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Direct arylation
Direct arylation is a method of biaryl synthesis whereby the formation of a direct aryl-aryl bond occurs via reaction of an aryl halide (or main group organometallic reagent) with an unfunctionalized arene in the presence of a transition metal catalyst.



Background
Over the past 100 years, methods for the synthesis of polyarenes and poly-heterocycles has progressed dramatically. In 1901, Fritz Ullman discovered the first synthetic route to creating carbon-carbon bonds to connect two aromatic rings. By using stoichiometric amounts of copper, he reductively coupled haloarenes for the synthesis of symmetrically substituted biaryls. Since then, the ability to instigate cross-coupling reactions between aryl halides and aryl organometallics based on the preactivation of carbon fragments has revolutionized the formation of biaryl compounds. However, reactions that use this method, such as the Suzuki reaction and Stille reaction, have some downsides. The synthetic route is quite complicated as it requires the activation of two aromatic carbon fragments with halides and electropositive groups such as boronic acids. The multiple synthetic steps generate waste from reagents, solvents, and purification, which don't follow the rules of waste prevention for green chemistry. Aside from this, the synthesis for the generation of the preactivated arenes can be complicated, expensive, and time consuming.

For these reasons, direct arylation has become an area of interest for many chemists. Direct arylation processes are an important class of C-H functionalization reactions pioneered by Keith Fagnou, a Canadian organic chemist. While teaching at the University of Ottawa, he developed a research group that was mainly focused on studying direct arylation for the purpose of medicinal chemistry. During that time, his research group published many papers on the subject, many of which are cited in this document. Direct arylation reactions have progressed immensely in the last ten years and is an exciting area of research.

Because of the strength of the C-H bond that makes it inert to many organic reagents, the option of synthesizing a biaryl carbon-carbon bond without ring activation has been ignored for a long time. With direct arylation, one of the preactivated arenes is replaced by a simple arene. π-excessive heterocyclic compounds such as furans, thiphenes, oxazoles, thiazoles, imidazoles, indoles, and indolizines can be used as nucleophiles which negates the need for an organometallic functional group. Not needing to synthesize an organometallic coupling partner helps to bring down the expenses of the reaction while increasing the efficiency. Fagnou and his group have developed many direct arylation reactions on electron deficient benzenes and have proven the possibility of using it for reaction with completely unactivated arenes such as benzene itself.

While direct arylation has emerged as an important synthetic tool, it is not without problems. Since one of the arenes is unactivated, the reactivity is determined by the inherent properties of the heterocycle itself. This can complicate regioselectivity, lead to low yields, and necessitate extreme reaction conditions. The search for a catalyst that will allow the polymerization of unactivated arenes has also been difficult to realize. However, recent research has lead to the development of Palladium catalyzed direct arylation polymerization reactions that can synthesize the active ingredient of organic solar cells. This is explained in more detail in the applications section.

Direct arylation is considered to be a more efficient and atom economical process than classical cross-couplings. Metal-catalyzed transformations at C-H bonds lead to the possibility of introducing desired functional groups at specific locations. It can use a variety of transition metal catalysts, with palladium, ruthenium, and rhodium being the most common, in the presence of base to realize what would otherwise be far more complicated synthetic goals. Possible mechanisms, various catalysts, and the many applications of direct arylation will be discussed in the rest of this article.

Reaction Mechanism
As for many transition-metal catalyzed reactions, the definitive mechanism of direct arylation remains largely ambiguous. The mechanism is proposed to occur by first generating an arylmetal complex via oxidative addition of the aryl halide to the transition metal complex, analogous to that of other transition-metal catalyzed carbon-carbon bond forming reactions. The oxidative addition product is then presumed to react with the arene reagent ultimately forming the biaryl product. Several mechanistic pathways have been proposed for the reaction of the arylmetal complex with the arene reagent. It should be noted that changes in experimental parameters such as ligand, substrate, transition metal, solvent, base and/or temperature are likely to have an effect on the mechanistic pathway.

Electrophilic Aromatic Substitution
One plausible mechanism is electrophillic attack of the arylmetal complex on the arene accompanied by loss of HX, followed by reductive elimination of the product. The majority of published experimental data supports this type of pathway, however there has yet to be decisive evidence eliminating all other plausible mechanistic pathways.

C-H Bond Activation
It has been proposed that the mechanism could proceed by way of a C-H activation, either via a concerted metallation-deprotonation, by a σ-bond metathesis  , or by concerted SE3 process in the presence of base.

Heck-type Carbometallation
In 2003, Sharp ''et. al.'' proposed that the palladium-catalyzed direct arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides occured via a mechanism similar to that of the Heck reaction. This mechanistic pathway could occur via either an anti-β-hydride elimination (elimination of the trans β-hydride) or isomerization followed by a syn β-hydride elimination. Shortly after in 2004, Gevorgyan ''et. al.'' published data that opposed the Heck-type mechanism, reporting an inability to produce neither a cascade Heck reaction nor a reductive Heck reaction on a C-2 functionalized indolizine. Further evidence negating the Heck-type mechanism was provided by Trauner ''et. al.'' in the total synthesis of (-)-frondosin B which utilized an intramolecular direct vinylation. Had the reaction been proceeding via a Heck mechanism whereby the product of migratory insertion underwent syn β-elimination of a hydridopalladium species, it would be expected that rearomatization to afford the product enol ether would result in racemization of the C-8 stereocenter. However, this was not observed.

Catalysts
In the early 1970s, Kumada and Corriu reported cross-coupling of Grignards reagents with aryl halides and Ni(acac)2 with DPPE in the presence of nickel catalysts. Catalysts for both cross-coupling and direct arylation have existed for many years but only recently have these catalysts been optimized for use in organic chemistry. Historically, a wide variety of transition metals have been used to catalyze cross-coupling reactions but recently, much of the research in catalysis has been focused on second row transition metals such as palladium, ruthenium, and rhodium. Of these transition metals, palladium catalysts, such as Pd(PPh3)4 or Pd(OAc)2, are the most widely used due to there versatility and catalytic activity.

The activation of the catalyst and the subsequent organometallation are important steps in the direct arylation process. Once the catalysts have been activated though the loss of a ligand, the formation of a carbon metal bond between the reactive species, usually an aryl halide, and the metal center can occur. This bond is the result of oxidative addition of the reactive C-X species and the metal catalysts. Palladium is widely used as a catalyst in transition metal catalysis because it has a tendency to form square planer complexes with low valence counts that easily undergo oxidative addition. Oxidative addition results in a change from four to six coordinate complexes while reductive elimination is the opposite. Palladium in low valence counts can easily interconvert between 16 and 18 electron, 4 and 6 coordinate, which is one reason why it is a widely used metal for catalysis. During the process of oxidation many palladium catalysts are oxidated from pd (0) to Pd (II). These react well with aryl halides and organometallic reagents as well as a large variety of other reagents.

Ruthenium
Since the early 1990's, a great deal of work has gone into the development of ruthenium as an alternative to palladium catalysts. Ruthenium is a cheaper transition metal making it more practical in industry and in other commercial applications. The two popular types of ruthenium catalysts use ruthenium in different oxidation states Ru (0) and Ru (II). Catalysts using Ru (II) are becoming more popular because they are generally more efficient and stable and easier to generate and use. Ruthenium (II) complexes catalyze the direct arylation of aryl halides though a Ru(II) – Ru(IV) mechanism and can be used on substrates that lack protecting groups. In comparison to palladium catalysts, ruthenium-catalyzed direct arylations include intermediates with higher oxidation states, making ruthenium well suited for direct arylation with arenes containing directing groups that are capable of coordinating through a nitrogen or oxygen. Those arenes, which are capable of undergoing direct arylation in the presence of a ruthenium catalyst, include arene electrophiles such as aryl bromides, chlorides, and tosylates.

Ruthenium(II)-phosphine complexes of the form RuH2(CO)(PPh3)3 have proven to be successful in catalyzing the direct arylation of aromatic compounds bearing pyridyl substituents with organic halides, resulting in an ortho-arylated product.



Rhodium
Many rhodium species can be easily generated through transmetallation. Compared to palladium complexes, they are relatively electron rich. The electron rich nature of rhodium complexes allows them to react with aldehydes and alpha- beta unsaturated carbons. In addition to this rhodium compounds catalyze the arylation of indoles, pyrroles, benzimidzoles and benzoxazoles as well as arenes with imine groups. They are thought to go though Rh(I) and Rh(III) intermediates. They have also been reported to catalyze arylation of arenes and other nucleophilic aryl compounds.



Alternative Metals for Catalysts
One drawback to the use of palladium and other second row metals in catalysis is the price. The high cost of palladium has driven research into the use of alternate metals in catalysis such as copper. Copper is a far less expensive and far more available metal then other transition metals making it ideal for use in industry. While copper chemistry is still in development, the simplicity of the catalytic cycle shows promise. While palladium catalysts have a much wider range of uses, the complexity of their mechanisms means that they are often developed by trial and error. Copper catalysts have a far simpler and more predictable mechanism involving an acid base reaction followed by carbon-carbon bond formation.

Copper cataysts are still in development but have been shown to successfully functionalize relatively acidic species where the pKa is 35 at the most acidic position. The mechanism for this reaction is functionally similar to Kumada, Negishi, and Castro cross-couplings and could lead to the use of other metals, such as nickel or cobalt for arylation reactions.

Modification for Control of Functionalization
In most cases, the active form of the catalyst has an empty coordination site that has been generated by the loss of ligand(s) to solution. This empty coordination site allows for bond formation between the metal center and the reactive species. By tailoring the ligands on a catalyst, the site specificity and efficiency can be altered. Simple palladium salts, ligandless catalysts such as Pd(OAc)2, show no site specificity allowing the reaction to proceed quickly but without any control of stereochemistry. Adding ligands to solutions of simple metal salts results in the coordination of the ligand to the metal center. As an example, see below, by adding pyridine to a solution of palladium salt, the reaction will have a preference towards the generation of less hindered products.



Applications
Direct arylation has the potential for both scientific and commercial value. Its many applications range from electronics to medicine.

Organic Light-Emitting Diodes
Recent research has lead to the development of organic light-emitting diodes (OLEDs). These are composed of a layer of organic material in between two electrodes which is the emissive electroluminescent layer. The delocalization of π-electrons caused by the conjugation of the rings results in conduction. Light is emitted in response to an electric current. This type of LED has the potential to revolutionize popular technology with curved display screens. Polyaryls are an effective component in OLEDs because of ring conjugation that leads to superior electron and hole transport.

OLEDs can be used in television screens, computer monitors, mobile phones, and gaming consoles. However, some research must still be done for the OLED display screens to be favoured over their competition. Their blue-light emission is not as stable or as long lasting as that of regular LEDs. This is a rather large deficit considering red, green, and blue light emissions are all requirements for a display screen. Success has been found in hybridizing OLEDs with LEDs to overlook this issue. Research is also going into the development of white OLEDs for solid-state lighting.

Liquid Crystals
First discovered in 1888, Liquid crystals are in a phase that is neither solid nor liquid. In fact, many liquid crystals exhibit polymorphism where more than one phase can be observed. Liquid crystals are less ordered than a solid and therefore have more translational freedom, but they still keep more order than a liquid. These properties have lead to the development of liquid crystal displays. The chemistry of these displays can be manipulated to show fixed or random images such as the numbers of a digital alarm clock. They can be found anywhere from a calculator to an airplane cockpit. LCD screens are efficient and can also be made in a larger variety of sizes than plasma screens.

Liquid crystal technology has also been put to use in thermometers. Their heat-sensitivity causes them to change colour with changes in temperature, which will correspond to the temperature of a person's fever. Liquid crystal thermometers are seen to be a better alternative to mercury thermometers due to mercury's toxic nature. However, they don't have the same accuracy. Surprisingly, this important technology is also the contributor that has made the forever fashionable "mood ring" a possibility. The liquid crystals embedded in the jewellery respond to the body temperature of the wearer and will change colour accordingly. Direct arylation may become a prominent synthetic method for the design of liquid crystals.

Organic Solar Cells
Low-bandgap conjugated polymers have shown high performance as the active material in organic photovoltaic cells (also known as organic solar cells). Organic photovoltaic cells are simple to fabricate and cheap to produce since they are mostly made out of plastic. They use conductive organic polymers to absorb sunlight which is then converted into electricity via the photovoltaic effect. These organic polymers can be synthesized using direct arylation. Chang et al. have shown a polymerization mechanism for this using a palladium catalyst as shown on the right.

Medicine
Heterocyclic structures are the building blocks of medicinal chemistry. Even before the development of modern chemistry, heterocyclic alkoloids were the active ingredients in most of the drugs available. A good example of this is morphine. With chemistry as it is today, it is possible to synthesize heterocyclic rings for the treatment of diseases and ailments and the development of new and better drugs. Direct arylation is becoming a very useful method for this purpose.

Direct arylation can be used for the synthesis of many precursors to important drugs. For example, colchicine is a microtubule, antitumour agent that works through mitotic poisoning. Unfortunately, the use of colchicine for cancer treatment is impossible due to its high level of toxicity. Interest has been redirected to allocolchicines which are a promising and less toxic alternative. These have a benzene ring in place of the colchicine's tropolone ring and stop mitosis of the tumour cells through inhibition of tubulin polymerization.

ZD6126 was a promising, water-soluble phosphate drug that converts to N-acetylcolchinol inside of the patient's body. It has proven to be quite effective in the treatment of malignant tumours in animals, however, the needed dose is too cardiotoxic and clinical trials have been stopped. Before direct arylation, all synthetic routes to the development of allocolchicines needed to go through colchicine itself which greatly limited the type and position of structural variation. Using direct arylation catalysed by a Pd(0) catalyst, this unfavourable method of synthesis can be avoided. Perhaps, with the structural variations that are possible through direct arylation, a less cardiotoxic drug will be able to be synthesized for cancer treatment. An example of the direct arylation of allocolchicine can be viewed on the left.

More medically important heterocycles can be found within the carbazole family .Carvedilol is a beta-blocker used to treat hypertension and angina while ellipicine shows anti-tumour activity. These compounds can be synthesized through intramolecular direct arylation. A synthetic pathway discovered by Bedford et al. can be seen above.