Heck Reaction

An Introduction to Heck Reaction

The Heck reaction is a coupling chemical reaction where an unsaturated halide or triflate reacts with an alkene in the presence of a base and a palladium catalyst. The reaction thereby produces a substituted alkene. This reaction is often known as Mizoroki-Heck reaction after the name of Richard F Heck, who was awarded Nobel Prize in chemistry in the year 2010. 

This cross-coupling reaction is significant because it is capable of forming a carbon-carbon bond in accordance with Palladium (o) or Palladium (II) cycle. Moreover, this reaction is stereo-selective in nature, which means it has other reactive pathways to yield substituted alkene. However, the popular pathway is the most effective. 


Heck Reaction Mechanism

The Heck reaction takes place following several interrelated steps. They are discussed below. 

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Fig1: Heck Coupling Mechanism


Palladium Catalyst Pre-activation

The first step of reaction involves the pre-activation of a palladium catalyst. The highly catalytic agent Pd(II)(OAc)2 coupled with monodentate phosphine ligands like PPh3 is generally added to catalyse the heck coupling. However, it is necessary for Pd (II) complex to reduce into Pd(0) to participate in the catalytic cycle. It can be performed generally using two methods which also include phosphine-mediated Pd(II) reduction.

Nonetheless, Pd(0) catalyst must also have a coordinate number before entering the cycle. The reason behind it is if it contains several monophosphine ligands, it may hinder the catalyst. 

Another way to activate the catalyst is by using triethylamine, a useful reagent that can reduce Pd (II).

Oxidative Addition

It is the most complex step of catalytic cycle. It is to be noted that since phosphine ligands contain electron-donating groups, they can activate the catalyst. Moreover, it breaks the R-X bonds and forms Pd-R and Pd-X, respectively. However, the oxidative addition rate heavily relies upon Halides’ chemical property. 


Olefin Addition 

Before Olefin’s migratory insertion to Palladium-R bond, it has to be linked with palladium complex. For that, first, it calls the need for disassociation from existing ligands. Furthermore, this step comprises a vital step in heck coupling reaction mechanism as it influences the Regioselectivity and Stereoselectivity of the reaction. For example, Sterics governs the Regioselectivity for a neutral Pd complex, whereas electronics do the same in a cationic Pd complex. 


Elimination of B- Hydride

β-Hydride elimination produces a new substituted alkene. At this stage, the palladium and its associated hydride have to be syn-coplanar to begin the elimination process. However, the product having Z-conformation is mainly disfavoured due to the steric interaction during transition state.  

Once this step is over, the newly formed product, palladium-alkene complex, initiates olefin isomerisation and ends up forming an unwanted Heck product. 

These additional reactions take place since it is a reversible reaction. Moreover, this concern arises if the rate of olefin dissociation is very slow. However, adding silver salts or bases, we can significantly lower the probability of alkene isomerisation. It can be done by introducing reductive elimination and resulting in an H-X bond. 


Palladium Catalyst Regeneration                   

It is the concluding step of heck coupling. In this step, an additional base is added to inhibit L2PdHX complex. Some of the popular bases used in the mechanism of heck reaction are mainly trielamines, like Et3N and inorganic salts like AcONa.

Finally, a proton sponge or Ag (I) or Tl (I) salts are added to close the reaction. 


Stereoselectivity and Regioselectivity

Regioselectivity reactions in neutral mechanism occurred in different olefins classes. A few important points regarding it are as follows.

  • After aryl triflates were used as leaving groups, examination for Regioselectivity was held via the cationic mechanism.

  • These reactions were conducted with aryl triflate leaving groups and aryl halides, with bidentate phosphorus ligands and with Pd(OAc)2.

  • These reactions produced branched products more rapidly than neutral mechanism.

In a neutral mechanism, regioselectivity is associated with steric factors and coordination-insertion path. The R group migrated towards less substituted carbon, forming linear products is seen to be effective in a neutral mechanism. A cationic mechanism is different in case of electronic factors play a vital role in deciding regioselectivity. 

Scientists studied stereoselective intermolecular couplings using aryl triflate as chiral (R)-BINAP and the leaving group. Various reactions were conducted in analogous conditions, and then their products were compared. As expected from triflate leaving group, those reactions followed a cationic mechanism. The reactions were seen to be most selective while using both the triflate leaving group and chiral BINAP. It needs to be noted that (R)-BINAP determination of selectivity only takes place in electron-rich systems. Hence it is ascertained that Cationic mechanism depends largely on electronic factors and in that, systems that are electron-rich react more efficiently than the ones lacking many electrons.

Overman stated for quaternary carbons a stereoselective synthesis through an asymmetric intramolecular Heck coupling. It was noteworthy because they challenged the widely held and popular belief that extended time of reaction will lead to the double bond isomerisation and multiple undesired product formation. To prove that, PMP was employed as a base in the reaction in the absence of Ag(I) salt. These reactions demonstrated good selectivity despite the slow reaction time along with the difficulty in transferring chirality through a neutral mechanism. It was confirmed that using flexible substrates, the products turned out to be nearly racemic. Nonetheless, using rigid substrates, (R)-BINAP’s single Phosphorus coordination was capable of transferring the chirality through a neutral mechanism. 

Intramolecular Heck Coupling

The Intramolecular Heck reaction proposes several merits which are not available in intermolecular heck reaction.

  • In an intermolecular reaction, only mono or non-substituted alkenes can participate in Pd complex. However, via Intramolecular mechanism tri- and tetrasubstituted alkenes can coordinate readily.

  • Due to entropic consideration, Intramolecular heck reaction is much more useful and appropriate than the intermolecular one.

  • In case of Intramolecular Heck reaction, stereoselectivity and regioselectivity are improved drastically in the reaction.

Pondering upon these advantages, Shibasaki and Overman started exploring the asymmetric effect in this particular Heck reaction. Also, they eventually discovered the first asymmetric Intramolecular Heck reactions. This phenomenal discovery has opened a new horizon for natural substance synthesis.


Limitations 

The usage of Heck coupling reaction is prevalent in medical, industrial and pharmaceutical industry due to its ability to generate large, stable polycyclic structures. However unfortunately, this useful cross-coupling reaction has a few disadvantages. One such disadvantage is that the Palladium catalyst will not be available at the end of catalytic cycle. Hence, it is needful for scientists to look for an effective procedure to recycle the Pd catalyst. Nonetheless, another major drawback of this reaction is that the phosphine ligands linked with palladium catalyst are to a great extent, expensive and toxic. Therefore, we should look for a phosphine-free alternative of ligands to enhance the reaction efficiency. 


Heck Coupling Application

Following are the major applications of heck coupling. 

  • It is useful for the synthesis of several y-keto derivatives which are fruitful for organic synthesis. 

  • Also synthesises Indolines, a compound with biological significance. 

  • Synthesises styrene derivatives. It also synthesises the following. 

  1. Chromenone derivatives, for example, neoflavones and flavones. 

  2. Drugs, bioactive natural materials, etc. 

  3. Taxol, used in chemotherapy and an asthma drug called Singulair. 

Hence, heck chemistry is essential in several fields. 


Recent Trends and Research

Organic cyclic carbonates have been proposed as suitable greener solvents which can be used in Heck reactions. They are effective alternatives in comparison to dipolar aprotic solvents which were traditionally used. These were associated with risks like high toxicity.

  • The mechanism of the redox-relay Heck reaction has been studied using deuterium-labelled substrates.

  • Neopentyl phosphine ligands were investigated for promoting the Heck coupling of aryl bromides with alkenes.

For further reference of Heck reaction organic chemistry, stay tuned to our website. We have a plethora of study material from which you can choose any topic and make your concept clear. Along with that, you can also register for our online chemistry classes to clear your doubts if any. You can now also download our Vedantu app for enhanced access to these detailed study materials.

FAQ (Frequently Asked Questions)

1. What Reactants Are Used In Heck Reaction?

Heck reaction is a cross-coupling reaction between alkenes and organohalides. In the presence of a base and palladium catalyst, these two compounds react to produce a substituted alkene. 

2. What Are The Usages Of Heck Coupling?

Heck coupling has several applications. For instance, dehydrocostus lactone and aryl halides form derivatives of guaianolide sesquiterpene lactones through this coupling, which are useful in terminating acute leukemic cells. Also, it is used in synthesising Chantix, a smoking cessation aid.

3. What Is Heck Oxyarylation?

Heck Oxyarylation displaces the palladium substituent with a hydroxyl group during a syn addition process. The variation, however, results in a dihydrofuran ring. 

4. What Are The Ligands And Bases Are Used In Heck Reaction?

The main supporting ligands used in heck reaction are PHOX, BINAP, triphenylphosphine, etc. Also, the common bases are potassium carbonate, sodium acetate, Triethylamine, etc.