Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

1,4-addition of lithium diisopropylamide to unsaturated esters: role of rate-limiting deaggregation, autocatalysis, lithium chloride catalysis, and other mixed aggregation effects.

ABSTRACT: Lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C undergoes 1,4-addition to an unsaturated ester via a rate-limiting deaggregation of LDA dimer followed by a post-rate-limiting reaction with the substrate. Muted autocatalysis is traced to a lithium enolate-mediated deaggregation of the LDA dimer and the intervention of LDA-lithium enolate mixed aggregates displaying higher reactivities than LDA. Striking accelerations are elicited by <1.0 mol % LiCl. Rate and mechanistic studies have revealed that the uncatalyzed and catalyzed pathways funnel through a common monosolvated-monomer-based intermediate. Four distinct classes of mixed aggregation effects are discussed.

SUBMITTER: Ma Y

PROVIDER: S-EPMC2989387 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

1,4-addition of lithium diisopropylamide to unsaturated esters: role of rate-limiting deaggregation, autocatalysis, lithium chloride catalysis, and other mixed aggregation effects.

Ma Yun Y Hoepker Alexander C AC Gupta Lekha L Faggin Marc F MF Collum David B DB

Journal of the American Chemical Society 20101101 44

Lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C undergoes 1,4-addition to an unsaturated ester via a rate-limiting deaggregation of LDA dimer followed by a post-rate-limiting reaction with the substrate. Muted autocatalysis is traced to a lithium enolate-mediated deaggregation of the LDA dimer and the intervention of LDA-lithium enolate mixed aggregates displaying higher reactivities than LDA. Striking accelerations are elicited by <1.0 mol % LiCl. Rate and mechanistic studies have r ...[more]

PMID: 20961095

Similar Datasets

Lithium diisopropylamide-mediated ortholithiations: lithium chloride catalysis.

Project description:Ortholithiations of a range of arenes mediated by lithium diisopropylamide (LDA) in THF at -78 degrees C reveal substantial accelerations by as little as 0.5 mol % of LiCl (relative to LDA). Substrate dependencies suggest a specific range of reactivity within which the LiCl catalysis is optimal. Standard protocols with unpurified commercial samples of n-butyllithium to prepare LDA or commercially available LDA show marked batch-dependent rates--up to 100-fold--that could prove significant to the unwary practitioner. Other lithium salts elicit more modest accelerations. The mechanism is not discussed.

| S-EPMC2765536 | biostudies-literature

Regioselective lithium diisopropylamide-mediated ortholithiation of 1-chloro-3-(trifluoromethyl)benzene: role of autocatalysis, lithium chloride catalysis, and reversibility.

Project description:Ortholithiation of 1-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C displays characteristics of reactions in which aggregation events are rate limiting. Metalation with lithium-chloride-free LDA involves a rate-limiting deaggregation via dimer-based transition structures. The post-rate-limiting proton transfers are suggested to involve highly solvated triple ions. Autocatalysis by the resulting aryllithiums or catalysis by traces (<100 ppm) of LiCl diverts the reaction through di- and trisolvated monomer-based pathways for metalation at the 2 and 6 positions, respectively. The regiochemistry is dictated by a combination of kinetically controlled metalations overlaid by an equilibration involving diisopropylamine that is shown to occur by the microscopic reverse of the monomer-based metalations.

| S-EPMC3102585 | biostudies-literature

Autocatalysis in lithium diisopropylamide-mediated ortholithiations.

Project description:Ortholithiation of 3-fluorophenyl-N,N-diisopropyl carbamate by lithium diisopropylamide (LDA) in THF at -78 degrees C affords unusual rate behavior including linear decays of the carbamate, delayed formation of LDA-aryllithium mixed dimers, and evidence of autocatalysis. A mechanistic model in conjunction with numeric integration methods accounts for the time-dependent changes in concentration. The two critical rate-limiting steps in the model entail (1) an LDA dimer-based metalation of arylcarbamate, and (2) a rate-limiting condensation of the resulting aryllithium with the LDA dimer to form two isomeric LDA-ArLi mixed dimers. One isomer elicits a highly efficient (post-rate-limiting) metalation of aryl carbamate, in turn, regenerating aryllithium. The prevalence and implications of such autocatalysis are discussed.

| S-EPMC2643095 | biostudies-literature

Lithium diisopropylamide-mediated ortholithiation of 2-fluoropyridines: rates, mechanisms, and the role of autocatalysis.

Project description:Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at -78 °C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Autocatalysis stems from ArLi-catalyzed deaggregation of LDA proceeding via 2:2 LDA-ArLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from LiCl-catalyzed LDA dimer-monomer exchange and a subsequent monomer-based ortholithiation. Fleeting 2:2 LDA-LiCl mixed tetramers are suggested to be key intermediates. The mechanisms of both the uncatalyzed and catalyzed deaggregations are discussed. A general mechanistic paradigm is delineated to explain a number of seemingly disparate LDA-mediated reactions, all of which occur in tetrahydrofuran at -78 °C.

| S-EPMC3644364 | biostudies-literature

Lithium diisopropylamide-mediated reactions of imines, unsaturated esters, epoxides, and aryl carbamates: influence of hexamethylphosphoramide and ethereal cosolvents on reaction mechanisms.

Project description:Several reactions mediated by lithium diisopropylamide (LDA) with added hexamethylphosphoramide (HMPA) are described. The N-isopropylimine of cyclohexanone 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.

| S-EPMC2823296 | biostudies-literature

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

Project description:Lithiation of 1,4-bis(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran at -78 °C occurs under conditions at 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 is presented that captures the critical features of the LiCl catalysis, focusing on the influence of LiCl-catalyzed re-aggregation of the fleeting monomer that can reside above, at, or below the equilibrium population without catalyst.

| S-EPMC4788392 | biostudies-literature

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones.

Project description:The organocatalytic Michael addition of malonates to symmetric unsaturated 1,4-diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C-C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and calculated VCD spectra of the reaction product 3a.

| S-EPMC3458770 | biostudies-literature

Computational studies of lithium diisopropylamide deaggregation.

Project description:Density functional theory computations [MP2/6-31G(d)//B3LYP/6-31G(d)] on the deaggregation of lithium diisopropylamide (LDA) dimer solvated by two tetrahydrofuran ligands to give the corresponding trisolvated monomer show eight structurally distinct minima. The barriers to exchange are comparable to those expected from experimental studies showing rate-limiting deaggregations. The role of conformational isomerism in deaggregation and the extent that deaggregation rates dictate LDA reactivity under synthetically important conditions are considered.

| S-EPMC3184385 | biostudies-literature

Isothiourea-Catalyzed Enantioselective Michael Addition of Malonates to α,β-Unsaturated Aryl Esters.

Project description:An enantioselective Michael addition of malonates to α,β-unsaturated para-nitrophenyl esters was achieved using the Lewis basic isothiourea HyperBTM, giving excellent levels of product enantioselectivity (up to >99:1 enantiomeric ratio) in good yields and with complete regioselectivity (>20:1 regioselectivity ratio) in the presence of alternative (phenyl ketone and ethyl ester) Michael acceptors. Density functional theory calculations indicate that N-acylation is rate-limiting. This constitutes a rare example of a highly enantioselective addition of simple, readily available malonates to α,β-unsaturated esters.

| S-EPMC9278409 | biostudies-literature

Isothiourea-catalysed enantioselective Michael addition of N-heterocyclic pronucleophiles to α,β-unsaturated aryl esters.

Project description:The isothiourea-catalysed enantioselective Michael addition of 3-aryloxindole and 4-substituted-dihydropyrazol-3-one pronucleophiles to α,β-unsaturated p-nitrophenyl esters is reported. This process generates products containing two contiguous stereocentres, one quaternary, in good yields and excellent enantioselectivities (>30 examples, up to > 95 : 5 dr and 99 : 1 er). This protocol harnesses the multifunctional ability of p-nitrophenoxide to promote effective catalysis. In contrast to previous methodologies using tertiary amine Lewis bases, in which the pronucleophile was used as the solvent, this work allows bespoke pronucleophiles to be used in stoichiometric quantities.

| S-EPMC8133005 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data