Heck Reaction
Introduction to Heck Reaction
Heck reaction is one of the most widely used carbon carbon coupling reaction in organic chemistry. Heck reaction is a palladium catalyzed cross coupling reaction in which olefins and aryl or vinyl halides (or trifluoromethanesulfonate) are used to synthesize substituted olefins.1,2 The reaction needs to be carried out under alkaline conditions with high regioselectivity and stereospecificity. The Heck reaction was first discovered by Richard F. Heck and Tsutomu Mizoroki in the late 1960s, hence the Heck reaction is also known as the Mizoroki Heck reaction.3 Mizoroiki Heck also won the 2010 Nobel Prize in Chemistry for this reaction.4
Figure 1. Heck reaction
Mechanism of the Heck reaction
Heck reaction is a cross coupling reaction with olefins and organic halides as raw materials in the presence of strong base and palladium catalyst, which is mainly carried out through the following four steps:
1. Oxidative Additon
2. Migratory -Insertion
3. Ssynβ-hydride Elimination
4. Reductive Elimination
The Heck reaction mechanism largely depends on the selection of palladium catalysts, ligands, and bases. By changing these factors, reactions can be optimized for various substrates. Heck reaction is one of the important reactions for constructing carbon carbon bonds in organic synthesis, and significant progress has been made in this field.
Factors Affecting Heck reaction
The following factors can affect the efficiency and selectivity of Heck reaction, including:
1. Selection of palladium catalyst: The selection of palladium catalyst will significantly affect the reaction results. Different palladium complexes have different reactivity and selectivity. Choosing suitable catalysts can improve the yield and selectivity of the reaction.
2. Ligand structure: The selection of ligands also affects the reaction results. Ligands play a crucial role in forming stable palladium complexes and controlling their reactivity. Different ligands can promote different reaction pathways and alter the selectivity of the reaction.
3. Selection of alkali: Alkali can affect the reaction result by controlling the acidity of the reaction mixture and promoting the deprotonation of olefins. Different bases can affect the reaction rate and product selectivity.
4. Substrate structure: The structure of the substrate can significantly affect the reaction results. The electronic and spatial characteristics of the substrate can affect the reaction rate, product selectivity, and byproduct formation.
5. Reaction conditions: The reaction conditions, including temperature, solvent, and reaction time, also affect the efficiency and selectivity of the Heck reaction. The yield and selectivity of the reaction can be improved by optimizing these factors.
Applications of Heck reaction
Heck reaction can be used for the following applications:
1,In the application of neopentyl phosphine ligands in the coupling of aryl bromides with olefins, it was found that the degree of olefin isomerization was controlled by the choice of ligands. Among them, Di-tert-butylneopentylphosphine(DTBNpP) improves the selectivity for 2-aryl-2,3-dihydrofurans in the reaction under the conditions of Pd(dba)2 as a catalyst, and trineopentylphosphine(TNpP) improves the selectivity for isomeric 2-aryl-2,5-dihydrofurans in the reaction. 5
The above synthesis scheme:
1,Heck coupling reaction of benzene phthalide with different olefins in dioxane solvent under Pd(OAc)2 catalyst and triethylamine (TEA) conditions led to the organic synthesis of γ-keto acid derivatives in high yields. 6
The above synthesis scheme:
1,Di-tert-butyldiazaindone synthesizes indolines by Heck reaction. Indoline is one of the compounds of great biological importance in the field of synthetic chemistry.7
2,The Heck reaction allows for the efficient synthesis of various ortho-trifluoroethyl-substituted styrenes.8
3,The Heck reaction allows the highly compatible synthesis of important benzopyran derivatives such as flavones and neoflavones.9
4,Stilbene derivatives can be produced by the Heck reaction without the use of transition metal catalysts.10
Research and Trends in Heck Reaction
1,A study on the application of neopentyl phosphine ligands in the Heck coupling reaction of aryl bromides with alkenes. It was found that in the Heck coupling of cyclic olefins, the degree of olefin isomerization was found to be controlled by the choice of ligands.5
2,On the asymmetric Heck coupling reaction of benzyl electrophile using phosphoramidite as a novel efficient chiral ligand. The Heck coupling reaction using benzyl trifluoroacetate and 2,3-dihydrofuran as raw materials and phosphoramidite as ligand gave ideal yields and excellent stereoselectivity to yield the main product 2-benzyl-2,5-dihydrofuran.11
The above synthesis scheme:
Limitations of Heck reaction
The Heck reaction has the following limitations:
Functional group tolerance: limited by the presence of acid sensitive and alkali sensitive groups. These groups will irreversibly inactivate or undergo side reactions during the reaction process.
Spatial hindrance: The presence of a large number of substituents on the substrate or ligand can hinder the reaction or alter the selectivity of the product.
Regioselectivity: The reaction sometimes shows poor regioselectivity, especially in the case of terminal olefins. The formation of non target region isomers limits the efficiency and selectivity of the reaction.
Catalyst poisoning: palladium catalyst is deactivated or poisoned due to impurities in the reaction mixture or the presence of some functional groups.
Experimental cost: The cost of the palladium catalyst used in the reaction may be high, limiting its practicality in certain applications.
Nevertheless, the Heck reaction is still an important reaction for the formation of C-C bonds in organic synthesis. The development of new palladium catalysts, ligands and reaction conditions will help overcome some of these limitations and improve the yield and regioselectivity of the reaction.
References:
1.Biffis A, Zecca M, Basato M. 2001. Palladium metal catalysts in Heck C?C coupling reactions. Journal of Molecular Catalysis A: Chemical. 173(1-2):249-274. https://doi.org/10.1016/s1381-1169(01)00153-4
2.Li JJ. 2009. Name Reactions. https://doi.org/10.1007/978-3-642-01053-8
3.Oestreich M. 2009. The Mizoroki?Heck Reaction. https://doi.org/10.1002/9780470716076
4.Ruan J, Xiao J. 2011. From ?-Arylation of Olefins to Acylation with Aldehydes: A Journey in Regiocontrol of the Heck Reaction. Acc. Chem. Res.. 44(8):614-626. https://doi.org/10.1021/ar200053d
5.Lauer MG, Thompson MK, Shaughnessy KH. 2014. Controlling Olefin Isomerization in the Heck Reaction with Neopentyl Phosphine Ligands. J. Org. Chem.. 79(22):10837-10848. https://doi.org/10.1021/jo501840u
6.Shashikumar ND, Krishnamurthy G, Bhojyanaik HS. 2014. A Facile Synthesis of Novel Cyclic Esters of ?-Keto Acid Derivatives by Heck Coupling Reaction. J. Heterocyclic Chem.. 51(S1):E354-E357. https://doi.org/10.1002/jhet.1898
7.Zheng H, Zhu Y, Shi Y. 2014. Palladium(0)-Catalyzed Heck Reaction/C?H Activation/Amination Sequence with Diaziridinone: A Facile Approach to Indolines. Angew. Chem.. 126(42):11462-11466. https://doi.org/10.1002/ange.201405365
8.Zhang H, Chen P, Liu G. 2014. Palladium-Catalyzed Cascade C?H Trifluoroethylation of Aryl Iodides and Heck Reaction: Efficient Synthesis ofortho-Trifluoroethylstyrenes. Angew. Chem. Int. Ed.. 53(38):10174-10178. https://doi.org/10.1002/anie.201403793
9.Khoobi M, Alipour M, Zarei S, Jafarpour F, Shafiee A. 2012. A facile route to flavone and neoflavone backbones via a regioselective palladium catalyzed oxidative Heck reaction. Chem. Commun.. 48(24):2985. https://doi.org/10.1039/c2cc18150a
10.Shirakawa E, Zhang X, Hayashi T. 2011. Mizoroki-Heck-Type Reaction Mediated by Potassium tert-Butoxide. Angew. Chem.. 123(20):4767-4770. https://doi.org/10.1002/ange.201008220
11.Yang Z, Zhou J(. 2012. Palladium-Catalyzed, Asymmetric Mizoroki?Heck Reaction of Benzylic Electrophiles Using Phosphoramidites as Chiral Ligands. J. Am. Chem. Soc. 134(29):11833-11835. https://doi.org/10.1021/ja304099j