From stoichiometry and rate law to mechanism

Lithiation of 1,4-bis(trifluoromethyl)benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C occurs under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. Under such nonequilibrium conditions, a substantial number of barriers compete to be rate limiting, making the reaction sensitive to trace impurities (LiCl), reactant concentrations, and isotopic substitution. Rate studies using the perdeuterated arene reveal odd effects of LiCl, including catalyzed rate acceleration at lower temperature and catalyzed rate inhibition at higher temperatures. The catalytic effects are accompanied by corresponding changes in the rate law. A kinetic model that captures the critical features of the LiCl catalysis focusing on the influence of LiCl-catalyzed reaggregation of the fleeting monomer that can reside above, at, or below the equilibrium population without catalyst.

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“…The results are interpreted in the context of the mechanism and rate law described by eqs 5–7. 18

- d [ArD] / d normalt = k_{1} k_{2} [ArD] [A_{2} S_{2}] [S] / (k_{- 1} + k_{2} [ArD])

- d [ArD] / d normalt = (k_{1} k_{2} / k_{- 1}) [ArD] [A_{2} S_{2}] [S]

A_{2} S_{2} ⇌_{k_{- 1}}^{k_{1} [S]} [A_{2} S_{3}] \overset{k_{2} [ArD]}{\to} ArLi

…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition

et al. 2015

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“…Without an understanding of solution structure, detailed mechanistic studies are not possible. 10,11,12 In the study described below, we characterize simple ketone enolates 1-3 coordinated by N,N,N',N'-tetramethylethylenediamine (TMEDA), tetrahydrofuran (THF), and 1,2-dimethoxyethane (DME). The strategy relies on the method of continuous variation in which ensembles of homo-and heteroaggregated enolates are monitored by 6 Li NMR spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Lithium Enolates of Simple Ketones: Structure Determination Using the Method of Continuous Variation

et al. 2008

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The method of continuous variation in conjunction with 6 Li NMR spectroscopy was used to characterize lithium enolates derived from 1-indanone, cyclohexanone, and cyclopentanone in solution. The strategy relies on forming ensembles of homo-and heteroaggregated enolates. The enolates form exclusively chelated dimers in N,N,N',N'-tetramethylethylenediamine and cubic tetramers in tetrahydrofuran and 1,2-dimethoxyethane.

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“…Dehydrobrominations of alkyl bromides proceed by mono-, di-and trisolvated monomers (14)(15)(16)(17)(18)(19) as well as triple ions (20). 5 The highly variable solvation numbers are unusual when compared with LDA-mediated reactions in standard ethereal solvents.…”

Section: Introductionmentioning

confidence: 99%

Lithium Diisopropylamide-Mediated Reactions of Imines, Unsaturated Esters, Epoxides, and Aryl Carbamates: Influence of Hexamethylphosphoramide and Ethereal Cosolvents on Reaction Mechanisms

Collum

2007

J. Am. Chem. Soc.

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Several reactions mediated by lithium diisopropylamide (LDA) with added hexamethylphosphoramide (HMPA) are described. The N-isopropylimine of cyclohex-anone lithiates via an ensemble of monomer-based pathways. Conjugate addition of LDA/HMPA to an unsaturated ester proceeds via di-and tetra-HMPA-solvated dimers. Deprotonation of norbornene epoxide by LDA/HMPA proceeds via an intermediate metalated epoxide as a mixed dimer with LDA. Ortholithiation of an aryl carbamate proceeds via a mono-HMPA-solvated monomer-based pathway. Dependencies on THF and other ethereal cosolvents suggest that secondary-shell solvation effects are important in some instances. The origins of the inordinate mechanistic complexity are discussed.

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From stoichiometry and rate law to mechanism

Cited by 61 publications

References 10 publications

Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition

Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition

Lithium Enolates of Simple Ketones: Structure Determination Using the Method of Continuous Variation

Lithium Diisopropylamide-Mediated Reactions of Imines, Unsaturated Esters, Epoxides, and Aryl Carbamates: Influence of Hexamethylphosphoramide and Ethereal Cosolvents on Reaction Mechanisms

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