Lithiation and Organolithium Reactions

Lithiation refers to the process by which a lithium atom replaces a hydrogen atom in an organic molecule. The resultant molecule is described as an organolithium compound. The C-Li bond is highly polarized, the carbon atom is electron rich, and therefore organolithium compounds are strongly basic and nucleophilic. As a result, lithiations and organolithium reactions are among the most important in organic synthesis and are useful in the synthesis of complex molecules (e.g. building C-C bonds). 

Organolithium reagents are used for lithium-halogen exchange, ortho metalation and to produce other nucleophilic organometallics, such as boron reagents. Organolithium reagents are themselves produced for example, by halogen-metal exchange, lithiation of organic halides or deprotonation of alkyl or aryl molecules. 

Organolithium compounds have a range of reactivity, but all are water- and oxygen-sensitive and in some cases, such as t-butyl lithium, are pyrophoric. The structures of organolithium reagents are quite variable, and the relationship of the structure to both reactivity and mechanism in reactions is highly dependent on the specific organolithium reagent and such variables as the solvent and temperature. As they belong to classes of compounds that are considered electron deficient, orgnaolithium compounds typically form aggregates and polymers in solution.

As an example, lithium diisopropylamide (LDA) is a commonly used reagent with a structure that is dependent on solvent and temperature. It is highly polar and forms aggregates that are structurally dependent on the type of solution. LDA is a solvated dimer in tetrahydrofuran but in non-polar solvents it forms temperature dependent oligomers (i.e. trimers, tetramers, pentamers, etc.). As another example, t-butyllithium exists as a tetramer with a cubane-like structure.

Due to the sensitive nature of organolithium reagents (air-, moisture- and/or temperature-sensitive), characterizing reactions involving this type of reagents is difficult by offline analysis methods. Real-time, in-situ FTIR spectroscopy provides a direct method to track and monitor the reaction mechanics (initiation, intermediate, endpoint and overall reaction kinetics), while maintaining a closed reactor environment and at temperature. 

Organolithium reagents (RLi) are generally strong bases that are capable of deprotonating most hydrocarbon compounds. In this role, they are more reactive than lithium amides or Grignard reagents. As a result of their extraordinary basicity, they are among the most important reagents and widely used in both organic and inorganic syntheses. Organolithium reagents readily deprotonate weak acids such as aldehydes, ketones, esters alcohols, amines, aromatic and aliphatic hydrocarbons. N-butyllithium is commonly used to initiate elastomer polymerization. When forming a bond with a carbon atom, organolithium reagents act as nucleophiles. For example, the reaction of organolithium reagents with the electrophilic carbonyl groups in aldehydes and ketones result in the formation of C-C bonds. Certain organolithium complexes are excellent at directing substitution to synthesize compounds that are regioselective, diastereoselective and enantioselective.

As an example, with respect to reactivity, as aliphatic hydrocarbon substitution increases, acidity decreases and therefore tert-butyllithium is a far stronger base than methyllithium. For these commonly used organolithium reagents, basicity is as follows: phenyllithium < methyllithium < n-butyllithium < s-butyllithium < t-butyllithium. The basicity of alkyllithium compounds are influenced by other molecules present. For example, whereas n-butyllithium is not basic enough to deprotonate aromatic compounds, the addition of tetramethylethylenediamine (TMEDA) increases its basicity to form lithiated arenes.

Lithium metal is a strong reducing agent and reacts with organic halides to form the simple, yet widely used alkyllithium compounds such as n-butyllithium.

In the case where the lithiation reaction is too slow or not selective, lithium – metal exchange reactions are employed. These transmetallations occur rapidly and are carried out at low temperatures since often less stable organolithium reagents are produced. These exchange reactions are particularly effective in synthesis of aryl lithium compounds.

If the substrate compound has an acidic hydrogen, lithiation is an effective means to create an organolithium reagent. Essentially, this is an acid-base type reaction. A broad range of functionalized organolithium reagents can be synthesized via lithiation, using n-BuLi or the alkyl lithiums with higher basicity, s-BuLi and t-BuLi. 

Researchers at Cornell University* first demonstrated the use of ReactIR for lithiation by investigating LDA-mediated ester-enolization reactions. Because organolithium reactions are often run at low temperatures and are air- and moisture-sensitive, in-situ FTIR measurements via ReactIR have proven particularly valuable for studying this important class of reactions. Over the past two decades, numerous articles have appeared chronicling the use of this technology for investigating lithiations and other organolithium reactions.

Low temperature chemical reactors allow performing reactions at temperatures as low as -90°C. EasyMax LT enables automated and unattended control of reaction variables for low temperature organolithium chemistry. The combination of ReactIR and EasyMax LT provide an exceptionally valuable chemistry workstation for investigating organolithium and other sub-ambient temperature reactions. 

*Sun, X., Kenkre, S., Remenar, J., Gilchrist, J., & Collum, D. (1997). Mechanism of Lithium Diisopropylamide-Mediated Ester Deprotonation:  The Role of Disolvated Monomers. J. Am. Chem. Soc., 119, 4765-4766.

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The highly reactive organolithium reactant creates an opportunity for synthetic chemists to design complex molecules. However, the outcome of these organometallic reactions is susceptible to reaction parameters that influence pathways, impacting yield and selectivity. Therefore, precise reaction parameter control is needed to drive synthetic reactions onto desired paths.

With precise temperature and parameter controls, the EasyMax LT workstation enables fully automated and unattended reactions. 

The ReactIR 702L is the first system that truly merges the power of real-time, in-situ FTIR with equivalent operational convenience. ReactIR is ready for every chemist and for every experiment.

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ReactIR 702L uses solid-state cooling technology to deliver best-in-class performance - without the need for liquid nitrogen. By eliminating hazardous setup and repetitive Dewar refills, scientists can easily monitor chemistry over extended periods.

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Small, stackable units save valuable space in the fume hood offers flexibility to deploy ReactIR in various locations across the lab. An “always on“ detector reduces set up time and enables scientists to start collecting data with confidence at a moment‘s notice.

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Probe- and flow-based sampling technologies enable scientists to study liquid and gas phase chemistry in batch or continuous setups. Fit-for-purpose materials of construction make data collection straightforward in acidic and corrosive environments across a wide range of temperatures and pressures.

Dunn, A. L., Leitch, D. C., Journet, M., Martin, M., Tabet, E. A., Curtis, N. R., Williams, G., Goss, C., Shaw, T., O’Hare, B., Wade, C., Toczko, M. A., & Liu, P. (2018). Selective Continuous Flow Iodination Guided by Direct Spectroscopic Observation of Equilibrating Aryl Lithium Regioisomers. Organometallics, 38(1), 129–137.

Researchers developed a selective lithiation/iodination process for the development of an intermediate compound. Due to the requirement for careful control of reaction variables, continuous flow chemistry was used for the C-H metalation. They found that though phenyl lithium gave satisfactory yields of the 3-iodo product in screening experiments, upon scale-up, an unwanted by-product and reduced yield of the product resulted. For this reason, they used LDA as the lithiating agent, which led to the formation of two regioisomeric ArLi species. The ability to track the interconversion of these two isomers via ReactIR enabled the identification of the optimum set of reaction variables to ensure the formation of the thermodynamically preferred 3-Li species. These insights enabled the development of a highly selective and efficient larger scale process. 

Rao, K. S., St-Jean, F., & Kumar, A. (2019). Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation Using Inline IR Spectroscopy and Modeling. Organic Process Research & Development, 23(5), 945–951.

Researchers report using ReactIR to investigate the synthesis of a tetrasubstituted acyclic olefin by way of ketone enolization and tosylation. One of the variables that affected the amount of a minor, undesirable isomer that formed was the base used in the enolization process. The bases investigated included lithium tert-butoxide, and the relationship of the rate of formation of the enolate intermediate to the tosylate product was characterized.

To quantitate consumption of the ketone during enolization, univariate modeling based on tracking the loss of the ketone carbonyl peak was employed. Via PLS modeling of the ReactIR data and offline HPLC measurements, the minor stereoisomer in a mixture of tetrasubstituted vinyl sulfonate stereoisomers could be quantified. This method formed the basis for analyzing further reactions in order to determine the amount of this isomer as a function of varying reaction conditions.