Organometallic chemistry is discipline devoted to the study, not only of the compounds and intermediate species with metal-carbon bonds, but also the comprehensive study of all transformations and interaction between organic molecules and a inorganic metal from the main groups, transition series, lanthanides and actinides (Astruc, 2007; Crabtree, 2005). This interface discipline, between classical organic chemistry, coordination chemistry and inorganic chemistry, has proved, in the last decades, very useful to provide some important conceptual insights, new structures, and catalysts for different applications areas of organic synthesis, both in the academic and in the industrial fields (Crabtree, 2005). Organometallic chemistry also began to have a major impact on other areas such as: biochemistry with the discovery of enzymes that carry out organometallic catalysis; chemistry of materials due to the proprieties of some organometallic compounds to be used was precursors for depositing materials on various substrates via thermal decomposition of the metal compound; nanoscience and nanotechnology due to the proprieties of some organometallic compounds to be used precursors for nanoparticles; and green chemistry by minimizing both energy use and chemical waste of several organic synthesis (Crabtree, 2005).

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The first organometallic substance to be prepared was synthesized in 1760, in a military pharmacy in Paris, by Louis Claude Cadet de Gassicourt. This French chemist, who was working on cobalt-containing inks, used arsenic-containing cobalt salts for their preparation. From this work was resulted the so-called “Cadet’s fuming liquid” which contains a mixture of tetramethyldiarsine and cacadoyl oxide (the first documented organometallic compound) by carrying out the following reaction (Equation (1)):

(1)

However, despise several organometallic compound discovered, along the eighteenth and nineteenth century’s, the truly “boom” of organometallic chemistry only occurred during the third quarter of the twenty century, in especially in countries like the United States of America, England and Germany (Astruc, 2007). One of the facts that contributed to this was the recognition of the potential of some d-block transition metals (i.e. nickel, palladium, platinum, rhodium, and ruthenium) organometallic reagents and intermediates as superior catalysts for new bond formation (i.e. carbon-carbon bonds) and their unique property to activate a wide range of organic molecules (Negishi, 2002; Schlosser, 2013).

In this review, one of these d-block transition metals and their organometallic reagents based and intermediates will be put in broader perspective, the palladium. The use of this metal, has truly revolutionized the organic synthesis field over the last three decades, being nowadays, the most widely used element in organic synthesis (Crabtree, 2005). Probably the most notable example of its importance of the palladium intermediates as catalyst in organic synthesis is the attribution, by the Swedish Nobel Committee, of the 2010 Nobel Prize in Chemistry to Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki for their work in “palladium-catalysed cross couplings in organic synthesis” (Nobelprize.org, 2013). This review will attempt to highlight some of the outstanding properties of the organopalladium reagents and intermediates, identifying the main ways of preparation of these components, some of the most important analysis procedures to obtain their structural characterization, and present some of the numerous applications and reactions where these compounds play an important role.

2. Organopalladium reagents and intermediates

2.1. The characteristic features for the use of palladium in organometallic chemistry

Palladium is a chemical element discovered and isolated in 1803 by William Hyde Wollaston who named it after the asteroid Pallas, which was discovered a year before. Is a transition metal and belong to the 10^th group, 5 period, and d-block of the periodic table. This atom, with atomic number of 46 and average atomic weight of 106.4 could occur naturally in seven isotopes, which includes six stable isotopes.

Palladium, is nowadays one of the most versatile, selective, ubiquitous and significant metals used for organic synthesis and had truly impacted this field in the last four decades (Negishi, 2002). This fact is mainly because no other transition metals can offer such versatile to the abundance of possibilities of carbon–carbon bond formation that the palladium reagents and intermediates can offer (Tsuji, 2004). Furthermore, despite the palladium complexes are, in several reactions, highly reactive are stable enough to be used as recyclable reagents and intermediates, in catalytic processes (Negishi, 2002). In this sense palladium-mediated processes have become essential in several applications, namely in the syntheses of natural products, polymers, agrochemicals, and pharmaceuticals (Caspi, 2008).

Despite the palladium being a rare and very expensive noble metal, there are several characteristic features and chemical properties which make reactions involving palladium reagents and intermediates particularly suitable in organic synthesis. One of the most important characteristic feature appears to be its moderately large atomic size factor which contribute to the moderate stability of its compounds and their controlled but wide-ranging reactivity leading (Negishi, 2002; Tsuji, 2004). Furthermore, its moderated size associated with high d-electron count, and its relatively high electronegativity (2.20 and 1.57 in Pauling and Sanderson scales, respectively), classified this element as “soft” element, which makes it a real alternative to the more traditional and “hard” organometallic reagents, such as the magnesium (Grignard) and lithium compounds (Negishi, 2002). Other important characteristic features is the tolerance from the palladium reagents and intermediates to several functional groups (i.e. carbonyl and hydroxy groups) and which means that the palladium-catalysed reactions can be carried out without protection of these functional groups (Tsuji, 2004). Furthermore, palladium reagents and intermediates have a low tendency to undergo one-electron or generate radical in the reaction processes, reducing the possibility of unwanted side reactions and making the palladium-catalysed reactions quite clean and selective. Finally, another important feature, especially in the green chemistry context is their lack of toxicity problems associated and therefore they do not require too many special handling cares (Negishi, 2002).

2.1.1. Oxidation States of Palladium

The most common oxidation states of palladium are 0, +1, +2, +3, and +4 (Pd(0), Pd(I), Pd(II), Pd(III), and Pd(IV), respectively). The palladium oxidation states of +1, +2, +3, and +4 correspond to d⁹, d⁸, d⁷, and d⁶ electron configurations, respectively, as shown in Figure 1.

Figure 1.Representative d electron configuration of Pd(I), Pd(II), Pd(III), and Pd(IV) oxidation states (based on reference (Mirica and Khusnutdinova, 2013))

The vast majority of palladium-catalysed reactions, until the beginning of the twentieth-one century, were only focused in the reactions involving Pd(0) and Pd(II) oxidation states, since Palladium strongly favours this two oxidation states (Mirica and Khusnutdinova, 2013; Negishi, 2002). Despite the bulk of the organopalladium literature is centered on the use of Pd(0) and Pd(II) oxidation states, already in 2002, in the Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi point out that the utilization of other oxidation states (Pd(II), Pd(III), or Pd(IV)), although it is still very rare, could become o be very significant in the future (Negishi, 2002).

More than ten years later, and with the rapid evolution in the organopalladium chemistry, complexes with palladium in these oxidation states, especially the Pd(IV), have demonstrated their potential and they improved significantly their role in organic synthesis. Although the development of Pd(IV) chemistry has just begun, this has already made possible the development of a number of significant new transformations. Pd(IV)-catalysed reactions usually show a high selectivity and synthetic robustness, and in almost all of them the use of catalysts are generated in situ from commercially available palladium salts, making them particularly attractive from the viewpoint of cost effectiveness (Muñiz, 2009).

However, by comparison with the Pd(0), Pd(III), or Pd(IV), complexes of odd-electron Pd(I) and Pd(III) oxidation states are much less used. Yet, despite the study of this oxidation states remains in its infancy, Pd(I) complexes have already been employed as pre-catalysts in organic synthesis (Canty, 2011) and despite the potential role of Pd(III) intermediates in catalysis is currently more speculative, this subject beginning to emerge considerable interest, as can be highlighted by the different articles and reviews on the subject (Canty, 2011; Mirica and Khusnutdinova, 2013; Powers and Ritter, 2011).

2.2. Preparation of organopalladium reagents and intermediates

In the majority of the organic reactions that use palladium as catalyst, the organopalladium species are generated in situ during the course of the reaction, instead of a preparation of stoichiometric organopalladium reagents, ensuring that only a catalytic amount of palladium is used. In these cases, the reaction mechanisms should include a step were the organopalladium species are formed, the steps in which the formed species react with other reagents to generate a particular product(s), and the step in which organopalladium species are regenerated in a catalytically active form (Carey and Sundberg, 2007).

There are several types of organopalladium intermediates extensively used in reactions with considerable importance in several synthetic applications. As reviewed by Schlosser (2013), more than 64000 entities with a palladium-carbon bond are known. Consequently, in this review, only the preparation of some of the most common organopalladium reagents and intermediates will be addressed.

As special cares to have in the preparation of these complexes, palladium complexes, unlike the organometallics from the Group I and Group II, are not water sensitive. Consequently, in almost cases, strict exclusion of water is not necessary. Although, some reactions can beneficiate from the presence of water traces or can even be performed in water as solvent or co-solvent. Furthermore, palladium complexes could be quite to moderately air stable. Consequently, it is advised to conduct reactions using these complexes under an inert gas (i.e. argon or nitrogen) (Schlosser, 2013).

2.2.1. π-Ally Palladium Complexes

One of the most important organopalladium intermediates are π-allyl complexes. The most common π-allyl palladium complex, the dimer [(n³-C₃H₅)PdCl]₂, was discovered more than 50 years, serves as starting material for a number of other complexes (Schlosser, 2013).

π-allyl complexes, can be synthesize from Pd(II) salts, allylic acetates, and other compounds with the potential of leaving groups in an allylic position, or can be prepared directly from alkenes by reaction with PdCl₂ or Pd(O₂CCF₃)₂. In this second scenario, the reaction occurs by electrophilic attack on the π electrons followed by loss of a proton, as represented in Scheme 1 (Carey and Sundberg, 2007).

Scheme 1.Synthesize of π-Ally Palladium Complexes by electrophilic attack on the π electrons (based on reference (Carey and Sundberg, 2007)).

Due to the low electrophilic power, these complexes usually reacted with less-substituted allylic terminus of a variety of nucleophiles. After this reaction occurs, the resulting organopalladium intermediate breaks down by elimination of Pd(0) and H⁺, as described in Scheme 2 (Carey and Sundberg, 2007).

Scheme 2.The overall transformation of the allylic substitution. (based on reference (Carey and Sundberg, 2007)).

2.2.2. Cyclic aryl palladium complexes

Another important organopalladium intermediates are the cyclic aryl palladium complexes, or palladacycles (Schlosser, 2013). This complexes, are quite relevant role in cascade transformations leading to complex molecular architectures, in the proximally) directed arylation reactions, and in several intramolecular cross-coupling reactions (Beletskaya and Cheprakov, 2004).

Palladacycles intermediates can easily be obtained by palladation reactions starting from Pd(II) salts and an arene having a directing group (Schlosser, 2013).

Scheme 3.Palladacycles intermediates obtained by palladation reactions (R = NR2, PR2, etc., and Y = alkyl, aryl, etc.). Based on reference (Schlosser, 2013).

In the cases where the directing group is an amine (e.g., benzyl or homobenzyl amines) or a phosphine (e.g., aryl phosphines), as represented in the Scheme 3A, the mechanism occurs by an electrophilic addition to the arene, and could include Pd(IV) intermediates. On the other hand, as represented in the Scheme 3B, Alkylarenes can also be substrates for palladacycles, in which, the activation of sp3-carbons next to an arene is presumably forced by agostic interactions (Schlosser, 2013).

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2.2.3. Palladium Olefin and Diene Complexes

The major group of organopalladium intermediates are the palladium Olefin and Diene Complexes. Pd(II) complexes having olefin ligands (i.e. 1,5-cyclooctadiene (COD), norbornene, or norbornadiene) can be obtained by reaction of Pd(II) chloride in the presence of the appropriate alkene (Carey and Sundberg, 2007; Schlosser, 2013). In this reaction the alkenes react with Pd(II) to give π complexes that are subject to nucleophilic attack. However, the products formed from the resulting intermediates are depending of the specific reaction conditions used. In the first case, represented in Scheme 4 as the path a, palladium can be replaced by hydrogen under reductive conditions. On the other hand, in the absence of a reducing agent occurs the obliteration of the Pd(0) and a proton, leading to the substitution of a vinyl hydrogen by the nucleophile, as represented in path b of the Scheme 4. (Carey and Sundberg, 2007).

Scheme 4.Synthesize of the Palladium Olefin complexes. Based on reference (Carey and Sundberg, 2007).

However, it is important to note that several of these palladium Olefin and Diene complexes are already commercially available (Schlosser, 2013).

2.2.4. Palladium-TV-Heterocyclic Carbene Complexes

Palladium-TV-Heterocyclic Carbene (NHC) complexes have been recently introduced as powerful ligands for palladium. These NHC complexes have as main advantage the fact that they are quite stable, easy to handle, air-stable and can be easily be prepared from the ligand and palladium precursors (Chartoire et al., 2012; Schlosser, 2013). The NHC-based palladium complexes have been used very successfully for a series of different reactions, namely some cross-coupling reactions and aryl amination (Chartoire et al., 2012; Schlosser, 2013). In Figure 2 are shown some examples of these NHC-palladium catalysts, already used to ensure the efficiency of those reactions.

Figure 2.Examples of NHC-palladium complexes: A) [Pd(NHC)(R-allyl)Cl] developed by Nolan; B) [Pd-PEPPSI-NHC] developed by Organ; and C) [Pd(IPr*)(cinnamyl)Cl] developed by Chartoire et al.. Figure adapted from the reference (Chartoire et al., 2012).

2.3. Methods for structural characterisation of organopalladium reagents

The identification and structural characterization of the organopalladium reagents and intermediates, is of utmost importance in organic synthesis field, to understand the behaviour and proprieties of these compounds. However, it can be quite challenging and somewhat tricky task to accomplish. To achieve the identification and structural characterization of the organopalladium reagents and intermediates, the main analytical methods used rely on the complementarity of information provide from spectroscopic and crystallographic techniques, such as multinuclear nuclear magnetic resonance (NMR) spectroscopy, infrared spectroscopy, and x-ray crystallography.

2.3.1. Nuclear Magnetic Resonance Spectroscopy

Multinuclear NMR spectroscopy is certainly the key methodology to elucidate molecular structures in solution. Consequently, just as has already happened in organic chemistry or biochemistry, it is now routine to measure NMR spectra of diamagnetic organometallic and coordination compounds. Nowadays, on a routine basis, organometallic chemists daily measure hundreds or even thousands NMR spectra, not only to identify and characterize the molecular structure of a given organometallic but also to verify if a reaction has taken place (Pregosin, 2012).

The most investigated active nuclei in organometallic chemistry are, by far, ¹H and ¹³C. However, there are several others readily measurable spin = ½ nuclei, such as ¹⁵N, ¹⁹F and ³¹P, that provide structurally valuable chemical shifts and a diagnostic spin-spin coupling constants. Furthermore, often the measure of ¹H and ¹³C NMR spectra alone may not be sufficient, especially when it is necessary understand the immediate environment of the metal canter and these probes are spaced apart from the metal (Pregosin, 2012).

NMR is therefore widely applied for analysis to organopalladium reagents. For example, ¹H NMR is the most reliable characterization technique which can be used on hydridopalladium complexes (Negishi, 2002). Moreover, there are several examples in the literature of the application of multinuclear NMR to organopalladium complexes (Leznoff et al., 1999; Pañella et al., 2006; Satake et al., 2000; Schlosser, 2013). Even the ¹⁵N, and ³¹P NMR methodologies, are also are widely used in the characterization of organopalladium reagents, being possible to find studies in this field with more than thirty years (Motschi et al., 1979).

2.3.2. Infrared spectroscopy

Infrared (IR) spectroscopy provides the spectral information corresponding to vibrational modes of a molecule. The position of the bands in the Infrared (IR) spectrum depends mainly of the on the strength of the bond(s) involved as measured and the reduced mass of the system calculated using the atomic weights of the atoms involved in the molecule (Crabtree, 2005). Consequently, IR spectroscopic are very useful to obtain a fast confirmation of the presence of some functional groups (i.e. C=O, C=N). However, this method should not be used as a sole characterization technique, since, for example, although the hydride ligands from the hydridopalladium complexes are expected to have υ(Pd-H) stretches occurring in the distinctive region of 1950–2060 cm^-1 in the infrared spectrum, they are often very weak signals and are also rather dependent on the trans effect of the opposite ligand (Negishi, 2002).

2.3.3. X-Ray crystallography

The structural characterization in the solid state, namely that provided by X-ray crystallography is an extremely important part of organometallic chemistry. In the method, a beam of monochromatic X-rays pass through a single crystal of the sample. Consequently, this beam is diffracted in the crystal in various angles, providing in photography the pattern of the crystal spots. The intensity of this set of diffracted beams will depend on the nature and arrangement of the atoms in the unit cell. Thus, the intensities provide the information about the locations of the atoms in the unit cell, while the relative positions of the spots on the photography film carry the information about the arrangement of the unit cells in space (Negishi, 2002). The results of an X-ray structural determination should be represented as a diagram showing the positions of all the atoms in the molecule, as represented in the Figure 3 for two different organopalladium complex (i.e.{Pd[(p-(Noxyl-tert-butylamino-2-)phenyl)diphenylphosphine]2Cl2}, and{(η-C3H5)Pd [(p-(Noxyl-tert-butylamino-2-)phenyl)diphenylphosphine](Cl)}) (Leznoff et al., 1999).

Figure 3.A typical X-ray crystallographic characterisation of two different organopalladium complex (from the reference (Leznoff et al., 1999))

However, in addition to being assured that organometallic compounds (i.e. organopalladium complex) allow the growth of crystals to be used in this technique, there are some limitations than need to be overcome. First of all, since the X-ray diffraction results are usually based on one only crystal, is necessary to ensure that this crystal is representative of the bulk and free of impurities. One way to check that each crystal is the same material as the bulk of the sample is using the information from the IR spectrum. Furthermore, it is necessary to ensure that the solid state is really the same as the structure of the same material in solution, since several organometallic complexes exist as one isomer in solution but as another in the solid state. This point is especially relevant when the solid state X-ray results are compared with the solution NMR data. Again, in this aspect IR spectroscopy can be also very useful because we can obtain a spectrum both in solution and in the solid state, which emphasizes the need for the information complementarity of these characterization techniques (Negishi, 2002).

3. Applications of palladium-catalysed organic reactions

As already pointed out, since the second half of the twenty century, palladium had increased its relevance and role in organic chemistry, in particular in metal-catalysed reactions. Palladium, together with some other transition metals, have the unique property to activate a wide range of organic molecules and thus to catalyse various bond formations. This metal, by far is the most commonly used metal, is thus of utmost importance in a wide range of applications, not only in academic circles but also in industry (Schlosser, 2013). An example of this application is the Wacker process. This reaction, discovered in the 1960s, uses catalytic amounts of palladium to oxidize ethylene to acetaldehyde, and is still widely used in industrial applications (in 2007, was generating four million tons of acetaldehyde per year (Astruc, 2007)).

Another factor that has emphasized the importance of using palladium as a catalyst of organic reactions in academic and industrial applications was the introduction of several palladium-catalysed carbon-carbon cross coupling reactions. This fact can easily be verified by more than 200 natural products and biologically active molecules synthesized making use of the Heck reaction (section 3.1.1) and the “ton scale” fine chemicals produced in the industry using the Suzuki reaction (section 3.1.3) (Schlosser, 2013). Furthermore, these reactions also allowed the total syntheses of molecules used in the in the production of several medical drugs such as Naproxen (anti-inflammatory drug), Taxol (anti-cancer drug), (Z)-tamoxifen (anti-cancer drug), and morphine (Carey and Sundberg, 2007; Schlosser, 2013).

3.1. Palladium-catalysed carbon-carbon cross coupling reactions

The introduction, in the last quarter of the twenty century, of palladium as catalyst in carbon-carbon cross coupling reactions, a new paradigm for carbon–carbon bond formation has emerged allowing the assembly of highly complex molecular structures and completely changed how the chemical synthesis is performed (Nicolaou et al., 2005).

The capability of this reactions to forge carbon–carbon bonds between or within functionalized and sensitive substrates have received an enormous amount of attention among the synthetic chemists, and their scope has been very significantly expanded during the last several years, not only in not only in total synthesis but also in medicinal, biology and nanotechnology (Nicolaou et al., 2005).

In general, the palladium-catalysed carbon-carbon cross coupling reactions can be represented by the Scheme 5. However, in this equation, for any given combination of R¹ and R², several parameters should be changed or optimized, namely the metal countercation M, the leaving group X, the palladium catalyst, the introduction of some additives or co-catalysts, the solvent, and even others parameters such as temperature, time, concentration, and mode of addition (Schlosser, 2013).

Scheme 5.Geral model of the palladium-catalysed carbon-carbon cross coupling reactions (based on reference (Schlosser, 2013)).

The characteristics of an ideal palladium-catalysed cross-coupling reaction can be listed as follows (Schlosser, 2013):

Varied and inexpensive methods to set up the coupling substrate functionality from commercially available starting materials
Easily activated high-yielding coupling under mild conditions;
Generation of the minimal amount of by-product preferably by employing low-molecular-weight donors;
Excellent functional group compatibility;
General stability of the cross-coupling substrates;
Low toxicity of precursors, substrates, and generated by-products.

In this review, despite the extremely long list of all the possible carbon-carbon cross coupling reactions involving Palladium as catalyst, it will focus on the reactions that embody several of the above mention characteristics and are most commonly used namely, the Heck, Stille, Suzuki, Sonogashira, Tsuji–Trost, and the Negishi reactions. These reactions, have truly revolutionized the organic synthesis field (Nicolaou et al., 2005), and, as already mentioned, should be noted that the authors and works that gave birth to three of these reactions (Heck, Negishi, and Suzuki) were recently awarded the Nobel Prize in chemistry 2010 (Nobelprize.org, 2013), which emphasizes even more the importance of these reactions.

3.1.1. The Heck reaction

The Heck cross coupling reaction has been developed independently by Mizoroki, (Mizoroki et al., 1971), and improved by Heck (Heck and Nolley, 1972) in the early seventies of the twentieth century. However, it took more than a decade for the potential of this reaction, be explored by the wider synthetic organic community, namely with the development of catalytic asymmetric Heck reactions (Nicolaou et al., 2005).

The Heck reaction, as presented in Scheme 6, can be broadly defined as the palladium-catalysed coupling of a vinyl, aryl, benzyl halide or a trifluoromethanesulfonate (OTf) group with an olefin to yield products which result from the substitution of a the hydrogen atom in the olefin coupling partner (Nicolaou et al., 2005).