12.2 Organolithium compounds

Organolithium compounds are powerful tools in organic synthesis, featuring a unique carbon-lithium bond with both ionic and covalent character. These versatile reagents play crucial roles in various chemical transformations, from simple additions to complex total syntheses.

Understanding organolithium compounds is essential for mastering organic reactions. Their high reactivity as strong bases and nucleophiles, combined with their ability to form new carbon-carbon bonds, makes them invaluable in creating complex molecular structures and pharmaceutical intermediates.

Structure of organolithium compounds

• Organolithium compounds play a crucial role in organic synthesis due to their unique reactivity and versatility
• These compounds consist of a carbon-lithium bond, which exhibits both ionic and covalent character
• Understanding the structure of organolithium compounds provides insights into their behavior in various chemical reactions

Bonding in organolithium compounds

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• Carbon-lithium bond exhibits partial ionic and partial covalent character
• Electronegativity difference between carbon and lithium contributes to bond polarity
• Electron-deficient nature of lithium leads to aggregation in solution and solid state
• Aggregates form clusters (dimers, tetramers, hexamers) depending on solvent and temperature

Types of organolithium reagents

• Alkyllithium compounds (methyllithium, butyllithium, tert-butyllithium)
• Aryllithium compounds (phenyllithium, 2-lithiopyridine)
• Vinyllithium and allyllithium reagents
• Lithium enolates and lithium acetylides

Physical properties

• Generally colorless or pale yellow liquids or solids
• Highly reactive towards air and moisture
• Low melting points compared to inorganic lithium compounds
• Soluble in non-polar organic solvents (hexane, diethyl ether, THF)
• Aggregation state affects reactivity and solubility

Preparation methods

• Organolithium compounds can be synthesized through various methods in organic chemistry
• These preparation techniques allow for the creation of diverse organolithium reagents
• Understanding different synthetic routes enables chemists to choose the most suitable method for specific applications

From alkyl halides

• Direct reaction of lithium metal with alkyl halides (Wurtz-type coupling)
• Halogen-lithium exchange using another organolithium reagent
• Transmetalation reactions with organomercury or organotin compounds
• Factors affecting reaction rate include halide type (I > Br > Cl) and alkyl group structure

From alkenes

• Hydrolithiation of alkenes using lithium metal and a proton source
• Carbolithiation reactions involving addition of organolithium to alkenes
• Regioselectivity influenced by alkene substitution pattern and reaction conditions

From alkynes

• Deprotonation of terminal alkynes using strong lithium bases (LDA, n-BuLi)
• Hydrolithiation of alkynes to form vinyllithium compounds
• Carbolithiation of alkynes to generate substituted vinyllithium reagents

From other organometallic compounds

• Transmetalation reactions with Grignard reagents (RMgX + Li → RLi + MgX)
• Lithium-tin exchange using organostannanes
• Lithium-boron exchange using organoboranes
• Metal-halogen exchange with organomercury compounds

Reactivity and applications

• Organolithium compounds exhibit high reactivity due to their strong basicity and nucleophilicity
• These reagents participate in various organic transformations, making them valuable synthetic tools
• Understanding their reactivity patterns allows for strategic use in complex molecule synthesis

As strong bases

• Deprotonation of weakly acidic compounds (pKa up to ~35)
• Generation of enolates from ketones and esters
• Formation of lithium acetylides from terminal alkynes
• Ortho-lithiation of aromatic compounds with directing groups

As nucleophiles

• Addition to carbonyl compounds (aldehydes, ketones, esters)
• Nucleophilic aromatic substitution reactions
• 1,2-addition to α,β-unsaturated carbonyl compounds
• Michael additions to electron-deficient alkenes

In carbon-carbon bond formation

• Alkylation of carbonyl compounds and their derivatives
• Coupling reactions with organic halides
• Addition to imines and nitriles
• Carboxylation reactions using CO2 to form carboxylic acids

In synthesis of alcohols

• Addition to aldehydes and ketones to form primary and secondary alcohols
• Reduction of esters to form primary alcohols
• Ring-opening reactions of epoxides
• Stereoselective additions to chiral carbonyl compounds

Reactions with carbonyl compounds

• Organolithium reagents readily react with various carbonyl compounds
• These reactions form the basis for many important synthetic transformations
• Understanding the mechanisms and outcomes of these reactions is crucial for organic synthesis

Additions to aldehydes

• Nucleophilic addition forms lithium alkoxides
• Subsequent hydrolysis yields secondary alcohols
• Stereochemistry determined by approach of organolithium reagent
• Chelation-controlled additions with α-heteroatom-substituted aldehydes

Additions to ketones

• Formation of tertiary alcohols upon hydrolysis
• Steric hindrance affects reaction rate and yield
• Enantioselective additions using chiral ligands or auxiliaries
• Reduction of ketones to secondary alcohols using LiAlH4

Reactions with esters

• Double addition to form tertiary alcohols
• Single addition followed by elimination to yield ketones
• Weinreb amides as alternatives for controlled single additions
• Transesterification reactions in the presence of alcohols

Reactions with carboxylic acids

• Initial deprotonation followed by nucleophilic addition
• Formation of ketones upon workup
• Competing enolization reactions with α-hydrogen-containing carboxylic acids
• Use of lithium di-tert-butylcuprate for improved yields

Reactions with other functional groups

• Organolithium compounds react with various functional groups beyond carbonyls
• These reactions expand the synthetic utility of organolithium reagents
• Understanding these transformations allows for diverse bond-forming strategies

With epoxides

• Nucleophilic ring-opening reactions
• Regioselectivity influenced by substitution pattern and reaction conditions
• Formation of β-lithio alcohols as reactive intermediates
• Stereospecific additions in chiral epoxides

With nitriles

• Addition to form imine intermediates
• Hydrolysis of imines to yield ketones
• Formation of tertiary amines upon reduction of imine intermediates
• Use in the synthesis of α,α-disubstituted aldehydes and ketones

With alkyl halides

• Halogen-metal exchange reactions
• Formation of new carbon-carbon bonds via coupling
• Generation of Wurtz-type coupling products as side reactions
• Chemoselectivity issues with polyhalogenated compounds

Synthetic utility

• Organolithium compounds serve as versatile reagents in organic synthesis
• Their applications span from small-molecule synthesis to industrial-scale production
• Understanding their synthetic utility enables efficient planning of complex synthetic routes

In total synthesis

• Key steps in natural product synthesis
• Generation of complex molecular frameworks
• Stereoselective transformations using chiral organolithium reagents
• Construction of challenging quaternary carbon centers

In pharmaceutical production

• Synthesis of drug precursors and intermediates
• Large-scale preparation of active pharmaceutical ingredients (APIs)
• Development of new synthetic routes for improved efficiency
• Use in the production of chiral drug molecules

In polymer chemistry

• Initiation of anionic polymerization reactions
• Synthesis of functionalized monomers
• Preparation of block copolymers and other specialized polymers
• End-group modification of polymers

Handling and safety considerations

• Organolithium compounds require special handling due to their high reactivity
• Proper safety measures are essential when working with these reagents
• Understanding the potential hazards and precautions ensures safe laboratory practices

Air and moisture sensitivity

• Rapid decomposition upon exposure to air or moisture
• Formation of flammable and corrosive byproducts (lithium hydroxide, alkanes)
• Use of inert atmosphere techniques (Schlenk lines, glove boxes)
• Proper sealing and storage of organolithium solutions

Storage and disposal

• Storage in sealed containers under inert gas atmosphere
• Use of moisture-free, low-temperature conditions for long-term storage
• Proper labeling and segregation from incompatible chemicals
• Controlled quenching and neutralization before disposal

Protective equipment

• Use of personal protective equipment (PPE) (goggles, gloves, lab coat)
• Face shields for additional protection when handling large quantities
• Proper fume hood ventilation during reactions and transfers
• Fire extinguishers and safety showers readily accessible

Spectroscopic characterization

• Spectroscopic techniques play a crucial role in analyzing organolithium compounds
• These methods provide valuable information about structure and purity
• Understanding spectroscopic data aids in reaction monitoring and product identification

NMR spectroscopy

• 7Li NMR for direct observation of lithium species
• 13C NMR shows characteristic shifts for carbon-lithium bonds
• Dynamic NMR studies reveal aggregation states in solution
• 1H NMR used to monitor reaction progress and product formation

IR spectroscopy

• Characteristic C-Li stretching frequencies in the far-IR region
• Identification of functional groups in organolithium compounds
• Monitoring of reaction progress through disappearance of starting material bands
• Detection of impurities and byproducts

Mass spectrometry

• Electron impact (EI) and chemical ionization (CI) techniques
• Fragmentation patterns provide structural information
• High-resolution mass spectrometry for accurate mass determination
• Coupling with gas chromatography (GC-MS) for mixture analysis

Organolithium compounds vs other organometallics

• Comparison of organolithium reagents with other organometallic compounds
• Understanding the relative reactivity and selectivity of different organometallics
• Choosing the most suitable reagent for specific synthetic applications

Grignard reagents vs organolithiums

• Organolithiums generally more reactive than Grignard reagents
• Grignard reagents more tolerant of certain functional groups
• Organolithiums form tighter ion pairs compared to Grignard reagents
• Different aggregation states affect reactivity and selectivity

Organozinc compounds vs organolithiums

• Organozinc compounds exhibit lower basicity and nucleophilicity
• Higher functional group tolerance of organozinc reagents
• Organolithiums more reactive in carbonyl addition reactions
• Organozinc compounds useful in transition metal-catalyzed cross-couplings

Advanced topics

• Exploration of cutting-edge applications of organolithium chemistry
• Development of new methodologies for asymmetric synthesis
• Understanding complex reaction mechanisms and stereochemical outcomes

Chiral organolithium compounds

• Synthesis and stability of configurationally stable chiral organolithiums
• Use of chiral ligands to control stereochemistry
• Dynamic kinetic resolution of racemic organolithium compounds
• Applications in asymmetric synthesis of natural products

Asymmetric synthesis applications

• Enantioselective additions to prochiral carbonyl compounds
• Stereoselective alkylation reactions using chiral auxiliaries
• Asymmetric deprotonation strategies
• Kinetic resolution of racemic substrates using chiral organolithium reagents

Catalytic use of organolithiums

• Lithium amide-catalyzed asymmetric Michael additions
• Enantioselective alkynylation reactions using substoichiometric lithium acetylides
• Catalytic asymmetric carbolithiation reactions
• Development of new chiral ligands for catalytic applications