The Heck reaction (also known as the Heck-Mizoroki reaction) was first developed by Richard F. Heck in 1968 when he studied the formation of a new carbon-carbon bond in the coupling reaction between olefin and aryl compounds when catalysed by certain transition metals. Scheme11* This was at a time when there was little known about tranisition metal chemistry and interest in the subject was only starting to take off, and Heck's new reaction did not prove to be especially practical as it was carried out using toxic metals such as mercury and to be most efficient required the expensive metal palladium.
In 1971, Tsutomu Mizoroki at the Tokyo Institute of Technology further developed Heck's original reaction making it more practical and manageable. It followed Heck's original scheme of coupling alkenes with substituted aromatic rings using Palladium. However there are several key differences between Mizoroki's reaction and Heck's, Mizoroki replaced the toxic mercury and tin on the aromatic rings Heck used with Iodine and used a recyclable palladium catalyst. Scheme 12*
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Heck published more, independently discovered, work on the same coupling reaction in 1972 where he made the reaction furthermore manageable and user friendly by replacing the catalyst with palladium acetate and Mizoroki's potassium acetate with a hindered amine and eliminated the need for pressurized reaction containers and a solvent. Scheme 13*
There have been many derivations of this reaction carried out since but the result of this early work was the basic Heck reaction which has become extremely useful and is now involved in many chemical processes across all sectors and in 1974 Heck published yet more work on the reaction this time replacing the substituted aromatic ring systems with phosphines.
In more recent times the focus on Heck chemistry has been on creating more efficient heterogeneous phase catalysts to allow for better catalyst recyclability and product/catalyst separation, and on replacing the metal palladium catalysts altogether with other more environmentally friendlier and "greener" catalysts.
As evidence of how important the initial work by Heck proved to be, the Nobel Prize for Chemistry in 2010 was awarded to Richard Heck jointly with Akira Suzuki and Eiichi Negishi "for palladium-catalysed cross couplings in organic synthesis".
The Heck catalytic cycle is one of a series of reactions which leads to the formation of new carbon-carbon bonds and over the years has proven to be one of the most popular tools to do so. So much so that its presence can now be seen across a variety of industrial processes. One of the reasons for this popularity, despite its use of the expensive precious metal palladium, is its versatility and wide variation of substrates and solvents with which the reaction can be carried out.
One of the first examples of its use on an industrial scale was in the manufacture of the agricultural herbicide Prosulfuron by Novartis (then Ciba-Geigy) *figure 1
The Heck coupling reaction may possess several advantages over other more industrially common techniques for instance less waste, the reactions may be carried out under more user friendly, milder conditions and in some cases has shortened the overall reaction.
Other examples of the Heck reaction in industry include the production of monomers as part of polymer production by Dow Chemicals and surprisingly there are a few instances of the Heck reaction in full scale pharmaceutical manufacturing.
Usually when the production pathways of new pharmaceutical products are being "scaled up", reactions such as the Heck are avoided at all costs. This is due to the presence of palladium, a heavy metal and as such cannot be present in any significant amount in the final product in case of risk to the patient. Examples of where it has proved advantageous to use are in the production of the asthma drug Singulair by Merck, the anti-inflammatory drug Naproxen by Albermarle and the Migraine drug Eletriptan by Pfizer amongst others. In the case of Singulair, the Heck reaction was utilised due to its ability to form new carbon-carbon bonds without the need for strong bases such as Grignard reagents and so it could be used in later stages of the production process. Figure 2*
Heck Reaction Mechanism
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It is generally accepted that the Heck reaction follows a cycle comprising of several key steps which shall be discussed in detail. The reaction may proceed through either a neutral or a catalytic cycle. With regards the neutral pathway, the overall cycle, as can be seen in scheme 1*, is driven by the redox capability of the palladium catalyst to switch between its Pd(0) and Pd(II) states as the cycle progresses. Therefore, for the reaction to begin, the active palladium catalyst must first be generated.
The activation process is usually achieved in situ, most commonly by the reduction of palladium (Pd(II) to Pd(0)) with acetate or triphenylphosphine scheme 2*
The first real step in the heck catalytic cycle is the oxidative addition reaction. In order for this step to proceed the palladium catalyst complex must be orientated with a coordination shell comprising of two ligands (Pd(0)L2). This may hinder the amount of ligands which can be thus used in the reaction due to their associated steric factors.
The oxidative addition reaction mechanism itself occurs through a concerted process. The C-X bond of the halide (where X=Cl, Br, I etc.) breaks simultaneously with the formation of the C-Pd and Pd-X bonds. Scheme 3*
The trans-complex is usually the compound observed when the product is isolated after this step although it is clear that the cis-complex must be formed first and undergo rearrangement for this to occur. More importantly it is the cis-complex which enters the next step of the catalytic cycle. Scheme 4*
Possible switch ^*
Following the oxidative addition of the halide to the palladium complex, the olefin then attaches through the double bond to the metal centre. Scheme 5*
By nature of this step being a migratory insertion reaction, i.e. it could be a migration or insertion, there is no concrete mechanism for this step but there are a few possibilities, each more defendable than others depending on the type of compounds in question.
It is the key step within the whole the Heck catalytic cycle as it is here that the new C-C bond in the overall product is actually formed. It is also the stage thought to be responsible for all regio- and stereo-selectivity of the final compound.
Firstly it is important to note that studies have shown the palladium metal must first lose a ligand for coordination to the olefin to be possible. This rules out any 5 coordinate mechanistic approaches. It is also important to note that there are two pathways, one for the neutral cycle and one for the cationic cycle.
The most plausible mechanism can be most easily described by first illustrating the varying possibilities of the olefin addition to the palladium complex. For most cases, a concerted mechanism fits reaction process most readily. Scheme 6*. This is due to the electronic versatility of concerted transition states making them more stable and also because they are most easily understood despite the often complicated electronic parameters. This concerted mechanism cannot be thought of as a classical SN2 type process however. The complex cannot be described as an electrophile and measurements of the electronic parameters such as the charge transfer from the Pd complex to the olefin upon the addition of a carbine complex show that there is no charge build up at any point.
The results of these studies are not clear in so much as they point to a specific mechanism but they do go a long way to rule out the presence of an electrophilic or nucleophilic complex and thus an SN2 reaction.
From these low electronic effects, it can be said that steric and bulk effects must be more important when it comes to the chosen route for migratory insertion.
Termination / Î²-Hydride Elimination
As with the other steps in the reaction there are several possibilities through which the termination of the reaction and Î²-hydride elimination can occur. The most common of these routes is the syn-elimination of palladium and hydride using through an agostic reaction. Scheme 7*
Since the Î²-hydride elimination is a syn process, the hydride and palladium must be co-planar. This process forms the double bond in the product and is responsible for defining the stereoselectivity of the product. Elimination in this case usually follows the Curtin-Hammet principle which states that the product formed is as a result of the difference between the transition states and free energies of the possible products and not of the equilibrium constants. For this reason the trans isomer is the predominant product formed except in the case of where R is extremely small. Scheme 9*
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The Pd(0) catalyst is then regenerated by the reduction reaction using the base scavenger and the cycle begins once more. Scheme 10*
If the base does not quickly scavenge the eliminated palladium hydride, then there is the possibility that the PdH can bind to the double bond of the product. This can occur at either end because of its relatively small size and lead to new stereochemistry in the product upon elimination of the PdH for a second time. Scheme 8*
Reaction Rate Determination
Examples of Catalysts
We have already noted the vast importance of the heck catalytic cycle as a source of carbon-carbon bond formation in many different industrial sectors. One of the main problems the Heck reaction has faced since its first development in the late 60's is not just its reliance on the expensive precious metal palladium, but more specifically the efficient ability to separate from the product mixture and then reuse the metal catalyst.
In recent times the majority of research in the area of Heck chemistry has been focused on the development of efficient recyclable Heck catalysts. More specifically this amounts to phase separation catalysis whereby the catalyst is kept separate from the overall product mixture by immobilisation as part of a heterogeneous solid-liquid system, through the heterogenisation of homogenous catalysts or even by biphasic homogenous liquid-liquid systems. There are several challenges faced when designing these recyclable Heck systems, as was noted earlier the Heck reaction possesses great versatility in its wide range of suitable substrates and solvents but this also makes it very sensitive to change in the reaction parameters, often with detrimental effects on the reactions outcome. The other major faced by those designing new recyclable systems is the Heck's characteristic formation of by-products which poison the catalyst and result in the steady decline of activity and yield after each cycle. The poison in question is the salt formed from the reaction of the conjugate acid of the base used to scavenge the palladium, and the leaving group.
Homogenous Immobilised Catalysts
A homogenous, efficient recyclable catalyst which is easily separated would be the most ideal outcome of any research and development in the field as this would mean little or no drop in the yields and selectivity of the Heck reactions already studied in great detail using homogenous catalysis. Biphasic liquid/liquid catalysis is a possible solution to this and it involves the use of two immiscible solvents, usually polar and non-polar with the metal catalyst held in one, for example by the use of hydrophilic ligands, and the reagents/product mixture held in the other phase. Liquid/liquid catalysis has proven quite successful in other areas of chemistry such as in the case of the Shell Higher Olefin Process for the oligomerisation of olefins but it has not proven particularly popular in the case of Heck catalysis. This can be largely attributed to the "Achilles heel" which liquid/liquid catalysis suffers from that is the larger the separation of catalyst - reactants/product, the lower the rate of reaction.
Heterogeneous Immobilised Catalysts
Therefore in order to create a much more easily separated recyclable catalytic system, the focus was turned to heterogeneous catalysis and the heterogenisation of some of the homogenous catalysts previously used. This involved the development of solid-liquid systems whereby the catalysts was immobilised in the solid state on a support and the reactant/product mixture remained in solution. There are several types of solid support systems which have been developed for Heck catalysis and they remain much the same as the solid supports used in other catalytic reactions.
Some heterogeneous palladium catalytic methods include the support of the metal on materials such as porous glass or in one of the most common supported methods, Pd/C. This common catalyst is used for a variety of processes including hydrogenation reactions and is comprised simply of palladium covering the surface of porous activated carbon making for a large surface area over which the reaction can take place. When compared with similar homogenous catalytic reactions however the yield and reaction efficiencies of this supported catalyst are very low and the method also suffers from leaching which will be discussed in further detail later.
Another method of heterogeneous catalysis is the entrapment of the catalyst in zeolites. These are materials containing pores in which the catalyst can become immobilised. Conventional zeolites however have pores which are extremely small and so this has implications on the type of ligands which can be used with the palladium catalyst, for instance certain phosphine ligands can no longer be used. They do have one quite large advantage over other immobilisation methods because of this size restriction, since the pores are so small, the catalyst is not free to move into solution and so leaching is reduced, and also the catalysts molecules are not free to interact with one another and aggregate.
Mesoporous zeolites have been developed in order to try and overcome with the pore size restriction. These are simply zeolites where the pores are much wider and so allow for the immobilisation of larger molecules within them. There have been several studies carried out on Palladium immobilised on the molecular sieve MCM-41 which is one of a series of sieves which was originally developed by Mobil. The reactions carried out using this material show evidence that they retain much of the same advantages as the original zeolites. They yield high turnover numbers and a high turnover frequency especially when compared with other more common immobilisation techniques. They also do not result in high levels of metal leaching, although this level does increase with each run carried out. On average, they can be used up to three times but in any subsequent runs the structure begins to decay and with it the results due to the catalysts beginning to aggregate.
Some work has also gone into the manufacture of effective palladium colloidal/nanoparticle catalysts. In one example of this type of catalysis the palladium is stabilised by ammonium ions and introduced to the reactant mixture. Beller et al. reported that this type of catalyst was very active for reactions involving aryl bromides. This type of catalysis is not extremely useful from an industrial stand point however as when the reaction has been completed, the product must be separated from the resulting salts formed during the reaction and also recycling of the catalyst is more time consuming than the other forms already mentioned.
The final type of heterogeneous catalysis that will be discussed is a form whereby the palladium metal catalyst is intercalated to another metal to form a compound in a clay-like material. Some examples of these catalysts developed include palladium-graphite as used in certain polymerisation reactions. Another example of this form of catalysis involves the use of a Pd-Cu metal compound fused in K10 clay. This montmorillonite clay is manufactured via the acid treatment of the clay at high temperatures resulting in a material which is a soft Lewis acid and also an ion exchanger, both of these properties meaning it can promote in the Heck reaction by not just acting as the catalyst support. The Pd-Cu-K10 clay catalyst was reported as an easily recyclable compound which could be used efficiently for the Heck vinylation reactions. Other palladium catalysts were also prepared using K10 clay, for instance the addition of Pd(Cl)2 and Ph4PBr to the clay in order to catalyse the Heck reaction forming stilbene.
Heterogenised Homogeneous Immobilised Catalysts
The previous catalysts mentioned could be described as being the more common or conventional types of immobilised heterogeneous catalysts as they have been used widely for quite some time across a wide variety of reactions. The metal catalyst in those systems also could be described as being directly bound to the support surface whereas in the following examples which will be discussed the catalyst is immobilised through interactions between its ligands and the support surface. They are described as heterogenised homogeneous catalysts as the catalysts themselves are very similar to the general homogeneous mobile catalysts except they have been modified slightly to enable anchoring to a support.
The first example of this type of catalysis could also be described as a homogenous immobilised catalyst. They are liquid phase catalysts which have been immobilised on a solid support. As noted earlier the major problem with biphasic liquid catalysts were the greater the separation of the catalysts and reactant/product mixtures, the lower the reaction rate. In supported liquid phase catalysis this problem is slightly overcome. The liquid catalyst is in a hydrophilic solvent which is then spread over a support such as glass beads, the reactant/product mixture is then in another immiscible solvent as was carried out by Tonks et al. A reverse phase catalyst, with respect to this example, has also been shown to have high activity while allowing the catalyst greater mobility in solution.
There are some other examples of Heck catalysis where the catalyst is not strictly immobilised in a different phase to the substrate but which still yield a method where the product can be formed efficiently and easily separated from the catalyst ready for reuse.
An example of such a system would be involving ionic liquids. An ionic liquid is one which is composed entirely of ions, or in other words a salt which is in its liquid state. They possess strong solvating properties and it is due to this characteristic that they are a favourable reaction medium for catalytic cycles such as the Heck. In an example of this, Herrmann and Bohm achieved a 99% yield of stilbene using tetrabutyl ammonium bromide as the ionic solvent and because of the high solubility of the catalyst, the product could be easily removed by distillation and the catalyst recycled being used up to 13 times with a negligible loss of activity.