17.5 Alcohols from Carbonyl Compounds: Grignard Reaction

Grignard reactions are powerful tools for making alcohols from carbonyl compounds. They involve forming a carbon-magnesium bond, then adding it to a carbonyl group. This process creates new carbon-carbon bonds, turning simple molecules into more complex ones.

These reactions work with different carbonyl compounds, producing various alcohols. However, they're sensitive to moisture and don't play well with certain functional groups. Understanding their limitations is key to using them effectively in organic synthesis.

Grignard Reaction: Synthesis of Alcohols from Carbonyl Compounds

Mechanism of Grignard reactions

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• Grignard reagent formation:
  • Alkyl or aryl halide (methyl bromide) reacts with magnesium metal in anhydrous ether solvent (diethyl ether)
  • Electron transfer from Mg to the halide forms a carbon-magnesium bond (CH3-MgBr)
• Nucleophilic addition:
  • The nucleophilic carbon of the Grignard reagent attacks the electrophilic carbonyl carbon (acetone)
  • The carbonyl oxygen forms a bond with the magnesium, creating a tetrahedral alkoxide intermediate
• Protonation:
  • An aqueous acid workup (HCl) protonates the alkoxide intermediate
  • The carbon-magnesium and oxygen-magnesium bonds are cleaved, forming the final alcohol product (2-propanol)

Products of Grignard-carbonyl reactions

• Aldehydes (propanal):
  • Yield primary alcohols (1-propanol)
  • The Grignard reagent (ethylmagnesium bromide) adds a single alkyl or aryl group to the carbonyl carbon
• Ketones (cyclohexanone):
  • Yield tertiary alcohols (1-phenyl-1-cyclohexanol)
  • The Grignard reagent (phenylmagnesium bromide) adds a single alkyl or aryl group to the carbonyl carbon
• Esters (methyl benzoate):
  • Yield tertiary alcohols (triphenylmethanol)
  • Two equivalents of the Grignard reagent (phenylmagnesium bromide) are required
  • The first equivalent adds to the carbonyl carbon, and the second equivalent displaces the alkoxide group (CH3O-)
• Carbon dioxide:
  • Yields carboxylic acids (benzoic acid)
  • The Grignard reagent (phenylmagnesium bromide) adds to the carbon atom of CO2, forming a magnesium carboxylate intermediate
  • Aqueous acid workup (HCl) protonates the carboxylate, yielding the carboxylic acid

Limitations of Grignard reagents

• Moisture sensitivity:
  • Grignard reagents are highly reactive towards water and moisture
  • Anhydrous conditions and dry, oxygen-free solvents (diethyl ether, THF) are essential to prevent decomposition
• Functional group compatibility:
  • Grignard reagents are incompatible with acidic protons (alcohols, amines, carboxylic acids)
  • These functional groups must be protected (silyl ethers, esters) or avoided in the substrate
  • Grignard reagents also react with other electrophiles, such as nitriles and epoxides, limiting their selectivity
• Halide reactivity:
  • The reactivity of the alkyl or aryl halide decreases in the order: RI > RBr > RCl
  • Alkyl iodides and bromides (ethyl bromide) are preferred for Grignard reagent formation
  • Aryl chlorides and vinyl halides may require activation (metal catalysts, ultrasound) for Grignard formation
• Steric hindrance:
  • Bulky Grignard reagents (t-BuMgX) may exhibit reduced reactivity due to steric hindrance around the magnesium atom
  • The carbonyl substrate (2,2-dimethylpropanal) may also experience steric effects, slowing down the addition reaction

Organometallic Compounds and Reaction Characteristics

• Grignard reagents are organometallic compounds, containing a carbon-metal bond
• They act as nucleophiles in reactions with carbonyl compounds (electrophiles)
• The Grignard reaction is an addition reaction, forming a new carbon-carbon bond
• Stereochemistry of the product depends on the structure of the reactants and reaction conditions