262 research outputs found
A Conversation with Dave Collum
No full textDavid B. Collum, the Betty R. Miller Professor of Chemistry in the Department of Chemistry and Chemical Biology, describes his unusual entry into chemistry while an undergraduate at Cornell University, a exciting experience in graduate school at Columbia University, and his movement from organic synthesis to physical organometallic chemistry in his early days as an assistant professor at Cornell. The interviewer and former mentor, Professor Bruce Ganem, wander through life at Cornell, the temperament of the department, life as department chairman, and emerging interests in political economics.1_jr7635h
Aggregation Dynamics Of Lithium Diisopropylamide And Their Mechanistic Influence On Reactivity
No full textLithium diisopropylamide (LDA) is the premier base in organic chemistry ever since its development in 1950 by Hammel and Levine. In a comprehensive survey of reagents in approximately 500 natural product syntheses, LDA emerged at the top attesting to its wide range of synthetic applications and efficacy. Significant efforts to the understanding of its complex coordination chemistry and affiliated mode of reactivity has led to a review by Collum that painted a seemingly coherent and general picture of LDA-mediated reactions. This mechanistic view, however, was gleaned under conditions in which LDA aggregate equilibria proceeded very quickly compared to the rate of the reaction. The kinetics of LDA aggregation, therefore, were inconsequential and hidden to the investigator. While shifting the focus to more reactive substrates that required a reduction in temperature to -78 °C to maintain convenient time scales for monitoring reaction rates, something odd happened. Instead of conventional first-order substrate decays that had been observed for almost twenty years, we began to observe nonstandard curvatures with evidence of substrate-independent rates, autocatalysis and lithium salt catalysis. The mechanistic intricacy was eventually traced to one common culprit: the rate of LDA aggregation at -78 °C in tetrahydrofuran (THF) had become rate-limiting with the rate of substrate reaction now being post-rate-limiting. The work described herein presents three experimental accounts that peer into the mechanism of three LDA-aggregation limited reactions: LDA-mediated ortholithiations of fluoroand trifluoromethyl arenes and the 1,4-addition to unsaturated esters. Although the studies are internally consistent, a chaotic mechanistic picture emerged that appeared to lack coherency. A theoretical treatise of LDA aggregation concludes this work in an attempt to comprehend the source of this complexity and garner a more general understanding. Dozens of reactive forms of LDA emerged as part of a potential energy surface that began to explain our experimental findings. Despite significant advances, we have only scratched the surface of the mechanistic diversity of LDA aggregation. The kinetic tools and knowledge, however, are now in place to peer ever deeper into this mechanistic extravaganza
Structure And Reactivity Of O-Lithiated Species: Spectroscopic And Computational Investigations Of Solution Structure And Reaction Mechanism
No full textSolution structural characterization of organolithium aggregates has been advanced through the efforts of Collum and coworkers. These characterizations necessarily precede detailed mechanistic studies, and may guide the engineering of new aggregates of interest. Amino alkoxides used as chiral auxiliaries by Merck and DuPont have been characterized through the use of the method of continuous variations at high temperatures. The results are corroborated by low temperature NMR data, X-ray structures, and DFT computations. Chiral mixed aggregates of lithium hexamethyldisilazide and amino alkoxides of potential synthetic utility were discovered in the course of this work, and their structure elucidated through a new extension of the Method of Continuous Variations. In an effort to extend the utility of amino alkoxides as chiral auxiliaries, mixtures of achiral enolates and phenolates with amino alkoxides were explored. A detailed mechanistic study of an aza aldol addition is presented in Chapter II herein. Following structural studies, detailed mechanistic studies are performed to understand the origins of product ratios, and correlations between rate and reaction conditions that are necessary for optimization. This mechanistic study is presented in the context of previous assumptions about the aggregation dynamics along the reaction coordinate, and is the first mechanistic study of an aza aldol addition. The dimer-based reaction was uncloaked through the use of in-situ ReactIR, rapid inject NMR, and DFT computations
Mechanistic Studies Of Lithium Diisopropylamide-Mediated Ortholithiations Under Nonequilibrium Conditions
No full textLithium diisopropylamide (LDA) plays an integral role in organic synthesis. In a comprehensive survey of over 500 total syntheses conducted by Reich, LDA emerged as the most commonly used reagent attesting to its broad range of synthetic applications. Its widespread utility led Collum to investigate mechanisms of LDA-mediated lithiation; a survey of these studies was assembled into a review that paints a coherent picture of generalized LDA-mediated reactions conducted at or above -40 °C. Fast LDA aggregate exchange inherent at high temperatures precludes detailed mechanistic understanding of aggregation dynamics by rendering substrate lithiation rate-limiting. By lowering the temperature to -78 °C, the rate of aggregate exchange can become comparable to the rate of metalation in THF. Time dependent decays exhibit linear and sigmoidal curvatures under pseudo-first order conditions, foreshadowing mechanistic complexity. Under this non-limiting regime, aggregates are no longer in full equilibrium, causing the reaction to become sensitive to autocatalysis, exogenous salts, and trace impurities. Subtle changes to reaction conditions, including isotopic substitution, can shift the rate-limiting step unpredictably. The work described herein presents two experimental accounts for elucidating mechanisms of lithiation: ortholithiation of 1,4-difluorobenzene and ortholithiation of 1,4-bis(trifluoromethyl)benzene. Given the highly substrate-dependent mechanisms, both substrates present different views of LDA deaggregation with internal consistency. i The third experimental account presents a fruitful collaboration with Zakarian aimed at understanding the underlying chemical basis for enantioselective alkylations of the enediolate of phenylacetic acid in the presence of a lithiated C2-symmetric tetraamine ligand. The high facial selectivity was traced to the formation of a densely functionalized mixed aggregate. i
CONTROLLING ARCHITECTURE USING C2-SYMMETRIC CATALYSTS: FROM SMALL MOLECULES TO LARGE POLYMERS
No full textMy doctoral studies have concentrated on the use of C2-symmetic catalysts to control the three-dimensional construction of molecules. The first half of my thesis focuses on asymmetric addition of phenols into Pd π-allyl complexes. This work was inspired by the natural product, sch202596, an antagonist for the galinin receptor that contains a highly stereogenic and compact carbasurgar structure appended onto a phenol by an allylic aryl-ether bond. A transformation was developed in which racemic allylic oxides underwent a Tsuji-Trost reaction to give diastereomeric π-allyl complexes. Addition of a nucleophile resulted in enantioenriched regioisomers in good yields. We termed this approach allylic oxide regio resolution (AORR). Using this approach, four different carbasurgar natural products were synthesized: streptol, MK7607, cyathiformine B and polyporapyranone G. Additionally, this method was extended to append carbasugar-like molecules onto complex natural products.
Furthermore, C2-symmetic catalysts were used to synthesize polymers with stereoregularity, which will be the focus of the second half of my thesis. Utilizing advances in chain walking polymerization, 1-butene was polymerized resulting in a novel isotactic semi-crystalline polymer. The ligand framework and reaction conditions were probed in order to optimized the system, which gave an active catalyst that produced a polymer with few stereo and regioerros. Specifically, it was found that ortho-cumyl groups were necessary to maintain the stereochemical information through the chain walking steps. Additionally reaction conditions were explored and discovered that a reaction temperature of −40 °C and a concentration of approximately 8 M were the optimal conditions. Finally, the use of non-aromatic, high polarity, aprotic solvents proved beneficial
Stereoselective Epoxide Polymerization: Exploring Isoselective Bimetallic Catalysts, Ionic Cocatalysts, And The Use Of Alcohols As Chain Transfer Agents
No full textFor over 50 years, researchers have attempted to create catalysts for stereoselectively polymerizing epoxides. Until very recently, catalysts for the polymerization of racemic epoxides gave mixtures of atactic and isotactic material or moderate tacticity polyethers. In 2008, the Coates Research Group reported a bimetallic catalyst system for enantioselectively polymerizing racemic epoxides to highly isotactic enantiopure polyethers. Catalyst simplification led to a highly active, isoselective catalyst. This catalyst is capable of quantitatively polymerizing racemic terminal epoxides to yield isotactic polyethers. Organic ionic compounds were synthesized and investigated as cocatalyts. The identities of both the cation and anion were systematically varied and subsequent polymerization reactivity was studied. The nature of the ionic cocatalyst dramatically impacted the rate and enantioselectivity of the catalyst system. The ionic cocatalyst [P(N=P(N(CH2)4)3)4+][tBuCO2-] produced a catalyst system that exhibited the greatest activity and selectivity for a variety of mono-substituted epoxides. The addition of alcohols to these bimetallic polymerization systems leads a lowering of molecular weight due to chain transfer. Polymer end-groups can be determined by choice of alcohol, addition of diols allows for the synthesis of isotactic telechelic poly(propylene oxide) diols
Mechanistic Studies And Applications Of The Copper-Catalyzed Rearrangement Of Vinyl Heterocycles
No full textThe development of new synthetic methods advances the study of chemistry on many fronts, including new drugs for the treatment of human disease and new materials. The copper-catalyzed rearrangement of vinyl heterocycles is one such method, providing access to a wide array of five-membered oxygen, nitrogen, and sulfur-containing heterocycles. To harness the true potential of a new methodology, an understanding of the mechanistic underpinnings is required. Utilizing an array of mechanistic tools, the rearrangement of vinyl aziridines is studied in detail. Using mechanistically inspired metal additives, a dramatic acceleration of the rearrangement of vinyl aziridines was realized. Demonstrating the use of in situ reducing agents significantly accelerate the rearrangement, suggesting a copper(I) species is the active catalytic species. This was corroborated through the use of (COD)Cu(hfacac) as a copper(I) starting point. Detailed NMR kinetic studies revealed the relative importance of olefin and sulfonamide electronics, and that the rearrangement is first order in substrate and first order in catalyst. As a result, a new catalytic system was discovered, which provides enhanced chemoselectivity and milder reaction conditions towards five-membered heterocycles. In addition, studying the mechanism provided a new direction for future rational catalyst designs towards more active catalysts, and catalysts for chiral applications, such as asymmetric desymmetrization. To further demonstrate the utility of the new copper(I) catalytic system, an expedient and scalable approach was designed utilizing (COD)Cu(hfacac) in the first total synthesis of members of a family of heterocyclic labdane natural products. Through synthesis, conformation and clarification of the structural assignment of isolated smallmolecules was realized. The route provided access to quantities of material for biological screening purposes, and the versatility of the route could be used to provide synthetic analogues of the natural structures
Evans Enolates: The Influence Of Aggregation And Solvation On The Mechanism Of The Aldol Addition To Lithiated Oxazolidinone-Derived Enolates
No full textThe 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. Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from Evans enolates are described. The 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.
TUNING HOST-GUEST CHEMISTRY IN THE DEVELOPMENT OF ADSORBENTS FOR REMEDIATION OF ORGANIC POLLUTANTS
No full textPerfluoroalkyl substances (PFASs) are a group of anthropogenic chemicals that generate concerns globally due to its worldwide occurrence in aquatic systems, persistence and resistance to biological degradation. Unfortunately, conventional remediation methods are not efficient to sequester PFASs from water, including activated carbons, membrane filtration and other destructive technologies. This motivates effort to develop new adsorbents for PFASs remediation. β-Cyclodextrin (β-CD), which is capable of forming stable host-guest complex with a number of PFASs, has been incorporated into adsorbents to treat PFASs-contaminated water, whereas, the removal of PFASs by β-CD-based adsorbents at environmentally relevant concentrations (few ng/ L to μg/ L) is barely explored. Moreover, the relationship between the structure of β-CD-based adsorbents and their affinity for PFASs is poorly understood due to the insoluble nature of β-CD-based adsorbents (Chapter 1). We have focused on the development of β-CD-crosslinked polymers for PFASs remediation. We first demonstrated that the synthesis of β-CD with a perfluorinated arene decafluorobiphenyl (DFB) generates cross-linked polymer DFB-CDP that reduces PFOA from environmentally relevant concentration to below the 2016 U.S. EPA advisory level. The polymer was not fouled by humic acids, which are major constituents of NOM, and was regenerated and reused multiple times by washing with methanol (Chapter 2). We further studied the chemical structure of DFB-CDP intensively and determined important factors that affect the uptake potential of PFASs by β-cyclodextrin polymers (Chapter 3). We have applied host-guest chemistry to other systems and developed a high-surface-area calix[4]arene-based polymer which exhibited high capacities for benzene and other aromatic hydrocarbons (Chapter 4). This work shows that host-guest chemistry can be tuned to develop new adsorbents for the remediation of organic pollutants from water and air
Studies In Orbital Symmetry Constraints Of The Reactivity Of Group (V) Tri-Tert-Butyl Siloxide Compounds And In The Ephemeral Existence Of Destabilized 2-Aza-Allyl Anionic Ligands
No full textThe olefin complex (silox)3Nb(2-trans-1-phenyl-2-vinylcyclopropane) (2PhVicPr, silox = tBu3SiO) was synthesized as a means of testing the existence a hypothesized biradical transition state for olefin dissociation. The binding of the olefin to (silox)3NbPMe3 (2-PMe3) produces two diastereomeric complexes (2-maj and 2min) that undergo cyclopropane ring-cleavage and -H atom abstraction to yield isomeric alkylidene-ene products cis/trans-(silox)3Nb=CH-CH=CH-CH2CH2Ph (cis-2alk and trans-2-alk) upon thermolysis. The two diastereomers rearranged at different rates and kinetic models suggest that trans-2-alk converts to cis-2-alk prior to ring cleavage and rearrangement. Phenomenological kinetic isotope effects were consistent with the kinetic models. Efforts were undertaken to synthesize [(silox)3Ta]2N2 in order to circumvent the apparent kinetic barrier to dinitrogen activation by (silox)3Ta (1). Naminoazidirines reacted with (silox)3Ta to produce the parent imide (silox)3TaNH (1=NH) and with (silox)3Ta=CH2 to produce alkyl hydrazide complexes. The methyl hydrazide (silox)3Ta(CH3)NHNH2 (3-NHNH2) thermally degraded to the tetraazabimetallacycle [(CH3)(silox)2Ta](-NH-N)(-NHNH)[(CH3)(silox)2Ta]•2tBu3SiOH (4●2tBu3SiOH) with concomitant evolution of CH4. The dinitrogen complex [(silox)2Ta(Cl)]2N2 could be prepared via salt metathesis and methylated to produce [(silox)2Ta(CH3)]2N2. Attempts to oxidatively couple 1=NH or (silox)3TaNLi resulted only in decomposition or production of 1=NH. White phosphorus (P4) was found to react with 1 (at -78 °C) and 2-PMe3 (at room temperature) to produce [(silox)3M]2(1,1:2)P2 (M = Nb, Ta). When 2-PMe3 was treated with P4 at -78 °C for 16 h the novel complex [(silox)3Nb(cP3)]2 was formed. Attempts to create new ligands containing the 2-aza-allyl anion resulted in CCcoupling chemistry that produced interesting organic frameworks. Both 3- and 5membered rings and [4.4.0]-bicyclic systems could be constructed from the same precursor ligand, (CH3)2C(CHNCH2Py)2 , upon treatment with different metal complexes. Chromium, cobalt and nickel bis(amide) complexes produced unique metal-metal bonded species as a result of the triple CC-coupling reaction that produces 4,4,8,8-tetramethyl-2,6-di(pyridin-2-yl)-3,7-bis((E)-(pyridin-2-ylmethylene)amino)octahydro-1,5-naphthyridine (14) as an octadentate ligand
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