figure 7.** *Metal-based ortho substitution ation of 2-aryl pyridine.*

**Figure 8.** *C–H bond activation of pyridine or pyridine-linked ring.*

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].

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].

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].

*DOI: http://dx.doi.org/10.5772/intechopen.105544 Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation*

#### **Figure 9.**

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

**Figure 10.** *Azidation of 2-phenyl pyridine.*

In the ortho functionalization, the C–P bond was formed through the palladiumbased 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].

#### **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 11.** *Phosphonation of 2-phenyl pyridine.*

**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].

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].

#### **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

**Figure 13.** *Deuteration through pyridine template.*

*DOI: http://dx.doi.org/10.5772/intechopen.105544 Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation*

**Figure 14.** *Alkenylation through pyridine template.*

**Figure 15.** *Pyridine N-oxide and pyridine.*

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].

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.

### **Acknowledgements**

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.

### **Abbreviations**


*Pyridine Nucleus as a Directing Group for Metal-Based C–H Bond Activation DOI: http://dx.doi.org/10.5772/intechopen.105544*

#### **Author details**

Priyank Purohit1 \*, Gaurav Joshi1 and Meenu Aggarwal<sup>2</sup>

1 Graphic Era Hill University, Dehradun, India

2 Department of Chemistry, Aggarwal College Ballabgarh, Faridabad, Haryana, India

\*Address all correspondence to: priyank.niper@gmail.com; prpurohit@gehu.ac.in

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 2** The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine

*Adebimpe D. Adesina*

#### **Abstract**

The chemistry of pyridine and its derivatives is of considerable importance in the synthesis of intermediates leading to biologically active compounds and novel materials. Generally, derivatives of pyridine are stable and relatively unreactive but can be attacked by electrophiles at ring nitrogen and certain carbon atoms. Pyridines undergo radical substitution reactions preferentially at the 2-position. Simple pyridines and their benzo derivatives are weak bases that form salts with strong acids. Various Lewis acids form complexes with pyridine and its benzo derivatives. The quaternization of pyridine and its benzo derivatives using alkyl and acyl halides have been used as versatile synthetic intermediates to biologically active compounds as final products. Precursors to cyanine dyes have been prepared by means of the 1,4-addition of pyridines and quinolines to acrylamide. *N*-oxides, obtained by the oxidation of pyridine and its benzo analogues, are versatile intermediates in organic synthesis.

**Keywords:** benzo derivatives, pyridine, quinoline, isoquinoline, synthetic intermediates, electrophilic substitution, nucleophilic substitution

#### **1. Introduction**

Pyridine was first isolated in a pure state from bone oil by Anderson [1] who had earlier obtained picoline from coal tar. He established the molecular formula of pyridine and showed it to be a tertiary base, capable of forming quaternary salts. A Kekule-type structure was proposed for pyridine **1** by Korner (**Figure 1**) [2]. The proposed structure was confirmed by the reduction of pyridine to piperidine, by the reverse oxidation and by the synthesis of piperidine.

In addition to being attacked by electrophiles, strong nucleophiles can also react, at the α- or γ- ring carbon atoms of the pyridine ring [3, 4].

Quinoline **2** and isoquinoline **3** are the two possible structures in which a benzene ring is annelated to a pyridine ring. The effect that the benzene ring has on the reactivity of the pyridine ring, and *vice versa* should be considered. Electrophilic substitution favors the benzenoid ring, rather than the pyridine ring with preferred substitution at the 5- (**Figure 2**) and 8- positions.

The electron-deficiency of the carbons in pyridines, particularly the α- and γcarbons, and the ability of the heteroatom to accommodate negative charge in the

**Figure 1.**

*Structure of pyridine and its benzo-fused analogues.*

**Figure 2.**

*Electrophilic substitution of isoquinoline.*

**Figure 3.** *Selectivity of nucleophilic attack on halopyridines.*

intermediate thus produced, makes nucleophilic addition and, especially nucleophilic displacement of halide (and other good leaving groups), a very important feature of pyridine chemistry (**Figure 3**) [5]. Quinoline and isoquinoline are reactive to nucleophiles in the pyridine ring, especially at the positions α and γ to the nitrogen and, further, are more reactive in this sense than pyridines.

#### **2. Synthesis**

The synthesis of a pyridine ring can be achieved in many ways. Some of these will be described and exemplified.

#### **2.1 Condensation reactions**

One of the methods for constructing the pyridine nucleus is by way of condensation reactions. This is done by the combination of an amino group with two carbonyl groups followed by the loss of two or more equivalents of water. A final oxidation step was often necessary to obtain the aromatic ring system. Most condensations leading to a pyridine derivative **17** proceed through an intermediate which can be related to a 1,5-dicarbonyl compound **16** (**Figure 4**).

The Chichibabin pyridine synthesis is an example of the condensation method for synthesizing pyridine rings. The reaction involves the condensation of aldehydes, ketones, α, β-unsaturated carbonyl compounds, or any combination of these, with ammonia.

Frank and Seven [6] have reported the modified synthesis of pyridine by heating the carbonyl compounds or derivatives with aqueous ammonia and catalytic amounts of ammonium acetate to produce good yields of single products. But-2-enal was reacted with ammonia to form 5-ethyl2-methylpyridine (**Figure 5**). However, the use of a steel autoclave at high temperatures and pressures was a drawback in this process.

An improved Chichibabin synthesis was also investigated by Weiss [7] and a mechanism was proposed for the formation of the pyridine ring. The mechanism of the reaction of benzaldehyde **20** with acetophenone **21** involved an aldol condensation to form **22**, followed by a Michael-type reaction to give a 1,5-dicarbonyl **23,** which then condenses with ammonia to form a dihydropyridine **24**, which, in turn, is dehydrogenated to a pyridine **25** (**Figure 6**).

#### **2.2 Cycloaddition reactions**

Some 6π cycloadditions have been used to form pyridines. The first to be reported was the addition of a dienophile **28** to an oxazole **27** [8, 9]. When acrylonitrile was used, hydrogen cyanide was lost to aromatise and the oxazole oxygen retained to give 3-hydroxypyridines, while with the use of acrylic acid, the oxygen was lost as water (**Figure 7**).

**Figure 4.** *Typical pyridine ring synthesis.*

**Figure 5.** *An example of the Chichibabin synthesis.*

**Figure 6.** *An improved Chichibabin synthesis of pyridine.*

#### **Figure 7.**

*Synthesis of pyridines via cycloadditions.*

The interaction of propargylamine **32** with a cyclic ketone **31**, produced an enamine **33**, followed by a ring closure which when effected with a gold catalyst, gave a carbocyclic pyridine derivative **34** (**Figure 8**) [10].

#### **2.3 Cyclization reactions**

Pyridines can be formed by the cyclization of nitriles at either carbon or nitrogen. Cyclizations at nitrogen were more common and incorporated the nitrogen into the pyridine ring.

Methyl-substituted pyridine derivatives have been synthesized from the cyclization of cyclic precursors **36** which were prepared from the treatment of β-ketoesters *The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine DOI: http://dx.doi.org/10.5772/intechopen.108127*

**Figure 8.**

*Synthesis of a carbocyclic pyridine derivative.*

#### **Figure 9.**

*Synthesis of pyridine from nitrile cyclization.*

**Figure 10.** *Azatriene cyclizations to form pyridines.*

**35** with acrylonitrile (**Figure 9**) [11]. The dehydrogenation of the piperidine ring in the final step also resulted in the loss of the ester group.

The fusion of pyridines to other ring systems has been investigated via thermal electrocyclization [12]. The pyridines were formed from the oxidation of dihydropyridines which were generated from the electrocyclization of aza-1,3,5-trienes. However, the use of an oxime or hydrazine derivative, followed by the elimination of water or an amine *in situ* gave the pyridine directly (**Figure 10**).

#### **3. Reaction with electrophilic reagents**

#### **3.1 Addition to nitrogen**

#### *3.1.1 Protonation and salt formation*

Pyridines behave like tertiary aliphatic or aromatic amines in reactions that involves bond formation using the lone pair of electrons on the ring nitrogen. Simple pyridines and their benzo derivatives are weak bases that form crystalline, frequently hygroscopic, salts with most protic acids [3, 4].

Chromium salts of pyridine have become important reagents in organic synthesis because of their mild oxidizing capability. Pyridinium chlorochromate (Corey's

reagent), pyridinium dichromate, and (Py)2CrO3 (Collins' reagent) are the most widely used.

#### *3.1.2 Alkylation*

Alkyl halides and sulfates react readily with pyridine and its benzo derivatives at room temperature, giving quartenary *N*-substituted pyridinium salts, which have been used as versatile synthetic intermediates to biologically active compounds or as final products [13–15]. Quaternization of pyridine with alkyl halides or related compounds is an example of Menschutkin reaction (**Figure 11**).

A review on quartenary salts of pyridines and related compounds describing their synthesis, physicochemical properties, possible applications, and their biological activities has been published [16].

#### *3.1.3 Acylation*

Acylation of pyridines can be achieved at temperatures as low as 78°C. Acid halides react readily with pyridines to generate *N*-acylpyridinium salts in solution, and in some cases, as crystalline, non-hygroscopic solids (**Figure 12**) [17]. *N*-Acylpyridinium salts have been found to be more reactive than their *N*-alkyl counterparts and are susceptible to attack by nucleophiles.

#### *3.1.4 Halogenation*

Pyridines and their benzo derivatives react with halogens to give *N*halogenopyridinium salts. The complexes of pyridine with chlorine have been well studied [18]. Pyridine iodo compounds can be prepared by treating TiI3[AsF6] with pyridines, from which the pyridinium salt [C5H5NI]<sup>+</sup> [AsF6] has been isolated and characterized [19]. Several syntheses of *N*-fluoropyridinium salts have been reported.

**Figure 11.** *Alkylation of pyridine.*

**Figure 12.** *Acylation at nitrogen of 4-dimethylaminopyridine (DMAP).*

These compounds have received growing interest because of their use as fluorinating agents [20].

*N*´, *N*´-Difluoro-2,2<sup>0</sup> -bipyridinium bis(tetrafluoroborate) **47,** prepared in one pot by introducing BF3 gas into 2,20 -bipyridine **46** at 0°C followed by fluorine gas diluted with nitrogen, has been shown to be a highly reactive electrophilic fluorinating agent (**Figure 13**) [21].

#### *3.1.5* N*-oxidation*

*N*-Oxides, obtained from the oxidation of pyridine and its benzo analogues, are versatile intermediates in organic synthesis [22–24]. Reagents used for the *N*-oxide formation include peracids, [3] H2O2/AcOH, dioxiranes, [25] organic hydrotrioxides, [26] Caro's acid, oxaziridines [27] and oxygen with ruthenium trichloride as catalyst [28].

Similarly, there are many ways to deoxygenate pyridine *N*-oxides: samarium iodide, chromous chloride, stannous chloride with low-valent titanium, ammonium formate with palladium and catalytic hydrogenation at room temperature can be used [29–33]. The most frequently used methods have involved oxygen transfer to trivalent phosphorus [34] or divalent sulfur [35] (**Figure 14**).

#### **3.2 Electrophilic attack at carbon**

In most cases, electrophilic substitution of pyridines occurs very much less readily than for the correspondingly substituted benzene. This is because the electrophilic reagent, or a proton in the reaction medium, adds first to the pyridine nitrogen, generating a pyridinium cation, which is naturally very resistant to attack by an electrophile.

The electron-withdrawing effect of nitrogen in pyridine is profound at the 2- and 4-positions and diminished at the 3-position. When electrophilic attack does occur, it is generally at the 3-position.

**Figure 13.** *Fluorination of pyridine compounds at nitrogen.*

**Figure 14.** *Oxidation of pyridine at nitrogen.*

#### *3.2.1 Nitration*

The electron-deficient nature of pyridine makes its direct nitration difficult even under rigorous conditions, whereas pyridine *N*-oxide, pyridines and pyridinamines can be nitrated more easily [36].

Initial reaction of pyridines with dinitrogen pentoxide in sulfur dioxide proceeds by addition at 2-position forming a 1,2-dihydropyridine intermediate. Transfer of the nitro group to a β-position, via a [1,5]-sigmatropic migration, is then followed by elimination of the nucleophile, regenerating the aromatic system to give 3-nitropyridines **49** (**Figure 15**) [37].

#### *3.2.2 Halogenation*

The halogenation of pyridines can be achieved using a variety of reagents which are not always mild and compatible with other functionalities in the molecule. Due to the electron-deficiency of the pyridine ring, electrophilic halogenations are mostly difficult.

The reaction of bromine with pyridine in oleum has produced 3-bromopyridine **51** in good yield [38]. The reactive species in the process involves pyridinium-1-sulfonate. Similarly, 3-chloropyridine **50** has been produced by chlorination at 200°C, or at 100°C in the presence of aluminum chloride, although in low yield (**Figure 16**) [39].

#### *3.2.3 Sulfonation*

The reaction of pyridine with concentrated sulfuric acid only gave low yields of 3 sulfonic acid after prolonged reaction time at 320°C. However, a higher yield was achieved with the addition of mercuric sulfate in catalytic quantities at a somewhat lower temperature (**Figure 17**) [40].

The sulfonation of quinoline has been achieved under conditions of 30% oleum at 90°C, occurring at the 8-position to give **53** in good yield, whereas isoquinoline gave the 5-acid. At higher temperatures, under thermodynamic control, other isomers are produced, for example quinoline-8-sulfonic acid is isomerised to the 6-acid **54** (**Figure 18**) [41, 42].

#### *3.2.4 Oxidation*

Pyridines require vigorous conditions to be oxidized as they are generally resistant to oxidizing agents. Pyridines have been converted into 2-pyridones **55** using copper sulfate (**Figure 19**) [43]. A similar conversion using zinc sulfate heptahydrate or

**Figure 15.** *Nitration of pyridine and substituted pyridine.* *The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine DOI: http://dx.doi.org/10.5772/intechopen.108127*

**Figure 16.**

*Chlorination and bromination of pyridine.*

**Figure 17.** *Sulfonation of pyridine.*

*Sulfonation of quinoline.*

tricadmium sulfate octahydrate and oxygen has also been reported, although with low yield [44].

When quinoline was oxidized under ozonolysis conditions, it gave pyridine-2,3 biscarboxaldehyde. The oxidation of quinoline or isoquinoline with permanganate can occur in either the benzene or pyridine ring, depending on the conditions. Electronwithdrawing or donating groups can direct the oxidation to either the benzene or pyridine ring. The oxidation of 5-aminoisoquinoline occurred in the benzene ring; however, 5-nitroquinoline gave the product of pyridine ring oxidation [4].

#### **4. Reaction with nucleophilic reagents**

Nucleophilic substitution reactions are characteristic of pyridines just as electrophilic substitution reactions are characteristic of benzene and electron-rich

heteroaromatic compounds such as pyrrole and furan. The nucleophilic substitution of hydrogen usually involves a hydride transfer in the last step [5].

#### **4.1 Nucleophilic attack at carbon**

Although many nucleophiles react with halogenated pyridines effecting the displacement of halogen, only strong nucleophiles react with simple pyridine. However, pyridine *N-*oxide and certain pyridines readily undergo nucleophilic substitution [4].

Nitro group has been introduced into the position 1 of isoquinoline using a mixture of potassium nitrite, dimethylsulfoxide and acetic anhydride [45]. The mechanism is shown in the quaternisation reaction of a complex of dimethylsulfoxide and the anhydride at nitrogen followed by the key step, the nucleophilic addition of nitrite to the heterocycle (**Figure 20**).

#### *4.1.1 Alkylation and arylation*

Reaction with alkyl- or aryl-lithiums proceeds in two discrete steps: addition to give a dihydro-pyridine *N*-lithio-salt which can then be converted into the substituted aromatic pyridine by oxidation, disproportionation or elimination of lithium hydride (**Figure 21**) [46]. The *N*-lithio salts can be observed spectroscopically and, in some cases, isolated as solids [47].

#### *4.1.2 Amination*

Amination of pyridines and related heterocycles, generally at a position α to the nitrogen, is called the Chichibabin reaction, [48–50] the pyridine reacting with sodamide in toluene, xylene or dimethylaniline with the evolution of hydrogen. The 'hydride' transfer and production of hydrogen probably involve interaction of aminopyridine product, acting as an acid, with the anionic intermediate. Vicarious

**Figure 20.** *An example of nucleophilic attack at carbon of isoquinoline.*

**Figure 21.** *Arylation of pyridine.*

*The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine DOI: http://dx.doi.org/10.5772/intechopen.108127*

nucleophilic substitution permits the introduction of amino groups *para* (or *ortho* if *para* blocked) to nitro groups by reaction with 1-amino-1,2,4-triazole **61** (**Figure 22**).

The amination of quinoline with potassium amide in liquid ammonia can, depending on conditions, give 2- or 4-aminoquinoline. The quinoline-2-aduct rearranges to the more stable 4-aminated adduct at higher temperatures (**Figure 23**) [51]. Isoquinoline, however, reacts with potassium amide in liquid ammonia at room temperature to give 1-aminoisoquinoline [52, 53].

#### *4.1.3 Silylation*

The reaction of pyridine with trimethylsiliconide anion has afforded 4-trimethylsilylpyridine efficiently. This process probably proceeds via a 1,4-dihydro-adduct (which can be trapped as its *N*-CO2Et derivative by addition of ethyl chloroformate), to give the fully aromatic product via hydride shift to silicon (**Figure 24**) [54, 55].

**Figure 22.** *Amination of pyridine.*

**Figure 24.** *Silylation of pyridine.*

**Figure 27.** *Nucleophilic substitution of quinoline.*

#### *4.1.4 Hydroxylation*

Hydroxide ion attacks pyridine only at very high temperatures to produce 2 pyridone in low yield. This can be usefully contrasted with the much more efficient reaction of hydroxide with quinoline and isoquinoline and with pyridinium salts [56].

Quinoline and isoquinoline can be directly hydroxylated with potassium hydroxide at high temperature with the evolution of hydrogen to give 2-Quinolone and 1 isoquinolone as the isolated products (**Figure 25**).

#### **4.2 Nucleophilic substitution with displacement of good leaving groups**

Halogen, and some other good leaving groups such as nitro, alkoxysulfonyloxy and methoxy at α- or γ- positions of the pyridine ring are easily displaced by nucleophiles via an addition-elimination mechanism. The nucleophilic substitution of halopyridine and haloquinoline are shown in the **Figures 26** and **27** respectively.

#### **5. Metallation and reactions of** *C***-Metallated pyridines, quinolines and isoquinolines**

#### **5.1 Direct ring C-H metalation**

The heating of pyridine in MeONa-MeOD at 165°C causes an H-D exchange at all positions via small concentrations of deprotonated species. An example of the use of

*The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine DOI: http://dx.doi.org/10.5772/intechopen.108127*

**Figure 30.** *Metal-halogen exchange of pyridine.*

lithiated pyridines, is their nucleophilic addition to azines **82**, to produce bihetaryls **83** on oxidation during work-up (**Figure 28**) [57].

2-Lithiation of 1-substituted 4-quinolones and 3-lithiation of 2-quinolone provides derivatives with the usual nucleophilic propensity (**Figure 29**) [5].

#### **5.2 Metal-halogen exchange**

Lithio-pyridines behave as typical organometallic nucleophiles, as in the reaction of 3-bromopyridine with n-butyllithium in ether at 78°C (**Figure 30**) [5].

Nucleophilic addition is a competing reaction in the preparation of lithioquinolines and isoquinolines via metal-halogen exchange, however the use of low temperatures allow metal-halogen exchange at both pyridine [58] and benzene ring positions [59] in quinolines, and the isoquinoline-1-[60] and 4-positions, [61] subsequent reaction with electrophiles generating *C*-substituted products (**Figure 31**).

#### **6. Photochemical reactions**

The ultraviolet irradiation of pyridines can produce highly strained species that can lead to isomerised pyridines or can be trapped. When *N*-methyl-2-pyridone **92** was

**Figure 31.** *Metal-halogen exchange of quinoline.*

**Figure 32.** *Ultraviolet irradiation of pyridone.*

**Figure 33.** *Photolysis of pyridine-*N*-oxide.*

irradiated in aqueous solution, a mixture of regio- and stereoisomeric 4π plus 4π photo-dimers **93** were produced (**Figure 32**).

The photolysis of pyridine *N*-oxides in alkaline solution induced ring opening to cyano-dienolates (**Figure 33**) [62].

2-Quinolones undergo 2 + 2 photo dimerization involving the C-3-C-4 double bond [63].

#### **7. Conclusion**

The synthesis and reactions of pyridine and its benzo derivatives have been extensively discussed. The Chichibabin synthesis is a notable example of the condensation method of preparing pyridines. Electrophilic substitution reactions occur less readily than the nucleophilic reactions. These reactions have been used for the preparation of versatile intermediates and precursors for biologically active compounds.

*The Chemistry of Benzo and Carbocyclic Derivatives of Pyridine DOI: http://dx.doi.org/10.5772/intechopen.108127*

#### **Author details**

Adebimpe D. Adesina Federal University of Agriculture, Abeokuta, Ogun State, Nigeria

\*Address all correspondence to: adesinaad@funaab.edu.ng

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## Structural Diversity in Substituted Pyridinium Halocuprates(II)

*Marcus R. Bond*

#### **Abstract**

The flexible coordination sphere of the Jahn-Teller active Cu(II) ion provides access to a full spectrum of coordination geometries from 4-coordinate (tetrahedral or square planar) to 6-coordinate elongated octahedral. This is further enhanced in anionic halide complexes by the ability of the halide ligand to bridge between Cu(II) centers to generate extended oligomeric or polymeric complexes. Coordination geometry and extended structure of the anionic complex is very sensitive to the nature of the organic counterion. This is especially true for planar substituted pyridinium cations in which minor changes in the nature or position of the substituted group can generate completely different halocuprate(II) structures. Early work focused on reducing ligand-ligand repulsion through strong hydrogen bonding with the organic cation in order to manipulate the Cu(II) coordination sphere. However, many unique structures have been found in which quaternary pyridinium cations were employedincluding the remarkable thermochromic compound (1,2,6-trimethylpyridinium)2C uCl4- in which strong hydrogen bonding is absent. More recently aminopyridinium cations, which further increase structural diversity not only through the possibility of having mono- or di-protonated cations but also the ability of monoprotonated cations to coordinate to the Cu(II) center through the amino group, have been investigated.

**Keywords:** substituted pyridinium compounds, structural chemistry, copper(II) complexes, Jahn-Teller effect

#### **1. Introduction**

The *d*<sup>9</sup> Cu2+ ion is, perhaps, the best known example of a Jahn-Teller active ion with an extremely flexible coordination sphere—to the extent that it has been referred to as "a chameleon of coordination chemistry" [1]. To summarize standard arguments [2]: in octahedral coordination the degenerate electronic ground state of *d*<sup>9</sup> Cu2+ is further stabilized by distortion (typically by elongation of one octahedral axis) to yield a non-degenerate electronic ground state (**Figure 1**). (In tetrahedral coordination a flattening distortion toward the square planar limit serves a similar purpose).

The elongated octahedral geometry can be described as 4 + 2 coordinate with four short coordinate covalent bonds (typical Cu-Cl bond lengths in the 2.2–2.4 Å range) and two longer semicoordinate bonds (typical Cu⋅⋅⋅Cl bond lengths ranging from 2.7

#### **Figure 1.**

*Schematic diagram of the d-orbital splitting of an octahedral CuCl6 4− complex undergoing an elongated axis Jahn-Teller distortion.*

to well over 3 Å). The two semicoordinate bonds can be of different lengths leading to 4 + 1 + 1′ coordination. Further elongation of the longer bond eventually leads (conceptually) to removal of that ligand and results in 4 + 1 coordination. In some situations the semicoordinate bond of a 4 + 1 complex is short enough (Cu-Cl distance of 2.6 Å or less) to become a coordinate bond and yielding a five coordinate geometry that is usually found somewhere on the continuum between trigonal bipyramidal and square pyramidal due to a second order Jahn-Teller distortion [3]. Removal of the other semicoordinate ligand yields a 4-coordinate complex that is usually found in a flattened tetrahedral geometry with *trans* Cl-Cu-Cl angles between 130 and 140°. However, these angles are found with a range of values, including 180° in the square planar limit. Square planar CuCl4 2− complexes are rare, and square planar CuBr4 2− complexes are almost completely unknown—a fact attributed to the stronger ligandligand repulsion between the larger bromide ions. Thus a wide range of coordination numbers and geometries is available to a copper(II) complex, as depicted in **Figure 2**.

**Figure 2.** *Coordination numbers and geometries available to a Cu2+ complex.*

*Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

#### **Figure 3.**

*Bridging modes available to halocuprate(II) complexes.*

The focus of this chapter is on copper(II) halide complexes—ergo the bond length and angle examples previously given. Chloride complexes have been more thoroughly investigated than bromide complexes [4]. This may be due to the wide variety of colors exhibited by chloride complexes of differing geometries and coordination numbers: ranging from reds to orange to yellow to greens. The author has found in some situations crystals of three or four different colors growing in the same beaker as identifiably distinct compounds. In contrast, the visible spectra of bromide complexes is dominated by ligand-to-metal charge transfer to give an intensely dark purple color with little variation across compounds [5, 6]. In both cases, however, the chloride and bromide ligands can bridge between copper(II) centers, as shown in **Figure 3**, to increase structural complexity by forming oligomeric or polymeric species.

#### **2. The utility of pyridinium cations**

#### **2.1 Anionic halocupreates(II)**

Halocuprate(II) complexes, whether isolated monocopper(II) or oligomeric or polymeric, are anionic and in crystalline solids are always accompanied by a cationic species. Earliest studied compounds used highly symmetric alkali metal or ammonium cations [7–10] but a wide variety of conterions have been used, including cationic inorganic or organometallic complexes. A broad array of organic cations, often readily and commercially available, have been most frequently employed [2].

#### **2.2 Structures with organoammonium cations**

Organoammonium cations can quickly become bulky with larger groups and higher degrees of substitution which prevents formation of polymeric complexes. Consider, for example, the (Et)x(Me)4−*x* series of chlorocuprates with an approximate 1:1 ratio of organic cation to CuCl2. For tetramethylammonium (*x* = 0) a tribridged chain of face sharing CuCl6 octahedra is found in (Me4N)CuCl3 [11]. For x = 1, in EtMe3N)4Cu5Cl14 a linear chain is also found, but with a mix of bi- and tribridging that "stretches" the chain in order to accommodate the bulkier organic cation [12]. For *x* = 2, a (Cu4Cl11 3−)n with even more frequent bibridging is found [13]. Organic cations with *x* = 3 and 4 are so bulky that a continuous chain is no longer possible, and isolated Cu3Cl9 3− [2, 14] and Cu4Cl12 4− [15] oligomers are found. Primary alkylammonium cations favor formation of layer perovskite *A*2Cu*X*4 (A = monopositive cation and X = Cl, Br) compounds in which layers of corner sharing Cu*X*6 octahedra are separated by bilayers of organic cations with −NH3 head groups directed toward the inorganic layer to form multiple N-H…*X* hydrogen bonds [16].

#### **2.3 Structures with anilinium versus structures with pyridinium cations**

Substituted planar aromatic cations, i.e. anilinium or pyridinium, provide a wealth of counterion possibilities while avoiding the bulkiness found with organoammonium ions. With a protonated −NH3 + head group, an anilinium cation can function structurally as a primary ammonium cation. Indeed, (anilinium)2CuCl4 exists as a layer perovskite system [17]. With pyridinium cations, however, the ring nitrogen acts as a single hydrogen bond donor (when protonated) that generally forms a single direct or a bifurcated hydrogen bond to halide(s) on a neighboring complex. The ring nitrogen can also be readily quaternized to examine halocuprate(II) structures in the absence of N-H hydrogen bonding. Pyridinium compounds have been more heavily studied than anilinium compounds: a Cambridge Structural Database (CSD) substructure search [18] on the anilinium core versus the pyridinium core with tetrachlorocuprate(II) complexes yields 24 compounds (14 of which are layer perovskites) and 120 compounds, respectively. This difference might be due to the tendency for anilinium cations to decompose in the presence of Cu(II) (presumably acting as a one-electron oxidation catalyst). In the author's experience, crystal growth under ambient conditions of anilinium chlorocuprate(II) compounds often yields brown or black residues. Indeed, there are no reported structures of ring substituted methyl or dimethylanilinium chlrocuprate(II) compounds in the CSD, whereas there are a handful of chlorozincate(II) compounds (where Zn(II) with a *d*10 configuration does not have access to a + 1 oxidation state) and numerous ring substituted methyl or dimethylpyridinium chlorocuprate(II) compounds.

#### **3.** *A***2Cu***X***4 compounds containing isolated Cu***X***<sup>4</sup> 2− complexes**

#### **3.1 General properties**

Compounds containing isolated Cu*X*<sup>4</sup> 2− complexes are readily prepared by slow evaporation of a solution, e.g. hydrohalic acid or alcoholic, containing a stoichiometric amount of organic cation halide and copper(II) halide, and examples are regularly reported. These most commonly contain flattened tetrahedral complexes with *trans X*-Cu-*X* angles in the range 130–140°. Strong hydrogen bonding between the organic cation and the halide ions of the inorganic complex is thought to reduce ligand-ligand repulsion and allow for larger *trans X*-Cu-*X* angles. Examples of these complexes are more rare, especially those with larger *trans* angles, Crystals containing chloro complexes with the commonly found *trans* angle are yellow/orange in color and become progressively more green in coloras the *trans* angle increases to reach an intensely dark green color at the square planar limit (180°) [19].

#### **3.2 Square planar complexes**

A recent example of square planar CuCl4 2− is in the isonicotinamidium (H-INAc) salt where strong bifurcated hydrogen bonds from the protonated ring nitrogen stabilize the *sp* geometry (**Figure 4**). This particular compound is also interesting since there is a companion compound in which neutral isonicotinamide molecules coordinate to the copper(II) center as terminal ligands in di-μ2-chloro polymeric chains. Exposure of these chains to moist HCl vapor protonates the pyridine and generates the *sp* complex in a reversible process [20]. In some cases green *sp* complexes undergo *Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

**Figure 4.**

*Ball-and-stick model of the formula unit of bis(isonicotinadium) tetrachlorocuprate(II) showing the strong, bifurcated hydrogen bonds that stabilize the sp geometry.*

abrupt (green to yellow) thermochromic phase transitions to *tet* complexes on heating as increased thermal motion weakens the hydrogen bonding that stabilizes the *sp* geometry [19]. While no such transition is reported for the H-INAc salt, it is possible that heating might result in deprotonation of the pyridine before a transition occurs.

#### **3.3 Polymorphism and supramolecular interactions**

Polymorphic crystalline forms of these systems can be obtained and studied with different polymorphs possible upon crystallization from different solvents or using different methods. An example occurs with 2,6-dimethylpyridinium in which a monoclinic structure (*C2/*c) is obtained from acidic aqueous solution [21] and an orthorhombic (P*bcn*) polymorph is obtained from ethanol [22]. Supramolecular interactions were examined in both polymorphs, which illustrates a common application of *A*2Cu*X*4 systems. Since they are readily prepared, it is convenient to use them to study supramolecular interactions with variations in pyridinium ring substitution, e.g. a recent study of halogen bonding in (chloromethyl)pyridinium salts [23].

#### **3.4 Catalytic ring substitution**

Willett et al. provided a classic series of papers detailing Cu(II) as a catalytically active species in serendipitous ring substitution reactions of pyridines. For example, recrystallization of 2-amino, 3-methylpyridine with CuBr2 in a slightly acidic solution yielded partial bromination of the pyridine to give (2-amino, 5-bromo, 3-methylpyridinium)(2-amino, 3-methylpyridinium) tetrabromocuprate(II) [24]. Likewise, recrystallization of 2,6-diaminopyridine with CuCl2⋅2H2O in slightly acidic solution yields (2,6-diamino, 3,5-dichlropyridinium) tetrachlorocuprate(II) [25] (the bromo analog more recently reported [26]).

#### **3.5 Structural complexity**

*A*2Cu*X*4 systems can also provide examples of structural complexity, e.g. through complex packing arrangements or symmetrically inequivalent Cu*X*<sup>4</sup> 2− complexes with different degrees of flattening. Well known older examples, the incommensurate phase of [(CH3)4N]CuCl4 [27] and the thermochromic compound [CH3CH2NH3]2CuCl4 (which contains three distinctly different CuCl4 2− complexes with one unit cell axis length ~ 45 Å) [28], do not contain pyridinium cations but there are more recent examples that do. The compound [bis(pyridinium-3-ylmethyl) ammonium]4(CuCl4)5Cl2 contains four distinct CuCl4 2− complexes with *trans* Cl-Cu-Cl angles ranging from 128 to 155° [29]. The high symmetry compound (1,3,4-trimethylpyridinium)2CuCl4 crystallizes in orthorhombic *Fdd*2 with complex anions found between layers of organic cations. The diamond glide symmetry

generates a four organic cation layer repeat sequence and leads to a ~ 35 Å *b*-axis length. The corresponding bromide compound is in lower symmetry monoclinic *P*21/*c* with symmetrically inequivalent organic cations that are segregated into separate layers, as another form of structural complexity [30].

This *Fdd*2 structure is found across a range of (1,3,4-trimethylpyridinium)2*M*Cl4 compounds (*M* = Co, Ni, Zn [31–33]) but larger metal ions (Mn, Cd [34, 35]) crystallize in monoclinic *C*2/*c*. A CSD search shows that *C*2/*c* is the second most commonly reported space group for pyridinium *A*2CuCl4 compounds (~40 structures) and slightly exceeds the number of compounds reported in the most commonly reported space group for all compounds, monoclinic *P*21/*c*. (The most commonly reported space group from pyridinium *A*2CuCl4 structures is triclinic *P* 1 with ~60 structures.) Since in the *C*2/*c* structure both organic cations are symmetrically equivalent, this suggests a strategy in pursuing structurally complex compounds by mixing different organic cations to give *A*′*A*CuCl4 structures. A few examples are known, such as the 2-amino-3-methylpyridinium example cited above in which organic cations are similar, or the (dimethylammonium)(3,5-dimethylpyridinium)CuCl4 structure [36] where the organic cations are quite different. A systematic study could be conducted by redissolving existing stocks of *A*2CuCl4 compounds in a 1:1 molar ratio and recrystallizing.

#### **4. Quasi-planar oligomers**

#### **4.1 Overview**

Halocuprate(II) complexes can form linear multicopper complexes through edge sharing of neighboring Cu*X*4 complexes. At the simplest level this is a dicopper(II) complex which, with a monopositive organic cation, has the typical formulation *A*2Cu2*X*6 for a 1:1 organic cation:Cu(II) stoichiometry More copper rich stoichiometries are needed for longer Cun*X*2n + 2 2− oligomers. Crystallization of a particular type of oligomer is not predictable, unlike the 2:1 stoichiometry *A*2Cu*X*4 compounds which are readily formed. Thus it is common when exploring the halocuprate(II) structural landscape to prepare solutions of different stoichiometries, e.g. 2:1, 1:1, and 1:2. The stoichiometry of the crystals obtained from solution is not necessarily the same as starting stoichiometry. These compounds require crystallographic analysis to establish their identities as dissolution destroys the compounds.

#### **4.2 Stacking of quasiplanar oligomers**

With bulky organic cations the oligomers are isolated and are formed from edgesharing Cu*X*4 flattened tetrahedra. For planar or less bulky cations, the oligomers are now quasi planar, formed from edge sharing of Cu*X*4 square planes, and are no longer isolated with halide ions from one oligomer form semicoordinate bonds with Cu(II) centers on neighboring oligomers to aggregate into stacks [4]. Neighboring oligomers are offset from each other by a half-integral multiple of a Cu*X*4 edge length with the pattern simply communicated by a bracketed pair. For example, 2[1/2,1/2] indicates that neighboring dicopper oligomers are offset from one another by ½ an edge length parallel to the long axis of the oligomer and ½ an edge length perpendicular (the 2 in front of the bracket identifies these as dicopper(II) complexes). These stacking

*Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

**Figure 5.**

*(a) 2[1/2,1/2] stacking in (2-amino-4-bromo-3-hydroxopyridinium)2Cu2Br6*⋅*2H2O (water molecules omitted for clarity) [38], (b) 3[1/2,1/2] stacking in (4-chloropyridinium)2Cu3Cl8 [39], and (c) 4[5/2,1/2] stacking in (1-meth ylpyridinium)2Cu4Br10 [40].*

patterns vary by compound, and can become more complicated with different oligomers in the stack having different stacking environments [37]. A selection of different oligomer structures with associated stacking patterns are shown in **Figure 5**.

#### **4.3 Pyridinium cation interactions in oligomer stacking**

While many different kinds of cations generate oligomer stacks, distinctions can be observed for pyridinium cations. Where hydrogen bonding is present, the oligomer is often terminated with a bifurcated hydrogen bond which mimics the bibridged structure within the oligomer, as shown in **Figure 6**.

Oligomer stacks can often be visualized as sections of a layer from the Cu*X*<sup>2</sup> parent structure. This is particularly true for situations where hydrogen bonding is not possible and the structures can be described as Cu*X*2 layers in which organic cation pairs replace (Cun*X*2*n*-2) 2+ fragments, as illustrated in **Figure 7** for (1-methylp yridiniuim)2Cu4Br10 [40]. In this case the shape of the organic cation may have more to do with templating the inorganic structure rather than directed intermolecular interactions.

**Figure 6.** *Hydrogen bonding scheme in (4,4*′*-diazenediyldipyridinium) Cu2Cl6 [41].*

**Figure 7.** *Layer structure of (1-methylpyridinium)2Cu4Br10.*

#### **4.4 High-nuclearity oligomers**

Oligomers containing more than four Cu(II) centers are rare. Only one example of a Cu5*X*<sup>12</sup> 2− oligomer is known (in 2-chloro-1-methylpyridinium)2Cu5Br10 [40]) in which oligomers are still found in isolated stacks (the neutral pentacopper oligomer Cu5Cl10(n-CH3CH2CH2OH)2 has long been known [42]). 1,2 dimethylpyridinium crystallizes with a hexacopper oligomer (Cu6Cl14 2−) and a heptacopper oligomer (Cu7Br16 2−) [43]. For these longer oligomers the stacks are no longer isolated, but overlap one another to form layers with the organic cations sandwiched between layers, as illustrated in **Figure 8**.

2-Chloro-1-methylpyridinium also crystallizes with a Cu7Br16 2− oligomer in a structure that is almost identical to that of 1,2-dimethylpyridinium. The chloro and methyl groups are disordered, indicating no directed intermolecular interaction with the oligomer and templating of the oligomer on the cation shape may be more important [40].

The longest reported oligomer is found in (3,5-dibromopyridinium)Cu10Br22. The authors rationalize formation of the decacopper(II) oligiomer in terms of halogen bonding contacts with the organic cation [44]. This laboratory has obtained also a Cu10Br22 2− for 2,6-dimethylpyridinium shown in **Figure 9** [45]. In spite of similarity in shape of the cation and similar unit cell parameters, the two structures are not superimposable. Longer oligomers are certainly possible, but these high copper(II) stoichiometries are rarely investigated so that further discoveries are likely to be serendipitous.

*Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

#### **Figure 8.**

*Overlapping of oligomer stacks to form a layer with one organic cation shown for the compound (1,2-dimethylpyr dinium)2Cu7Br16.*

#### **Figure 9.**

*Thermal ellipsoid plot (at the 50% level) of the formula unit of (2,6-dimethylpyridinium)2Cu10Br22 at 295 K. H-atoms are drawn as circles of arbitrary radii.*

#### **4.5 Asymmetrically bridged dicopper(II) oligomers**

An exception to the symmetrically bridged oligomers discussed above are situations where two Cu*X*4 square planes stack offset from each other to form long semicoordinate bonds between halide ligands of one complex and the Cu(II) center of the other. This leads to two asymmetric bridges with one short Cu-*X* bond and one long Cu⋅⋅⋅*X* bond, as shown in **Figure 10**. Stacks of Cu*X*4 square planes are not known, but such stacking would lend itself to formation of linear chain structures—which are known.

#### **Figure 10.**

*Asymmetric dicopper(II) oligomer in 4,4*′*-((cyclohexane-1,2-diylbis(ammoniumdiyl))bis(methylene)) bis(pyridin-1-ium Cu2Cl8*⋅*H2O [46]. Hydrogen atoms and water molecule are omitted for clarity. Bond distances in the dimer bridge are shown in units of Å.*

#### **Figure 11.**

*(a) The tribridged chain in 1-(4*′*-nitrobenzyl)-4-methylpyridinium CuCl3, (b) the bibridged chain in cyclohexylammonium CuCl3 showing the ammonium head group in postion to hydrogen bond to canted apical chloride ligands, and (c) the bibridged chain in 2-amino-6-methylpyridinium CuCl3 showing hydrogen bonds from the pyridine and amino N atoms that stabilize the apical chloride ligand as non-bridging.*

#### **5.** *A***Cu***X***3 linear chains**

The CsNiCl3 structure consisting of chains of face-sharing NiCl6 octahedra separated by monopositive cations is the parent structure for *A*Cu*X*3 linear chains. In the parent structure each Ni(II) ion is linked to its neighbor by three symmetric bridges. However, due to the axial Jahn-Teller distortion of the CuCl6 octahedron, in *A*Cu*X*<sup>3</sup> chains each Cu(II) is linked to its neighbor by two asymmetric bridges and only one symmetric bridge. In the absence of hydrogen bonding interactions from the counterion, in the case of Cs, (CH3)4N+ , or the quaternary4-methyl-1-(4′-nitrobenzyl)-4 methylpyridinium (shown in **Figure 11a** [47]) cations, the tribridged chain is observed. Hydrogen bonding from the cation to the halides of the chain provides charge compensation to the halides that permits lengthening of the Jahn-Teller elongated Cu-Cl bond. For strong enough hydrogen bonding the semicoordinate bond is broken and the chain is converted into a symmetrically bibridged chain of CuCl5 square pyramids. This is illustrated by the (cyclohexylammonium)CuCl3 structure where hydrogen bonding from the ammonium head group leads to elongation of the Jahn-Teller axial bond to a distance of 3.48 Å (as compared to elongated distances of 2.76 and 2.96 Å in the chain shown in 11(a)). At this distance the chloride ligand is, at best, weakly interacting with the neighboring Cu(II) center and a nascent CuCl5 square pyramid has formed with two symmetric bridges now connecting Cu(II) centers with the apical Cu-Cl bond still canted at an acute angle relative to the chain axis (see **Figure 11b** [48]). In 2-amino-6-methylpyridinium CuCl3 both the pyridine nitrogen and amino group serve as hydrogen bond donors forming multiple hydrogen bonds to the apical chloride and providing sufficient charge compensation that the apical Cu-Cl bond is perpendicular to the chain axis and no longer involved in bridging (see **Figure 11c** [49]).

#### **6. Quaternary pyridinium cations**

#### **6.1 Overview**

While hydrogen bonding has traditionally been seen as a means to control halocuprate(II) geometry, quaternary pyridinium cations provide a means of *Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

examining the effect of a lack of N-H hydrogen bonding on structure. Common methods used (in this laboratory) for preparation of quaternary pyridinium cations are (1) reaction of a substituted pyridine with an excess of iodomethane, then anion exchange with an excess of the appropriate silver halide in H2O or (2) direct combination of condensed chloro- or bromomethane (in excess) with chilled substituted pyridine in a pressure vessel that is then sealed and allowed to warm to room temperature for 24 hr. Examples of structures containing quaternary pyridinium cations have been mentioned in passing already. Here two particularly interesting systems are discussed.

#### **6.2 "Knobby" chains in (1,4-dimethylpyridinium)4Cu5Cl14**

The quaternary 1,4-dimethylpyridinium cation might be expected to crystallize with a tribridged (CuCl3)n chain due to the lack of hydrogen bonding—just as the quaternary cation example cited in the previous section and as is, notably, the case for (1,4-dimethylyrdinium) PbBr3 [50]. Instead it templates a highly unusual (Cu5Cl14)n "knobby" chains in which CuCl4 flattened tetrahedral "knobs" edge-share so as to bridge adjacent Cu(II) ions in the central chain [12]. The chain structure is distinctive since it exhibits the three major coordination numbers of Cu(II). Besides the flattened tetrahedral "knobs" on the outside of the chain, the central Cu(II) ion of the Cu5Cl14 repeat unit has the elongated octahedral 4 + 2 coordination. This bibridges on either side to 5-coordinated Cu(II) complexes with the intermediate *sqp*/*tbp* geometry. These 5-coordinate complexes then bibridge to 5-coordinate complexes on neighboring Cu5Cl14 units to complete the chain (**Figure 12**). With the lack of directed intermolecular interactions, the inorganic structure must template on the cation shape, although it is difficult to discern specifically the driving force behind formation of the structure. The knobs on the chain are found between stacks of organic cations with bridging chlorides close to the pyridinium N atoms as the most prominent point of interaction. There has been no reported attempt to prepare the bromide analog.

#### **6.3** *sp* **to** *tet* **phase transitions in (1,2,6-trimethylpyridinium)2Cu***X***<sup>4</sup>**

The second interesting case is the (1,2,6-trimethylpyridinium)2Cu*X*4 system [51]. Both the chloride and the bromide salts contain square planar Cu*X*<sup>4</sup> 2− in a low temperature phase (below 60°C for the chloride and below −48°C for the bromide). Both compounds undergo a solid-solid phase transition on heating to a high temperature phase in which Cu*X*<sup>4</sup> 2− is flattened tetrahedral, resulting in a thermochromic transition for the chloride salt (from dark green to yellow). As previously described, these

**Figure 12.** *A section of the "knobby" chains found for (1,4-dimethylpyridinium)Cu5Cl15.*

*sp* to *tet* transitions are thought to occur due to a weakening of hydrogen bonding. Furthermore *sp* CuBr4 2− is not expected, even with strong hydrogen bonding, due to the greater ligand-ligand repulsion of the larger bromide. So the occurrence of *sp* complexes and *sp* to *tet* transitions in systems without strong hydrogen bonding is highly unusual, if not unprecedented. (It is also worth mentioning that the transitions go from higher symmetry (monoclinic *C*2/m) to lower symmetry (triclinic *P* **1** ), which is also quite unusual.)

The quaternary ammonium cations in the low temperature structures form zipperlike ribbons with *sp* CuCl4 2− complexes between the ribbons, as shown in **Figure 13**, that act to template the *sp* geometry. Crystallographic mirror planes are perpendicular to this layer and bisect both the organic cation and the CuCl4 2− complex. The three dimensional structure is built up by stacking these layers so that organic cations of one layer sit above or below CuCl4 2− complexes in another so that the complexes are truly isolated. The structural transformation that occurs on heating disrupts this ribbon structure and results in two symmetrically inequivalent organic cations with aromatic planes tilted with respect to each other.

The 1,2,3-trimethylpyridinium cation has a similar shape as 1,2,6-trimethylpyridinium, and also crystallizes as zipper-like ribbons with chlorocuprate(II) complexes between the ribbons to from layers. However the complexes formed are not isolated CuCl4 2− but asymmetrically bridged [CuCl3(H2O)]2 dicopper complexes [52]. **Figure 14** illustrates the similar layer structure, right down to similar symmetry: monoclinic *C*2/m. As before, the mirror plane is perpendicular to the layer and bisects the organic cation. In this case, however, the N-atom lies off the mirror plane resulting in two-fold positional disorder that is not present in the 1,2,6-trimethylpyridinium analog. Does positional disorder stabilize a different structure?

#### **Figure 13.**

*Layer structure of (1,2,6-trimethylpyridinium)2CuCl4 showing the zipper-like ribbons of organic cations with methyl groups directed toward the center of the ribbon and with isolated sp CuCl4 2− between the ribbons. Mirror plane symmetry is perpendicular to the layer and bisects the organic cations and CuCl4 2− complexes.*

*Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

#### **Figure 14.**

*Layer structure in (1,2,3-trimethylpyridinium) CuCl3(H2O) showing the zipper-like ribbons of organic cations separating inorganic complexes. Another layer stacks with offset inorganic complexes to form asymmetrically bridged dimers. Mirror plane symmetry is perpendicular to the layer and bisects the organic cations and the inorganic complex to produce two-fold positional disorder of the organic cation.*

That is a difficult question to answer. Nevertheless, the *sp* Cu*X*4 complex appears to be inaccessible with the 1,2,3-trimethylpyridinium cation. While (1,2,3-trimeth ylpyridinium)2CuBr4 is known, it is a conventional flattened tetrahedral complex that is isostructural to (1,2,3-trimethylpyridinium)2CoCl4 (both in monoclinic *C*2/*c*). Preliminary work from this laboratory indicates that mixed crystals of (1,2,6-trimethylpyridinium)x(1,2,3-trimethylpyridinium)2−*x*CuCl4 do contain *sp* complexes in a situation where positional disorder is reduced [53]. In any case, these two examples indicate how minor changes in cation can produce major differences in halocuprate(II) structure. It would be interesting to study structures produced by the shape-similar 2,3,4- and 3,4,5-trimethylpyridinium cations which would now also introduce N-H hydrogen bonding interactions. Since these pyridines are not commercially available, a collaboration with a synthetic organic chemist is underway to prepare them.

#### **7. Systems with 3-aminopyridines**

Aminopyridines of various types have been prominent in the preparation of halocuprate(II) compounds, with some examples cited already. 3-Aminopyridines, in contrast to 2- or 4-aminooyridines, are capable of protonating both the pyridine and amino N-atoms. Typically the pyridine N-atom protonates first, and if a monoprotonated cation is desired care must be taken to crystallize compounds from solutions that are weakly acidic to avoid diprotonation. At the same time, the monoprotonated cation is capable of coordinating Cu(II) through the amino N-atom—which enables even further structural diversity. Willett et al. reported the earliest compounds with 3-aminopyridine and copper(II) halides. The 3-ammoniumpyridinium cation is found in Cu*X*4 layer perovskite structures for both the chloride and bromide by virtue

**Figure 15.**

*(a) The symmetrically bridged [CuCl3(3-aminopyridinium]2 dicopper complex and, (b) the asymmetrically bridged [CuBr3(3-aminopyridinium)]2 dicopper(II) complex as a monohydrate.*

of the **−**NH3 head group [54]. Other reported compounds have coordinated 3-aminopyridinium ligands: a symmetrically and asymmetrically bridged dicopper(II) complex for the chloride and the bromide (as a monohydrate in the latter case), respectively, as shown in **Figure 15** [55].

A structure for (3-aminopyridinium)2CuCl4 has been reported as a typical compound containing flattened tetrahedral CuCl4 2−. This reported structure, however, is almost identical to that of (2-aminopyridinium)2CuCl4, in both unit cell constants and atom positions, and is, in all likelihood, misreported [56]. In order to check this structure, this laboratory undertook crystal growth from acidic aqueous solution and managed to obtain crystals of (3-aminopyridinium)2CuCl4 by means that can only be described as serendipitous. These crystals gave completely different unit cell constants than the, likely, misreported structure.

In an effort to rationally synthesize crystals of this compound, crystals were grown from various organic solvents (1-proponal, acetonitrile, and tetrahydrofuran) by a thermal gradient technique in sealed, screwcap test tubes placed in a heater block with wells maintained at 40°C. Green crystals of (3-ammoniumpyridinium)CuCl4 were loaded into individual test tubes containing each organic solvent and crystal growth commenced. Another portion of these green crystals were ground together with a stoichiometric amount of 3-aminopyridine and a red-orange solid obtained. Portions of this solid were similarly loaded for crystal growth.

Two new compounds (**Figure 16**) have been obtained in crystal growth from 1-proponal: (1) green crystals of an asymmetrically bridged dicopper complex isomeric to the symmetrically bridged dimer reported by Willett el al.; and (2) red

#### **Figure 16.**

*Thermal ellipsoid plots of (a) the asymmetrically bridged dicopper(II) complex [CuCl3(3-aminopyridine]2 and (b) the formula unit of (3-aminopyridinium) [CuCl4(3-aminopyridinium)].*

#### *Structural Diversity in Substituted Pyridinium Halocuprates(II) DOI: http://dx.doi.org/10.5772/intechopen.107124*

crystals of a monocopper complex with a coordinated 3-aminopyridinium ligand and a 3-aminopyridinium lattice cation. The latter compound, [3-aminopyridinium] [(3-aminopyridinium)tetrachlorocuprate(II)], is identical in formulation to (3-aminopyridinium)2CuCl4 but with one organic cation moved to the inner coordination sphere. (Crystal growth from acetonitrile yields the known compounds (3-ammoniumpyridinium)CuCl4 and (3-aminopyridinium)2CuCl4) [57]. So far five different compounds have been obtained from the 3-aminopyridine:CuCl2 system just by varying crystal growth conditions. Studies are underway to investigate compounds of the corresponding bromides and of substituted 3-aminopyridines such as 3-amino-2-methylpyridine.

#### **8. Conclusion**

The use of pyridinium cations as counterions for halocuprate(II) complexes has provided a wealth of unusual structures due, in part, to the thin profile of the cation, the variety of possible substituent groups, and the easy ability to form a quaternary cation. Previous work has relied heavily on pyridines that are commercially available, but future advances may greatly benefit from targeted pursuit of synthetically prepared pyridines. Mixed cation structures, particularly of *A*2Cu*X*4 systems, have been rarely studied and offer the potential for discovery of new compounds with structural complexity. Different crystallization conditions and solvents have been used in the past to prepare different polymorphs, but now find use in preparation of diverse 3-aminopyridinium halocuprate(II) compounds. While pyridinium halocuprate(II) compounds have been widely studied and dispayed an amazing range of structural diversity, recent discoveries show that they still have the capacity to surprise.

#### **Notes**

#### **Structure graphics software used**

Ball-and-stick diagrams were plotted using *Mercury 4.0* [58]. Thermal ellipsoid plots were drawn using *ORTEP-3 for Windows* [59].

#### **Crystal data for (2,6-dimethylpyridinium)2Cu10Br22**

Triclinic, P 1 , 295 K, a = 9.4862(5) Å, b = 10.0507(5) Å, c = 13.0217(5) Å, α = 104.108(3)°, β = 90.442(3)°, γ = 92.708(3)°, V = 1202.5(1) Å3 , Z = 2. Reflections total/observed = 10,393/3691. θ(max) = 35.139°. Number of least squares parameters = 218. *R*ovserved = 0.0926, *wR*observed = 0.2117, goodness of fit = 1.001, Δρ(max/ min) = 2.181/−2.585 e− /Å3 .

*Exploring Chemistry with Pyridine Derivatives*

#### **Author details**

Marcus R. Bond Department of Chemistry and Physics, Southeast Missouri State University, Cape Girardeau, MO, USA

\*Address all correspondence to: mbond@semo.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### Section 2
