The Grignard reagent is one of the most widely used reagents in organic synthesis. It was discovered by French chemist Victor Grignard in 1901, for which he won the 1912 Nobel Prize in Chemistry. Halide reacts with metal magnesium in anhydrous ether or tetrahydrofuran to generate alkyl magnesium halide RMgX. This organic magnesium compound is called a Grignard reagent. As a nucleophile, Grignard reagents can undergo addition reactions with compounds such as aldehydes, ketones, and carboxylic acids. This type of reaction is called a Grignard reaction. Once the Grignard reagent was discovered, this reaction became a very important method of C-C bond formation.
Preparation of Reagents
To react with haloalkane, directly use magnesium shavings (not magnesium powder, because the reaction is too violent and the surface of magnesium powder easily forms an oxide film). Active haloalkanes can be initiated by direct heating, and less active haloalkanes can be initiated by adding a small amount of iodine or 1,2-dibromoethane. If the reaction solution is cloudy and the temperature rises, the reaction has started. If the above phenomenon does not occur, it is necessary to continue adding a little initiator, which can be slightly heated, and the temperature should not be too high. After the reaction has started, the heating should be stopped because the reaction is exothermic. After initiation, the temperature will be higher, and coupling (Wurtz Reaction) will easily occur, so the temperature should be lowered.
In general, when halogenated compounds are not very active, they can also be prepared by exchange of highly active format reagents.
In the process of preparing the Grignard reagent, anhydrous is the most important reaction condition, otherwise, the resulting Grignard reagent will be hydrolyzed and inactivated. So anhydrous solvent should be used, and the reaction system should be protected by inert gas. Attention should also be paid to the use of magnesium. Pure magnesium strips or magnesium scraps are generally used to reduce the occurrence of side reactions, and low-purity magnesium will reduce the yield of Grignard reagents. Magnesium strips placed for a long time should first remove the oxide film on the surface with dilute hydrochloric acid and then wash with ethanol and ether before drying. The dosage is generally 5%~10% in excess. Grignard reagents can also react with oxygen and CO2, so they should also be avoided.
Common Side Reactions in Grignard Reactions
- When preparing Grignard reagents, the generated reagents will undergo a Wurtz reaction with halides for coupling (slow down the speed of adding halides, and control the temperature not to be too high);
- When the anhydrous and oxygen-free conditions are not strict in the Grignard reaction, it will react with water to form alkanes, and react with oxygen to form alkoxides;
- When the carbonyl compound contains α-H, the substrate will undergo enolization;
- When the Grignard reagent containing β-H reacts with a carbonyl compound with a large steric hindrance, intermolecular hydrogen transfer may occur to reduce the carbonyl compound.
Reaction Mechanism
In the reaction solution, the Grignard reagent does not exist alone in the form of RMgX but is a mixture of various substances such as R: Mg, MgX, (RMgx)n, etc., and each substance exists in a dynamic equilibrium in the solution. Usually, most Grignard reagents exist in the form of tetrahedral and triangular bipyramidal molecular junctions in solvents.
The preparation mechanism of the Grignard reagent is realized by a single electron transfer (SET) process, and the reaction is realized on the surface of magnesium metal. The reaction between Grignard reagents and carbonyl compounds may be realized through two mechanisms: the cooperative reaction mechanism and the free radical single electron transfer mechanism. The reaction between substrates with low electron nucleophilicity and Grignard reagents is usually carried out by a cooperative reaction mechanism through a ring transition state. Substrates with a large steric hindrance and large steric Grignard reagents are more inclined to carry out the free radical mechanism, and the Grignard reagents carry out electron transfer to the substrate to initiate the reaction.
