Browsing by Author "Widenhoefer, Ross A"

In the last two decades, the field of homogeneous gold catalysis has been

extremely active, growing at a rapid pace. Another rapidly-growing field—that of

computational chemistry—has often been applied to the investigation of various gold-

catalyzed reaction mechanisms. Unfortunately, a number of recent mechanistic studies

have utilized computational methods that have been shown to be inappropriate and

inaccurate in their description of gold chemistry. This work presents an overview of

available computational methods with a focus on the approximations and limitations

inherent in each, and offers a review of experimentally-characterized gold(I) complexes

and proposed mechanisms as compared with their computationally-modeled

counterparts. No aim is made to identify a “recommended” computational method for

investigations of gold catalysis; rather, discrepancies between experimentally and

computationally obtained values are highlighted, and the systematic errors between

different computational methods are discussed.

The wide-spread occurrence of biologically active nitrogen-containing heterocycles and allylic amines inspired us to develop atom-economical methods for their syntheses.

A cationic gold(I) N-heterocyclic carbene complex catalyzed the intermolecular hydroarylation of allenes with indoles to form (E)-allylic indoles in modest to good yield at room temperature. The protocol was effective for monosubstituted, 1,3-disubstituted, and tetrasubstituted allenes and various indoles.

Platinum(II) bis(phosphine) complexes catalyzed the intermolecular hydroamination of monosubstituted allenes with secondary alkylamines in good yield with selective formation of (E)-allylic amines. The scope of the protocol included aryl and alkyl monosubstituted allenes as well as a variety of both cyclic and acyclic secondary alkylamines.

The scope of gold(I)-catalyzed intermolecular hydroamination of 1-alkenes with 1-methyl-2-imidazolidinone was expanded to include additional 1-alkenes functionalized with carboxylic acid derivatives. However, a nucleophile screen failed to identify nucleophiles other than cyclic ureas and 2-oxazolidinone that efficiently undergo hydroamination with 1-alkenes. Various carbamates, arylamines, amide derivatives, sulfur-containing amide derivatives, and α-heteroatom compounds failed to react with 1-octene under gold(I)-catalyzed conditions.

A chiral bis(gold) phosphine complex catalyzed the stereoconvergent, intermolecular enantioselective hydroamination of chiral, racemic 1,3-disubstituted allenes with carbamates to form N-allylic carbamates in good to high yield with up to 92% ee. In addition, enantiopurity experiments suggested the nature of the catalytically active species changes with increasing concentration of N-allylic carbamate.

Allylic amines are important and fundamental building blocks due to their wide-spread occurrence in many natural products and the ability to further functionalize them by transformations on the double bond to generate a diverse range of compounds. Transition-metal catalyzed allylic substitution represents an attractive and efficient approach towards the synthesis of these allylic amines. However, limitations associated with the traditional methods developed for such allylic amination in terms of regiospecificity, atom economy and generality in these transformations, combined with the importance of allylic amination, prompted us to develop novel atom efficient and regiospecific methods for their synthesis.

A 1:1 mixture of AuCl[P(t-Bu)₂o-biphenyl] (5 mol %) and AgSbF₆ (5 mol %) catalyzed the intermolecular amination of underivatized allylic alcohols with 1-methyl-2-imidazolidinone and related nucleophiles. The first examples of intermolecular allylic amination was developed that in the case of gamma-unsubstituted and gamma-methyl-substituted allylic alcohols, occurred with high gamma-regioselectivity and syn-stereoselectivity.

A 1:1 mixture of AuCl[P(t-Bu)₂o-biphenyl] (5 mol %) and AgSbF₆ (5 mol %) also served as a very efficient catalytic system for the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. The protocol was effective for a range of secondary as well as primary alkylamines as nucleophiles with different substitutions on the alkyl chain tethering the nucleophile to the allylic alcohol. The method was also extended towards the total synthesis of the naturally occurring alkaloid (S)-(+)-coniine in two steps from the starting (R,Z)-8-(N-benzylamino)-3-octen-2-ol. In addition, gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield and 96% ee that established the net syn-addition of the nucleophile with respect to the departing hydroxyl group.

A bis(gold) phosphine complex (S)-Au₂Cl₂(DTBM-MeOBIPHEP) (2.5 mol %) and AgClO₄ (5 mol %) catalyzed the intramolecular enantioselective dehydrative amination of allylic alcohols with carbamates to form the corresponding substituted pyrrolidines, piperidines, morpholines and piperazines in excellent yields and with up to 95% ee. This general and effective protocol tolerated a range of carbamates as well as sulfonamides as nucleophiles. Cyclization of chiral amino allylic alcohols that possessed a stereogenic homoallylic or hydroxy-bound carbon atom occurred with an overriding catalyst control of asymmetric induction. In addition, stereochemical analysis of the cyclization of a chiral non-racemic secondary allylic alcohol established the net syn-displacement of the hydroxy group by the carbamate nucleophile.

Alongside allylic amination, a cationic gold(I)-N-heteocyclic carbene complex catalyzed the intermolecular etherification (alkoxylation) of allylic alcohols in a regiospecific and syn-stereoselective fashion. The transformation was highly efficient to utilize unactivated primary and secondary alcohols as nucleophiles with different allylic alcohols to undergo regiospecific etherification. Employment of a chiral nonracemic secondary allylic alcohol, trans-5-(benzyloxy)pent-3-en-2-ol (98% ee) showed a high level of chirality transfer on reaction with n-butanol to the corresponding allylic ether, (2-butoxypent-3-en-1-yloxy)methylbenzene (97% ee) and established the net syn-addition of the alcohol nucleophile with respect to the departing hydroxyl group of the allylic alcohol.

Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, especially, has attracted enormous attention because of its atom-economical characteristic to synthesize amine moieties. As a result, numerous publications have been reported relating the hydroamination reaction using various metal catalysts. However, the hydroamination of unactivated alkenes still remains a challenge task because of the low reactivity of the CC double bond. Recent development of superior gold(I) catalysis in many organic transformations stimulated us to develop efficient gold(I)-catalyzed methods for enantioselective intra- and intermolecular hydroamination of unactivated alkenes.

A gold(I)-catalyzed system for enantioselective intramolecular hydroamination of unactivated alkenes has been developed. For the effective gold(I)-catalyzed method, various gold(I)-catalysts have been synthesized and tested. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives, most effectively. The method was effective for both carbamates and ureas to form pyrrolidine derivatives with up to 85 % ee.

The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee.

Polymer-embedded ligands have been synthesized to demonstrate proofs of concepts for fluxional mechanocatalysis. We applied a certain shear stress using a rheometer in the course of palladium-catalyzed asymmetric allylic alkylation to examine catalytic reactivity change under the mechanical force.

The transition metal-catalyzed hydroamination of a C−C multiple bond represents an efficient entry into the synthesis of nitrogen-containing heterocycles and acyclic amine derivatives. Nonetheless, the development of general methods for catalytic hydroamination has been met with challenge along the way. Gold(I)-catalysis has shown particular activity for catalytic hydroamination, especially in the context of allenes and alkynes. However, the development of gold(I)-catalyzed methods for the hydroamination of simple alkenes has lagged behind significantly. Chapter 1 will review the area of gold(I)-catalyzed hydroamination of unactivated and activated alkenes from 2006 to the present. Additionally, the hydroamination of 1,3-dienes and dehydrative amination of underivitized allylic alcohols will also be reviewed. In an effort to glean revelatory information for the further development of gold(I)-catalyzed hydroamination, particular attention will be made to experimental mechanistic analysis and the study of putative reaction intermediates.

The cationic gold phosphine complex [(P(t-Bu)2o-biphenyl)Au(NCMe)]+ SbF6–catalyzes the intramolecular hydroamination of 6-alkenyl-2-pyridones to form 1,6-carboannulated 2-pyridones in high yield. The hydroamination of 6-(γ-alkenyl)-2-pyridones was effective for monosubstituted and 1,1- and 1,2-disubstituted aliphatic alkenes, and the method was likewise effective for the hydroamination of 6-(δ-alkenyl)-2-pyridones. Spectroscopic analysis of mixtures of 6-(3-butenyl)-2-pyridone, (2.2)AuCl, and AgSbF6 established the N-bound 2-hydroxypyridine complex [(2.2)Au(NC6H3-2-OH-6-CH2CH2CH=CH2)]+ SbF6– as the catalyst resting state.

The cationic gold phosphine complex [(PCy2o-biphenyl)Au(NCMe)]+ SbF6– catalyzes the selective intermolecular, anti-Markovnikov hydroamination of the C=C bond of monosubstituted and cis- and trans-disubstituted alkylidenecyclopropanes (ACPs) with 1-methyl-imidazolidin-2-one to form 1-cyclopropyl alkylamine derivatives in high yield and with high regio- and diastereoselectivity. This method was likewise effective for other classes of nitrogen nucleophiles, such as 2-pyridones and 1,2,3-benzotriazole. Mechanistic studies on the intermolecular, anti-Markovnikov hydroamination of ACPs with 1-methyl-2-imidazolidione were conducted in an effort to reveal the catalyst resting state, the overall kinetic order of the reaction, as well as the nature of both the C−N bond formation and protodeauration steps of the reaction. It was found that the title reaction exhibited first order behavior in ACP, 1-methyl-2-imidazolidinone, and gold catalyst. Further, the reaction exhibited behavior consistent with product inhibition and showed inverse first-order behavior in 1,3-dimethyl-2-imidazolidinone. Kinetic analysis was consistent with a scenario involving turnover-limiting C−N bond formation, followed by facile protodeauration. Computational analysis of the gold-catalyzed ACP hydroamination likewise supports turnover-limiting C−N bond formation. DFT analysis also revealed that a stronger C−Au and C−N bond in the anti-Markovnikov pathway favors the observed regiochemistry of the reaction. Similarly, Fukui analysis on the purported gold-π-ACP intermediate reveals electrophilic character at the terminal alkene carbon atom in the presence of an incoming nucleophile.

Cationic gold complexes containing an N-heterocyclic carbene ligand catalyze the intermolecular anti-Markovnikov hydroarylation of monosubstituted and cis- and trans-disubstituted methylenecyclopropanes (MCPs) with N-alkyl and 1,2-dialkyl indoles to form the corresponding 3-(cyclopropylmethyl)indoles in high regio- and diastereoselectivity and in good to excellent chemical yield.

The importance of nitrogen-containing compounds in human life has drawn us to focus on the preparation of amine derivatives, combined with the limitations associated with traditional methods for the formation of C-N bonds has prompted us to develop new and efficient syntheses, of amine and ether derivatives and explore the mechanisms of the gold(I)-catalyzed reactions.

A mixture of AuCl[P(t-Bu)2o-biphenyl] (5 mol %) and AgOTf (5 mol %) served as an effective catalyst for the intermolecular hydroamination of allenes with arylamines to form N-prenylaniline and N,N-diprenylaniline derivatives. This gold(I)-catalyzed protocol was effective for the formation of arylamines at non-forcing conditions with wide substrate scope in both allene and aniline, in high yields with good regioselectivity diastereoselectivity.

The mechanism of the gold(I)-catalyzed hydroalkoxylation and hydroamination of alcohols and carbamates with allenes, catalyzed by AuIPrCl (IPr= 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgOTf was investigated. The experimental rate laws for both reactions indicate first-order behavior in nucleophile and catalyst and zero-order behavior in catalyst. We propose an outer-sphere mechanism with turnover limiting protonolysis for the gold(I)-catalyzed hydrofunctionalization of allenes with alcohols or carbamates based on kinetic isotope effect, saturation behavior, and stereochemical analysis of hydroalkoxylation.

The mechanism of gold(I)-catalyzed hydroamination of allenes with arylamines was examined. Specifically, we explored the hydroamination of 3-methy-1,2-butadiene with aniline catalyzed by AuCl[P(t-Bu)2o-biphenyl] (5 mol %) and AgOTf (5 mol %) in dioxane at 45 °C to form N-prenylaniline and N,N-diprenylaniline. The kinetics of this reaction were determined to be first-order in aniline, allene, and catalyst. We have concluded that the mechanism for the gold(I)-catalyzed intermolecular hydroamination of allenes with arylamines involves outer-sphere attack of aniline on the gold--allene complex based on stereochemical analysis of the hydroamination product from the reaction of an enantiomerically enriched allene, (R)-1-phenyl-1,2-butadiene, with 3-bromoaniline.

Methylenecyclopropanes (MCPs) are highly strained and serve as useful building blocks in organic synthesis. When activated by a gold catalyst, subsequent nucleophilic attack can result in ring opening (ring-expansion) of the cyclopropane moiety. Gold(I)-catalyzed ring-opening of MCPs at the distal carbons can result in an exo or internal allylic amine, with exo double bonds providing an important handle for further functionalization in natural product synthesis.

This work explores the scope of MCP ring opening reactions with aniline derivatives with the goal of optimizing for the exo allylic amine. Although nonpolar solvent resulted in a clean and fast reaction, the selectivity between isomers was minimal. With increasing polarity of coordinating solvents there was an increase in selectivity for the desired isomer, but with reaction rates slowing dramatically. Lewis basicity of the aniline nucleophile proved to be a crucial aspect in the progress of the reaction, with electron rich anilines failing to proceed. MCP scope showed that larger ring sizes of bicyclic MCPs favor the competing reaction, hydroamination of the C1 carbon. Overall, ring opening reactions of bicyclic MCPs with electron deficient aniline derivatives proved to offer high selectivity and moderate to high yields.

Apratoxin D, recently isolated from two species of cyanobacteria, L. majuscula and L. sordida, exhibits highly potent in vitro cytotoxicity against H-­‐‑460 human lung cancer cells with an IC50 value of 2.6 nM. The potent biological activity exhibited by apratoxin D combined with its intriguing molecular architecture has led to the pursuit of its asymmetric total synthesis. Studies toward and completion of the first asymmetric total synthesis of apratoxin D are reported. Key transformations include a Kelly thiazoline formation, Paterson anti-­‐‑aldol and an Evans syn-­‐‑aldol. The synthesis was completed in 2.1% total yield over 31 steps from (R)-­‐‑citronellic acid.

Cationic gold (I) complexes are highly efficient catalysts for the cycloisomerization of 1,6-­‐‑enynes, a transformation capable of providing a great amount of structural complexity from simple starting materials. The in situ spectroscopic analysis of the catalytic cycloisomerization of a 7-­‐‑phenyl-­‐‑1,6-­‐‑enyne, as well as the tandem gold/silver-­‐‑catalyzed cycloaddition/hydroarylation of 7-­‐‑aryl-­‐‑1,6-­‐‑enynes is described. The cycloaddition/hydroarylation reaction provides 6,6-­‐‑ diarylbicyclo[3.2.0]heptanes in good yield under mild conditions. Experimental observations point to a mechanism involving gold-­‐‑catalyzed cycloaddition followed by silver-­‐‑catalyzed hydroarylation of a bicyclo[3.2.0]hept-­‐‑1(7)-­‐‑ene intermediate.

The control of bond scission and formation by mechanocatalysis has potential in a variety of applications, including biomedical devices, mechanical sensors and self-­‐‑

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healing materials. The synthesis and study of C2-­‐‑symmetric bis(phosphine) ligands with applications toward mechanocatalysis is described. Additionally, the synthesis and study of a tetradentate ligand designed toward mechanochemical activation of a latent catalytic complex is reported. These studies have allowed further development in the design of transition metal complexes capable of activation by mechanical force.

Cationic gold(I) complexes have recently contributed to significant developments in homogenous catalysis. Such complexes have been praised as highly effective catalysts for the functionalization of C-C multiple bonds, leading to research on cationic gold-catalysts developing at an aggressive pace. Despite the progress being made surrounding gold(I)-catalysis, there are still many gaps in our fundamental understanding of the key intermediate complexes and their reactivity in these transformations, exemplified by the often evoked gold alpha-oxo carbene species. While there are existing computational studies suggesting the instability of gold alpha-oxo carbene species, there lacks any experimental evidence to support the stability and reactivity of alternate key intermediate species, such as gold alpha-oxo carbenoid species and gold N-alkenoxypyridinium/sulfonium complexes. Herein, we address the issues surrounding the formation of gold alpha-oxo carbene species in reported literature. We report the synthesis and reactivity of gold pyridinium alpha-oxo carbenoid complexes, gold sulfonium alpha-oxo carbenoid complexes, and gold alpha,alpha-dioxo carbenoid complexes. We then report the direct observation of a gold N-alkenoxysulfonium complex in a gold-catalyzed alkynyl sulfoxide rearrangement reaction and the synthesis of a series of gold-oxide compounds. Together, this research addresses the gaps in knowledge surrounding key intermediate species in gold(I)-catalyzed transformations.

Mechanical forces are known to drive a range of covalent chemical reactions and have a number of applications, including access to new reaction pathways, polymer transformations, degradable polymers, stress/strain sensing in bulk materials, and the release of small molecules/protons. In switchable catalysis, mechanical forces have been mainly exploited to activate latent catalysts by unplugging inhibiting ligands. However, mechanical forces offer more opportunities beyond breaking bonds due in part to the reversibility and continuous/wide adjustability. As an complementary strategy, force may be applied to a spectator ligand to toggle the structure and reactivity of the transition metal complex incrementally and reversibly among multiple states, without incurring scissile events. In this dissertation, we study force-activity relationships of elementary steps and isolated catalytic transformations under this strategy, to build knowledge toward such multi-state mechanocatalysts. We introduce force probe ligands, a series of macrocyclic bis(phosphine) ligands containing a stiff-stilbene photoswitch, as tools to quantify force effect (Chapter 2). Each force probe ligand has a known force applied to the bis(phosphine), which is quantified by DFT methods. When employed in transition metal complexes, force probe ligands enables the measurements of force-dependent properties. In Chapter 3, we quantify the rate of C(sp2)–C(sp2) reductive elimination from platinum(II) diaryl complexes containing force probe ligands as a function of mechanical force applied to these ligands, as our first step toward force-dependent elementary step reactivity. DFT computations reveal complex dependence of mechanochemical kinetics on the structure of the force-transducing ligand. We experimentally validated the computational finding for the most sensitive of the ligand designs, based on MeOBiphep, by coupling it to a macrocyclic force probe ligand. Consistent with the computations, compressive forces decreased the rate of reductive elimination whereas extension forces increased the rate relative to the strain-free MeOBiphep complex with a 3.4-fold change in rate over a ~290 pN range of restoring forces. The calculated natural bite angle of the free macrocyclic ligand changes with force, but 31P NMR analysis and calculations strongly suggest no significant force-induced perturbation of ground state geometry within the first coordination sphere of the (P–P)PtAr2 complexes. Rather, the force/rate behavior observed across this range of forces is attributed to the coupling of force to the elongation of the O…O distance in the transition state for reductive elimination. The results suggest opportunities to experimentally map geometry changes associated with reactions in transition metal complexes and potential strategies for force-modulated catalysis. In Chapter 4, we move forward to mechanistic study on how forces are coupled to reactions by kinetic experiments on the stilbene isomerization (E to Z) of force probe ligand with/without platinum(II) coordination. We obtained the activation energies of free force probe ligands and (P–P)PtCl2 complexes, and results reveal the energy difference between free ligand and coordinated complex increases with restoring force, with ~ 6 kcal/mol activation energy difference change over ~ 120 pN ranges of forces on force probe ligands. We further simulated the activation energies of untethered stiff-stilbene under different tension, and found a decent consistency of computational data with empirical activation energies for free ligand. Taking the simulated energy/force relationship as a calibration curve, we estimated force experienced by stilbene in (P–P)PtCl2 complexes, which showed > 100 pN can be generated through Pt(II) coordination. The results suggest an allosteric effect by distal metal-ligand coordination can generate large forces and could drive orders-of-magnitude (up to ~104) changes in the rate of a coupled unimolecular trans/cis alkene isomerization. In Chapter 5, we quantify the rate of C(sp3)–C(sp2) reductive elimination of N,N,4-trimethylaniline from palladium(II) methyl aryl complexes employing force probe ligands, as an effort to explore other useful scopes and metal influence in force sensitivity. Analysis of the resulting first-order rate constants revealed that the rate of reductive elimination was largely invariant of ligand restoring force, as kobs varied by < 20% across the series of ligands employed. Different from the aforementioned (P–P)PtCl2 complexes, (P–P)PdArMe complexes are not stable at ambient conditions and thus generated in situ for kinetic experiments, which introduced 2 equiv. of bromide. We propose the formation of anionic complex [(P–P)PdBrArMe]- under this condition deactivates force coupling to the reductive elimination pathway. Finally, in Chapter 6, we close the catalytic cycle by demonstrations of isolated catalytic transformations of Rh(I)-catalyzed hydroformylation of 1-octene/styrene and Cu–H-catalyzed hydrosilylation of acetophenone, likewise employing force probe ligands. Over a range of ~230 pN, we found the linear to branch regioselectivity of 1-octene hydroformylation changed ~1.7 folds, and the enantioselectivity of styrene hydroformylation changed ~ 10% in ee. Cu–H-catalyzed hydrosilylation of acetophenone showed ~ 20% increase in ee as force decreases over ~ 290 pN. Low temperature NMR studies indicate the structure of (P–P)RhH(CO)2 complexes, the key intermediate that determines selectivity, remains the same across the series of ligands applied with regard to equatorial/equatorial or equatorial/apical bis(phosphine) coordination modes, while vast changes in selectivity are often resulted from changes in the coordination modes. Therefore, we propose force couples to mentioned reactions as a dynamic effect, in contrast to toggling the intermediate structure. With the limited force range accessible with this series of force probe ligand, observed changes in reaction selectivity are also limited. However, this research provides a bridge from elementary step study to polymeric matrix-supported switchable mechanocatalysis, in which wider range of forces can be achieved to provide opportunities in better force-regulated transformations.

Cationic gold carbene complexes have attracted significant attention, being postulated as intermediates in a range of gold-catalyzed transformations. Regardless of the remarkable progress in the gold (I) catalysis, our fundamental understanding on the key intermediate species and the subsequent reactivity, and mechanistic insight is deficient. This is mainly due to the lack of proper model system with sufficient reactivity, as the majority of known gold carbene complexes are heteroatom stabilized or sterically hindered, and because of a dearth of direct intermediate observations in catalytic systems. Lewis acid mediated leaving group abstraction from a neutral gold precursor provides a convenient method for the generation of rare examples of reactive gold carbene species in high yield and purity, addressing the issue with isolation of such transient species as well as allowing in situ spectroscopic analysis. Subsequent trapping experiment with nucleophiles provides kinetic information about relevant catalytic transformations, and the -ionization strategy is further extended toward generation of transient  -cationic propyl gold species for studying gold to alkene carbene transfer reaction.

Cationic gold(I) complexes containing phosphine and N-heterocyclic carbene based ligands are a powerful catalysts for the hydrofunctionalization of C-C multiple bonds with carbon and heteroatom based nucleophiles as well as the cycloisomerization of enynes and related π-systems. Mechanisms involving outer sphere, nucleophilic attack an activated gold π-complex are typically invoked for both hydrofunctionalizations and cycloisomerizations, however, direct experimental evidence for these mechanisms remain limited.

Gold(I) catalyzed allene racemization is an important background reaction in the hydrofunctionalization of 1,3 disubstituted allenes. It can compromise chirality transfer or be exploited to realized stereoconvergent synthesis of allylic alcohols and amines. The kinetics of the racemization of aromatic 1,3-disubstituted allenes catalyzed by gold(I) phosphine complexes has been investigated. The rate of racemization displayed first order dependence on allene and gold concentration. Kinetic analysis gold(I) catalyzed racemization of allenes as a function of allene and phosphine donor ability established a depletion of electron density on the terminal allene carbons and an accumulation of electron density on the phosphine ligand in the rate-limiting transition state.

Investigation of the mechanism of gold(I) catalyzed hydrofunctionalization of allenes with alcohols, carbamates, and anilines established a variable catalyst resting state depending on the equilibrium binding affinities of the nucleophile and the relative concentrations of allene and nucleophile that are employed. Reversible C-X bond formation may explain the difference in regioselectivity observed for hydroalkoxylation and hydroamination with carbamates. Additionally, in situ analysis of the hydrofunctionalization of enatiopure 1,3-disubstituted allenes for enatiopurity of the allene and product ruled out trapping of an achiral η1-intermediate and established concomitant allene racemization as the cause of loss of enatiopurity.

Finally we report the two gold(I) carbene complexes not stabilized by π-conjugated heteroatoms. First, we report the hydride abstraction from a neutral gold cycloheptatrienyl complex that was isolated and characterized in solution and by single crystal X-ray diffraction. This complex represents the first example of a gold carbenoid complex that lacks conjugated heteroatom stabilization. Second we report the synthesis of the first gold(I) vinylidene via hydride abstraction from a gold (disilyl)ethylacetylide complex to form a cationic β,β-disilacyclopentyl vinylidene complex. The C1 and C2 carbon atoms of the vinylidene complex underwent facile interconversion presumably through the gold π-disilacyclohexyne.

Cationic gold(I) complexes have been recognized as efficient catalysts for a wide array of transformations, including carbene transfers to form cyclopropanes and hydrofunctionalization reactions. While there have been great strides made in the development of these reactions, far less is understood about the mechanisms by which these transformations occur. Here are reported kinetic and mechanistic analyses of gold(I)-catalyzed reactions as well as the interrogation of the properties of cationic gold(I) carbene complexes, which are commonly proposed intermediates in gold(I)-catalyzed transformations.

A series of gold(I) sulfonium benzylide complexes were synthesized by nucleophilic substitution of -chloro gold(I) carbenoid complexes with sulfides. These complexes reacted efficiently with alkenes and dimethylsulfoxide to form cyclopropanes and benzaldehyde, respectively. Kinetic analysis of these reactions is consistent with the intermediacy of cationic gold(I) benzylidene complexes. Further mechanistic analysis revealed that alkene stereochemistry is preserved during cyclopropanation and a Hammett analysis of the reaction suggests a concerted mechanism for cyclopropanation.

To evaluate the electron donor ability of (L)Au fragments in cationic gold(I) carbene complexes, a series of cationic gold (β,β‐disilyl)vinylidene complexes and cationic gold (fluorophenyl)methoxycarbene complexes were synthesized. 29Si and 19F NMR analysis of these complexes compared to organic model compounds revealed that (L)Au fragments are significantly more inductively donating and comparably π‐donating as p-substituted aryl groups. A comparison of various ligands showed that (P(t-Bu)2-o-biphenyl)Au fragments are nominally stronger electron donors than (IPr)Au fragments, both of which are significantly more electron donating that (PPh3)Au and [P(OMe)3]Au fragments.

Kinetic and mechanistic analysis of the gold(I)-catalyzed hydrofunctionalization of 3-methyl-1,2-butadiene with alcohols and anilines was performed. Experimental data suggest a mechanism for the gold(I)-catalyzed hydroalkoxylation involving endergonic allene displacement of triflate from gold, followed by an outer-sphere attack of alcohol on gold(I)--allene complex, followed by rapid protodeauration. In contrast, for the gold(I)-catalyzed hydroamination, the active catalyst is the gold(I) bound nucleophile complex and a buildup of bis(gold) vinyl complex suggests a slow protodeauration.

A brief study evaluating student learning in the classroom is also presented. A series of team-based learning applications based on the spiropyran to merocyanine transformation were developed and assessed relative to a series of control application problems. There was no statistically significant difference in student outcomes based on the applications used in class, but student feedback suggests that the interconnected, and real-life examples were more engaging.

Soluble gold(I) complexes are highly efficient catalysts for the functionalization of C-C multiple bonds through the addition of carbon- or heteroatom-nucleophiles across π-bonds or cycloisomerizations of enynes and related π-systems. Mechanisms involving outer-sphere attack of a nucleophile on the electrophilic π-ligand of a cationic gold π-complex are typically invoked for gold(I)-catalyzed hydrofunctionalization and cycloisomerization processes, but direct experimental evidence for this mechanism is limited.

As an extension of the pioneering research in the Widenhoefer lab on the synthesis and characterization of gold(I) π-complexes, a diverse family of 15 gold(I) π-complexes in three distinct series are reported herein. First, the synthesis, characterization, and solution behavior of a series of seven gold(I) π-diene complexes is reported. In each case, gold binds preferentially to the less substituted C═C bond of the diene, but intermolecular exchange of the complexed and uncomplexed C═C is facile. The gold-alkene interaction is stabilized via substitution-dependant donation of electron density from the uncomplexed C═C bond to the complexed C═C bond of the diene.

In addition, a pair of axially chiral dicationic, bis(gold) π-alkene complexes that contain a 2,2′-bis(phosphino)biphenyl ligand are reported. The complexes show no intramolecular Au-Au interactions or facial selectivity for complexation, but solution analyses suggest that the environment about one gold center affects the behavior of the proximal gold center through a yet unknown mechanism. Gold(I) π-alkene, alkyne, diene, and allene complexes that bear a triphenylphosphine supporting ligand have also been synthesized and characterized in situ. The π-ligands in the triphenylphosphine gold complexes were considerably more labile than those bearing bulky, electron rich phosphine or N-heterocyclic carbene ligands, and the complexes decomposed in solution above -20 °C.

Mechanistic investigation of the gold-catalyzed cycloisomerization of a 7-aryl-1,6-enyne led to characterization of the first organometallic complex directly observed in the course of an enyne cycloisomerization. The complex is best described as a gold π-(bicyclo[3.2.0]heptane) complex with a domination metallacyclopropane binding interaction and undergoes an acid-catalyzed rearrangement to yield a stable bicyclo[3.2.0]heptane product which can further isomerize in the presence of Ag+. In a further effort to understand the reactive species in catalytic cycloisomerizations, the first example of a gold cyclopropyl carbene was synthesized and fully characterized.

Finally, in an effort understand the mechanistic distinctions between electrophilic metal-catalyzed hydrofunctionalization and similar Brønsted acid-catalyzed additions, the kinetics and stereochemistry of intramolucar acid-catalyzed hydrofunctionalizion were studied. In all cases, the transformations were > 95 % selective for anti-addition and displayed rate laws similar to those expected for metal-catalyzed variants. A concerted C-H, C-X bond forming mechanism for addition is proposed.

It is now well appreciated that coupled mechanical forces can influence the rates and outcomes of covalent chemical reactions in isolated polymers and in bulk polymeric materials. Mechanochemical reactions have been widely used in mechanocatalysis, release of small molecules and protons, biasing and probing reaction pathways, stress reporting, stress strengthening and degradable polymers. Mechanochemical reactions involve much more than simply breaking of bonds, and there exist rich opportunities for new reactions to be developed for a wide range of potential applications. In this dissertation, we report new mechanochemical reactions of three types: addition, elimination, and isomerization.Mechanical forces have been used previously to activate latent catalysts by accelerating dissociation of an inhibiting ligand, but tuning catalytic activity by force remains limited to a single demonstration of force-dependent enantioselectivity of Heck and Trost reactions. Chapter 2 describes how force affects the rate of oxidative addition, often the first step within a catalytic cycle. We study the effect of force applied to the biaryl backbone of a bisphosphine ligand on the rate of oxidative addition of bromobenzene to a ligand-coordinated palladium center. Local compressive and tensile forces on the order of 100 pN are generated using a stiff stilbene force probe. We find that a compressive force increases the rate of oxidative addition, whereas a tensile force decreases the rate, relative to that of the parent complex of strain-free ligand. Rates vary by a factor of ~6 across ~340 pN of force applied to the complexes. The applied forces exert an opposite effect on oxidative addition relative to that for reductive elimination, laying the groundwork for mechanically switchable catalysts that can be optimized for individual steps within a closed catalyst cycle. Chapter 3 demonstrates a new mechanochemical elimination reaction, namely the mechanical release of hydrogen fluoride, and its application to triggered polymer degradation. As a versatile reagent for material remodeling, hydrogen fluoride has applications in self-immolative polymers, remodeled siloxanes, and degradable polymers. The responsive, in situ generation of HF in materials therefore holds promise for new classes of adaptive material systems. We achieve the mechanochemically coupled generation of HF from 2-methoxy-gem-difluorocyclopropane (MeO-gDFC) mechanophores in polymers. Pulsed ultrasonication of a MeO-gDFC containing polymer leads to one equivalent of HF release per MeO-gDFC activation. We further quantify the mechanochemical reactivity of MeO-gDFC by single molecule force spectroscopy, and force-coupled rate constants for ring opening reach ~36 s-1 at a force of ~890 pN, 400 pN lower than is required in dialkyl gDFC mechanophores that lack the methoxy substituent. The SMFS and sonication results suggest that MeO-gDFC is a more efficient mechanophore source of HF than its 2-methoxy-gem-dichlorocyclopropane analog is of HCl, in contrast to expectations based on trends in force-free reactivity. We apply the mechanical release of HF to accelerate the degradation of a copolymer containing both MeO-gDFC (3 mol%) and an HF-cleavable silyl ether (25 mol%). The mechanochemical reaction of MeO-gDFC thus provides a mechanically coupled mechanism of releasing HF for polymer remodeling pathways that complements previous thermally driven mechanisms. Finally, in Chapter 4, we report the mechanically driven isomerization of cubane, a compound of longstanding fascination to chemists due to its structure, symmetry, and strain. The mechanical coupling is explored at three regiochemical dispositions: ortho, meta and para. In contrast to the fact that all compounds can be activated thermally, cubane is mechanically activated only when coupled at ortho positions. Through mechanical activation, cubane reacts to form a thermally inaccessible syn-tricyclooctadiene product, in comparison to cyclooctatetraene, which is observed in thermal rearrangements of cubane. Pulsed ultrasonication of such cubane-containing polymer leads to efficient isomerization (57% activation after 4 h sonication). We further quantify the mechanochemical reactivity of cubane by single molecule force spectroscopy, and force-coupled rate constants for ring opening reach ~33 s-1 at a force of ~1.55 nN, lower than required forces of cyclobutanes which are typically 1.8-2.0 nN.

The ability of gold(I) complexes to function as catalysts for myriad organic transformations has led to a dramatic increase in their utilization. Among the homogeneous reactions catalyzed by gold(I), carbon-carbon and carbon-heteroatom bond forming processes are of particular interest for the fields of organic synthesis and pharmaceutical development. Discussed herein are gold(I)-catalyzed methods for the intra- and intermolecular functionalization of alkenes, alkynes, and allenes with nitrogen- and oxygen-based nucleophiles leading to new C‒X bonds (X = N, O).

Approximately 26 cationic gold π-alkene complexes, containing either IPr [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] or P(t-Bu)2o-biphenyl ancillary ligands, were isolated or generated and six complexes were analyzed by X-ray crystallography. Spectroscopy, X-ray crystallography, and alkene binding studies are in accord with a gold−(π-alkene) interaction dominated by σ-donation from the alkene to gold. Kinetic analyses of degenerate isobutylene exchange in both the IPr and phosphine systems are consistent with associative pathways for isobutylene exchange involving cationic bis(alkene) intermediates.

Reaction of a 1:1 mixture of (L)AuCl [L = P(t-Bu)₂o-biphenyl or IPr] and AgSbF₆ with internal alkynes led to isolation of the corresponding cationic, two-coordinate gold π-alkyne complexes in ≥90% yield. Equilibrium binding studies show that the binding affinities of alkynes to gold(I) are strongly affected by the electron density of the alkyne and to a lesser extent on the steric bulk of the alkyne. Treatment of a suspension of (IPr)AuCl and AgSbF₆ with terminal arylacetylenes led to the formation of thermally unstable gold π-alkyne complexes of the form [(IPr)Au(eta2-HC≡CAr)] SbF₆ in ≥86 ± 5% yield, which were characterized by spectroscopy without isolation. Warming these complexes to 0 °C led to C(sp)-H bond cleavage and formation of dinuclear gold(I) σ,π-acetylide complexes of the form {[(IPr)Au]₂(eta1,eta2-C≡CAr)} SbF₆, three of which were isolated in 99% yield and one of which was characterized by X-ray crystallography.

A family of 7 cationic gold(I) π-allene complexes were isolated and fully characterized in solution, and in three cases by X-ray crystallography. Degenerate intermolecular allene exchange kinetic studies for three of the allene complexes are in accord with a two-term rate law of the form rate = k1[complex] + k2[complex][allene] with with Gibb's free energy barriers of 17.4 - 18.8 kcal mol-1 (1) and 15.2 - 17.6 kcal mol-1 (2). Variable temperature NMR analysis of these complexes established facile intramolecular -face exchange through 1-allene intermediates or transition states with barriers of 8.9 - 10.9 kcal mol-1 for phosphine and 9.5 - 12.2 kcal mol-1 for IPr complexes.

Mechanistic investigation of gold(I)-catalyzed intramolecular allene hydroalkoxylation established a mechanism involving rapid and reversible C-O bond formation followed by turnover-limiting protodeauration from a mono(gold) vinyl complex. This on-cycle pathway competes with catalyst aggregation and formation of an off-cycle bis(gold) vinyl complex.

Recent advances in photo-driven reactions have dramatically expanded thescope of transformations no longer exclusively dependent on thermal energy to drive cross-coupling activity of transition metal catalysts. Of these catalysts, nickel has emerged as one of the most versatile due, in part, to its flexibility in adopting all integer oxidation states from 0 to +4, as well as its lower cost and higher abundance in comparison to precious metal catalysts. Carbon–heteroatom and carbon–carbon cross-couplings are areas of particularly resurgent expansion in photo-driven reaction development. These classes of couplings are essential in the production of innumerable compounds including fine chemicals and natural product synthesis, as well as pharmaceuticals and agrochemicals. Disclosed herein are investigations into dual photo-/nickel-catalyzed reactions for C–N and C–C cross-coupling with (hetero)aryl bromides in sulfamides and sulfamate esters, respectively. The reactivity demonstrated in the N-(hetero)arylation of sulfamides is complementary to that previously demonstrated in traditional, palladium-catalyzed processes. Moreover, the radical C(sp2)–C(sp3) cross-coupling guided by a 1,6-HAT process in sulfamate esters is the first example of this type of nickel-/photocatalyzed reaction and has been long sought after by pioneers of the field. This represents the first plank in a new platform for internally guided, nickel-catalyzed cross-coupling reactions. The development of these complementary technologies constitutes a substantive advancement in access to chemically diverse sulfamides and C–H functionalization technologies, respectively.