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Organic Chemistry
Table of Contents
Unit 10 Overview: Organohalides
10.1 Names and Structures of Alkyl Halides
10.2 Preparing Alkyl Halides from Alkanes: Radical Halogenation
10.3 Preparing Alkyl Halides from Alkenes: Allylic Bromination
10.4 Stability of the Allyl Radical: Resonance Revisited
10.5 Preparing Alkyl Halides from Alcohols
10.6 Reactions of Alkyl Halides: Grignard Reagents
10.7 Organometallic Coupling Reactions
10.8 Oxidation and Reduction in Organic Chemistry

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10.6 Reactions of Alkyl Halides: Grignard Reagents

Citation:

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

  • 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
  • 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

Key Terms to Review (29)

Organometallic: Organometallic compounds are chemical compounds that contain at least one bond between a carbon atom of an organic molecule and a metal, including alkaline, alkaline earth, and transition metals. These compounds play a crucial role in the field of organic chemistry, especially in reactions involving the formation of new carbon-carbon bonds.
Organometallic compound: An organometallic compound is a substance that contains a bond between a carbon atom of an organic molecule and a metal. These compounds are critical in various chemical reactions, including those used to form new carbon-carbon bonds.
Grignard reagent (RMgX): A Grignard reagent is an organomagnesium compound formed by reacting an alkyl halide with magnesium metal in dry ether. It is a powerful nucleophile and base that is widely used in the formation of carbon-carbon bonds in organic synthesis.
Carbanion: A carbanion is an ion that contains a carbon atom with a negative charge due to an extra pair of electrons. It acts as a nucleophile in organic reactions, readily forming bonds with electrophiles.
Carbonyl: The carbonyl group is a functional group consisting of a carbon atom double-bonded to an oxygen atom. It is a key structural feature in many organic compounds, including aldehydes, ketones, carboxylic acids, and esters, and plays a crucial role in their chemical reactivity and properties.
Carbanions: A carbanion is a negatively charged carbon atom with three bonds and a lone pair of electrons. These reactive intermediates play a crucial role in various organic chemistry reactions and concepts, including formal charges, reaction intermediates, alkyne acidity, and Grignard reagents.
Nucleophilic: A nucleophile is a species that donates an electron pair to form a new covalent bond. Nucleophilicity is a key concept in organic chemistry, as it governs the reactivity of many important chemical reactions, including those discussed in the topics of formal charges, Grignard reagents, and substituent effects on acidity.
PKa: pKa, or the acid dissociation constant, is a measure of the strength of an acid in a solution. It represents the pH at which a particular acid is 50% dissociated into its conjugate base. This value is crucial in understanding the behavior and properties of acids, bases, and their reactions in organic chemistry.
Electrophile: An electrophile is a species that is attracted to electron-rich regions and seeks to form new bonds by accepting electron density. Electrophiles play a crucial role in many organic reactions, including polar reactions, electrophilic aromatic substitution, and nucleophilic acyl substitution, among others.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Exothermic: Exothermic refers to a chemical reaction or process that releases energy in the form of heat to the surrounding environment. These reactions release more energy than they absorb, resulting in an overall decrease in the system's internal energy.
Alkyl Halides: Alkyl halides are organic compounds that consist of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). They are widely used in organic synthesis and have various applications in chemistry and biology.
Radical Anion: A radical anion is a species that contains an unpaired electron and a negative charge. These reactive intermediates are important in various organic chemistry reactions, including the reduction of alkynes and the formation of Grignard reagents.
Grignard Reagents: Grignard reagents are a class of highly reactive organometallic compounds that are widely used in organic synthesis. They are formed by the reaction of an alkyl or aryl halide with magnesium metal and play a crucial role in various organic transformations.
Magnesium Salts: Magnesium salts are a class of ionic compounds formed by the combination of magnesium ions (Mg2+) and various anions. They are important in the context of the reactions of alkyl halides, particularly in the formation of Grignard reagents.
Magnesium Amide: Magnesium amide is a chemical compound consisting of a magnesium cation and one or more amide anions. It is an important reagent in organic chemistry, particularly in the context of the Grignard reaction, where it is used to form new carbon-carbon bonds.
Alkynyl Grignard Reagents: Alkynyl Grignard reagents are organometallic compounds formed by the reaction of alkynyl halides with magnesium. They are useful in organic synthesis for the introduction of alkynyl groups into various molecules.
Addition Products: Addition products are the result of a chemical reaction where two or more reactants combine to form a single product. This is a key concept in the context of reactions involving Grignard reagents, which are an important class of organometallic compounds used in organic synthesis.
Oxidative Addition: Oxidative addition is a fundamental organometallic reaction in which a metal complex adds an atom or molecule across a covalent bond, resulting in the metal center increasing its oxidation state and coordination number. This process is crucial in understanding the reactivity of alkyl halides, organometallic coupling reactions, and the reactions of arylamines.
Schlenk Equilibrium: The Schlenk equilibrium is a dynamic equilibrium that occurs between organometallic compounds, particularly Grignard reagents, and their dimerized or aggregated forms. This equilibrium is crucial in understanding the reactivity and stability of these important synthetic intermediates.
THF: THF, or tetrahydrofuran, is a cyclic ether compound that is commonly used as a solvent and in various organic chemistry reactions. It is a versatile and widely-used chemical that plays a crucial role in several important topics in organic chemistry.
Magnesium Hydroxide: Magnesium hydroxide is an inorganic compound with the chemical formula Mg(OH)2. It is a white, odorless, and slightly basic compound that is commonly used in various applications, including as an antacid, laxative, and in the production of Grignard reagents.
Alkoxide: An alkoxide is a functional group consisting of an alkyl group (R-) bonded to an oxygen atom (O-). Alkoxides are important intermediates in many organic chemistry reactions, including Grignard reactions, elimination reactions, and carbonyl condensation reactions.
Organometallic Compounds: Organometallic compounds are a class of chemical compounds containing at least one covalent bond between a carbon atom and a metal atom. These compounds exhibit unique properties and reactivity patterns, making them valuable in various applications, including organic synthesis, catalysis, and materials science.
Wurtz Reaction: The Wurtz reaction is a method for the synthesis of alkanes from alkyl halides and metallic sodium. It involves the coupling of two alkyl halides to form a higher alkane, facilitated by the reactive sodium metal.
Anhydrous Conditions: Anhydrous conditions refer to the absence of water or moisture in a chemical reaction or process. This term is particularly important in the context of certain organic chemistry reactions where the presence of water can interfere with the desired outcome.
Diethyl Ether: Diethyl ether is a colorless, highly volatile, and flammable liquid ether that has been widely used as an anesthetic, as a solvent, and in various organic chemistry reactions. It is an important compound that is closely tied to several key topics in organic chemistry.
Transmetalation: Transmetalation is a type of ligand exchange reaction in organometallic chemistry where a metal center is substituted with a different metal. This process is particularly important in the context of Grignard reagents and organometallic coupling reactions, as it allows for the transfer of organic groups between different metal species.
Carbon-Magnesium Bond: The carbon-magnesium bond is a covalent bond formed between a carbon atom and a magnesium atom. This bond is a crucial component in the formation of Grignard reagents, which are important organometallic compounds used in organic synthesis.