Jennifer Ann Love

Professor

Relevant Degree Programs

 

Great Supervisor Week Mentions

Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.

 

Qualities of excellent researchers, mentors, and leaders -- @JenniferLoveUBC #WHRISym18 @J9_Austin #greatsupervisor

 

I owe so much to my research supervisors @JenniferLoveUBC and @LaurelSchafer for all they have taught me! During #GreatSupervisor week at UBC I'm reminded of how much work our PIs put in for us behind the scenes; all the grants, paper edits, and networking to further our success.

 

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
1,3-N,O-Chelated complexes of rhodium and iridium : harnessing metal-ligand cooperativity for bond activation processes (2017)

This thesis explores the use of 1,3-N,O chelating ligands, amidates and phosphoramidates as ligands for rhodium and iridium in the +1 and +3 oxidation states. Toward this end, a series of novel group 9 complexes were prepared, characterized, and employed for cooperative small molecule activation and element-hydrogen (E-H) bond cleavage reactions. In Chapter 1, amides and phosphoramides are introduced as ligands for late transition metals. In particular, it is highlighted that such ligands have traditionally been used to form early transition metal and lanthanide N,O-chelated complexes, with the late transition metal chemistry being highly underdeveloped. In Chapter 2, the fundamental reactivity of rhodium(I) complexes having amidate ancillary ligands is presented including catalytic oxygen atom transfer using O₂ – the products of such reactions: η²-O₂ complexes were characterized using NMR spectroscopy and density functional theory (DFT). Chapter 3 details the use of 1,3-N,O chelated complexes of monovalent Rh(I) and Ir(I) for the controlled capture of HBCy₂, providing six-membered genuine metallaheterocycles bearing a δ-B-H agostic interaction, which can be employed for chemoselective boron transfer reactions. In this chapter, the inclination of this ligand class to change the chemoselectivity of HBCy₂ hydroboration toward carbonyl-containing substrates (in the presence of an alkene) is provided. Chapter 4 examines the preparation of the first unsaturated Cp*Ir(III) (Cp* = C₅Me₅) phosphoramidate complex for use in element-hydrogen (E-H) bond activation (E = H, C, Si, B). The syntheses of coordinatively unsaturated (E)-vinyloxy Cp*Ir(III) complexes, which are prepared from regioselective 1-alkyne C-H bond activation and O-phosphoramidation is discussed. This regioselectivity is completely inverted from that of free phosphoramidates, which undergo preferential N-alkylation. Finally, we illustrate how aminoborane (H₂B=NR₂) B-N bond rotation can be accessed using joint metal-ligand stabilization between Ir and a phosphoramidate coligand. All complexes were rigorously characterized using NMR spectroscopy, X-ray diffraction, as well as by DFT. Chapter 5 surmises a new protocol for rhodium-mediated ethylene amination (nitrogen-carbon bond formation) using diazenes (RN=NR) as the N-atom source. This work provides a “proof-of-principle” for the functionalization of simple C₂-synthons using easily handled nitrogen-sources, providing rhoda(III)heterocycles, which undergo [Rh]-N bond protonolysis to provide ethyl-substituted hydrazine complexes.

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Harnessing the reactivity of late transition metals for the making and breaking of C-X (X = O, S, N) bonds (2017)

This thesis explores the fundamental reactivity of π-complexes of rhodium and nickel, their reactivity to form well-defined 2-metallaoxetanes, as well as subsequent functionalization chemistry of these rare metallacycles. More generally, we also examine C-O and C-S bond cleavage processes.In Chapter 1, we discuss the history of 2-metallaoxetanes, as well as outline some of the fundamental organometallic chemistry of group 10 transition metal complexes.In Chapter 2, the chemistry of a well-defined 2-rhodaoxetane with unsaturated electrophiles is explored. In all cases, insertion into the Rh-O bond is observed. When electron-deficient alkynes are used as substrates, rhodadihydropyrans are formed. Reactivity studies have found these complexes to be robust. In contrast, when aldehydes are used, the product rhodaacetals are much less stable. Curiously, the aldehyde insertions were found to be reversible.Chapter 3 outlines the reactivity of low-valent nickel complexes with three-membered oxacycles. When epoxides were used, isomerization to the corresponding aldehyde was observed as the primary reaction pathway. Experiments with tetrasubstituted epoxides indicate that these reactions occur via 2-nickela(II)oxetane intermediates. Further, catalytic functionalization was achieved using HBpin or B2pin2. When using oxaziridines as the three-membered heterocycle, N-O oxidative addition was found to rapidly generate oxazanickela(II)cyclobutanes. Fragmentation of these metallacycles resulted in the formation of a mixture of imine and aldehyde products.Chapter 4 discusses the synthesis, mechanism of formation and reactivity of a family of well-defined 2-nickela(II)oxetanes. These nickelacycles are formed with retention of configuration, which had not been observed previously. Computational calculations were performed, whichsupport an unexpected bimetallic mechanism of oxidative addition that would allow for the observed stereochemistry. Reactivity studies indicate that the nickelaoxetanes are susceptible to protonolysis, insertion and oxidatively-induced reductive elimination reactions.Chapter 5 describes the chemistry of nickel with esters and thioesters. For thioesters, Cacyl-S bond cleavage followed by decarbonylation was observed to form methyl-thiolate complexes of nickel(II). In contrast, aryl esters were found to undergo Caryl-O oxidative addition, producing aryl-acetate nickel(II) complexes. Both of these classes of compounds were found to be competent in stoichiometric Suzuki-type cross-coupling reactions, but attempts to render the reactions catalytic have so far been unsuccessful.

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Mechanistic investigations of rhodium-catalyzed alkyne hydrothiolation (2016)

Herein, thorough mechanistic investigations into alkyne hydrothiolation catalyzed by [Tp*RhI(PPh₃)₂] (Tp* = tris(3,5-dimethylpyrazolyl)borate) are reported. The mechanism is shown to proceed through an intermediate [Tp*RhIIIH(SR)] complex (R = alkyl, aryl). Alkyne migratory insertion is shown to occur chemoselectively into the Rh-SR bond, despite the availability of a Rh-H bond, to produce a rhodathiacyclobutene intermediate. The regioselectivity of product formation is revealed to be the result of a competition between 1,2 and 2,1 migratory insertion of the alkyne to produce regioisomeric rhodathiacyclobutene intermediates. Product formation occurs upon reductive elimination, which is associatively induced by coordination of thiol.Putative off-cycle intermediates [Tp*RhH(SR)(PMe₃)] (R = alkyl, aryl) have been successfully synthesized from [Tp*RhH(CH₃)(PMe₃)]. The mechanism of formation of the [Tp*RhH(SR)(PMe₃)] complexes is proposed to involve the reductive elimination of methane, associatively induced by coordination of thiol. This mechanism is analogous to the mechanism proposed for alkyne hydrothiolation catalyzed by [Tp*Rh(PPh₃)₂]. Alkyne hydrothiolation reactions in the presence of [Tp*RhH(SR)(PMe₃)] are shown to produce the same product regioisomer as reactions catalyzed by [Tp*Rh(PPh₃)₂].The synthesis of the vinyl sulfone-containing drug K777, currently in clinical trials for the treatment of Chagas disease, via alkyne hydrothiolation methodology catalyzed by [RhCl(PPh₃)₃], is reviewed. The methodology proves to be versatile in the synthesis of K777 and related analogues. The analogues are assessed in terms of their reactivity towards Michael addition as a method of predicting pharmacodynamics properties.The methanolic pKAs of a series of para-substituted aryl thiols are reported and correlated to their predicted aqueous pKA values. The Hammett dual parameter correlation to the experimental data reveals that the acidity constants are more dependent on the inductive effects of the para-substituent compared to the resonance effect. The dual parameter correlation also allows for the prediction of the methanolic and aqueous acidity constant of any para-substituted aryl thiol, as long as the substituent’s resonance and induction Hammett constants are known.

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Oxa- and azarhodacyclobutanes as potential intermediates in novel catalytic transformations (2013)

Oxa- and azametallacyclobutanes are commonly invoked as reactive intermediates in transition-metal catalyzed reactions. However, experimental and theoretical support for their involvement in certain transformations is often scarce. In recent years, our group has been investigating the chemistry of oxa- and azarhodacyclobutanes to gain a deeper understanding of their formation and reactivity. The reactivity of oxarhodacyclobutanes (rhodaoxetanes) with organometallic reagents was investigated. Successful transmetalation with a variety of organoboron nucleophiles was achieved in good yields. This constitutes the first step in a proposed carbohydroxylation protocol. Studies towards reductive elimination have been performed but have to date remained unsuccessful. Rhodaoxetanes were also found to undergo migratory insertion with electron deficient alkynes. The resulting six-membered oxarhodametallacycles were fully characterized.Substituted rhodaoxetanes were prepared from the corresponding rhodium-olefin complexes. Exclusive selectivity for incorporation of the oxygen atom on the more substituted olefin carbon was achieved.Oxidation of rhodium ethylene complexes with a selection of nitrene precursors led to formation of azarhodacyclobutanes as two isomers. Appropriate choice of solvent and oxidant allowed for the selective preparation of either isomer. Preliminary reactivity studies revealed the high thermal and chemical stability of the product complexes.Similar to rhodaoxetanes, substituted azarhodacyclobutanes were formed by oxidation of rhodium complexes bearing substituted olefins. In this case, one isomer was formed as the major or sole product with good-to-excellent selectivity for incorporation of the nitrogen atom on the less substituted olefin carbon.Preliminary mechanistic considerations suggest that two independent mechanisms are operative including oxidation of a coordinated olefin and cycloaddition with a free olefin in solution.

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Studies towards the synthesis of functionalized aryl fluorides : transition metal catalyzed cross-coupling and fluorination of organoboron reagents (2013)

This thesis covers several synthetic approaches to the generation of highly functionalized aryl fluorides. PtCl₂(SMe₂)₂ and PtCl₂(DMSO)₂ have been applied to catalytic methylation of polyfluoroaryl imines as user-friendly precatalysts. These complexes have demonstrated high selectivity for ortho C-F activation and subsequent functionalization, exhibiting high functional group tolerance while proving more thermal, moisture and air stable than our original catalyst, [PtMe₂(SMe₂)]₂. Nickel-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions allow rapid functionalized of C-F bonds; we have been able to obtain a variety of highly functionalized aryl-, heteroaryl-, and alkyl-substituted aryl fluoride molecules under mild reaction conditions. Furthermore, we have described a novel fluorination procedure that employs organoboron reagents and electrophilic fluorine sources. This method is rapid, high yielding and can be carried out without inert atmosphere protection and dry solvents.

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Synthesis and applications of alkvl and arvl vinyl sulfides and sidearm-substituted bisoxazolines (2012)

No abstract available.

Regioselective rhodium-catalyzed alkyne hydrothiolation with alkane thiols : substrate scope and mechanistic investigations (2011)

The optimization and substrate scope of ClRh(PPh₃)₃-catalyzed alkyne hydrothiolation with alkane thiols producing E-linear vinyl sulfides is presented. The reactions generally proceed in good yields with good selectivities for a variety of alkane thiols and alkynes. Bulky aliphatic alkynes result in the best selectivity, while aryl alkynes with para-substituted electron donating groups give the best yields. The presence of coordinating functional groups in either the substrate or solvent negatively affects the reaction both in yield and selectivity. Deuterium-labeling studies indicate that the reaction proceeds via thiol oxidative addition, migratory alkyne insertion into the Rh-H bond, followed by reductive elimination.Investigations into the mechanism of Tp*Rh(PPh₃)₂-catalyzed alkyne hydrothiolation are discussed. Five mechanisms are identified as being the most likely for this process; experiments were designed to support or refute each of these possibilities. Two mechanisms are definitively dismissed and another is dismissed as highly unlikely. The results cannot distinguish between the remaining two. The product distribution of hydrothiolation is analyzed and compared to other precatalysts. Stoichiometric reactivity of Tp*Rh(PPh₃)₂ with benzyl thiol is presented. Two new complexes, proposed to be Tp*Rh(PPh₃)₂(HSBn) and Tp*Rh(H)(SBn)(PPh₃), are generated. Presumed Tp*Rh(H)(SBn)(PPh₃), prepared in situ, does not catalyze alkyne hydrothiolation. Kinetic analysis was complicated by reaction inhibition at high thiol concentrations and competing side-reactions at high alkyne concentrations. Kinetic isotope effect experiments indicate that the alkyne is not involved in the rate-determining step; however, differences in the reactivity of several para-substituted phenyl acetylenes suggest that the rate-determining step is influenced by alkyne electronics. Overall, the reaction appears to obey the following rate law under normal catalytic reaction conditions rate = k[Tp*Rh(PPh₃)₂]¹[thiol]¹[alkyne]⁰. The reaction is hypothesized to proceed by thiol oxidative addition, migratory alkyne insertion into the Rh-S bond, followed by reductive elimination.

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Pt-catalyzed cross-coupling of arylfluorides : reaction development and mechanistic analysis (2009)

Fluoroaromatics have been widely utilized in practical applications such as plastics, refrigerants, pharmaceuticals and pesticides. In fact, it has been reported that 30% of new agrochemicals and 20% of new drugs contain fluorine. However, as no aryl fluorides have been isolated from natural products, fluoroaromatic building blocks are only available through synthesis. Partial functionalization of polyfluoroaromatics is a promising methodology to generate functionalized fluoroarenes.The work reported in this thesis firstly focuses on the development of Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines. This methodology has been applied to a wide range of polyfluoroaryl imines with a variety of functional groups, producing methylated fluoroaryl imines in high yields and with high selectivity for the imine-directed ortho position, even in the presence of much weaker Br-aryl and CN-aryl bonds. These methylated fluoroaryl imine products are potential synthetic building blocks for the construction of pharmaceutically active molecules and agrochemicals.Next, insight into the mechanism of this Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines is provided. We propose that the catalytic reaction involves the following steps: C-F activation, transmetalation and reductive elimination. Specifically, the Me₂Pt(IV)-F complex formed in the C-F activation step with Me₂Pt(II) undergoes transmetalation with Me₂Zn to generate a Me₃Pt(IV) species. Reductive elimination from Me₃Pt(IV) leads to the formation of the methylated imine product and re-generates Me₂Pt(II), which can then promote C-F activation of remaining substrates, thus completing the catalytic cycle. Both transmetalation and reductive elimination occur from 5-coordinate species. Finally, examples of unusual preference for Csp²-Csp³ coupling over Csp²-Csp² or Csp³-Csp³ coupling are illustrated. We anticipated that a biphenyl product would be formed in the reductive elimination of a tetrafluorinated aryl-Me₂Pt(IV)Ph complex, based on the premise that Csp²-Csp² coupling is much faster than Csp²-Csp³ or Csp³-Csp³ coupling. However, the dominant organic products in the reductive elimination from a tetrafluorinated aryl-Me₂Pt(IV)Ph complex are methylated imine and toluene, both of which result from Csp²-Csp³ coupling. In contrast, the biphenyl product is only formed in trace amounts. These unexpected results can be explained by Hartwig’s “push-pull” theory that the largest difference of electronic properties between two ligands leads to the fastest rate of reductive elimination.

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Master's Student Supervision (2010 - 2018)
Tuning the reactivity of low valent nickel complexes towards epoxide ring-opening and exploring the reactivity of nickel η²-carbonyl complexes (2018)

This thesis explores the effects of tuning the ancillary phosphine ligands of low-valent nickel complexes on the ring-opening of epoxide, and also the reactivity of nickel η²-carbonyl complexes that are derived from epoxide isomerization. Chapter 1 describes the history of 2-metallaoxetanes, as well as the history of η²-carbonyl nickel complexes. Chapter 2 discusses the reactivity of low valent nickel complex 2.1 towards a variety of epoxides. While styrenyl and stilbene oxides were found to isomerize to η²-carbonyl complexes, tetrasubstituted epoxide 2.13 was found to form a 5-membered metallacycle, due to rapid β-hydride elimination and rapid reinsertion. Efforts in synthesizing a well-defined 2-nickelaoxetane by tuning the phosphine ligands on a nickel(0) centre are illustrated. Results show that monodentate phosphines such as triphenylphosphine and triisopropylphosphine lead to side reactions instead of facilitating the formation of 2-nickelaoxetanes. When triisopropylphosphine is used in combination with Ni(COD)₂ and epoxide 1.62, cyclotrimerization of the alkyne was observed instead of epoxide ring-opening . Chapter 3 explores the reactivity of epoxide-derived η²-carbonyl complexes towards a series of nucleophiles and electrophiles. These carbonyl complexes show no reactivity towards organozinc reagents. However, reaction with electrophiles such as benzyl bromide leads to the formation of dibromide complex 3.20, while reaction with Ph₃CBF₄ gives an unknown nickel (II) complex.  

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Ni-catalyzed ortho-directed trifluoromethylthiolation of aryl chlorides and bromides (2015)

This thesis describes a novel method to generate trifluoromethanesulfenyl arene or heteroarene products via Ni-catalyzed ortho-selective C-X (X = Cl or Br) activation. Successful C-X activation requires directing groups, but it is highly selective and allows aryl chlorides to be used and shows an appreciable substrate scope. The protocol tolerates various nitrogen-containing directing groups including imines, pyridines, pyrimidines, amides and oxazolines. The method is also compatible with aryl halides bearing substituents with a wide rage of electronic properties, including electron-donating or withdrawing abilities, as well as potentially sensitive functional groups. It also produces trifluoromethylthiolated arenes in good-to-excellent yields at ambient temperatures. [formula omitted]

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Nickel-catalyzed decarbonylative coupling for access to biaryl motifs (2015)

The goal of this research project was to design a sustainable catalytic cross-coupling reaction using nickel and carboxylic acid derivatives and apply it to the synthesis biaryls. A low-cost route to a variety of functionalized bis(hetero)aryl and biaryl motifs has been developed using aryl esters and boronic acids. This Suzuki-Miyaura-type decarbonylative cross- coupling is catalyzed by an affordable low-toxic catalyst system composed of Ni(cod)2 and PCy3. Electron-rich arylboronic acids gave the highest yields. A variety of functional groups including methyl ethers, esters, fluorine substituents and acetals are compatible with the reaction conditions. The reaction did not tolerate boronic acids possessing halogen or cyano functionalities. Aryl esters with and without nitrogen atoms were also accommodated in the reaction. The methodology reveals challenges associated with nickel and esters in cross- coupling chemistry. Additionally, it presents an attractive alternative to the use of palladium catalysis currently used in industry to acquire such biaryls.

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Application of rhodium-catalyzed alkyne hydrothiolation to the syntheses of K777 and analogues : potential therapeutics for the treatment of Chagas' disease (2012)

Chagas’ disease is a neglected global disease that affects millions of people in LatinAmerica and has started to spread to different areas around the world. This disease is the leadingcause of heart failure in Latin America and has many other symptoms including digestive trackproblems and myocardial damage. The causative organism of this disease is T. Cruzi, which isspread though an insect vector as well as human methods such as blood transfusions, organdonation and food contamination.Current drug therapies are not sufficient; they suffer from lengthy dosage duration andhave many dangerous side effects. In the last two decades the organism’s cysteine protease,cruzain has become a desired target for inhibition. Many cysteine protease inhibitors have beenstudied in the last two decades with one potential therapeutic - K777, an irreversible cysteineprotease inhibitor, having the most promise. K777 contains a potent vinyl sulfone warhead,which acts as a Michael-acceptor to the cysteine residue in the catalytic triad of cruzain. K777 iscurrently entering phase 1 clinical trials.The potent warheard vinyl sulfone in K777 is of interest to the laboratory of Dr. JenniferLove due to our methodology for synthesizing vinyl sulfides. We proposed that we couldsynthesize K777 and a variety of analogues using our rhodium-catalyzed alkyne hydrothiolationmethod as the first application of this method in total synthesis. Here we present the totalsynthesis of K777 and analogues highlighting the wide substrate scope of our methodology.

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