Organic Chemistry: The Formation of Carbon-carbon Bonds

Background

There is no doubt that some of the most crucial transformations in the organic chemistry synthesis are the ones that create new carbon-carbon bonds. This new bond formation reactions produce many significant molecules that range from very simple compounds to very complex systems such as polymers, materials, drugs, etc. 1,2During the last decades, metal catalyzed cross coupling reactions have been utilized extensively in the synthesis of organic materials. They have been the most common method of choice for the formation of carbon-carbon bonds because of their significant advantages over different methods. This method has been optimized and perfected over the decades to produce efficient and reliable compounds even using mild protocols.

Some examples of the more well-known and utilized methods include the Heck, Kumada, Stille and Suzuki coupling reactions. 2Prior to the development of these methods, the Ullman reaction was the most popular method to produce biaryls. This reaction involves the coupling of aryl halides with the aid of finely divided copper. Even though this reaction is not quite used nowadays, it is still of value and seldom used for specific synthesis.

The reason why this reaction lost popularity is more than obvious; better approaches has been discovered with time, the fact of comparing the limitations of the Ullman reaction with the new reactions has made this old method to remain almost forgotten. This reaction requires significantly high temperatures (up to 200 °C) which as a consequence limits the use of thermally sensitive substrates. Also, this reaction requires very high quantities of copper (stoichiometric amounts) which results in an enormous amount of metal waste. This results in significant damage to the environment over time and its production is economically unfavorable. So, being aware of the negative effects that this specific reaction entails, there was a need for a better method to produce the carbon-carbon bonds.

Given its widespread popularity and extensive utilization in both academic and industrial settings, it can be argued that these needs have been best fulfilled by the Suzuki cross coupling reaction. Researchers have been focusing in this reaction for the last decades, they have published many articles on this specific reaction. Since its discovery, this reaction has become the method of choice for the formation of new carbon-carbon bonds in many synthetic strategies. Early Suzuki Cross Coupling ReactionsThe first successful Suzuki cross-coupling reaction was employed by Suzuki and his coworkers in 1979.

Their reaction protocol coupled alkenyl boranes along with alkenyl halides or alkynyl halides by using a palladium catalyst and in presence of a base to give conjugated dienes or enynes. Even though the reaction involved alkenyl and alkynyl reagents initially, Suzuki rapidly extended its scope by including the coupling of carbons in aryl, heteroaryl and alkyl groups under different conditions.The first method towards the preparation of biaryls was reported by Suzuki and Miyaura in 1981 and used the conditions shown below: The reaction was performed using aqueous Na2CO3 as a base (homogeneous conditions).

The reaction was also tried under heterogeneous conditions and good yields where found. However, too many bases have been tested for the Suzuki cross coupling reaction, for example; K3PO4, Tl2CO3, CsCo3 and K2CO3, all of them gave the product expected with good yields. Other bases such as Ba(OH)2, NaOH and TlOH achieved better results for more challenging biaryl cross coupling reactions (steric hindered). Also, other bases such as Bu4NF38, KF and CsF were used on milder conditions and have synthesized biaryls containing base-sensitive functional groups.

Advantages of the Suzuki Cross Coupling ReactionThe discovery of the Suzuki coupling reaction has had a great impact on academic research and industry, as well as on production. Over the last decades, it has become undoubtedly one of the most popular and preferred methods for the production of biaryl or substituted aromatic moieties. Throughout the last decades, it has been obvious that Suzuki cross coupling has many advantages compared to other protocols.

A summary of such advantages is stated as follows:

• The Suzuki cross coupling reaction tipically produces very high yields and good selectivity when the right conditions are applied to the substrates.
• Suzuki works very well either with symmetrical or unsymmetrical reactions.
• The reaction demonstrates high tolerance for different functional groups, either on the organometallic partner or in the electrophile. The protocol being very flexible is a huge advantage because it demonstrates many synthetic routes and very high yields.
• A significant benefit is that the organoboron reagent (boronic acid) is thermally stable and inert to oxygen and water, which enables working with this reagent without special precautions.
• The starting materials (esters and boronic acids) are commercially available and not expensive.
• The starting materials are non-toxic, meaning that they are not a hazard to the environment or humans. Also, the inorganic by-product formed in the reaction is non-toxic and can be removed very easily from the reaction.
• The reaction is usually performed at room temperature, demonstrating the green chemistry.
• Water can be used as a solvent, it doesn’t affect the reaction of the substrates.
• This reaction requires very low amounts of the ligand or ligandless catalyst (palladium) to perform the reaction efficiently.
• Heterogeneous catalysts are easily removed from the mixture and can be recycled for later.Limitations of the Suzuki Cross Coupling ReactionEven though Suzuki coupling reactions brings many advantages to the organic synthesis there are a few unfavorable aspects associated with the protocol:
• Some mixtures such as boroxines can be hard to remove from the starting materials (boronic acids), making it difficult to purify them. Boroxines don’t intervene with the coupling mechanism pattern but they make stoichiometric calculations difficult to perform.
• The hetero coupling product can be contaminated with another coupled reagent containing the aryl group originating from the phosphine ligand (ligand scrambling).
• Deboronation side reaction either hydrolytic or protolytic can be faced, this is the case with highly hindered substrates.
• Reagents showing a very high degree of steric hindrance (bearing three or four ortho substituents) are difficult to couple even though a lot of progress has been shown in the recent years.

If the previous mentioned advantages are analyzed, it can easily be concluded that the benefits that this reaction entails far outweigh the limitations. Therefore, it is nothing surprising to notice that the Suzuki cross coupling reaction has being exploited so much since its discovery. It has become one of the most utilized protocols for the carbon-carbon bond formation, it has been used in the laboratory for research, in the industry for the synthesis of large-scale processes. Notable applications of the Suzuki coupling reaction include use in the synthesis of natural products such as michellamine, vancomycin, and ellipticine as well in the construction of ligands and polymers.

General catalytic cycle

Just as in the other type of coupling reactions, the mechanism is not strictly defined. Instead there is a catalytic cycle that has been accepted for this type of reactions. This catalytic cycle mainly involves three steps;

1. (i) oxidative addition,
2. (ii) transmetallation,
3. (iii) reductive elimination.

The complete catalytic cycle for the Suzuki cross coupling reaction is shown below. The oxidative addition step is often the rate limiting step for many reactions, although many studies in the synthesis of these reactions have shown that either one of the other steps might be the rate determining step depending on the substrates and the conditions employed. Oxidative addition In this step, our transition metal (in this case palladium) is inserted into the Ar-X bond producing a cleavage of the sigma bond and the formation of two new sigma bonds.

As it is obviously seen, the name given to this step is because of the oxidation state increase of the catalyst, going from a 0 charge to a 2+ charge. Also, the coordination number is increased, forming the new coordination species arranged in a cis configuration. Therefore, in order for this step to take place, the catalyst of choice needs to be in a coordinatively unsaturated fashion and a low oxidation state. Higher electron density at the center of the metal is known to facilitate the oxidative addition step, some sigma donor ligands such as tertiary phosphines have been proven to increase the electron density.The catalytic cycle is believed to be slightly different depending on the organohalide substrate that is being employed.

The cycle can proceed via one of the two methods: The first catalytic cycle scenario(shown below) is very similar to a simple nucleophilic aromatic substitution reaction, in which the nucleophile is the metal catalyst. Some data collected from different studies were found to follow this mechanism, it has been observed that the cleavage of the carbanion intermediate bond with the aryl halide is the rate-determining step. This can be confirmed based on the reactivity shown by aryl halides towards oxidative addition, increasing the strength of the aryl halide bond decreases reactivity. In addition, another feature characteristic of SNAr reactions is shown. This is the considerably enhanced rate of oxidative addition observed when electron withdrawing groups are attached on the aromatic ring.

The other possible pathway that the mechanism can take is a concerted process with the attack of the catalyst at the aryl halide bond, forming a three centred transition state. This mechanistic pathway for the oxidative addition was the most common in the majority of the data seen in different investigations. Transmetallation and the role of the baseThis process initiates with the reaction of an organometallic species with the oxidative complex from the previous step, forming a new complex consisting of both organic groups added to the palladium complex. This step of the mechanism is known to be a key feature in the nature of the Suzuki coupling. According to the protocol of the catalytic cycle, this step occurs between the trans oxidative adduct and the activated arylborate anion, resulting in the transdiarylpalladium (II) complex and the borate salt as a by-product.