10.6 Reactions of Alkyl Halides: Grignard Reagents

Grignard reagents are powerful tools in organic synthesis, formed by reacting alkyl or aryl halides with magnesium. These compounds have a highly polar carbon-magnesium bond, making them strong nucleophiles and bases.

The reactivity of Grignard reagents depends on their structure and the compounds they encounter. They readily attack electrophilic centers and deprotonate acidic hydrogens, allowing for the formation of new carbon-carbon bonds and various functional group transformations.

Formation and Reactivity of Grignard Reagents

Formation of Grignard reagents

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• Grignard reagents have the general formula $RMgX$ ($R$ = alkyl or aryl group, $X$ = halogen like Cl, Br, I)
• Formed by reacting an alkyl or aryl halide with magnesium metal in anhydrous ether solvents (diethyl ether, THF)
  • Halide acts as an electrophile, magnesium as a nucleophile undergoing oxidative addition
  • Forms a new carbon-magnesium bond ($R-MgX$) and a radical anion intermediate
  • Radical anion reacts with another equivalent of halide forming the Grignard reagent and magnesium dihalide salt
• Reaction is highly exothermic requiring anhydrous conditions as Grignard reagents rapidly react with water and protic solvents
• Formation rate depends on halide reactivity: iodides react fastest, then bromides, chlorides; fluorides typically do not form Grignard reagents
• Carbon-magnesium bond is highly polar with carbon being nucleophilic and basic due to the electropositive magnesium

Properties of carbon-magnesium bonds

• Carbon-magnesium bond is highly polarized with carbon bearing a partial negative charge acting as a strong nucleophile and base
  • Due to the electropositive magnesium readily donating its electrons to the more electronegative carbon
• As nucleophiles, Grignard reagents attack electrophilic centers (carbonyl groups in aldehydes, ketones, esters) forming new carbon-carbon bonds
  • Nucleophilicity depends on steric and electronic properties of the $R$ group with less hindered, more electron-rich groups being more reactive
• As bases, Grignard reagents deprotonate acidic hydrogens (pKa < 25) forming new carbon-magnesium bonds
  • Includes terminal alkynes ($HC\equiv CR$) forming alkynyl Grignard reagents ($RC\equiv CMgX$)
  • Also heteroatom-hydrogen bonds in alcohols ($ROH$), amines ($R_2NH$), thiols ($RSH$) forming corresponding magnesium salts ($ROMgX$, $R_2NMgX$, $RSMgX$)

Reactivity of Grignard reagents

• As strong bases, Grignard reagents react with any compound containing an acidic hydrogen (pKa < 25)
• Relative acidity determines reactivity order, more acidic compounds react preferentially:
  1. Water and alcohols (pKa ~ 15-16) react rapidly and irreversibly forming magnesium hydroxide or alkoxide salts
  2. Amines (pKa ~ 25-30) and terminal alkynes (pKa ~ 25) react more slowly forming magnesium amide or alkynyl Grignard reagents
  3. Aldehydes and ketones (pKa ~ 20) react readily forming addition products, reaction is reversible so excess Grignard reagent often used
  4. Esters (pKa ~ 25) and nitriles (pKa ~ 25) react with Grignard reagents, but slower and may require heating
  5. Alkyl halides (pKa > 40) and ethers (pKa > 50) typically do not react under standard conditions
• With multiple reactive functional groups, most acidic group reacts first, then next most acidic, etc.
  • Example: compound with alcohol and ketone first forms magnesium alkoxide salt, then addition product with ketone

Organometallic Chemistry and Related Reactions

• Grignard reagents are a type of organometallic compound, featuring a carbon-metal bond
• The carbon atom in Grignard reagents can be considered a carbanion due to its high electron density
• Wurtz reaction: a coupling reaction between two alkyl halides using sodium metal, similar to Grignard formation but produces symmetrical alkanes
• Transmetalation: the transfer of an organic group from one metal to another, often used to modify Grignard reagents
• Schlenk equilibrium: the dynamic equilibrium between different species in Grignard reagent solutions, affecting their reactivity