Reich Lab Tribute

Masters Students, Doctoral Students & Postdocs

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Daniel A. Murcia -- MS 1972

Thesis Title

Stereochemistry of Degenerate Silyl Rearrangements.

Clarence L. Haile -- MS 1972

Thesis Title

Synthesis of Bromolium Ion Precursors.

Carole S. Cooperman -- MS 1973

Thesis Title

Stereochemistry of Triaryliodine Compounds.

Research Summary

Carole was the first graduate student to work on the hypervalent iodine project. She first prepared a triaryliodine compound suitable for measurement of degenerate isomerization by NMR spectroscopy. Sue Wollowitz , Steve Peake and Pat Green followed up on her work .

Papers “Structure and Stereolability of Triaryliodine (III) Compounds. Degenerate Isomerization of 5-Phenyl-5,H-dibenziodole,” H. J. Reich and C. S. Cooperman, J. Am. Chem. Soc. 1973, 95, 5077. PDF

Peter D. Clark -- MS 1975

Thesis Title

The Preparation and Reactions of Vinyl Selenides and Selenoxides.

Paul M. Gold -- MS 1976

Thesis Title

Synthesis of 7-Hydroxymyoporone–A Furano Sesquiterpene

Research Summary

Paul followed up on the work of Shrenik Shah and Flora Chow on lithiated propargyl selenides to develop a very efficient synthesis of 7-hydroxymyoporone.

Jay J. Rusek -- MS 1978

Thesis Title

Synthetic Applications of Silyl Ketones

Mel C. Schroeder -- MS 1983

Thesis Title

I. Electrophilic Additions of Selenium Substituted Allylic Stannanes. II. N-Hydroxypyrazoles — Attempts of Allylic Alcohol Protection and Subsequent Oxidation.

Research Summary

Mel developed a synthesis of allyl amines, based on the dual role of the phenylseleno group as both a carbanion stabilizing group, as well as a leaving group.

M. Y. Shirley Wong -- MS 1984

Carsten Bolm -- MS 1984

Thesis Title

Enol Silyl Ethers from α-Lithiosulfones and Silyl Ketones.

Research Summary

Carsten came to Madison for one year as a Fulbright Scholar and worked on a silyl ketone project – the preparation of enol silyl ethers by the reaction of metalated sulfones with acyl silanes. The reaction has good generality (similar reactions were studied earlier by Ron Holtan) , and can be used to make enol silanes such as the one below which are not accessible by direct enolization.

After he completed his work in Madison Carsten returned to Germany to complete his PhD with Manfred Reetz in Marburg. He then did postdoctoral work with Sharpless at MIT before returning to Germany to begin his academic career, first in Basel, then Marburg and finally his current position in Aachen.

Timothy D. Fitzpatrick -- MS 1988

Thesis Title

Synthesis of Hindered Selenenic Acid Precursors.

Michelle B. Anim-Appiah -- MS 1994

Thesis Title

Ate Complex Reactivity Studies in THF

Research Summary

The early work of Nancy Phillips as well as that of Pat Green, Wes Whipple and Joe Borst had shown clearly that treatment of organo-iodine, -tin and -tellurium compounds gave detectable ate complexes, and that these were probable intermediates in the lithium-metalloid exchange reactions. Michelle tackled the problem of whether these ate complex had interesting reactivity in their own right. She prepared the first tellurium acetylide ate complexes, as well as lithium pentaarylstannate and lithium bisalkynyl triarylstannate ate complexes and examined the stereochemistry of their reactions with Mike Bowe’s 2,5-diphenylcyclohexanone system, and with 2-phenylpropionaldehyde. In each case the identical products were formed with the lithium reagent or with the ate complex, suggesting that in each case the Curtin-Hammett principle applied and the chemistry was that of the lithium reagents in equilibrium with them, and not the ate complexes themselves.

Gwynne M. Wesley -- MS 1995

Thesis Title

The Effects of Ring Strain on the Structure of Allenyl- Propargyllithium Reagents.

Tamara G. Walker -- MS 1997

Woman with short hairThesis Title

Cyclobutylidene Allenyl-Propargyllithium Reagents

 

Woman and baby
Walker and Syd

Rui Tang -- MS 1997

Man in hat with glasses

Thesis Title

The Effects of Intramolecular Chelation on the Structures of Allenyllithium-Propargyllithium Reagents. Investigation into the Mechanism of an Unexpected Rearrangement.

Robert Edmonston -- MS 1999

Thesis Title

An Investigation into the Role of Lithium Catalysis on the Regioselectivity of Addition to , α,β -Unsaturated Ketones. I. Regioselectivity of cisoid Enone Addition. II. Kinetics of Bis(3,5-bis(trifluoromethyl)phenylthio)methyllithium. III. Regioselectivity of α -Lithiated Nitriles to Enones.

Research Summary

Bob followed up on Bill Sikorski’s work on the effect of HMPA on the regioselectivity of addition of lithium reagents to enones. He performed some very nice (and very difficult) kinetic work which showed clearly the strong rate-retarding effect of HMPA on the addition of metalated sulfides to cyclohexenone and other enones.

Salwa S. Salah -- MS 2004

Thesis Title

Preliminary Investigation of the α-Silyl Cyclopropyllithium System for Lithium Chelation Studies.

Stephanie A. Chan -- MS 2005

Thesis Title

Chelation Studies in Organolithium Reagents

 

Kimberly A. Smith -- MS 2005

Woman smiling paddling a boatThesis Title

The Effect of ion Pair Status on Nucleophilic Substitution Reactions

Research Summary

Mechanism of lithium reagent alkylation reactions

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Klaus J. Kulicke -- Postdoc 1995

Man with glassesThesis Title

Chelation Effects in Chiral Sulfur- and Silicon-Stabilized Organolithium Reagents

Research Summary

Dr. Kulicke joined the research group after completing his Ph. D. at the University of Basel in Giese’s group. He undertook the first detailed NMR spectroscopic explorations of the consequences of chelation in alkyllithium reagents, with especial attention to stereochemical effects. He measured the inversion barriers of a series of chelated organolithium reagents, and compared them to non-chelated analogs.

He also found that some chelated organolithium reagents form mono-HMPA complexes in which the fourth ligand at lithium, a solvent molecule, is on slow exchange on the NMR time scale below -150o. When there are two ether solvents, separate 31P signals can be seen for each solvent, so the relative coordination strength of solvents can be directly measured by NMR integration.

Dan Wherritt -- Postdoc 2010

Dr. Wherritt joined the research group after completing his Ph. D. at the Ohio State University in the Craig Forsyth group. His thesis work was on total synthesis efforts aimed at akadaic acid, apratoxin a and analogs of them. He worked on several projects in organolithium chemistry, most notably on the characterization of a monomeric acetophenone enolate, and its oligemrization path.

 

 

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Shrenik K. Shah -- Ph.D. 1977

Thesis Title

Preparation, Reactions and Further Transformations of α-Lithio Selenenides and Selenoxides. Synthetic Transformations Based on Propargyl Selenides.

Research Summary

Shrenik, after a year or so of making theoretically interesting organoselenium molecules, tackled the chemistry of metalated selenides and selenoxides, developing several interesting and useful transformations. He found that allyl propargyl selenide could be easily dimetalated to form the reagent we usually write as shown below, which was an effective double nucleophile. The propargyl selenide products, when oxidized under the right conditions, were transformed into enones.

One of the compounds Shrenik made using the monolithium reagent, the silyl ketone below, catalyzed a major effort on the chemistry of silyl ketones, developed by, among others, Rick Olson, Ron Holtan, Martha Kelly and Eric Eisenhart.

Shrenik also developed procedures for the in situ preparation of previously unknown α-lithio selenoxides, which were synthetically equivalent to vinyllithium reagents. These were also extensively studies by Flora Chow.

After finishing his thesis work at Wisconsin, Shrenik did a post-doc in Bob Coates laboratory at the U. of Illinois.

James M. Renga -- Ph.D. 1975

Thesis Title

Synthesis of α,β-Unsaturated Carbonyl Compounds Using Organoselenium Reagents.

Research Summary

Jim’s first project involved a test for cyclic conjugation of carbonium ions in spiro-fused cyclopropane rings. He compared the rates of formation of the cation 1 with 2 and 3. A small rate acceleration of 70 for 2 was found attributable to cyclic delocalization, after correction for the inductive effect of the double bond..

Jim then began a very productive investigation of a number of facets of the use of the selenoxide elimination for the synthesis of enones (first discovered by Ieva Reich). He greatly extended the generality of the synthetic method by establishing the principal side reactions that occurred, and developing experimental protocols that avoided these side reactions.

During these studies he first prepared N,N-dialkylselenenamides, and examined their chemistry.

Jim also investigated the use of bromomethyl selenides as alkylating agents for carbonyl enolates, a reaction later used effectively by Craig Jasperse in his work on selenocysteine analogs.

John E. Trend -- Ph.D. 1976

Thesis Title

Physicochemical Studies of Selenoxides and Related Hypervalent Organoselenium Compounds. Nuclear Magnetic Resonance Studies of Organoselenium Compounds, Selenium-77 Chemical Shifts.

Research Summary

John joined the group during my first year at Wisconsin. He quickly became the NMR expert, and performed a series of studies which made effective use of his expertise, including the discovery of two major errors in published reports of organosulfur and selenium structures.

A central theme of John’s work was the stereochemistry of selenoxides, where he showed that selenoxide inversions are many orders of magnitude faster than sulfoxide analogs, and proceed by three pathways – through the neutral selenoxide, as well as through the monoprotonated and diprotonated forms.

John also discovered that the decomposition products of selenoxides, transient selenenic acids, were good electrophiles, and easily added to olefins, either inter- or intramolecularly. This discovery was of considerable importance in debugging synthetic applications of selenoxide eliminations and [2,3]sigmatropic rearrangements, concurrently and subsequently studied by Sue Wollowitz, Shrenik Shah, Flora Chow , Rick Olson, Bill Willis, Debra Saez and others.

Shrenik K. Shah -- Ph.D. 1977

Thesis Title

Preparation, Reactions and Further Transformations of α-Lithio Selenenides and Selenoxides. Synthetic Transformations Based on Propargyl Selenides.

Research Summary

Shrenik, after a year or so of making theoretically interesting organoselenium molecules, tackled the chemistry of metalated selenides and selenoxides, developing several interesting and useful transformations. He found that allyl propargyl selenide could be easily dimetalated to form the reagent we usually write as shown below, which was an effective double nucleophile. The propargyl selenide products, when oxidized under the right conditions, were transformed into enones.

One of the compounds Shrenik made using the monolithium reagent, the silyl ketone below, catalyzed a major effort on the chemistry of silyl ketones, developed by, among others, Rick Olson, Ron Holtan, Martha Kelly and Eric Eisenhart.

Shrenik also developed procedures for the in situ preparation of previously unknown α-lithio selenoxides, which were synthetically equivalent to vinyllithium reagents. These were also extensively studies by Flora Chow.

After finishing his thesis work at Wisconsin, Shrenik did a post-doc in Bob Coates laboratory at the U. of Illinois.

Flora Chow -- Ph.D. 1978

Thesis Title

Synthetic Transformations Based on β-Hydroxy Selenides.

Research Summary

Flora discovered the “Chow” reaction (also known as the Reich-Krief reaction), the catalyzed reductive elimination of β-hydroxy selenides to give olefins. The reaction conditions she developed for this reaction (methanesulfonyl chloride-triethylamine) continue to be the preferred ones in use today. She perfected the handling and application of unstable α-lithio selenoxides (first successfully done by Shrenik Shah) for the preparation of olefins using the sequence below:

After finishing her thesis work at Wisconsin Flora did a post-doc in Carruther’s laboratory at the U. of Colorado.

Steven L. Peake -- Ph.D. 1979

Thesis Title

Oxidation of Aryl Iodides.

Research Summary

Steve Peake discovered that oxidation of alkyl iodides give olefins, much in the way that the oxidation of selenides does. The reaction proceeds with syn stereochemistry and probably goes by an isodoso syn elimination, analogous to selenoxide eliminations.

Steve also carried out some early spectroscopic studies on organolithium reagents, but the NMR instrumentation was not yet up to the tasks which were later so effectively performed by Nancy Phillips, Pat Green and a host of others who built on their work.

Martin L. Cohen -- Ph.D. 1979

Thesis Title

Organoselenium Chemistry. Some Mechanistic, Synthetic and Stereochemical Considerations.

Research Summary

Marty discovered an unusual (and somewhat controversial) effect: that some α-seleno and α-thio enolates alkylate on S or Se, rather than on carbon or oxygen, as is usually the case. He proved this effect by the clever experiment below, in which the intermediate S-alkylated ylide preferentially undergoes a [2,3] sigmatropic rearrangment of the previously present allyl group.

Marty also developed a new amine dealkylation process, which takes advantage of the fact that selenols are acidic enough to protonate amines in organic solvents. No corresponding dealkylation can be performed with thiols.

Susan Wollowitz -- Ph.D. 1980

Thesis Title

Reactivity and Rearrangement of Selenoxides and Sulfoxides.

Research Summary

Sue explored the comparative chemistry of selenoxides and sulfoxides. She, with some followup by Ken Yelm, found that the selenoxide [2,3]sigmatropic rearrangement was substantially more exothermic than that of sulfoxides (by at least 10 kcal/mol).

She discovered a very nice procedure for the regiospecific 1,4-dehydration of allyl alcohols using sequential [2,3]sigmatropic rearrangement of a sulfenate ester followed by a sulfoxide elimination, according to the following scheme.

William W. Willis -- Ph.D. 1982

Thesis Title

Synthetic Transformations Based on Vinyl Selenides and Selenoxides. The Preparation of Selenenic Acids. Selenium-77 NMR.

Richard E. Olson -- Ph.D. 1982

Thesis Title

Rearrangements of Propargyl Selenoxides. Siloxyallyl- and Allenyllithium Reagents from Acyl Silanes.

Research Summary

Rick worked on several projects in the silyl ketone area, most notably the synthesis of allenyl silyl ethers by the addition of lithium acetylides to acyl silanes followed by alkylation of the allenyllithium reagent formed by Brook rearrangement.

Kenneth E. Yelm -- Ph.D. 1984

Thesis Title

Synthesis of 2,3-Disubstituted 1,3-Butadienes via Organotin Precursors. Sulfoxide and Selenoxide [2.3] Sigmatropic Rearrangements.

Martha J. Kelly -- Ph.D. 1983

Thesis Title

Synthesis and Reactions of α,β -Unsaturated Silyl Ketones.

Research Summary

Martha developed the synthesis of a series of interesting previously unknown types of unsaturated silyl ketones. She used the chemistry allenol ethers, which was also being developed by Rick Olson and later by Ron Holtan and Mike Bowe.

These compounds could be used in the various applications of the Brook rearrangement which were the focus of this work. The synthesis of vinyl allenes developed by Martha was later used very effectively by Eric Eisenhart in sesquiterpene synthesis using intramolecular Diels-Alder reactions.

After finishing her thesis work at Wisconsin Martha did a post-doc in Oppolzer’s laboratory in Geneva, Switzerland.

Carl A. Hoeger -- Ph.D. 1983

Thesis Title

I. Formation, Observation and Reactions of A Selenolseleninate. II. An Investigation into the Chemistry of β-Ketoseleninic and Allylseleninic Acid.

Research Summary

Carl investigated the elusive selenenic acids which are intermediates in a number of important redox reactions of organoselenium compounds, including the chemistry involved in the selenoenzyne glutathione peroxidase. Carl was able to prepare systems which underwent selenoxide eliminations at temperatures as low at -50 deg C. Although he was able to detect and study the previously unknown selenolseleninates by multinuclear NMR spectroscopy, the selenenic acid precursors could not be detected.

After he completed his thesis work Carl did post-doctoral work with Okamura at the University of California Riverside before taking a position at the Salk Institute.

Debra J. Saez -- Ph.D. 1984

Thesis Title

Chemistry of Selenones.

Research Summary

Debbie investigated the preparation, properties and reactions of selenones, the selenium analogs of sulfones. This chemistry had, up to that time, been essentially undeveloped. She found that many of the selenones that had been reported were actually other compounds, and developed procedures for the preparation of authentic ones. Selenones turned out to be much more polar than sulfones, were more acidic by several pKa units, and were excellent alkylating agents. For example, methyl phenyl selenone was an order of magnitude more reactive than methyl iodide as an alkylating agents towards dimethyl sulfide (to form trimethylsulfonium).

She also discovered that selenones underwent a “selenone syn elimination,” analogous to the selenoxide elimination, a reaction that is unknown for sulfones.

Ronald C. Holtan -- Ph.D. 1984

Thesis Title

Stereocontrolled Synthesis of Silyl Enol Ethers Using α-Phenylthio Silyl Ketones.

Research Summary

Ron developed synthetic methodology for highly streoselective synthesis of enol ethers using the reaction of α-substituted silyl ketones (acyl silanes) with nucleophiles.

Eric K. Eisenhart -- Ph.D. 1985

Thesis Title

Intra- and Intermolecular Diels-Alder Reactions of Vinylallenes. Synthesis of Dehydrofukinone and Selina-4(14),7(11)-dien-8-one.

Research Summary

Eric explored the use of intra- and inter-molecular Diels-Alder reactions of vinyl allenes. He was one of three students (the others were Martha Kelly and Rick Olson) whose research exploited the chemistry of silyl ketones for the preparation of natural products, although he was the only one who actually made a sesquiterpene, in fact he made two related ones.

Craig P. Jasperse -- Ph.D. 1987

Thesis Title

The Chemistry of Isoselenazolidin-3-ones and a Selenenic Acid.

Research Summary

Craig’s thesis research was focused on models for intermediates in the catalytic cycle of the selenoenzyme glutathione peroxidase. In connection with the synthesis of some selenium heterocycles Craig developed the alkylation of ketone, ester, amide and carboxylic acid enolates with Ph-CH2-Se-CH2-Br and Ph-CH2-S-CH2-Br.

This methodology allowed exploration of the redox chemistry of a glutathione peroxidase mimic.

Since no authentic selenenic acids could be detected in the chemistry of the selenocysteine analogs, Craig explored the preparation of a selenenic acid protected by brute force steric effects.

After completing his thesis work Craig did postdoctoral work at Pittsburgh with Dennis Curran, and then accepted a faculty appointment at the University of North Dakota. After a few years he moved to his current position at Moorhead State University.

David Gschneidner -- Ph.D. 1987

Thesis Title

Syntheric Uses of Isoselenazolin-3-ones, Selenuranes and Selenones.

Research Summary

Dave studied a series of unusual hypervalent selenium compounds with potential as chiral dienophiles. The Diels-Alder products have selenium functionality which can be used for further transformations.

Dave also worked on the chemistry of selenones (together with Debbie Saez). He showed that vinyl phenyl selenone is an active bis-electrophile, which forms aziridines with primary amines and diazetidines with hydrazines.

James W. Ringer -- Ph.D. 1988

Thesis Title

Preparation of Stannanes from Allyl Selenides. Synthesis and Mechanism.

Research Summary

Jim developes a synthesis of organotin compounds based on the reaction of organoselenium compounds with trimethylstannyllithium. He found that a variety of activated selenides (propargyl, allyl and benzyl selenides, selenoketals) reacted smoothly with Me3SnLi to formally replace the C-Se bond with C-Sn. This allowed use of the chemistry of metalated selenides to prepare stannanes.

1,1-Bis-stannyl derivatives can be prepared by a novel “counterattacking” reaction:

Since selenides are not normally good substrates for SN2 substitutions, the mechanism here must be more complicated, and Jim performed a number of experiments to probe for intermediates in these substitutions. It seems likely that the reaction involves first a Li/Se exchange (perhaps through an electron-transfer process), followed by reaction of the Me3SnSePh with the allylic, propargylic or benzylic lithium reagent.

Nancy H. Phillips -- Ph.D. 1988

Thesis Title

Mechanistic Studies of the Lithium Metalloid Exchange Reaction.

Research Summary

Nancy was the first serious organolithium chemist in the group. Her work was so productive, especially after the AM 360 NMR spectrometer arrived, that eventually this became a primary focus of the group. She established that iodine, tin and tellurium ate complexes were formed in THF and THF-HMPA solutions both by kinetic techniques, as well as by direct spectroscopic observation, and established these as likely intermediates in the lithium-metalloid exchange reaction.

As part of this work, Nancy first correctly established the nature of PhLi solutions (later studied more intensively by Pat Green, Biggie Gudmundsson, Marco Medina and Wayne Goldenberg, among others).

A major part of Nancy’s work was devoted to the Li-Sn exchange reaction, where she characterized a series of previously unknown lithium pentaorganostannates, and did early experiments on the stereochemistry of the Li/Sn exchange at tin (later ably completed by Joe Borst and Mike Coplien). After her thesis work Nancy did post-doctoral work in Larry Miller’s laboratory at the University of Minnesota before starting her job at 3M.

J. Derek Mason -- Ph.D. 1988

Thesis Title

1. Investigation of Allenyl Lithium Species by Lithium-Metalloid Exchange. 2. Investigation of Chelation-Controlled Lithium-Metalloid Exchange.

Research Summary

Derek discovered and extensively documented a number of examples of the “Mason Efffect.” When allenylstannannes are treated with organolithium reagents (Li/Sn exchange) different ratios of allenyl and propargyl products products are formed depending on the conditions under which they are trapped – in situ or sequential.

This project was later taken up by John Holladay, who did extensive studies of the solution structure of allenyl lithium reagents to clarify the mechanism, and Bill Sikorski who helped put the finishing touches on the full paper.

D. Patrick Green -- Ph.D. 1989

Thesis Title

Studies of Phenyllithium, its Complexes in Donor Solvents, and its Role in the Lithium-Metalloid Exchange Reaction.

Research Summary

Pat was the second person to work extensively in the organolithium-ate complex area, following up on Nancy Phillip’s pioneering work. Pat did quantitative studies of PhLi in THF, and showed that TMEDA complexed PhLi but did not significantly activate it, whereas 12-crown-4 dramatically activated PhLi, but did not detectably complex with it. Both HMPA and PMDTA formed strong complexes with PhLi, and also greatly increased the reactivity.

Pat did extensive NMR and kinetic studies of the ate complexes formed between PhLi and PhI, Ph2Te and other metalloids in THF and THF-HMPA solutions. He showed that dibenzotellurophene formed a more stable ate complex with PhLi than did diphenyl telluride, and this set the stage for later work by Biggie Gudmundsson on stable selenium ate complexes.

Pat studied two more unusual ate complexes of the 12-electron type. In connection with the ate complex work, Pat was the first person to observe J coupling between lithium and phosphorus in lithium reagents, and he initiated the group’s very extensive studies on many lithium reagents and their interaction with HMPA and other strongly coordinating solvents which provided unprecedented details about solvation and ion pair structure. This includes work by Joe Borst. Bob Dykstra, Bill Sikorski, Jennifer Thopson, Biggie Gudmundsson, Klaus Kulicke, Aaron Sanders, Wayne Goldenberg and Kevin Jantzi.

Wesley L. Whipple -- Ph.D. 1990

Thesis Title

1. The Investigation of the Formation of 1,3-Dipoles from Silyl Ketones. 2. A Study of 2-Lithio-5-methylthiophene and Its Role in the Lithium-Iodine Exchange.

Michael D. Bowe -- Ph.D. 1990

Thesis Title

Lithium-Selenium Exchange Reaction: Configurational Stability of Unsubstituted and Sulfur and Selenium Stabilized Organolithium Reagents.

Research Summary

Mike worked on several projects, all involving applications of the lithium-selenium and lithium tellurium exchanges to the preparation of useful or interesting organolithium reagents. He discovered that α-lithio selenides and sulfides show an unexpected level of configurational stability. This work set the stage for several subsequent theses, those of Marco Medina, Robert Dykstra , and Jennifer Thompson, which explored various aspects of organolithium stereochemistry.

Joseph P. Borst -- Ph.D. 1991

Thesis Title

Stereochemistry of the Lithium-Tin Exchange. Ion Pair Structure of Lithium Reagent Species in THF/HMPA Solution.

Research Summary

Joe’s thesis research was concentrated in two principal areas. He followed up on Nancy Phillip’s work on the mechanism of the lithium-tin exchange by determining stereochemistry of substitution at the tin center. In ether the reaction occurred with strict retention of configuration, whereas in THF the product was racemized, as expected for an ate-complex mechanism.

He also took a very important observation made by Pat Green, that under suitable conditions it was possible to observe J coupling between lithium and phosphorous in lithium reagent HMPA complexes, and exploited this to determine the solution behavior of a wide variety of lithium reagents in THF-HMPA solutions. This work opened the door to an understanding of lithium reagent solution structure at an unprecedented level of detail, and set the stage for several other thesis projects, especially Bob Dykstra, Bill Sikorski, and Jennifer Thompson.

Robert R. Dykstra -- Ph.D. 1993

Thesis Title

Characterization of Lithium Ion Pair Structures in Solution. Effects of Ion Pair Separation on the Configurational Stability and Geometry of Sulfur- and Silicon-stabilized Organolithium Reagents.

Research Summary

Bob spent the first year or two years of his thesis work making substrates for asymmetric selenation of olefins, but then decided to join the lithium reagent folks and eventually coauthored 10 papers in the area. He followed up the work of Joe Borst on the behavior of organolithium reagents with HMPA as cosolvent, and perfected the NMR “HMPA titration” technique which has since become a standard experiment whenever a new lithium reagent is investigated in the group. Bob was among the first to detect triple ions and the unusual “sesquidimers” in ether-HMPA solutions, and performed an important stereochemical study on lithiated sulfides and selenides. During this work Bob made the astounding observation counter to chemist intuition and all previous experiments that some lithium reagents have a higher barrier to configurational inversion as a separated ion pair (lithium not connected to carbon) than as a contact ion pair.

Johnathan E. Holladay -- Ph.D. 1994

Thesis Title

Structure and Reactivity Studies of Allenyl-Propargyllithium Reagents

Research Summary

John’s research set the record straight on the solution structure of allenyl-propargyllithium reagents. He showed using mainly 13C NMR spectroscopy that most of these were localized allenyllithium reagents, but that a few were propargyllithiums.

There were even several that had intermediate structures. Although John found circumstantial evidence that these were mixtures of localized allenyl and propargyllithiums, it was Jennifer Thompson who later provided unambiguous proof of their structure using a Saunder’s NMR isotope perturation experiment.

John did postdoctoral work in Scott Denmark’s laboratory before moving to his first position at Union Carbide.

Craig L. Puckett -- Ph.D. 1995

Man smilingThesis Title

I. The Metal-Halogen Exchange. II. The Lithium-Tellurium Exchange. III. The Lithium-Selenium Exchange.

Man in sunglasses
Craig, thinking about “Rope-Skipping Molecules”

Marco A. Medina -- Ph.D. 1995

Man in front of treesThesis Title

I. Configurational Stability of Unsubstituted Organolithium Reagents. II. Aggregation Behavior of Phenyllithium in Diethyl Ether Solution.

Research Summary

Marco followed up on a project begun by Mike Bowe on the configurational stability of secondary organolithium reagents. Marco and Mike found that the Li/Te exchange was uniquely capable of forming secondary alkyllithiums with high stereochemical control. They made the remarkable observation that the rate of configurational inversion was increased both by going to solvents less polar than THF (such as ether), as well as by going to more polar solvents. Very slow epimerization rates were found in THF-PMDTA.

Marco also did some excellent work on the behavior of PhLi solutions, particularly in ether and ether-cosolvent mixtures.

Man, wife and children
Marco and family in 2000

Birgir Ö. Gudmundsson -- Ph.D. 1995

Man in sunglassesThesis Title

I. Solution Behavior of Chelated and Non-Chelated Aryllithium Compounds. II. A Mechanistic Study of the Lithium-Selenium Exchange.

Research Summary

Biggie started his graduate research with a foray into ate complex chemistry of 2nd and 3rd row elements S, Se and Br. He showed that even selenium could form ate complexes with a properly designed scaffold. This system also allowed the first test of whether ate complexes were true intermediates in the lithium metalloid exchange. The observable ate complex was not an intermediate in the exchange, i.e., the direct substitution on selenium (kdirect) which bypassed the ate complex was at least 100 faster than the path going through the ate complex (kate).

In connection with the work on the structures of various aryllithium reagents Biggie discovered that many aryllithiums formed substantial amounts of triple ions (Ar-Li-Ar- Li+), and this work started the group’s foray into chelated organolithium reagents. Biggie carried out a very detailed multinuclear NMR study of the 15N-labeled Hauser compound 2-lithio N,N-dimethylbenzylamine. He showed that several aspects of earlier work on this compound were incorrect, established that there were three “chelation isomers” (A, B, C below) by preparation of Li-6 and N-15 double labelled compounds, and found that the chelated compound was much more strongly dimerized than PhLi itself. These studies were extended by Wayne Goldenberg and Aaron Sanders.

Man and woman in a canoe
Biggie and Gully on the Kickapoo River (probably before they tipped…)

William H. Sikorski -- Ph.D. 1997

Man smilingThesis Title

Stabilized Organolithium Reagents I. Enone Addition Regioselectivity. II Triple Ions.

Research Summary

The central focus of Bill’s thesis work was an investigation of the remarkable effect of HMPA on the regioselectivity of the addition of some organolithium reagents to enones and other α,β-unsaturated carbonyl compounds.

He combined spectroscopic studies of the lithium reagents, using the HMPA titration technique of Joe Borst and Bob Dykstra, with product studies, kinetics (more of these done later by Bob Edmonston) , and stereochemistry. He found that there are two factors which control regioselectivity when HMPA was added: the formation of separated ion pairs, and the suppression of lithium catalysis.

Along the way Bill took several interesting detours, including the development of a superb 13C chemical shift thermometer (tris(trimethylsilyl)methane), and an extensive foray into chelated organolithium reagents and triple ions

Jennifer L. Thompson -- Ph.D. 1999

Woman with long hair smilingThesis Title

I. The Structure and Reactivity of Chelated Organolithium Reagents. II. Application of the Equilibrium Isotope Effect to Organolithium Reagents.

Research Summary

Jennifer performed an interesting experiment which directly addressed a question on the structures of allenyl-propargyllithium reagents which was raised by John Holladay’s work, i.e., are there localized allenyllithium and propargyllithium reagents, or are the equilibrium structures bridged, as predicted by calculations.

The experiment was the Saunders Isotope Perturbation experiment, which clearly showed that several of the silyl and phenyl-substituted allenyllithiums had localized structures, as shown by large remote isotope shifts of the various carbon signals in a partially deuterated sample.

Jennifer also carried out extensive experiments on the stereochemistry and reactivity of pyridyl and imidazole-chelated organolithium reagents, following up on earlier work by Bob Dykstra and Klaus Kulicke.

 

Woman and man smiling
Jen and Wayne at Superbowl Party, 1998

Wayne S. Goldenberg -- Ph.D. 1999

Thesis Title

I. The Effects of Intramolecular Chelation on Aryllithium Reagents. II. The Configurational Stability of Silicon- and Sulfur-Substituted Chiral Organolithium Reagents

Research Summary

Wayne, following up on work of Biggie Gudmundsson, prepared two series of aryllithium reagents with potential chelating groups in the ortho position capable of forming 5, 6, or 7 amine or ether chelates. Several of the amines were prepared 15N labelled to allow positive identification of Li-N contacts. In addition, Wayne studied several model systems without ortho chelating groups. His work provided clear evidence for the close relationship between chelation and aggregation of these aryllithiums. For example, the spectra below show that for the ortho-dimethylaminoethyl compound the dimer is chelated, but the monomer is not.

Aaron W. Sanders -- Ph.D. 2001

Man with glasses smiling
Aaron in the lab, ca 1998

Thesis Title

I. Addition of Sulfur Stabilized Lithium Regents to Epoxides. II. Rapid Injection NMR spectroscopy. III. Structure of Chelated Aryllithium Reagents.

Research Summary

Aaron carried out an extensive kinetic study of the reaction of epoxides with sulfur-substituted organolithium reagents. He found that the effect of HMPA was very complex. With some lithium reagents addition of HMPA caused large rate increases, with others large rate decreases. Aaron traced the origin of these effects to the ease of ion pair separation. Large rate increases were observed for hard-to-separate ion pairs like 2-lithio-1,3-dithiane, rate decreases were observed for those which were already partly or completely separated in THF solution.

In the course of the research on the structure and reactivity of organolithium reagents, there were a number of cases where several isomeric structures or aggregates were present. To address the issue of which of these was actually the reactive species in solution Aaron built the first generation of rapid-injection NMR devices (RINMR) which allowed the injection of samples into organolithium solutions (or vice-versa) and the measurement of NMR spectra within a second or two at temperatures down to -140 deg C. Most of his efforts were aimed at investigating the chemistry of the unusual lithium reagent (Me3Si)3CLi, first studied by Bill Sikorski.

Aaron also made major contributions to working out the details of the solution structure of several chelated aryllithium reagents, most notably he characterized the open dimer and pentacoordinate monomer of PMDTA-complexed 2-methoxymethylphenyllithium, which was first prepared and studied by Wayne Goldenberg.

Although he did not get to run many experiments on it, Aaron also constructed the rapid injection NMR (RINMR) apparatus, which was improved by Marty Bevan and then very effectively used by Amanda Jones , Kris Kolonko and Kristin Plessel to study previously inaccessible reaction rates of organolithium reagents under non-Curtin-Hammett conditions.

Marty J. Bevan -- Ph.D. 2003

Thesis Title

I. Dynamic and Thermodynamic Investigation of Thienyllithium Based Li/Te and Li/I Ate Complexes. II. Dynamic and Thermodynamic Investigation of Phenyllithium Based Li/I, Li/Sb, and Li/Sn Ate Complexes. III. The Investigation of Sulfur Stabilized Organolithium Reagent Ion Pair Status and Reactivity.

Research Summary

Dynamic and thermodynamic characterization of tellurium, tin, iodine and antimony ate complexes as intermediates in the lithium-metalloid exchange reaction. Correlation of ion pair structure with reactivity of alkyl halides and epoxides with organolithium reagents.

Men smiling
Marty and Kevin at Marty’s wedding

Kevin L. Jantzi -- Ph.D. 2004

Man with glasses smilingThesis Title

I. Solution and Chelation Properties of ortho-Substituted Phenyllithium Derivatives. II. Solution and Chelation Properties of 3-Substituted 2-Thienyllithium Derivatives. III. Development of a Quantitative Measure of Chelation Strength using α-Trimethylsilyl-Substituted Vinyllithium Reagents.

Group of people at a wedding smiling
Kevin, Margaret, Adam and friends at Marty’s wedding

Margaret M. Biddle -- Ph.D. 2005

Woman with glasses smilingThesis Title

I. Reaction of Lithiated Nitriles with Enones II. Studies on the Reactive Species in Fluoride-Mediated Carbon-Carbon Bond Forming Reactions III. Fluoride Sources

Woman smiling in the lab
Margaret having a good time in lab, 2002

Amanda C. Jones -- Ph.D. 2007

Person smilingThesis Title
Rapid Injection NMR and Organolithium Reactivity

Amanda took the Rapid Injection NMR (RINMR) apparatus developed by Aaron Sanders and modified by Marty Bevan and fine-tuned the system and procedures to make it into a reliable tool for the study of organolithium reagent reactivity. Her focus was mainly on the comparison of reactivity of different aggregates, although she also made significant observation on the comparison between various electrophiles, and on the detailed mechanism of reactions never before examined kinetically.

The largest part of her thesis work was devoted to a study of the reactivity of n-BuLi dimers, tetramers, and several n-BuLi mixed aggregates. She found that in the deprotonation of various acetylenes, the dimer was ca 108 times as reactive as the tetramer, and in the reaction with aldehydes at least 40,000 times as reactive.

Other comparisons, for example of the triple ion and monomer of (Me3Si)3CLi , and the tetramer and monomer of an aryllithium reagents, gave similar enormous reactivity differences of 109 and greater.

After her work at Wisconsin Amanda did two years of postdoctoral work in the Stolz group at CalTech, and then moved to her current faculty position at Wake Forest University.

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Kristopher J. Kolonko -- Ph.D. 2009

man in front of trees smilingThesis Title

RI-NMR Studies of Carbonyl Functionalities with Organolitium and Phosphazenium Reagents.

Kristin Plessel -- Ph.D. 2010

PlessalThesis Title

A. Addition Organolithium Reagents to Carbonyl Compounds. B. Chelation Strength in Organolithium Reagents

 

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