Open access peer-reviewed chapter

Imidazolium-Based N-Heterocyclic Carbenes (NHCs) and Metal-Mediated Catalysis

Written By

Vittal B. Gudimetla, Bony P. Joy and Sudeep Paul

Submitted: November 27th, 2021Reviewed: January 10th, 2022Published: March 2nd, 2022

DOI: 10.5772/intechopen.102561

From the Edited Volume


Edited by Satyen Saha and Arunava Manna

Chapter metrics overview

71 Chapter Downloads

View Full Metrics


The journey of “carbenes” is more than a century old. It began with a curiosity to understand a then less familiar carbon moiety in its divalent state. It reached an important milestone in the form of 1,3-imidazolium-based N-heterocyclic carbenes (NHCs), where the quest for bottleable carbenes was achieved through simple and elegant synthetic routes. The properties of these carbenes were finely tunable through the steric and electronic factors via chemical modifications. Thus, it became one of the unique and extensively studied ligands for its properties and applications. This chapter first briefs about structural details of NHCs and different synthetic routes for the preparation of imidazolium-based NHC precursors. The later section focuses on various methods for characterizing the steric and electronic properties of these ligands and their metal intermediates, which are crucial for developing efficient catalytic processes. Finally, the chapter concludes with NHC-metal-mediated catalytic applications and its immediate challenges.


  • N-heterocyclic carbenes
  • imidazolium salts
  • NHC-metal-mediated catalysis
  • steric and electronic properties
  • characterization of carbenes

1. Introduction

Carbon in its low coordinate divalent state is known as “carbene.” It is a well-known transient species in many catalytic reactions. Initially, the carbenes were considered to be very reactive and difficult to isolate. However, the carbenes were first stabilized as metal carbene complexes, which have found numerous applications in many important organometallic reactions. The challenge of isolating a stable metal-free carbene was ended in 1991, through the pioneering works of Arduengo et al. It was for the first time a stable metal-free N-heterocyclic carbene (NHC) was synthesized and isolated in the form of 1,3-di(adamantyl)imidazol-2-ylidene (IAd) by deprotonation of its 1,3-imidazolium salt precursor [1]. Thus, it enabled the easy synthesis of NHCs using simple synthetic routes and thereby extended its scope in synthetic organic chemistry. One such celebrated success is the role of NHCs as ligands in olefin metathesis [2].

1,3-Imidazolium salts are simple and stable precursors of NHCs. They are a good source for in situproduction of NHCs either by heating or upon reaction with a base. Chemically, these NHCs are nitrogen-containing heterocyclic compounds with a divalent carbene center [3]. Due to the available lone pair of electrons on the carbon, the carbene in these NHCs were often compared with phosphine ligands and validated for its effectiveness. The stability of this electron-rich carbene and its unique electronic properties are primarily due to the presence of two adjacent nitrogen atoms, which will have a push-pull electronic influence at the carbene center (Figure 1). The effect is synergistic in nature, where the N atom in the NHC withdraws the σ-electrons inductively and donates π-electrons to the imidazolium ring mesomerically. The inductive effect of the N-atom lowers the highest occupied molecular orbital (HOMO) energy level occupied by the p-orbital and thereby increases the energy gap between HOMO and lowest unoccupied molecular orbital (LUMO) levels of NHC. Hence, the second electron gets paired in the HOMO level resulting in the singlet form of carbene. Furthermore, the N-atom mesomerically donates a pair of non-bonding electrons from its p-orbital and overlaps with the empty p-orbitals of the C-atom, which reinforces the stability of the singlet carbene. Moreover, the cyclic bent structure of NHCs forces the carbene to a singlet state, whereas in acyclic carbenes, it exists in the triplet state [3, 4, 5, 6, 7, 8]. Singlet NHCs are capable of forming stable and stronger bonds with metals due to their good σ-donor and π-acceptor properties [9, 10], especially with electron-deficient metal atoms they act as good π-donors [11]. These unique electronic properties will equip NHCs to have similar or sometimes better reactivity than phosphines; hence, they are considered to be one of the important ligands in catalysis.

Figure 1.

Schematic representation of σ-withdrawing and π-donating electronic effects through the adjacent nitrogen atoms with the carbene carbonviainductive and mesomeric effects, respectively.

In addition to the unique electronic features, the structural diversity of the NHCs was another important aspect that attracted the attention of chemists. The scope for variation of the ring size from 4 to 7-membered ring structures and the possibilities for substituent variations either at the N-atom or on the C-atom of the ring have tremendously increased the structural diversity of NHCs. Dimer, trimer, and poly NHCs are also known in the literature. Thus, the relatively easy access to structurally diverse NHCs and its flexible metal coordination has resulted in a large number of NHC-metal complexes. Based on the metal coordination to the NHC unit, they have been classified as normal, abnormal, and remote NHCs (Figure 2). If it binds to the metal through the C2 atom, then it is known as normal NHC; similarly if it is through the C4 atom, it is known as abnormal NHC. If there is an absence of a heteroatom in the α-position of the carbenic coordination center, it is known as remote NHC. Compared with normal NHCs, the abnormal NHCs have stronger donor ability and hence have direct impact on its catalytic efficacy [12].

Figure 2.

Representative structures of (a) normal NHC; (b) abnormal NHC; and (c) remote NHC.

The typical synthesis of NHCs were often accomplished by deprotonation of azolium salts, such as imidazolium, thiazolium, and triazolium. The focus of this chapter is primarily on the imidazolium-based NHCs. In the synthesis of imidazolium-based NHCs, there are three key components, which form the NHC framework. They are (1) carbon backbone, (2) pre-carbenic unit, and (3) amino unit [13]. Different synthetic strategies were evolved based on the construction of these three key components (Figure 3). Apart from the conventional synthetic methods, other methods such as electrochemical, microwave, and solvent free synthetic methods were also known [15, 16, 17]. Recently, the incorporation of one or more NHC units into a single carbon backbone was also reported, and these multidentate ligands were used to make poly NHC-metal complexes. These poly NHCs are capable of exhibiting different steric and electronic properties than the normal NHCs. Moreover, due to the inherent structural chirality, they are often studied for applications in asymmetric catalysis [18, 19, 20, 21, 22, 23].

Figure 3.

Different synthetic strategies for making NHC precursors [14].

Considering the scope and potential applications of imidazolium-based NHCs viastructural refinement, it is essential to understand the factors that will control its properties and catalytic efficiency. Therefore, the following sections elaborates the methods to assess the steric and electronic properties of the NHCs.


2. Methods for assessing electronic and steric parameters of NHCs

2.1 IR spectroscopy: Tolman electronic parameters (TEP)

The most extensively used method for the determination of electronic properties of NHCs is based on the Tolman electronic parameters devised by Tolman in 1977, specifically for phosphines [24]. This technique uses tetrahedral Ni(CO)3L as model complex [25], where L is the ligand whose donor-acceptor abilities are under investigation. Carbonyl being a good π-acceptor has strong metal-to-carbonyl (dπ-pπ) back bonding. The introduction of ligands (L) with strong electron-donor properties will enhance the electron density around the metal (Ni) center in the Ni(CO)3L complex. Thus, by comparing the stretching frequencies of the carbonyl (CO) unit, various ligands (L) of interest were analyzed by their σ-donor properties. Ligands (L) with good σ-donor ability increase the metal-to-carbonyl back bonding. It results in stronger metal-ligand (Ni-L) bonding. Thus, it indirectly reduces the bond order of the carbonyl unit, and it will be reflected in the carbonyl IR stretching frequency (Figure 4). Nolan et al. were the first to systematically determine the TEP of NHCs using [Ni(CO)3(NHC)] as model complex. The critical limitation of this method is the preparation of a variety of nickel complexes using different NHC ligands. This synthesis requires the handling of NHCs with low boiling and toxic Ni(CO)4. Moreover, the TEP values are within a small window of 10 cm−1 and hence require high-resolution IR spectrophotometers. Any anomalies inherent to the IR measurement technique make this method more challenging. TEP depends on the steric factors since the steric can influence the complexes geometry, thereby the overlapping orbitals affect the TEP value. To overcome few of these shortcomings with respect to synthesis of analytical probes, Crabtree et al. [26] in 2003 reported the use of [(NHC)M(CO)2Cl], (M = Ir or Rh) complexes as the probe for determining the TEP. In 2008, Nolan et al. reported an extensive study on the Ir complexes for TEP determination of NHCs [27]. Compared with the earlier model complexes, an average of two carbonyl stretching vibration are taken into account due to cisarrangement of the carbonyl ligands in the [(NHC)M(CO)2Cl], (M = Ir or Rh) complex. Thus, the IR spectroscopy was found to be an useful tool to assess the Tolman electronic parameters (TEP). TEP of selected NHCs are given in Table 1.

Figure 4.

Determination of TEP using IR spectroscopy [25].

Sl. No.NHCTEP (cm−1)

Table 1.

TEP values for selected NHCs.

2.2 NMR spectroscopy: σ-donor and π-acceptor abilities of NHCs

NMR spectroscopy, especially 13C and 1H NMR, are the most efficient and reliable techniques to understand the properties of NHCs, the NHC precursors, and related NHC-metal complexes. In general, imidazolium proton (-N-C(H)-N-) in NHCs is acidic due to its connection to the two adjacent electron-withdrawing nitrogen atoms. Hence, this proton appears in the deshielded region of proton NMR, around 8–12 ppm. However, upon deprotonation, the imidazolium proton signal disappears in the proton NMR. The 13C{1H} NMR spectra of NHCs exhibit the carbene (-N-C-N-) carbon peak close to the highly deshielded region of around 200–250 ppm for free carbene, whereas it is approximately 130–160 ppm for its respective precursor imidazolium salt. Due to the increased shielding effect, the highly shielded carbene carbon upon metal complexation, will undergo an upfield shift. Apart from a diagnostic tool, the NMR technique is helpful to explore various properties of NHCs such as (a) the steric properties; (b) σ-donor ability from ligand to the metal center; and (c) π-back bonding from metal to carbene. Understanding these parameters of NHCs is crucial for controlling the catalyst selectivity, reactivity, and efficiency. Earlier, the Tolman electronic parameters (TEP) obtained from the CO stretching frequencies of metal complexes such as [Ni(CO)3L] and [MCl(CO)2L] (M = Rh or Ir) were used to assess the electronic properties. However, this method has limitations due to inherent inaccuracies in IR spectroscopy measurements of metal complexes. Also, the necessity of preparing these complexes under highly inert conditions, the requirement of expensive metals, and the usage of highly toxic CO gas are the important drawbacks of the TEP method. Moreover, the TEP only gives information about the overall electron density around the metal center but not independent σ-donor or π-back bonding abilities.

Huynh et al. reported the unique use of NMR for studying the donor properties of NHCs [28]. This method utilizes the 13C-NMR technique, where the trans-[PdBr2(iPr2-bimy)L]n− (iPr2-bimy = 1, 3-diisopropylbenzimidazolin-2-ylidene; L = NHC ligand under investigation) complex was the spectroscopic probe. In this complex, the presence of ligands (L) with the good σ-donor ability induces a downfield shift of the carbene carbon peak of the NHC (i.e., iPr2-bimy). Thus, it enabled easy comparison of NHCs with other significant ligands, such as phosphines, amines, and isocyanides. Moreover, this method utilizes easily preparable spectroscopic probes. Based on such carbene carbon chemical shift values, the NHC ligands are arranged on a unique σ-donor scale as shown in Figure 5.

Figure 5.

Arrangement of NHCs based on their σ-donor ability as per the 13C NMR data, using the spectroscopic probe-trans-[PdBr2(iPr2-bimy)L]n− [28].

Betrand et al. in 2013 reported the determination of π-acceptor ability of NHC ligands using the 31P chemical shift value of carbene-phosphine adducts, which exist in two different resonance forms “I” and “II” (Figure 6) [29]. The phosphaalkene form (I) has a P=C bond, and the form (II) has P-C dative bond with P having two lone pairs of electrons. The upfield phosphorus NMR chemical shift associated with P atom in the carbene-phosphine adducts agrees with the electron-rich resonance form (II). It suggests that the carbene carbon prefers a dative bond with phosphorus rather than a π bond. If the carbenes have π-accepting property, it should have reflected through a downfield shift in the 31P NMR.

Figure 6.

Arrangement of NHCs according to their π-accepting ability based on the 31P NMR chemical shift values [29].

Therefore, the NMR-based method provides an independent way to determine the π-accepting ability of NHC ligand, independent of its σ-donor abilities, which was one of the limitations of Tolman’s method for determining the electronic properties of NHCs. The arrangement of a few known NHCs according to their π-accepting ability, based on the 31P NMR chemical shift values, are provided in Figure 6.

Ganter et al. reported a similar technique in which the 77Se chemical shift of carbene-selenium adducts were used to assess the π-acceptor properties of the NHC ligands [30]. The carbene-selenium adduct exists in two different resonance forms (III) and (IV) (Figure 7), similar to that of carbene-phosphine adduct. The increase in the π-accepting property of the NHC is reflected through an increase in the chemical shift value of 77Se NMR. The arrangement of common NHCs according to their π-accepting ability was established based on the 77Se NMR chemical shifts (Figure 7). In addition to the π-acceptor ability, the σ-donor abilities of NHCs can also be found using carbon-selenium coupling constant values [31].

Figure 7.

Arrangement of NHCs according to their π-accepting ability based on the 77Se NMR chemical shift values [30,31].

Szostak et al. [32] in 2019 reported a simple and straightforward method for the determination of the σ-donor properties of NHCs based on the Ccarbene-H coupling constant (JC-H). The significance of this method in comparison to the earlier reported NMR techniques and TEP determination method is that there is no need for the synthesis of any metal complexes or adducts for the analysis. The 1H NMR is used for the characterization. The magnetic moment of a 13C nuclei couples to a bonded proton through the intervening bonding electrons, and it is represented by the carbon-proton coupling constant (JC-H). This value relies on the probability of finding bonding electrons at the two nuclei involved, that is, C and H. The likelihood of finding an electron at the nucleus of a pure p-orbital of carbon is zero, while it has a finite value in the case of an s-orbital. Based on this principle, an empirical relationship (i.e., JC-H = 500 x s) between the C-H coupling constant (JC-H) and the s-character of carbon atom (s-value = 0.25 (for sp3-C), 0.33 (for sp2-C), and 0.50 (for sp-C)) was derived, for a 500 MHz 1H NMR instrument. Therefore, carbon with increased “s” character is expected to have a large (JC-H) coupling constant.

Thus, a large carbene carbon and proton coupling constant (JC(carbene)-H) value corresponds to a weaker σ-donor property of the NHC ligand. The coupling constants (JC(carbene)-H) were obtained from the 13C satellite peaks of 1H NMR and the 1H coupled 13C NMR spectra. Based on the JC-H, coupling constant values, NHCs have been arranged according to their σ-donor properties (Figure 8).

Figure 8.

Arrangement of NHCs according to their σ-donor ability based on theJC(carbene)-Hcoupling constant values [32].

2.3 NMR and UV-Vis spectroscopy: pKa of NHC precursors

Basicity and catalytic reactivity of NHC precursors (azolium salts) are intertwined. Therefore, the pKa studies of NHCs are crucial for understanding the properties of the carbenes. Imidazolium salts upon deprotonation form NHCs (Figure 9). The pKa values reflect the ease of imidazolium salts to form NHC precursors. It also provides information about the nucleophilicity of NHCs. Often the NHCs are formed in situand in many NHC-catalyzed reactions, nucleophilic addition is the first and most crucial step. Hence, the details related to nucleophilicity of NHCs have gained considerable interest [33]. Moreover, it will be helpful to draw the correlation between the substituents, nature of the azolium ring, and its catalytic activity. This section highlights the use of NMR and UV-Visible spectroscopy tools for studying the pKa values of NHC precursors, that is, imidazolium salts.

Figure 9.

Deprotonation of imidazolium salts to form N-heterocyclic carbenes.

Alder et al. reported the pKa value of 1,3-diisopropyl-4,5-dimethylimidazolium cation to be 24.0 in DMSO-d6using 1H-NMR spectroscopy [34]. This study uses the NMR technique to assess the deprotonation ability of NHCs from acidic hydrocarbons of known pKa values (e.g., indene, 9-phenylxanthene, triphenylmethane, etc.) (Figure 10). If the NHC deprotonates the hydrocarbon (V), it gives a different proton signal for its corresponding anion (VI). Therefore, based on the proton integration and the equilibrium ratio of (V) and (VI), the pKa of NHCs can be determined.

Figure 10.

Deprotonation of hydrocarbon by NHC to form hydrocarbon anion [34].

Streitwieser et al. reported that the anomalies in the determination of pKa of imidazolium salts, is due to the interaction of acidic solvent (DMSO) with carbene. It can be eliminated through the use of inert solvents such as THF by using bracketing/overlapping indicator method [35]. In this process, the deprotonated form of the fluorene-based indicator (of known pKa value) shows a significant change in the UV-Vis absorption value upon adding the NHC precursor salt. It helps to monitor the equilibrium and thereby the pKa can be determined. Chu et al. extended this method for various alkyl imidazolium salts [36]. Harper et al., applied this method to determine the pKa values of different types of electronically, sterically diverse alkyl and aromatic imidazolium salts (Figure 11) [33]. Later the pKa values of a few imidazolium salts in aqueous medium were also reported by Amyes et al. [37] using deuterium exchange studies. Similar exchange studies by O’Donoghue et al. [38] on triazolium salts facilitated a detailed understanding of the correlation between the NHC precursor salt’s cationic structures and its acidity.

Figure 11.

Arrangement of imidazolium salts based on theirpKa values in DMSO as determined by Harper et al. using bracketing indicator method [33].

2.4 Electrochemical technique: redox potentials and basicity of NHCs

The architecture of NHC allows facile structural modifications, and hence, it provides an opportunity to fine-tune the properties. The reactivity of NHCs is controllable through the structural variations on its cyclic carbon backbone or the introduction of different heteroatoms such as S or O in the heterocyclic ring. The nature of counter anions in the precursor (i.e., imidazolium salts) will also affect the reactivity. Several external factors also contribute to the overall property of NHCs, such as the solvent effects, type of reagents in the reaction mixture, and temperature, etc. Therefore, considering all these factors, the electrochemical techniques will also be helpful for the easy identification of ideal conditions for optimizing the reactivity and efficient catalysis of NHCs. During the electrochemical reduction of imidazolium salt, the imidazolium proton (i.e., C2-H group of the cationic part) NHCH+ is reduced to NHC. In this case, the reactivity mainly depends on the NHC generated from the conjugated acid, that is, NHCH+.

The electrochemical studies of NHCs were first reported by Enders and Simonet et al. using triaryl-triazol-ylidene [39]. The cyclic voltammetry (CV) of imidazolium salts exhibited a reversible reduction, which can be due to single-electron reduction of NHCH+ to NHC (i.e., imidazolium salt to NHC) (Figure 12). Recently, Boydston et al. have also reported a systematic study on the redox behavior of a series of azolium salts, including benzothiazolium, thiazolinium, thiazolium, triazolium, imidazolium, and imidazolinium salts [40]. The study demonstrated that N-aryl moiety would be helpful to tune the reduction potential of the imidazolium ring [41]. The carbene generation usually depends upon the acidity of the NHCH+; hence, with an increase in the reduction potential, the acidity of the NHCH+ also increases [42]. Therefore, based on the electrochemical method, it is possible to choose appropriate NHC precursors [43]. A number of electrochemical studies related to the NHC metal complexes were also reported [44, 45, 46, 47, 48], the data of few selective NHC precursors (i.e., azolium salts) and its corresponding reduction potential are summarized from the literature (Table 2).

Figure 12.

Schematic CV representation of oxidation and reduction peaks of a model NHC [39,40,41].

Table 2.

Reduction potentials for azolium salts, in V vs.SCE [40, 41, 42, 43].

The overall electrochemical reduction potential will reflect the acidic nature of the cationic part of the NHC and its nucleophilicity (availability of lone pair). Therefore, the reduction potential data of the azolium salts will be helpful to gain insight into the nucleophilicity of different NHCs and identify the structural moieties that were crucial for a specific function or property. The catalytic efficiency of the NHC ligand primarily depends upon the nucleophilicity of carbene.


3. Steric properties of NHCs

Apart from the electronic properties, it is significant to understand the steric parameters of NHCs, since it plays a crucial role in the reductive elimination step of a catalytic cycle. In case of chiral NHCs, the steric parameters control the enantioselectivity of a catalytic reaction (Figure 13).

Figure 13.

Effect of carbon backbone and N-substituent modifications on enantioselectivity.

The earlier attempts to define the steric properties of NHCs were based on the Tolman cone angle [49], which is the solid angle made by an imaginary cone with metal atom at its apex, and ligands are at the outer edges (Figure 14a). The cone angle can be computationally calculated [51] or obtained from the single-crystal XRD data [52]. In the case of tertiary phosphine ligands, the cone angle was a well-defined concept; however, not in the case of NHCs, where it lacks a predominant three-dimensional symmetry. Thus, the determination of steric parameters, through the Tolman cone angle technique, was inappropriate for NHCs [49]. In order to overcome this, the concept of percentage of buried volume (%Vbur) was introduced by Nolan et al. [53], which is the percentage of total volume occupied by the ligand in an imaginary sphere of a well-defined radius and the metal atom residing at the center of the imaginary sphere (Figure 14b). This parameter can be determined either from the single-crystal XRD data or can be calculated computationally (Figure 14c). The nature of backbone, N-substituents, and the ring size are the various factors that influence the percentage of buried volume (% Vbur).

Figure 14.

(a) Tolman cone angle of NHCs; (b) percentage buried volume of NHC (%Vbur); and (c) %Vbur for some selected NHCs [50].

Several advancements in the steric parameter determination of NHCs came up with the introduction of Salerno molecular buried volume calculation (SambVca) by Cavallo et al. [54]. The online tool developed for this method utilizes the CIF file of NHC or metal-coordinated NHC as the input file to generate a two-dimensional color-coded contour map around the carbene, from which the catalytical active pockets of the complex or the sterics around the catalytic active sites can be visualized. A detailed steric map study of various types of NHC complexes was well explored by Nolan et al. [50].


4. Catalytic applications of NHC-metal complexes

In 1962, Wanzlick et al. made the early reports on the stability and reactivity of NHCs [55]. Later in 1968, the first NHC-mercury complex was isolated [56]. Despite this isolation, the studies related to the NHCs as ligands thrived only after the first isolation report by Arduengo et al. in 1991 [1]. This easy synthetic strategy facilitated the extensive studies of NHC-metal complexes and their catalytic applications. The catalytic applications of NHCs as ligands can be broadly classified into three types, and they are (a) NHCs for organocatalysis [57, 58, 59], (b) NHCs as ligands for transition metal catalysis, and (c) NHCs and main group elements-based adducts for catalysis [60]. The following section of this chapter focuses on few selective and important NHC-transition metal catalyzed reactions (Figure 15), since the complete details are beyond the scope of this chapter.

Figure 15.

Catalytic applications of NHC-transition metal complexes [14].

4.1 NHC-transition metal catalyzed cross-coupling reactions

The coupling reactions catalyzed by transition metal-NHC complexes involve both C-C bond formation reactions such as Mizoroki-Heck [61, 62], Sonogashira [63, 64, 65], Negishi [66, 67, 68], Hiyama [69, 70, 71], Suzuki-Miyaura [72, 73, 74], Kumada coupling [75, 76], C-X (X = B, N, O) bond formation reactions such as Buchwald-Hartwig amination [77, 78, 79] and Ullmann coupling [80, 81, 82] etc. Recently, the coupling reactions catalyzed by the NHC-transition metal complexes have found to be efficient with commercially viable metal salts such as iron, cobalt, and nickel. For example, the cross-coupling of methyl sulfonates and amines to afford sulfonamides uses Ni/NHC system to form the S-N bond [83]. Few well-known NHC-metal catalyzed reactions are shown in (Figure 16).

Figure 16.

Few well-known NHC-transition metal-based catalytic applications [13,61,62,63,64,65,66,67,68,69,70,71,72,73,74].

Recently, the Pd-NHC catalyzed metathesis of carbon-sulfur bonds seems to be one of the significant reactions, which is capable of altering the trends in the retrosynthetic approach for the preparation of organosulfur compounds [60] (Figure 17).

Figure 17.

Carbon-sulfur bond metathesis using Pd-NHC complex [60].

4.2 NHC-transition-metal-mediated metathesis reactions

One of the best examples to demonstrate the significance of organometallic complexes is their role as catalysts in olefin metathesis, which is having numerous synthetic applications and commercial significance. There are different types of olefin metathesis, namely ring-opening metathesis polymerization (ROMP), ring-closure metathesis (RCM), olefin cross metathesis, and enyne cross-metathesis. The ruthenium complex with a nonlabile NHC group and a labile phosphine group known to exhibit higher ring-closure metathesis (RCM) activity with better thermal stability and has tolerance toward many functional groups [14]. In general, the metathesis catalyst prefers the formation of thermodynamically favored E-isomer. However, subsequent modification on the NHC group yielded Z-isomer in significant yields. Chelating NHC-Ru complexes gave upto 95% Z selectivity. The unique steric and electronic parameters of chelating-Ru-based NHCs promote the olefin to attack cis to NHC and trans to the chelating group. This side-bound reaction mechanism results in Z-isomer as predominant product. One example of such Z-selective olefin metathesis using NHC chelated Ru-catalyst is shown (Figure 18) [84].

Figure 18.

NHC-Ru catalysts for Z-selective olefin cross-metathesis reaction [84].

4.3 NHC-transition-metal-mediated addition reactions

Hydrogenation [85], transfer hydrogenation [86], hydrosilylation [87], hydroboration, and hydroamination [88] are the different types of NHC-transition metal catalyzed addition reactions. A brief outline of the various addition reactions catalyzed by NHC-transition metal complexes is summarized in Figure 19.

Figure 19.

Representative examples of NHC-metal catalyzed addition reactions [85,86,87,88].

4.4 NHC-transition-metal-mediated catalysis—Flow chemistry

Continuous flow chemistry is a revolutionary technology that has developed rapidly during the past few years. The small size of channel reactors enables increased mass transfer, efficient heat transfer, and enhanced reaction efficiency. Moreover, this method enables the handling of dangerously toxic reagents remotely and thus reduces the potential health risks [89, 90, 91, 92]. Cole-Hamilton et al. [93] reported the first continuous flow-based olefin metathesis catalytic system with a homogeneous catalyst. In this method, the Ru-NHC catalyst was immobilized into silica pores, and CO2 was passed as the carrier gas (Figure 20). It gave the metathesis products with an overall turnover number > 10,000.

Figure 20.

Continuous flow reaction setup for olefin metathesis [93].

Jenson et al. [94] reported a continuous nanofiltration method in which the metathesis catalyst (Ru-NHC) was allowed to react homogeneously; upon the reaction completion, the catalyst is trapped into a nano-filter setup, and it is flushed back to continue the reaction cycle. Unlike other conventional methods, there are no modifications done to the catalyst to recover and reuse it. Fabrication of NHC-metal complexes onto solid supports such as silica is another strategy used in NHC-centered flow chemistry [95, 96, 97, 98]. Functionalized catalyst is packed into a reactor, and the reagents are forced to pass through it to yield final products (Figure 21).

Figure 21.

Solid-supported NHC-metal catalyst and continuous flow reaction [93,94,99].


5. Conclusions

The imidazolium-based N-heterocyclic carbenes (NHCs) have found to be excellent candidates for improvising their properties through chemical modifications. Basic understanding and assessment of the steric and electronic factors of NHCs are crucial to explore its catalytic applications. Therefore, this chapter attempts to provide a basic glimpse of imidazolium-based NHCs through the discussions on some important synthetic routes, different methods for characterizing the electronic and steric properties of NHCs, and finally, few selective catalytic applications. Even though the literature pertaining to the imidazolium-based NHCs and its applications is vast and rapidly increasing, the discussions were limited to few important topics. Despite the extensive studies on imidazolium-based N-heterocyclic carbenes, there is plenty of scope for improvement, particularly enhancing the catalytic efficiency of NHCs with inexpensive metals, reducing the catalyst load, exploring new catalytic reactions with variety of substrates, and most significantly, making the NHC-based catalysts ready for more green and sustainable reactions.



VBG gratefully acknowledges Science and Engineering Research Board (SERB), New Delhi, for research funding (EEQ/2016/000837) and fellowship to BPJ. Thanks to the funding, it gave us an opportunity to initiate and establish our work in this exciting field on imidazolium-based NHC chemistry. Authors are also thankful to the Department of Chemistry, School of Basic and Applied Sciences, Central University of Tamil Nadu, Thiruvarur, India.


Appendices and nomenclature

NHCN-heterocyclic carbene
HOMOhighest occupied molecular orbital
LUMOlowest unoccupied molecular orbital
TEPTolman electronic parameters
NMRnuclear magnetic resonance
CVcyclic voltammetry
SambVcaSalerno molecular buried volume calculation


  1. 1.Arduengo AJ, Harlow RL, Kline M. A stable crystalline carbene. Journal of the American Chemical Society. 1991;113(1):361-363. DOI: 10.1021/ja00001a054
  2. 2.Scholl M, Ding S, Lee CW, Grubbs RH. Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands. Organic Letters. 1999;1(6):953-956. DOI: 10.1021/ol990909q
  3. 3.Hopkinson MN, Richter C, Schedler M, Glorius F. An overview of N-heterocyclic carbenes. Nature. 2014;510(7506):485-496. DOI: 10.1038/nature13384
  4. 4.Herrmann WA, Köcher C. N-heterocyclic carbenes. Angewandte Chemie International Edition. 1997;36(20):2162-2187. DOI: 10.1002/anie.199721621
  5. 5.Bourissou D, Guerret O, Gabbaï FP, Bertrand G. Stable carbenes. Chemical Reviews. 2000;100(1):39-92. DOI: 10.1021/cr940472u
  6. 6.Huynh HV. Electronic properties of N-heterocyclic carbenes and their experimental determination. Chemical Reviews. 2018;118(19):9457-9492. DOI: 10.1021/acs.chemrev.8b00067
  7. 7.Nolan SP, editor. N-Heterocyclic Carbenes. 1st ed. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2014. p. 524. DOI: 10.1002/9783527671229
  8. 8.Huynh HV. The Organometallic Chemistry of N-Heterocyclic Carbenes. 1st ed. New Jersey: John Wiley & Sons Ltd.; 2017. p. 334. DOI: 10.1002/9781118698785
  9. 9.Hu X, Tang Y, Gantzel P, Meyer K. Silver complexes of a novel tripodal N-heterocyclic carbene ligand: Evidence for significant metal-carbene π-interaction. Organometallics. 2003;22(4):612-614. DOI: 10.1021/om020935j
  10. 10.Hu X, Castro-Rodriguez I, Olsen K, Meyer K. Group 11 metal complexes of N-heterocyclic carbene ligands: Nature of the metal-carbene bond. Organometallics. 2004;23(4):755-764. DOI: 10.1021/om0341855
  11. 11.Scott NM, Dorta R, Stevens ED, Correa A, Cavallo L, Nolan SP. Interaction of a bulky N-heterocyclic carbene ligand with Rh(I) and Ir(I). Double C-H activation and isolation of bare 14-electron Rh(III) and Ir(III) complexes. Journal of the American Chemical Society. 2005;127(10):3516-3526. DOI: 10.1021/ja043249f
  12. 12.Cazin CSJ, editor. N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis. 1st ed. Dordrecht: Springer; 2011. p. 340. DOI: 10.1007/978-90-481-2866-2
  13. 13.Cavallo L, Cazin CSJ. N-heterocyclic carbenes: An introductory overview. In: Cazin CSJ, editor. N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis. 1st ed. Dordrecht: Springer; 2011. pp. 1-22. DOI: 10.1007/978-90-481-2866-2.ch1
  14. 14.Pugh D, Danopoulos AA. Metal complexes with ‘pincer’-type ligands incorporating N-heterocyclic carbene functionalities. Coordination Chemistry Reviews. 2007;251(5–6):610-641. DOI: 10.1016/j.ccr.2006.08.001
  15. 15.Benhamou L, Chardon E, Lavigne G, Bellemin-Laponnaz S, César V. Synthetic routes to N-heterocyclic carbene precursors. Chemical Reviews. 2011;111(4):2705-2733. DOI: 10.1021/cr100328e
  16. 16.Gorodetsky B, Ramnial T, Branda NR, Clyburne JAC. Electrochemical reduction of an imidazolium cation: A convenient preparation of imidazol-2-ylidenes and their observation in an ionic liquid. Chemical Communications. 2004;1(17):1972-1973. DOI: 10.1039/B407386J
  17. 17.Aidouni A, Demonceau A, Delaude L. Microwave-assisted synthesis of N-heterocyclic carbene precursors. Synlett. 2006;3:493-495. DOI: 10.1055/s-2006-932455
  18. 18.Ikhile MI, Bala MD, Nyamori VO. A greener method towards the synthesis of 1,3-diarylimidazolium tetrafluoroborates. South African Journal of Chemistry. 2011;64:101-104
  19. 19.Biffis A, Baron M, Tubaro C. Poly-NHC complexes of transition metals: Recent applications and new trends. In: Pérez PJ, editor. Advances in Organometallic Chemistry. 1st ed. Vol. 63. Waltham: Elsevier Inc.; 2015. pp. 203-288. DOI: 10.1016/bs.adomc.2015.02.002.ch5
  20. 20.De S, Udvardy A, Czégéni CE, Joó F. Poly-N-heterocyclic carbene complexes with applications in aqueous media. Coordination Chemistry Reviews. 2019;400:212038-212068. DOI: 10.1016/j.ccr.2019.213038
  21. 21.Peris E, Crabtree RH. Recent homogeneous catalytic applications of chelate and pincer N-heterocyclic carbenes. Coordination Chemistry Reviews. 2004;248(21–24):2239-2246. DOI: 10.1016/j.ccr.2004.04.014
  22. 22.Poyatos M, Mata JA, Peris E. Complexes with poly(N-heterocyclic carbene) ligands: Structural features and catalytic applications. Chemical Reviews. 2009;109(8):3677-3707. DOI: 10.1021/cr800501s
  23. 23.Mata JA, Poyatos M, Peris E. Structural and catalytic properties of chelating bis- and tris-N-heterocyclic carbenes. Coordination Chemistry Reviews. 2007;251(5–6):841-859. DOI: 10.1016/j.ccr.2006.06.008
  24. 24.Tolman CA. Steric effects of phosphorus ligands in organometallic chemistry and homogeneous catalysis. Chemical Reviews. 1977;77(3):313-348. DOI: 10.1021/cr60307a002
  25. 25.Lappert MF, Pye PL. Carbene complexes. Part 12. Electron-rich olefin-derived neutral mono- and bis-(carbene) complexes of low-oxidation-state manganese, iron, cobalt, nickel, and ruthenium. Journal of the Chemical Society, Dalton Transactions. 1977;21:72-80. DOI: 10.1039/DT9770002172
  26. 26.Chianese AR, Li X, Janzen MC, Faller JW, Crabtree RH. Rhodium and iridium complexes of N-heterocyclic carbenes via transmetalation: Structure and dynamics. Organometallics. 2003;22(8):1663-1667. DOI: 10.1021/om021029+
  27. 27.Kelly RA, Clavier H, Giudice S, Scott NM, Stevens ED, Bordner J, et al. Determination of N-heterocyclic carbene (NHC) steric and electronic parameters using the [(NHC)Ir(CO)2Cl] system. Organometallics. 2008;27(2):202-210. DOI: 10.1021/om701001g
  28. 28.Huynh HV, Han Y, Jothibasu R, Yang JA. 13C NMR spectroscopic determination of ligand donor strengths using N-heterocyclic carbene complexes of palladium(II). Organometallics. 2009;28(18):5395-5404. DOI: 10.1021/om900667d
  29. 29.Back O, Henry-Ellinger M, Martin CD, Martin D, Bertrand G. 31P NMR chemical shifts of carbene-phosphinidene adducts as an indicator of the π-accepting properties of carbenes. Angewandte Chemie International Edition. 2013;52(10):2939-2943. DOI: 10.1002/anie.201209109
  30. 30.Liske A, Verlinden K, Buhl H, Schaper K, Ganter C. Determining the π-acceptor properties of N-heterocyclic carbenes by measuring the 77Se NMR chemical shifts of their selenium adducts. Organometallics. 2013;32(19):5269-5272. DOI: 10.1021/om400858y
  31. 31.Verlinden K, Buhl H, Frank W, Ganter C. Determining the ligand properties of N-heterocyclic carbenes from 77Se NMR parameters. European Journal of Inorganic Chemistry. 2015;2015(14):2416-2425. DOI: 10.1002/ejic.201500174
  32. 32.Meng G, Kakalis L, Nolan SP, Szostak M. A simple 1H NMR method for determining the σ-donor properties of N-heterocyclic carbenes. Tetrahedron Letters. 2019;60(4):378-381. DOI: 10.1016/j.tetlet.2018.12.059
  33. 33.Dunn MH, Konstandaras N, Cole ML, Harper JB. Targeted and systematic approach to the study of pKa values of imidazolium salts in dimethyl sulfoxide. The Journal of Organic Chemistry. 2017;82(14):7324-7331. DOI: 10.1021/acs.joc.7b00716
  34. 34.Alder RW, Allen PR, Williams SJ. Stable carbenes as strong bases. Journal of the Chemical Society, Chemical Communications. 1995;12:1267-1268. DOI: 10.1039/C39950001267
  35. 35.Kim YJ, Streitwieser A. Basicity of a stable carbene, 1,3-di-tert-butylimidazol-2-ylidene, in THF. Journal of the American Chemical Society. 2002;124(20):5757-5761. DOI: 10.1021/ja025628j
  36. 36.Chu Y, Deng H, Cheng J, June RV. An acidity scale of 1,3-dialkylimidazolium salts in dimethyl sulfoxide solution. The Journal of Organic Chemistry. 2007;72(4):7790-7793. DOI: 10.1021/jo070973i
  37. 37.Amyes TL, Diver ST, Richard JP, Rivas FM, Toth K. Formation and stability of N-heterocyclic carbenes in water: The carbon acid pKa of imidazolium cations in aqueous solution. Journal of the American Chemical Society. 2004;126(13):4366-4374. DOI: 10.1021/ja039890j
  38. 38.Massey RS, Collett CJ, Lindsay AG, Smith AD, O’Donoghue AC. Proton transfer reactions of triazol-3-ylidenes: Kinetic acidities and carbon acid pKa values for twenty triazolium salts in aqueous solution. Journal of the American Chemical Society. 2012;134(50):20421-20432. DOI: 10.1021/ja308420c
  39. 39.Enders D, Breuer K, Raabe G, Simonet J, Ghanimi A, Stegmann HB, et al. A stable carbene as π-acceptor electrochemical reduction to the radical anion. Tetrahedron Letters. 1997;38(16):2833-2836. DOI: 10.1016/S0040-4039(97)00493-0
  40. 40.Ogawa KA, Boydston AJ. Electrochemical characterization of azolium salts. Chemistry Letters. 2014;43(6):907-909. DOI: 10.1246/cl.140162
  41. 41.Schotten C, Bourne RA, Kapur N, Nguyen BN, Willans CE. Electrochemical generation of N-heterocyclic carbenes for use in synthesis and catalysis. Advanced Synthesis & Catalysis. 2021;363(13):3189-3200. DOI: 10.1002/adsc.202100264
  42. 42.Feroci M, Chiarotto I, D’Anna F, Gala F, Noto R, Ornano L, et al. N-heterocyclic carbenes and parent cations: Acidity, nucleophilicity, stability, and hydrogen bonding-electrochemical study and ab initio calculations. ChemElectroChem. 2016;3(7):1133-1141. DOI: 10.1002/celc.201600187
  43. 43.Feroci M, Chiarotto I, Inesi A. Advances in the knowledge of N-heterocyclic carbenes properties. The backing of the electrochemical investigation. Catalysts. 2016;6(11):178. DOI: 2073-4344/6/11/178
  44. 44.Galuppo C, Alvarenga J, Queiroz AC, Messias I, Nagao R, Abbehausen C. The electrosynthesis of gold(I) complexes: A clean, one-pot method. Electrochemistry Communications. 2020;110:106620. DOI: 10.1016/j.elecom.2019.106620
  45. 45.Lake BRM, Bullough EK, Williams TJ, Whitwood AC, Little MA, Willans CE. Simple and versatile selective synthesis of neutral and cationic copper(i) N-heterocyclic carbene complexes using an electrochemical procedure. Chemical Communications. 2012;48(40):4887. DOI: 10.1039/C2CC30862B
  46. 46.Chapman MR, Henkelis SE, Kapur N, Nguyen BN, Willans CE. A straightforward electrochemical approach to imine- and amine-bisphenolate metal complexes with facile control over metal oxidation state. ChemistryOpen. 2016;5(4):351-356. DOI: 10.1002/open.201600019
  47. 47.Stephen HR, Schotten C, Nicholls TP, Woodward M, Bourne RA, Kapur N, et al. A versatile electrochemical batch reactor for synthetic organic and inorganic transformations and analytical electrochemistry. Organic Process Research & Development. 2020;24(6):1084-1089. DOI: 10.1021/acs.oprd.0c00091
  48. 48.Schotten C, Taylor CJ, Bourne RA, Chamberlain TW, Nguyen BN, Kapur N, et al. Alternating polarity for enhanced electrochemical synthesis. Reaction Chemistry & Engineering. 2021;6(1):147-151. DOI: 10.1039/D0RE00399A
  49. 49.Fortman GC, Slawin AMZ, Nolan SP. Flexible cycloalkyl-substituted N-heterocyclic carbenes. Dalton Transactions. 2010;39(16):3923-3930. DOI: 10.1039/C003214J
  50. 50.Gómez-Suárez A, Nelson DJ, Nolan SP. Quantifying and understanding the steric properties of N-heterocyclic carbenes. Chemical Communications. 2017;53(18):2650-2660. DOI: 10.1039/C7CC00255F
  51. 51.Jover J, Cirera J. Computational assessment on the Tolman cone angles for P-ligands. Dalton Transactions. 2019;48(40):15036-15048. DOI: 10.1039/C9DT02876E
  52. 52.Ferguson G, Roberts PJ, Alyea EC, Khan M. Cone angle and ligand profile calculations for bulky phosphine ligands. Inorganic Chemistry. 1978;17(10):2965-2967. DOI: 10.1021/ic50188a058
  53. 53.Hillier AC, Sommer WJ, Yong BS, Petersen JL, Cavallo L, Nolan SP. A combined experimental and theoretical study examining the binding of N-heterocyclic carbenes (NHC) to the Cp*RuCl (Cp* = η5-C5Me5) moiety: Insight into stereoelectronic differences between unsaturated and saturated NHC ligands. Organometallics. 2003;22(21):4322-4326. DOI: 10.1021/om034016k
  54. 54.Falivene L, Cao Z, Petta A, Serra L, Poater A, Oliva R, et al. Towards the online computer-aided design of catalytic pockets. Nature Chemistry. 2019;11(10):872-879. DOI: 10.1038/s41557-019-0319-5
  55. 55.Wanzlick HW. Aspects of nucleophilic carbene chemistry. Angewandte Chemie International Edition. 1962;1(2):75-80. DOI: 10.1002/anie.196200751
  56. 56.Wanzlick H-W, Schönherr H-J. Direct synthesis of a mercury salt carbene complex. Angewandte Chemie International Edition. 1968;7(2):141-142. DOI: 10.1002/anie.196801412
  57. 57.Enders D, Niemeier O, Henseler A. Organocatalysis by N-heterocyclic carbenes. Chemical Reviews. 2007;107:5606-5655. DOI: 10.1021/cr068372z
  58. 58.Hollóczki O. The mechanism of N-heterocyclic carbene organocatalysis through a magnifying glass. Chemistry—a European Journal. 2020;26(22):4885-4894. DOI: 10.1002/chem.201903021
  59. 59.Wang N, Xu J, Lee JK. The importance of N-heterocyclic carbene basicity in organocatalysis. Organic & Biomolecular Chemistry. 2018;16(37):8230-8244. DOI: 10.1039/C8OB01667D
  60. 60.Doddi A, Peters M, Tamm M. N-heterocyclic carbene adducts of main group elements and their use as ligands in transition metal chemistry. Chemical Reviews. 2019;119(12):6994-7112. DOI: 10.1021/acs.chemrev.8b00791
  61. 61.Astakhov AV, Khazipov OV, Chernenko AY, Pasyukov DV, Kashin AS, Gordeev EG, et al. A new mode of operation of Pd-NHC systems studied in a catalytic Mizoroki-Heck reaction. Organometallics. 2017;36(10):1981-1992. DOI: 10.1021/acs.organomet.7b00184
  62. 62.Balinge KR, Bhagat PR. Palladium-N-heterocyclic carbene complexes for the Mizoroki-Heck reaction: An appraisal. Comptes Rendus Chimie. 2017;20(7):773-804. DOI: 10.1016/j.crci.2017.03.003
  63. 63.Wang Z, Zheng T, Sun H, Li X, Fuhr O, Fenske D. Sonogashira reactions of alkyl halides catalyzed by NHC [CNN] pincer nickel(II) complexes. New Journal of Chemistry. 2018;42(14):11465-11470. DOI: 10.1039/C8NJ02138D
  64. 64.Gallop CWD, Chen MT, Navarro O. Sonogashira couplings catalyzed by collaborative (N-heterocyclic carbene)-copper and palladium complexes. Organic Letters. 2014;16(14):3724-3727. DOI: 10.1021/ol501540w
  65. 65.Eremin DB, Boiko DA, Kostyukovich AY, Burykina JV, Denisova EA, Anania M, et al. Mechanistic study of Pd/NHC-catalyzed sonogashira reaction: Discovery of NHC-ethynyl coupling process. Chemistry—a European Journal. 2020;26(67):15672-15681. DOI: 10.1002/chem.202003533
  66. 66.Organ MG, Avola S, Dubovyk I, Hadei N, Kantchev EAB, O’Brien CJ, et al. A user-friendly, all-purpose Pd-NHC (NHC = N-heterocyclic carbene) precatalyst for the Negishi reaction: A step towards a universal cross-coupling catalyst. Chemistry—a European Journal. 2006;12(18):4749-4755. DOI: 10.1002/chem.200600206
  67. 67.Liu Z, Dong N, Xu M, Sun Z, Tu T. Mild negishi cross-coupling reactions catalyzed by acenaphthoimidazolylidene palladium complexes at low catalyst loadings. The Journal of Organic Chemistry. 2013;78(15):7436-7444. DOI: 10.1021/jo400803s
  68. 68.Hadei N, Kantchev EAB, O’Brien CJ, Organ MG. The first Negishi cross-coupling reaction of two alkyl centers utilizing a Pd-N-heterocyclic carbene (NHC) catalyst. Organic Letters. 2005;7(17):3805-3807. DOI: 10.1021/ol0514909
  69. 69.Yuen OY, So CM, Man HW, Kwong FY. A general palladium-catalyzed Hiyama cross-coupling reaction of aryl and heteroaryl chlorides. Chemistry—a European Journal. 2016;22(19):6471-6476. DOI: 10.1002/chem.201600420
  70. 70.Gu ZS, Shao LX, Lu JM. NHC-Pd(II)-Im (NHC = N-heterocyclic carbene; Im = 1-methylimidazole) complex catalyzed Hiyama reaction of aryl chlorides with aryltrimethoxysilanes. Journal of Organometallic Chemistry. 2012;700:132-134. DOI: 10.1016/j.jorganchem.2011.11.030
  71. 71.Yang J, Wang L. Synthesis and characterization of dinuclear NHC-palladium complexes and their applications in the Hiyama reactions of aryltrialkyoxysilanes with aryl chlorides. Dalton Transactions. 2012;41(39):12031-12037. DOI: 10.1039/C2DT31174G
  72. 72.Wang Q, Dai Z, Di X, Huang QF, Wang Y, Zhu J. Pd(NHC)(cinnamyl)Cl-catalyzed Suzuki cross-coupling reaction of aryl sulfonates with arylboronic acids. Molecular Diversity. 2020;24(4):903-911. DOI: 10.1007/s11030-019-10001-4
  73. 73.Zhou J, Berthel JHJ, Kuntze-Fechner MW, Friedrich A, Marder TB, Radius U. NHC nickel-catalyzed Suzuki-Miyaura cross-coupling reactions of aryl boronate esters with perfluorobenzenes. The Journal of Organic Chemistry. 2016;81(13):5789-5794. DOI: 10.1021/acs.joc.6b01041
  74. 74.Kaloğlu N, Özdemir İ. PEPPSI-Pd-NHC catalyzed Suzuki-Miyaura cross-coupling reactions in aqueous media. Tetrahedron. 2019;75(15):2306-2313. DOI: 10.1016/j.tet.2019.02.062
  75. 75.Xi Z, Liu B, Chen W. Room-temperature Kumada cross-coupling of unactivated aryl chlorides catalyzed by N-heterocylic carbene-based nickel(II) complexes. The Journal of Organic Chemistry. 2008;73(10):3954-3957. DOI: 10.1021/jo800197u
  76. 76.Ando S, Mawatari M, Matsunaga H, Ishizuka T. An N-heterocyclic carbene-based nickel catalyst for the Kumada-Tamao-Corriu coupling of aryl bromides and tertiary alkyl Grignard reagents. Tetrahedron Letters. 2016;57(30):3287-3290. DOI: 10.1016/j.tetlet.2016.06.042
  77. 77.Chartoire A, Frogneux X, Nolan SP. An efficient palladium-NHC (NHC = N-heterocyclic carbene) and aryl amination pre-catalyst: [Pd(IPr*)(cinnamyl)Cl]. Advanced Synthesis & Catalysis. 2012;354(10):1897-1901. DOI: 10.1002/adsc.201200207
  78. 78.Organ MG, Abdel-Hadi M, Avola S, Dubovyk I, Hadei N, Kantchev EAB, et al. Pd-catalyzed aryl amination mediated by well defined, N-heterocyclic carbene (NHC)-Pd precatalysts, PEPPSI. Chemistry—a European Journal. 2008;14(8):2443-2452. DOI: 10.1002/chem.200701621
  79. 79.Zhang Y, Lavigne G, César V. Buchwald-Hartwig amination of (hetero)aryl tosylates using a well-defined N-heterocyclic carbene/palladium(II) precatalyst. The Journal of Organic Chemistry. 2015;80(15):7666-7673. DOI: 10.1021/acs.joc.5b01272
  80. 80.Paul S, Joy BP, Sasikala G, Raghuthaman AG, Gudimetla VB. Copper-NHC based ullmann catalysis in water for selective N-arylation of 3-aminophenols. ChemistrySelect. 2020;5(47):15004-15009. DOI: 10.1002/slct.202003455
  81. 81.Paul S, Joy BP, Rajendran R, Gudimetla VB. Cost efficient synthesis of diaryl ethers catalysed by CuI, imidazolium chloride and Cs2CO3. ChemistrySelect. 2019;4(24):7181-7186. DOI: 10.1002/slct.201900473
  82. 82.Wu J-P, Saha AK, Haddad N, Busacca CA, Lorenz JC, Lee H, et al. Simple N-heterocyclic carbenes as ligands in Ullmann-type ether and thioether formations. Advanced Synthesis & Catalysis. 2016;358(12):1924-1928. DOI: 10.1002/adsc.201600316
  83. 83.Li GJ, Pan YL, Liu YL, Xu HF, Chen JZ. Ni/NHC-catalyzed cross-coupling of methyl sulfinates and amines for direct access to sulfinamides. Tetrahedron Letters. 2019;60(46):151260. DOI: 10.1016/j.tetlet.2019.151260
  84. 84.Endo K, Grubbs RH. Chelated ruthenium catalysts for Z-selective olefin metathesis. Journal of the American Chemical Society. 2011;133(22):8525-8527. DOI: 10.1021/ja202818v
  85. 85.Wei Z, Wang Y, Li Y, Ferraccioli R, Liu Q. Bidentate NHC-cobalt catalysts for the hydrogenation of hindered alkenes. Organometallics. 2020;39(17):3082-3087. DOI: 10.1021/acs.organomet.0c00498
  86. 86.Ma X, Guillet SG, Liu Y, Cazin CSJ, Nolan SP. Simple synthesis of [Ru(CO3)(NHC)(p-cymene)] complexes and their use in transfer hydrogenation catalysis. Dalton Transactions. 2021;50(37):13012-13019. DOI: 10.1039/D1DT02098F
  87. 87.Munro-Leighton C, Delp SA, Blue ED, Gunnoe TB. Addition of N-H and O-H bonds of amines and alcohols to electron-deficient olefins catalyzed by monomeric copper(I) systems: Reaction scope, mechanistic details, and comparison of catalyst efficiency. Organometallics. 2007;26(6):1483-1493. DOI: 10.1021/om061133h
  88. 88.Kaur H, Zinn FK, Stevens ED, Nolan SP. (NHC)Cu I (NHC = N-heterocyclic carbene) complexes as efficient catalysts for the reduction of carbonyl compounds. Organometallics. 2004;23(5):1157-1160. DOI: 10.1021/om034285a
  89. 89.Porta R, Benaglia M, Puglisi A. Flow chemistry: Recent developments in the synthesis of pharmaceutical products. Organic Process Research & Development. 2016;20(1):2-25. DOI: 10.1021/acs.oprd.5b00325
  90. 90.Cambié D, Bottecchia C, Straathof NJW, Hessel V, Noël T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chemical Reviews. 2016;116(17):10276-10341. DOI: 10.1021/acs.chemrev.5b00707
  91. 91.Dallinger D, Gutmann B, Kappe CO. The concept of chemical generators: On-site on-demand production of hazardous reagents in continuous flow. Accounts of Chemical Research. 2020;53(7):1330-1341. DOI: 10.1021/acs.accounts.0c00199
  92. 92.Jiao J, Nie W, Yu T, Yang F, Zhang Q, Aihemaiti F, et al. Multi-step continuous-flow organic synthesis: Opportunities and challenges. Chemistry—a European Journal. 2021;27(15):4817-4838. DOI: 10.1002/chem.202004477
  93. 93.Duque R, Öchsner E, Clavier H, Caijo F, Nolan SP, Mauduit M, et al. Continuous flow homogeneous alkene metathesis with built-in catalyst separation. Green Chemistry. 2011;13(5):1187-1195. DOI: 10.1039/C1GC15048K
  94. 94.O’Neal EJ, Jensen KF. Continuous nanofiltration and recycle of a metathesis catalyst in a microflow system. ChemCatChem. 2014;6(10):3004-3011. DOI: 0.1002/cctc.201402368
  95. 95.Lim J, Seong Lee S, Ying JY. Mesoporous silica-supported catalysts for metathesis: Application to a circulating flow reactor. Chemical Communications. 2010;46(5):806-808. DOI: 10.1039/B917986K
  96. 96.Sarmiento JT, Suárez-Pantiga S, Olmos A, Varea T, Asensio G. Silica-immobilized NHC-gold(I) complexes: Versatile catalysts for the functionalization of alkynes under batch and continuous flow conditions. ACS Catalysis. 2017;7(10):7146-7155. DOI: 10.1021/acscatal.7b02142
  97. 97.Martínez A, Krinsky JL, Peñafiel I, Castillón S, Loponov K, Lapkin A, et al. Heterogenization of Pd-NHC complexes onto a silica support and their application in Suzuki-Miyaura coupling under batch and continuous flow conditions. Catalysis Science & Technology. 2015;5(1):310-319. DOI: 10.1039/C4CY00829D
  98. 98.Di Marco L, Hans M, Delaude L, Monbaliu JCM. Continuous-flow N-heterocyclic carbene generation and organocatalysis. Chemistry—a European Journal. 2016;22(13):4508-4514. DOI: 10.1002/chem.201505135
  99. 99.Autenrieth B, Frey W, Buchmeiser MR. A dicationic ruthenium alkylidene complex for continuous biphasic metathesis using monolith-supported ionic liquids. Chemistry—a European Journal. 2012;18(44):14069-14078. DOI: 10.1002/chem.201201199

Written By

Vittal B. Gudimetla, Bony P. Joy and Sudeep Paul

Submitted: November 27th, 2021Reviewed: January 10th, 2022Published: March 2nd, 2022