David B. Collum

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Name: Collum, David; David B. Collum

Organization: Cornell University , USA

Department: Department of Chemistry and Chemical Biology

Title: (PhD)

TOPICS

Organic Chemistry

Chemicals
References

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

Co-reporter:Kyle A. Mack, Andrew McClory, Haiming Zhang, Francis Gosselin, and David B. Collum

Journal of the American Chemical Society September 6, 2017 Volume 139(Issue 35) pp:12182-12182

Publication Date(Web):August 8, 2017

DOI:10.1021/jacs.7b05057

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately Z-selective in neat tetrahydrofuran (THF) and E-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of E,E-, E,Z-, and Z,Z-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for E and Z isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in N,N-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing E and Z isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures.

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

Co-reporter:Kyle A. Mack, Andrew McClory, Haiming Zhang, Francis Gosselin, and David B. Collum

Journal of the American Chemical Society September 6, 2017 Volume 139(Issue 35) pp:12182-12182

Publication Date(Web):August 8, 2017

DOI:10.1021/jacs.7b05057

Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation

Co-reporter:Russell F. Algera, Lekha Gupta, Alexander C. Hoepker, Jun Liang, Yun Ma, Kanwal J. Singh, and David B. Collum

The Journal of Organic Chemistry May 5, 2017 Volume 82(Issue 9) pp:4513-4513

Publication Date(Web):April 3, 2017

DOI:10.1021/acs.joc.6b03083

The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under nonequilibrium conditions are reviewed. These conditions correspond to a class of substrates in which the rates of LDA aggregation and solvation events are comparable to the rates at which various fleeting intermediates react with substrate. Substrates displaying these reactivities, by coincidence, happen to be those that react at tractable rates on laboratory time scales at −78 °C. In this strange region of nonlimiting behavior, rate-limiting steps are often poorly defined, sometimes involve deaggregation, and at other times include reaction with substrate. Changes in conditions routinely cause shifts in the rate-limiting steps, and autocatalysis is prevalent and can be acute. The studies are described in three distinct portions: (1) methods and strategies used to deconvolute complex reaction pathways, (2) the resulting conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation reinforced by studies of LDA in tetrahydrofuran at −78 °C under nonequilibrium conditions.

Sodium Diisopropylamide: Aggregation, Solvation, and Stability

Co-reporter:Russell F. Algera, Yun Ma, and David B. Collum

Journal of the American Chemical Society June 14, 2017 Volume 139(Issue 23) pp:7921-7921

Publication Date(Web):May 30, 2017

DOI:10.1021/jacs.7b03061

The solution structures, stabilities, physical properties, and reactivities of sodium diisopropylamide (NaDA) in a variety of coordinating solvents are described. NaDA is stable for months as a solid or as a 1.0 M solution in N,N-dimethylethylamine (DMEA) at −20 °C. A combination of NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, N,N-dimethyl-n-butylamine, and N-methylpyrrolidine. Tetrahydrofuran (THF) readily displaces DMEA, affording a tetrasolvated cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and N,N,N′,N′-tetramethylethylenediamine quantitatively displace DMEA, affording doubly chelated symmetric dimers. The trifunctional ligands N,N,N′,N″,N″-pentamethyldiethylenetriamine and diglyme bind the dimer as bidentate rather than tridentate ligands. Relative rates of solvent decompositions are reported, and rate studies for the decomposition of THF and DME are consistent with monomer-based mechanisms.

Evans Enolates: Structures and Mechanisms Underlying the Aldol Addition of Oxazolidinone-Derived Boron Enolates

Co-reporter:Zirong Zhang and David B. Collum

The Journal of Organic Chemistry July 21, 2017 Volume 82(Issue 14) pp:7595-7595

Publication Date(Web):July 7, 2017

DOI:10.1021/acs.joc.7b01365

The soft enolization of an acylated oxazolidinone using di-n-butylboron triflate (n-Bu2BOTf) and trialkylamines and subsequent aldol addition was probed structurally and mechanistically using a combination of IR and NMR spectroscopies. None of the species along the reaction coordinate show a penchant for aggregating. Complexation of the acylated oxazolidinone by n-Bu2BOTf was too rapid to monitor, as was the subsequent enolization with Et3N (triethylamine). The preformed n-Bu2BOTf·Et3N complex, displaying muted Lewis acidity and affiliated tractable rates, reveals a rate-limiting complexation via a transition structure with a complicated counterion. n-Bu2BOTf·i-Bu3N bearing a hindered amine shifts the rate-limiting step to proton transfer. Rate studies show that the aldol addition with isobutyraldehyde occurs as proffered by others.

Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Alkene Isomerizations and Diene Metalations

Co-reporter:Russell F. Algera, Yun Ma, and David B. Collum

Journal of the American Chemical Society August 23, 2017 Volume 139(Issue 33) pp:11544-11544

Publication Date(Web):July 22, 2017

DOI:10.1021/jacs.7b05218

Sodium diisopropylamide in tetrahydrofuran is an effective base for the metalation of 1,4-dienes and isomerization of alkenes. Dienes metalate via tetrasolvated sodium amide monomers, whereas 1-pentene is isomerized by trisolvated monomers. Facile, highly Z-selective isomerizations are observed for allyl ethers under conditions that compare favorably to those of existing protocols. The selectivity is independent of the substituents on the allyl ethers; rate and computational data show that the rates, mechanisms, and roles of sodium–oxygen contacts are substituent-dependent. The competing influences of substrate coordination and solvent coordination to sodium are discussed.

Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones: Solvent, Cosolvent, and Isotope Effects on Competing Monomer- and Dimer-Based Pathways

Co-reporter:Gabriel J. Reyes-Rodríguez, Russell F. Algera, and David B. Collum

Journal of the American Chemical Society 2017 Volume 139(Issue 3) pp:1233-1244

Publication Date(Web):January 12, 2017

DOI:10.1021/jacs.6b11354

Lithium hexamethyldisilazide (LiHMDS)-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone in THF–hydrocarbon mixtures shows unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling. Four mechanisms corresponding to monosolvated monomers, trisolvated dimers, octasolvated monomers, and octasolvated dimers were identified. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground-state stabilization and transition-state tunneling.

Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition

Co-reporter:Michael J. Houghton, Christopher J. Huck, Stephen W. Wright, and David B. Collum

Journal of the American Chemical Society 2016 Volume 138(Issue 32) pp:10276-10283

Publication Date(Web):August 8, 2016

DOI:10.1021/jacs.6b05481

A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (E)-N-phenyl-1-[2-(trifluoromethyl)phenyl]methanimine. The selectivity is sensitive to tetrahydrofuran (THF) concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion–LDA mixed aggregate.

Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries

Co-reporter:Kai Yu, Ping Lu, Jeffrey J. Jackson, Thuy-Ai D. Nguyen, Joseph Alvarado, Craig E. Stivala, Yun Ma, Kyle A. Mack, Trevor W. HaytonDavid B. Collum, Armen Zakarian

Journal of the American Chemical Society 2016 Volume 139(Issue 1) pp:527-533

Publication Date(Web):December 7, 2016

DOI:10.1021/jacs.6b11673

Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several classes of reactions, most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported.

Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism

Co-reporter:Michael J. Houghton, Naomi A. Biok, Christopher J. Huck, Russell F. Algera, Ivan Keresztes, Stephen W. Wright, and David B. Collum

The Journal of Organic Chemistry 2016 Volume 81(Issue 10) pp:4149-4157

Publication Date(Web):April 1, 2016

DOI:10.1021/acs.joc.6b00459

Lithium enolates derived from protected pyroglutaminols were characterized by using 6Li, 13C, and 19F NMR spectroscopies in conjunction with the method of continuous variations. Mixtures of tetrasolvated dimers and tetrasolvated tetramers in different proportions depend on the steric demands of the hemiaminal protecting group, tetrahydrofuran concentration, and the presence or absence of an α-fluoro moiety. The high steric demands of the substituted bicyclo[3.3.0] ring system promote dimers to an unusual extent and allow solvents and atropisomers in cubic tetramers to be observed in the slow-exchange limit. Pyridine used as a 6Li chemical shift reagent proved useful in assigning solvation numbers.

Sodium Diisopropylamide in N,N-Dimethylethylamine: Reactivity, Selectivity, and Synthetic Utility

Co-reporter:Yun Ma, Russell F. Algera, and David B. Collum

The Journal of Organic Chemistry 2016 Volume 81(Issue 22) pp:11312-11315

Publication Date(Web):October 21, 2016

DOI:10.1021/acs.joc.6b02287

The reactivities and chemoselectivities of sodium diisopropylamide (NaDA) in N,N-dimethylethylamine (DMEA) are compared with those of lithium diisopropylamide (LDA) in tetrahydrofuran (THF). Metalations of arenes, epoxides, ketones, hydrazones, dienes, and alkyl and vinyl halides are represented. The positive attributes of NaDA–DMEA include high solubility, stability, resistance to solvent decomposition, and ease of preparation. The high reactivities and chemoselectivities often complement those of LDA–THF.

Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings

Co-reporter:Michael J. Houghton and David B. Collum

The Journal of Organic Chemistry 2016 Volume 81(Issue 22) pp:11057-11064

Publication Date(Web):October 17, 2016

DOI:10.1021/acs.joc.6b02067

Enolization of O-methyl hydroxamic acids (Weinreb amides) in tetrahydrofuran solution with lithium diisopropylamide affords predominantly tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The aggregation states are assigned by using the method of continuous variation in conjunction with 6Li NMR spectroscopy. Decoalescence of the tetramer resonance below −100 °C shows considerable spectral complexity attributed to isomerism of the methoxy-based chelates. Density functional theory calculations were used to examine the consequences of the bite angle of five-membered chelates in cubic tetramers and resulting solvation numbers that were higher than anticipated.

Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Co-reporter:Dr. Yun Ma;Kyle A. Mack;Dr. Jun Liang;Dr. Ivan Keresztes; David B. Collum; Armen Zakarian

Angewandte Chemie 2016 Volume 128( Issue 34) pp:10247-10251

Publication Date(Web):

DOI:10.1002/ange.201605199

Abstract

A combination of ¹H, ⁶Li, ¹³C, and ¹⁵N NMR spectroscopies and density functional theory computations explores the formation of mixed aggregates by a dilithium salt of a C₂-symmetric chiral tetraamine (Koga's base). Lithium halides, acetylides, alkoxides, and monoalkylamides form isostructural trilithiated mixed aggregates with few exceptions. ⁶Li–¹³C and ⁶Li–¹⁵N couplings reveal heretofore undetected transannular contacts (laddering) with lithium acetylides and lithium monoalkylamides. Marked temperature-dependent ¹⁵N chemical shifts seem to be associated with this laddering. Computational studies shed light on the general structures of the aggregates, their penchant for laddering, and the stereochemical consequences of aggregation.

Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Co-reporter:Dr. Yun Ma;Kyle A. Mack;Dr. Jun Liang;Dr. Ivan Keresztes; David B. Collum; Armen Zakarian

Angewandte Chemie International Edition 2016 Volume 55( Issue 34) pp:10093-10097

Publication Date(Web):

DOI:10.1002/anie.201605199

Abstract

Evans Enolates: Solution Structures of Lithiated Oxazolidinone-Derived Enolates

Co-reporter:Evan H. Tallmadge

Journal of the American Chemical Society 2015 Volume 137(Issue 40) pp:13087-13095

Publication Date(Web):October 5, 2015

DOI:10.1021/jacs.5b08207

The results of a combination of 6Li and 13C NMR spectroscopic and computational studies of oxazolidinone-based lithium enolates—Evans enolates—in tetrahydrofuran (THF) solution revealed a mixture of dimers, tetramers, and oligomers (possibly ladders). The distribution depended on the structure of the oxazolidinone auxiliary, substituent on the enolate, and THF concentration (in THF/toluene mixtures). The unsolvated tetrameric form contained a D2d-symmetric core structure, whereas the dimers were determined experimentally and computationally to be trisolvates with several isomeric forms.

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

Co-reporter:Jun Liang; Alexander C. Hoepker; Russell F. Algera; Yun Ma

Journal of the American Chemical Society 2015 Volume 137(Issue 19) pp:6292-6303

Publication Date(Web):April 21, 2015

DOI:10.1021/jacs.5b01668

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.

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

Co-reporter:Evan H. Tallmadge; Janis Jermaks

Journal of the American Chemical Society 2015 Volume 138(Issue 1) pp:345-355

Publication Date(Web):December 6, 2015

DOI:10.1021/jacs.5b10980

Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from acylated oxazolidinones (Evans enolates) are described. Previously characterized trisolvated dimeric enolates undergo rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity in high yield along with small amounts of one anti isomer. The efficacy of the addition depends critically on aging effects and the reaction quench. Unsolvated tetrameric enolates that form on warming the solutions are unreactive toward isobutyraldehyde and undergo retroaldol reaction under forcing conditions. Additions to cyclohexanone are relatively slow but form a single isomeric adduct in >80% yield. The ketone-derived aldolates are robust. All attempts to control stereoselectivity by controlling aggregation failed. Rate studies of addition to cyclohexanone trace the lack of aggregation-dependent selectivities to a monomer-based mechanism. The synthetic implications and possible utility of lithium enolates in Evans aldol additions are discussed.

Solid-State and Solution Structures of Glycinimine-Derived Lithium Enolates

Co-reporter:Kyoung Joo Jin

Journal of the American Chemical Society 2015 Volume 137(Issue 45) pp:14446-14455

Publication Date(Web):November 10, 2015

DOI:10.1021/jacs.5b09524

A combination of crystallographic, spectroscopic, and computational studies was applied to study the structures of lithium enolates derived from glycinimines of benzophenone and (+)-camphor. The solvents examined included toluene and toluene containing various concentrations of tetrahydrofuran, N,N,N′,N′-tetramethylethylenediamine (TMEDA), (R,R)-N,N,N′,N′-tetramethylcyclohexanediamine [(R,R)-TMCDA], and (S,S)-N,N,N′,N′-tetramethylcyclohexanediamine [(S,S)-TMCDA]. Crystal structures show chelated monomers, symmetric disolvated dimers, S4-symmetric tetramers, and both S6- and D3d-symmetric hexamers. 6Li NMR spectroscopic studies in conjunction with the method of continuous variations show how these species distribute in solution. Density functional theory computations offer insights into experimentally elusive details.

Method of Continuous Variation: Characterization of Alkali Metal Enolates Using 1H and 19F NMR Spectroscopies

Co-reporter:Laura L. Tomasevich

Journal of the American Chemical Society 2014 Volume 136(Issue 27) pp:9710-9718

Publication Date(Web):June 10, 2014

DOI:10.1021/ja504365z

The method of continuous variation in conjunction with 1H and 19F NMR spectroscopies was used to characterize lithium and sodium enolates solvated by N,N,N′,N′-tetramethylethyldiamine (TMEDA) and tetrahydrofuran (THF). A strategy developed using lithium enolates was then applied to the more challenging sodium enolates. A number of sodium enolates solvated by TMEDA or THF afford exclusively tetramers. Evidence suggests that TMEDA chelates sodium on cubic tetramers.

Solution Structures of Lithium Amino Alkoxides Used in Highly Enantioselective 1,2-Additions

Co-reporter:Angela M. Bruneau ; Lara Liou

Journal of the American Chemical Society 2014 Volume 136(Issue 7) pp:2885-2891

Publication Date(Web):January 28, 2014

DOI:10.1021/ja412210d

Lithium ephedrates and norcarane-derived lithium amino alkoxides used to effect highly enantioselective 1,2-additions on large scales have been characterized in toluene and tetrahydrofuran. The method of continuous variations in conjunction with 6Li NMR spectroscopy reveals that the lithium amino alkoxides are tetrameric. In each case, low-temperature 6Li NMR spectra show stereoisomerically pure homoaggregates displaying resonances consistent with an S4-symmetric cubic core rather than the alternative D2d core. These assignments are supported by density functional theory computations and conform to X-ray crystal structures. Slow aggregate exchanges are discussed in the context of amino alkoxides as chiral auxiliaries.

Preferential Geminal Bis-silylation of 3,4-Benzothiophane Is Caused by the Dominance of Electron Withdrawal by R3Si over Steric Shielding Effects

Co-reporter:Yifeng Han, Yun Ma, Ivan Keresztes, David B. Collum, and E. J. Corey

Organic Letters 2014 Volume 16(Issue 17) pp:4678-4679

Publication Date(Web):August 26, 2014

DOI:10.1021/ol502348y

Benzylic C–H lithiation of 3,4-benzothiophane and subsequent treatment with triphenyl- or trimethylchlorosilane under a variety of conditions leads to α,α- rather than α,α′-bis-silylation products as a consequence of anion stabilization by R3Si and very fast deprotonation of the intermediate monosilylated product, even with a sterically bulky base such as lithium diisopropylamide.

Lithium Diisopropylamide-Mediated Lithiation of 1,4-Difluorobenzene under Nonequilibrium Conditions: Role of Monomer-, Dimer-, and Tetramer-Based Intermediates and Lessons about Rate Limitation

Co-reporter:Jun Liang, Alexander C. Hoepker, Angela M. Bruneau, Yun Ma, Lekha Gupta, and David B. Collum

The Journal of Organic Chemistry 2014 Volume 79(Issue 24) pp:11885-11902

Publication Date(Web):July 7, 2014

DOI:10.1021/jo501392r

Lithiation of 1,4-difluorobenzene with lithium diisopropylamide (LDA) in THF at −78 °C joins the ranks of a growing number of metalations that occur under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. As such, a substantial number of barriers vie for rate limitation. Rate studies reveal that rate-limiting steps and even the choice of reaction coordinate depend on subtle variations in concentration. Deuteration shifts the rate-limiting step and markedly alters the concentration dependencies and overall rate law. This narrative is less about ortholithiation per se and more about rate limitation and the dynamics of LDA aggregate exchange.

Enediolate–Dilithium Amide Mixed Aggregates in the Enantioselective Alkylation of Arylacetic Acids: Structural Studies and a Stereochemical Model

Co-reporter:Yun Ma ; Craig E. Stivala ; Ashley M. Wright ; Trevor Hayton ; Jun Liang ; Ivan Keresztes ; Emil Lobkovsky ; David B. Collum ;Armen Zakarian

Journal of the American Chemical Society 2013 Volume 135(Issue 45) pp:16853-16864

Publication Date(Web):May 8, 2013

DOI:10.1021/ja403076u

A combination of X-ray crystallography, 6Li, 15N, and 13C NMR spectroscopies, and density functional theory computations affords insight into the structures and reactivities of intervening aggregates underlying highly selective asymmetric alkylations of carboxylic acid dianions (enediolates) mediated by the dilithium salt of a C2-symmetric chiral tetraamine. Crystallography shows a trilithiated n-butyllithium–dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non-dimerized trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state. Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model.

Azaaldol Condensation of a Lithium Enolate Solvated by N,N,N′,N′-Tetramethylethylenediamine: Dimer-Based 1,2-Addition to Imines

Co-reporter:Timothy S. De Vries ; Angela M. Bruneau ; Lara R. Liou ; Hariharaputhiran Subramanian

Journal of the American Chemical Society 2013 Volume 135(Issue 10) pp:4103-4109

Publication Date(Web):February 17, 2013

DOI:10.1021/ja400345c

The lithium enolate of tert-amylacetate solvated by N,N,N′,N′-tetramethylethylenediamine (TMEDA) is shown to be a doubly chelated dimer. Adding the dimeric enolate to 4-fluorobenzaldehyde-N-phenylimine affords an N-lithiated β-amino ester shown to be monomeric using 6Li and 15N NMR spectroscopies. Rate studies using 19F NMR spectroscopy reveal reaction orders consistent with a transition structure of stoichiometry [(ROLi)2(TMEDA)2(imine)]⧧. Density functional theory computations explore several possible dimer-based transition structures with monodentate and bidentate coordination of TMEDA. Supporting rate studies using trans-N,N,N′,N′-1,2-tetramethylcyclohexanediamine showing analogous rates and rate law suggest that TMEDA is fully chelated.

Structure Determination Using the Method of Continuous Variation: Lithium Phenolates Solvated by Protic and Dipolar Aprotic Ligands

Co-reporter:Laura L. Tomasevich and David B. Collum

The Journal of Organic Chemistry 2013 Volume 78(Issue 15) pp:7498-7507

Publication Date(Web):June 27, 2013

DOI:10.1021/jo401080n

The method of continuous variation (MCV) was used in conjunction with 6Li NMR spectroscopy to characterize four lithium phenolates solvated by a range of solvents, including N,N,N′,N′-tetramethylethylenediamine, Et2O, pyridine, protic amines, alcohols, and highly dipolar aprotic solvents. Dimers, trimers, and tetramers were observed, depending on the precise lithium phenolate–solvent combinations. Competition experiments (solvent swaps) provide insights into the relative propensities toward mixed solvation.

Lithium Diisopropylamide-Mediated Ortholithiation of 2-Fluoropyridines: Rates, Mechanisms, and the Role of Autocatalysis

Co-reporter:Lekha Gupta, Alexander C. Hoepker, Yun Ma, Mihai S. Viciu, Marc F. Faggin, and David B. Collum

The Journal of Organic Chemistry 2013 Volume 78(Issue 9) pp:4214-4230

Publication Date(Web):December 27, 2012

DOI:10.1021/jo302408r

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.

Methode der kontinuierlichen Variation: Verwendung von Job-Plots zur Untersuchung molekularer Assoziationen in der metallorganischen Chemie

Co-reporter:Dr. Joseph S. Renny;Laura L. Tomasevich;Evan H. Tallmadge ; David B. Collum

Angewandte Chemie 2013 Volume 125( Issue 46) pp:12218-12234

Publication Date(Web):

DOI:10.1002/ange.201304157

Abstract

Dieser Aufsatz beschreibt Anwendungen der Methode der kontinuierlichen Variation (MCV oder Job-Plots) auf Fragen der metallorganischen Chemie. Die MCV bietet qualitative und quantitative Einblicke in die Stöchiometrien, die der Assoziation von m Molekülen A und n Molekülen B zur Bildung von A_mB_n zugrunde liegen. Auch komplexere Fälle von Metallclustern und Aggregaten sind beschreibbar. Job-Plots, in denen Reaktionsgeschwindigkeiten verfolgt werden, liefern relative Stöchiometrien geschwindigkeitsbestimmender Übergangsstrukturen. In einer speziellen Variante werden von den Liganden oder dem Lösungsmittel abhängige Reaktionsgeschwindigkeiten in Grundzustands- und Übergangszustandsbeiträge aufgegliedert, was einen Einblick in die vollständige Reaktionskoordinate mithilfe eines einzigen Job-Plots ermöglicht. Die Lücken in der Literatur werden aufgezeigt und besprochen.

Method of Continuous Variations: Applications of Job Plots to the Study of Molecular Associations in Organometallic Chemistry

Co-reporter:Dr. Joseph S. Renny;Laura L. Tomasevich;Evan H. Tallmadge ; David B. Collum

Angewandte Chemie International Edition 2013 Volume 52( Issue 46) pp:11998-12013

Publication Date(Web):

DOI:10.1002/anie.201304157

Abstract

Applications of the method of continuous variations (MCV or the Method of Job) to problems of interest to organometallic chemists are described. MCV provides qualitative and quantitative insights into the stoichiometries underlying association of m molecules of A and n molecules of B to form A_mB_n . Applications to complex ensembles probe associations that form metal clusters and aggregates. Job plots in which reaction rates are monitored provide relative stoichiometries in rate-limiting transition structures. In a specialized variant, ligand- or solvent-dependent reaction rates are dissected into contributions in both the ground states and transition states, which affords insights into the full reaction coordinate from a single Job plot. Gaps in the literature are identified and critiqued.

Regioselective Lithium Diisopropylamide-Mediated Ortholithiation of 1-Chloro-3-(trifluoromethyl)benzene: Role of Autocatalysis, Lithium Chloride Catalysis, and Reversibility

Co-reporter:Alexander C. Hoepker ; Lekha Gupta ; Yun Ma ; Marc F. Faggin

Journal of the American Chemical Society 2011 Volume 133(Issue 18) pp:7135-7151

Publication Date(Web):April 18, 2011

DOI:10.1021/ja200906z

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.

Computational Studies of Lithium Diisopropylamide Deaggregation

Co-reporter:Alexander C. Hoepker and David B. Collum

The Journal of Organic Chemistry 2011 Volume 76(Issue 19) pp:7985-7993

Publication Date(Web):September 2, 2011

DOI:10.1021/jo2015642

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.

1,4-Addition of Lithium Diisopropylamide to Unsaturated Esters: Role of Rate-Limiting Deaggregation, Autocatalysis, Lithium Chloride Catalysis, and Other Mixed Aggregation Effects

Co-reporter:Yun Ma ; Alexander C. Hoepker ; Lekha Gupta ; Marc F. Faggin

Journal of the American Chemical Society 2010 Volume 132(Issue 44) pp:15610-15623

Publication Date(Web):October 20, 2010

DOI:10.1021/ja105855v

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.

Mechanism of Lithium Diisopropylamide-Mediated Substitution of 2,6-Difluoropyridine

Co-reporter:Mihai S. Viciu ; Lekha Gupta

Journal of the American Chemical Society 2010 Volume 132(Issue 18) pp:6361-6365

Publication Date(Web):April 16, 2010

DOI:10.1021/ja910834b

Treatment of 2,6-difluoropyridine with lithium diisopropylamide in THF solution at −78 °C effects ortholithiation quantitatively. Warming the solution to 0 °C converts the aryllithium to 2-fluoro-6-(diisopropylamino)pyridine. Rate studies reveal evidence of a reversal of the ortholithiation and a subsequent 1,2-addition via two monomer-based pathways of stoichiometries [ArH•i-Pr2NLi(THF)]‡ and [ArH•i-Pr2NLi(THF)3]‡. Computational studies fill in the structural details and provide evidence of a direct substitution without the intermediacy of a Meisenheimer complex.

Reaction of Lithium Diethylamide with an Alkyl Bromide and Alkyl Benzenesulfonate: Origins of Alkylation, Elimination, and Sulfonation

Co-reporter:Lekha Gupta, Antonio Ramírez, and David B. Collum

The Journal of Organic Chemistry 2010 Volume 75(Issue 24) pp:8392-8399

Publication Date(Web):November 16, 2010

DOI:10.1021/jo101505x

A combination of NMR, kinetic, and computational methods are used to examine reactions of lithium diethylamide in tetrahydrofuran (THF) with n-dodecyl bromide and n-octyl benzenesulfonate. The alkyl bromide undergoes competitive SN2 substitution and E2 elimination in proportions independent of all concentrations except for a minor medium effect. Rate studies show that both reactions occur via trisolvated-monomer-based transition structures. The alkyl benzenesulfonate undergoes competitive SN2 substitution (minor) and N-sulfonation (major) with N-sulfonation promoted at low THF concentrations. The SN2 substitution is shown to proceed via a disolvated monomer suggested computationally to involve a cyclic transition structure. The dominant N-sulfonation follows a disolvated-dimer-based transition structure suggested computationally to be a bicyclo[3.1.1] form. The differing THF and lithium diethylamide orders for the two reactions explain the observed concentration-dependent chemoselectivities.

Lithium Phenolates Solvated by Tetrahydrofuran and 1,2-Dimethoxyethane: Structure Determination Using the Method of Continuous Variation

Co-reporter:Timothy S. De Vries ; Anandarup Goswami ; Lara R. Liou ; Jocelyn M. Gruver ; Emily Jayne

Journal of the American Chemical Society 2009 Volume 131(Issue 36) pp:13142-13154

Publication Date(Web):August 24, 2009

DOI:10.1021/ja9047784

The method of continuous variation in conjunction with 6Li NMR spectroscopy was used to characterize lithium phenolates solvated by tetrahydrofuran and 1,2-dimethoxyethane. The strategy relies on the formation of ensembles of homo- and heteroaggregated phenolates. The symmetries and concentration dependencies of the heteroaggregates attest to the aggregation numbers of the homoaggregates. The structurally diverse phenols afford substrate- and solvent-dependent combinations of lithium phenolate monomers, dimers, trimers, tetramers, and pentamers. We discuss the refinement of protocols for characterizing O-lithiated species. Computational studies examine further the substituent and solvent dependencies of aggregation.

Lithium Diisopropylamide: Solution Kinetics and Implications for Organic Synthesis

Co-reporter:David B. Collum;Anne J. McNeil;Antonio Ramirez

Angewandte Chemie International Edition 2007 Volume 46(Issue 17) pp:

Publication Date(Web):23 MAR 2007

DOI:10.1002/anie.200603038

Lithium diisopropylamide (LDA) is a prominent reagent used in organic synthesis. In this Review, rate studies of LDA-mediated reactions are placed in the broader context of organic synthesis in three distinct segments. The first section provides a tutorial on solution kinetics, emphasizing the characteristic rate behavior caused by dominant solvation and aggregation effects. The second section summarizes substrate- and solvent-dependent mechanisms that reveal basic principles of solvation and aggregation. The final section suggests how an understanding of mechanism might be combined with empirical methods to optimize yields, rates, and selectivities of organolithium reactions and applied to organic synthesis.

Lithiumdiisopropylamid: Reaktionskinetik in Lösung und Folgerungen für die organische Synthese

Co-reporter:David B. Collum ;Anne J. McNeil;Antonio Ramirez

Angewandte Chemie 2007 Volume 119(Issue 17) pp:

Publication Date(Web):23 MAR 2007

DOI:10.1002/ange.200603038

Lithiumdiisopropylamid (LDA) ist ein herausragendes Reagens in der organischen Synthese. Dieser Aufsatz diskutiert kinetische Untersuchungen von LDA-vermittelten Reaktionen, wobei eine Unterteilung in drei Abschnitte vorgenommen wird. Der erste Teil gibt eine Einführung in die Reaktionskinetik von LDA-Lösungen mit Schwerpunkt auf dem charakteristischen Reaktionsgeschwindigkeitsverhalten, das von Solvatations- und Aggregationseinflüssen bestimmt wird. Im zweiten Teil werden substrat- und solvensabhängige Mechanismen zusammengefasst, aus denen sich grundlegende Prinzipien der Solvatation und Aggregatbildung ableiten lassen. Im abschließenden Teil werden Vorschläge gemacht, wie sich Erkenntnisse zu den Reaktionsmechanismen mit empirischen Methoden kombinieren lassen, um Ausbeuten, Reaktionsgeschwindigkeiten und Selektivitäten von Organolithiumreaktionen zu optimieren.