& Mechanism
Green Chem
& Mechanism
Reaction & Reagents info
- Heck coupling: C-C bond formation involving alkene and organohalide to generate substituted alkene
- Reactant-1 (Nucleophile): Alkene
- Reactant-2 (Electrophile): Organohalide [Aryl, Benzyl, Alkenyl, or Alkyl (with no β Hydrogens)]
- Solvents: DMF
- Catalyst: Catalytic Palladium [Pd(PPh3)4 (tetrakis), (Ph3P)2PdCl2 (dikis)]
- Bases: KOAc, NaOAc, NaHCO3, 2° or 3° amine
Useful Links on Reagent & Reaction:
- Heck Coupling (SynArchive) – Excellent compilation of reaction schemes with references
Mechanism
Heck Coupling – General Mechanism
- With the exception of the Heck reaction, all of the coupling reactions (Suzuki, Buchwald, Stille, Sonogashira and Negishi) follow the same general catalytic cycle: 1) oxidative addition of the organic halide; 2) ligand substitution of the nucleophile for the halide and 3) reductive elimination of the new organic product.
- The Heck reaction follows a similar mechanism involves: 1) oxidative addition; 2) ligand substitution by the alkene; 3) migratory insertion; 4) ß-hydride elimination and 5) reductive elimination
Heck Coupling – Mechanism with specific example
Additional details
General Procedure-1 :
Bromo-aromatic ring (1 equiv.), methyl acrylate (5 equiv.), TEA (1.5 equiv.), catalyst Pd(OAc)2 (0.1 equiv.), and P(o-Tolyl)3 (0.1 equiv.) were mixed in acetonitrile (depends on the scale). The mixture was degassed and heated to reflux for 5 hours under nitrogen atmosphere. The resulting mixture was filtered with celite and the filtrate was concentrated. The resultant residue was purified by silica gel column to give rise to the desired compound.
Note:
- The reaction conditions tolerate a wide range of functional groups on the olefin (Esters, ethers, carboxylic acids, nitriles, phenols, dienes are well tolerated on the olefin component. However, allylic alcohols tend to undergo rearrangement)
- Heck Coupling is stereospecific. Both the migratory insertion and the hydride elimination proceed with syn stereochemistry.
- Aryl chlorides are not good substrates, as they tend to react slowly, resulting in lower yields.
- Substrates with beta-hydrogen atoms undergoes beta-elimination, leading to olefin formation
- When the olefin substrate is more substituted, the reaction proceeds slower
For more details, refer to the tab “Reaction, Reagents & Mechanism”
Typical Procedure:
WO2010045258, page no. 92
Green Chem
Swern oxidation could be carried out on large-scale. However, the reaction involves the liberation of 1 eq. each of the gases such as Me2S (dimethylsulphide), CO (carbon monoxide), CO2. Appropriate safety controls are to be ensured while performing manufacturing. During work-up, HCl gets converted to amine salt (such as NEt3.HCl).
- Swern Oxidation is one of the inexpensive methods to manufacture aldehydes or ketones from Alcohols
- The liberation of gases viz., malodrous dimethylsulphide (Me2S), poisonous carbon monoxide (CO) and CO2 are to be handled appropriately
- It is important to maintain the reaction mixture at -78 oC. If the temperature is not maintained, there is a possibility of formation of mixed thioacetals (see mechanism in General Info section)
Scale-Up Typical Procedure:
- An Improved and Efficient Process for the Production of Donepezil Hydrochloride (OPRD, 2008) – 4 Kg batch; 3.5 Kg of DMSO & 3.7 Kg of (COCl)2 have been used
- Convergent Catalytic Asymmetric Synthesis of Camptothecin Analog GI147211C (Tetrahedron, 1997) – 100 g batch
Green Chemistry Aspects: