What Is Heck Reaction?
The Heck reaction is a coupling reaction of aryl or alkenyl halides, aryl or alkenyl esters of trifluoromethanesulfonic acid, iodide salts or diazonium salts with alkenes under the catalysis of Pd(II). Heck was the first to report the form of this type of palladium-catalyzed coupling reaction in 1968, followed by Mizoroki and Heck in 1971 and 1972, respectively. Heck subsequently systematically studied this reaction and developed it into a suitable method for organic synthesis. Therefore, this reaction is often called the Heck reaction, also known as the Mizoroki-Heck reaction.
- Reagents: Pd catalyst (e.g., Pd(OAc)2, Pd(PPh3)4 or Pd2(dba)3) + ligand (PPh3, bulky biaryl phosphines, NHCs), base (K2CO3, Cs2CO3, Et3N), common solvents (DMF, DMAc, toluene).
- Reactants: An aryl/vinyl electrophile (Ar–X, X = I, Br, OTf, sometimes Cl) and an alkene (terminal or internal; e.g., styrenes, acrylates).
- Products: Substituted alkene (Ar–CH=CH–R or vinyl–vinyl coupling), typically the trans (E) isomer; intramolecular variants give cyclic alkenes.
- Reaction Type: Pd-catalyzed C–C cross-coupling reaction.
- Related Reactions: Hiyama coupling reaction, Fukuyama coupling reaction, Negishi coupling reaction, Kumada coupling reaction, Suzuki coupling reaction.
- Ligand Role: They stabilize the Pd(0) species, preventing the formation of inactive palladium black, and they modulate the electron density and steric bulk around the metal center, which can dramatically influence the rate of oxidative addition and the selectivity of the insertion step.
Fig 1. Heck reaction and its mechanism. [1]
Mechanism of Heck Reaction
The widely accepted mechanism for the Heck reaction follows a classical Pd(0)/Pd(II) catalytic cycle.
- Oxidative Addition: The active, low-valent Pd(0) catalyst inserts into the carbon-halogen bond of the electrophile. This step is the rate-determining step for most aryl halides, and its ease follows the trend: I > OTf > Br >> Cl. The resulting organopalladium(II) complex is electrophilic.
- Coordination and Migratory Insertion (Syn-Carbopalladation): The alkene substrate coordinates to the palladium center. Subsequently, the alkyl (or aryl) group on palladium migrates to the terminal carbon of the alkene in a syn addition. This forms a new C–C bond and a σ-alkyl-Pd(II) complex. The regioselectivity (which carbon the aryl group adds to) is influenced by electronic and steric factors; with electron-deficient alkenes like acrylates, addition occurs almost exclusively at the β-carbon.
- Syn-β-Hydride Elimination: The key step that regenerates the alkene product. A hydrogen atom on the carbon syn to the palladium atom is eliminated. This step is stereospecific, leading predominantly to the trans-(E)-alkene due to its greater thermodynamic stability. The result is a hydrido-palladium(II) species, [Pd(H)X(L)_n].
- Reductive Elimination and Catalyst Regeneration: The base deprotonates the [Pd(H)X(L)_n] complex, facilitating reductive elimination of H-X (which is trapped by the base) and regenerating the active Pd(0) catalyst, closing the cycle.
Application Examples of Heck Reaction
- Example 1: Cheng, Cang, et al. developed an enantioselective intramolecular carbonylation Heck reaction using formate as a CO source and carried out under palladium catalysis, and successfully synthesized quaternary ammonium salt-type 3,4-dihydroisoquinoline for the first time. This reaction has been successfully applied to the first asymmetric synthesis of the aldose reductase inhibitors as Minalrestat analogues. [2]
- Example 2: M.-Lluïsa Bennasar et al. started from a tricyclic ABC substructure intermediate containing a central eight-membered or nine-membered ring, inserted a 2-ethylpropylene unit by N-alkylation, completed the construction of the carbon skeleton, and then carried out a complex intracyclic vinyl halide Heck cyclization on the double bond left by the RCM step. This strategy successfully achieved the construction of the alkaloid bridged tetracyclic skeleton and was applied to the synthesis of (±)-cleavamine and (±)-dihydrocleavamine. [3]
Fig 2. Synthetic examples via Heck reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 244-247.
- Cheng, Cang, et al. Chemical Science 10.42 (2019): 9853-9858.
- Bennasar, M-Lluïsa, et al. Tetrahedron 69.12 (2013): 2534-2541.
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