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The two projects described in this dissertation demonstrate the wide utility of noble metal N-heterocyclic carbene (NHC) complexes. The first project details the design of iridium NHC amino acid complexes for asymmetric transfer hydrogenation (ATH) of prochiral ketones. Iridium(I) bis-NHC complexes were found to undergo oxidative addition with a variety of alpha-amino acids, generating chiral iridium(III) complexes of the form Ir(NHC)2(aa)(H)(X) (aa = amino acid, X = halide). The complexes were screened for ATH of aryl and alkyl ketones, and optimization studies found enantioselectivity in this system was highly sensitive to the reaction temperature, NHC ligand, and amino acid. Incorporation of secondary amino acids was essential to enantioselectivity. Aryl ketones were reduced in high conversion and enantioselectivity when employing the Ir(IMe)2(L-Pro)(H)(I) catalyst in isopropyl alcohol, in some cases giving over 90% ee of the alcohol products. Density functional theory calculations were conducted in order to gain insight into the active catalytic species, and the results suggest that the high enantioselectivity of this system primarily arises from steric effects. The second project details the design of rhodium and iridium NHC piano-stool complexes featuring derivatized tetramethylcyclopentadienyl ligands (Cp*R, R = alkyl or aryl substituent) for antimicrobial applications. Complexes of the form (Cp*R)M(NHC)Cl2 (M = Rh or Ir) were synthesized by transmetallation of the NHC ligand using silver(I) oxide in the presence of the desired noble metal Cp*R dimer. The complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of these compounds were highly active against Mycobacterium smegmatis, displaying minimum inhibitory concentrations (MICs) as low at 0.25 microgram per mL. Analysis of structure-activity relationships found that incorporation of the NHC ligand greatly enhances the antimicrobial properties of rhodium and iridium piano-stool complexes, more so than previously investigated diamine, amino acid, or beta-diketonato ligands. Cytotoxicity studies on one of the rhodium NHC complexes showed this compound was nontoxic towards mammalian cells at low concentrations, which strengthens the potential of these types of compounds as viable drug candidates. / Doctor of Philosophy / This dissertation describes two practical applications of a series of complexes featuring the noble metals rhodium and iridium. In all of these complexes, the metal center is bonded to one or two groups known as N-heterocyclic carbenes (NHCs). The most common structural variant of NHCs are five-membered rings. The metal is usually bonded to a carbon atom on these rings, which is flanked by two nitrogen atoms. Noble metal complexes containing NHCs are widely investigated in contemporary chemical literature for a variety of reactions, primarily because noble metals form exceptionally strong bonds with NHCs, making these complexes very stable. N-Heterocyclic carbene compounds are also fairly easy to synthesize and structurally modify, which allows fine-tuning for specific applications. The first project in this dissertation employed iridium NHC amino acid complexes for the selective production of alcohols, meaning only one structure of the alcohol product is favorably generated. This is an important transformation in the chemical and pharmaceutical industries, which often require the synthesis of highly pure products. These complexes were found to be quite successful for this application on a range of model substrates, in some cases generating as high as 95% of one alcohol product over the other. Product selectivity was found to depend on the specific structure of the NHC compound. The second project investigated the antimicrobial properties of rhodium and iridium NHC complexes. In recent years, the growing threat of antimicrobial resistance against traditional pharmaceuticals has led to an interest in the development of metal-based drugs, which may allow for metal-specific mechanisms of drug action that are not possible for commonly employed antimicrobial agents. These NHC complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of the complexes displayed high activity against Mycobacterium smegmatis, comparable to those displayed by other clinical drugs such as ampicillin or streptomycin. These results were highly encouraging, as Mycobacterium smegmatis often serves as a model to study other mycobacteria.

Yes / Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. / RMP and MS funded by Yorkshire Cancer Research (pump priming grant BPP 046). IJS and AL funded by NIHR Research & Innovation Division, Strategic Project Funding 2013 and Manchester Pharmacy School Fellowship.

2-Phosphanyl-substituted imidazolium salts 2-PR2(4,5-Cl-Im)[OTf] (9a,b[OTf]) (4,5-Cl-Im = 4,5-dichloro-1,3-bis(2,6-di-isopropylphenyl)-imidazolium) (a: R = Cy, b: R = Ph) are prepared from the reaction of R2PCl (R = Cy, Ph) with NHC 8 (4,5-dichloro-1,3-bis(2,6-di-isopropylphenyl)-imidazolin-2-ylidene) in the presence of Me3SiOTf. 5-Phospanyl-substituted imidazolium salts 5-PR2(2,4-Cl-Im)[OTf] (10a,b[OTf]) are obtained in quantitative yield when a slight excess of the NHC 8 is used. 5-Phosphonio-substituted imidazolium salts 5-PR2Me(2,4-Cl-Im)[OTf]2 (14a,b[OTf]2) and 5-PR2F(2,4-Cl-Im)[OTf]2 (16a,b[OTf]2) result from methylation reaction or oxidation of 10a,b[OTf] with XeF2 and subsequent fluoride abstraction. According to our quantum chemical studies the Cl1 atom at the 2-position at the imidazolium ring of dication 14b2+ carries a slightly positive charge and is therefore accessible for nucleophilic attack. Accordingly, the reaction of 14a,b[OTf]2 and 16a,b[OTf]2 with R3P (R = Cy, Ph) affords cationic 5-phosphonio-substituted NHCs 5-PR2Me(4-Cl-NHC)[OTf] (17a,b[OTf]) and 5-PR2F(4-Cl-NHC)[OTf] (18a,b[OTf]) via a SN2(Cl)-type reaction. A series of transition metal complexes such as [AuCl(5-PPh2Me(4-Cl-NHC))][OTf] (19[OTf]), [CuBr(5-PPh2Me(4-Cl-NHC))][OTf] (20[OTf]), [AuCl(5-PPh2F(4-Cl-NHC))[OTf] (21[OTf]) and [RhCl(cod)(5-PPh2Me(4-Cl-NHC))][OTf] (23[OTf]) are prepared to prove the coordination abilities of carbenes 17b[OTf] and 18b[OTf]. The isolation of a rare example of a tricationic bis-carbene silver complex [Ag(5-PPh2Me(4-Cl-NHC))2][OTf]3 (22[OTf]3) is achieved by reacting 14b[OTf] with Cy3P in the presence of AgOTf. NHC 17b[OTf] represents a very effective dehydrocoupling reagent for secondary (R2PH, R = Ph, Cy, iBu) and primary (RPH2, R = Ph, Cy) phosphanes to give diphosphanes of type R4P2 (R = Ph, Cy, iBu) and oligophosphanes R4P4, R5P5 (R = Ph, Cy), respectively. Methylation of 17b+ and subsequent deprotonation reaction with LDA affords the cationic NHO (N-heterocyclic olefin) 35+ of which the gold complex 36+ is readily accessible via the reaction with AuCl(tht).

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Thesis advisor: Amir H. Hoveyda / Chapter 1. Through the use of quantum theory of atoms in molecules (QTAIM) the similarities and differences between transition metal complexes ligated by phosphines and N-heterocyclic carbenes (NHC) were elucidated. Among the key findings, the phosphines were identified as stronger charge donors than NHCs; however, the latter class of ligands exhibits a weaker p-accepting character than the former. Furthermore, Tolman electronic parameter (TEP) was determined to be an inadequate gauge for the total electron donating ability of phosphines and NHCs; rather TEP can serve as a measurement of population of dp set of orbitals of a metal center in question. Computational and experimental studies of the mechanism of NHC-catalyzed boron and silicon addition to a,ß-unsaturated carbonyls reactions were carried out. Through the use of radical traps the mechanisms involving homolytic cleavage of B-B or B-Si bonds were ruled out. Computational (DFT) studies of the mechanism identified two pathways: (1) direct activation of diboron or borosilyl reagents through coordination of NHC to the B atom, (2) net oxidative addition of the diboron or borosilyl reagents to the carbon (II) of the NHC. The insights gained from the aforementioned studies were employed to rationalize the observed lack of reactivity of NHC-activated diboron complexes in the presence of aldehydes. Chapter 2. New C(1)-symmetric chiral monodentate N-heterocyclic carbenes were prepared, and corresponding chiral Ru-carbene complexes were synthesized. These complexes were employed to gain empirical understanding of factors that govern stereoselectivity in Ru-catalyzed enantioselective olefin ring-closing metathesis. The data thus obtained was employed to infer that syn-to-NHC reaction pathways are competitive and non-selective. One plausible mechanism, through which syn-to-NHC pathways can be accessed, involves Berry pseudorotations. Through the use of stereogenic-at-Ru complexes diastereomeric Ru-carbenes were isolated (silica gel chromatography) and spectroscopically characterized in solution phase. The diastereomeric Ru-carbenes were found to undergo non-metathesis stereomutations at Ru center, thereby providing additional support for the above hypothesis regarding accessibility of syn-to-NHC olefin metathesis pathways. Non-metathesis stereomutation at Ru was found to be accelerated in the presence of protic additives, suggesting the plausibility of hydrogen bonding between the acidic proton and the X-type ligands on Ru. Occurrence of hydrogen bonding was corroborated through the use of chiral allylic alcohols in Ru-catalyzed diastereoselective ring-opening/cross metathesis, which was developed into a versatile method for highly diastereoselective functionalization of terminal olefins. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Earth-abundant first-row transition metals have seen a renaissance in chemistry in recent years due to their relatively low toxicity and cost in comparison to precious metals. Furthermore open-shell transition metal complexes exhibit useful one-electron redox processes which contrasts to their heavier d block anologues. This thesis aims to synthesize and analyse the structure and reactivity of low-coordiante first-row transition metal complexes of from groups 7-9 with an aim to utilize these species in catalysis. The divalent compound [Co{N(SiMe3)2}2] reacts with the primary phosphines PhPH2 in the presence of an NHC ligand (IMe4) to yield the phosphinidene bridged dimer [(IMe4)2Co(µ-PMes)]2. The complex has interesting magnetic properties due to strong antiferromagnetic coupling between the two cobalt(II) centres. Increasing the steric bulk of the NHC yielded carbene-phosphinidene adducts (NHC·PAr). This transformation was shown to be catalytic. The structure and reactivity of complexes of the type [(NHC)xMn{(N(SiMe3)2}2] were investigated. The complexes exhibit similar structural properties to their iron and cobalt analogues; however their reactivity has been shown to differ. The addition of primary phosphines to complexes of the type [(NHC)xMn{N(SiMe3)2}2] yielded a range of manganese phosphide complexes. [Mn{N(SiMe3)2}2] also reacts with imidazolium salts at elevated temperatures to yield heteroleptic manganese NHC complexes. The reaction of [Mn{N(SiMe3)2}2] with IPr·HCl afforded the abnormal carbene complex [(aIPr)Mn{N(SiMe3)2}µ-Cl]2. A new monoanionic bidentate ligand is reported which has shown to be a useful ligand system to stabilize three-coordiante iron(II) complex. The reaction of [(L)Fe(Br)] with mesitylmagnesium Grignard or n-butyllithium yield the iron hydrocarbyls [(L)Fe(Mes)] and [(L)Fe(nBu)] with the latter being stable to β-hydrogen elimination. Finally [(L)Fe(nBu)] has been utilized as a pre-catalyst in the hydrophosphination of internal alkynes, showing selectivity for the E-isomeric vinylphosphine.

This thesis describes the synthesis and isolation of silver, mercury, ruthenium and palladium complexes of bidentate N-heterocyclic carbenes (NHCs), derived from imidazolium-linked cyclophanes and related bis-imidazolium salts. The cyclophane structures contain two imidazolyl links between ortho- and meta- substituted aromatic rings and the related structures are ortho-, meta- and para-xylyl linked bis-imidazolium salts. The complexes have been characterised by NMR spectroscopy and X-ray crystallography. The synthesis of five new silver complexes has been achieved via a simple complexation reaction of the cyclophane and bis-imidazolium salts with the basic metal source Ag2O. The new silver carbene systems are thermally stable. Three of the complexes are dinuclear, cationic complexes, while two are mononuclear complexes, one cationic and one neutral. A number of mono- and di-nuclear mercury(II)-NHC complexes have been synthesised from the ortho- and meta-linked cyclophanes and the related meta-linked bis-imidazolium salts. The mercury complexes were prepared by direct mercuration method using mercury(II) acetate. The syntheses were perfomed in air and the complexes are stable to air and moisture. Mercury complexes I and II represent the first example of mononuclear metal complexes derived from meta-substituted imidazolium-linked cyclophanes. NHC-ligand transfer reactions from NHC-silver complexes and NHC-mercury complexes are described. An ortho-cyclophane ligand was successfully transfered from a silver complex to its palladium counterpart. Furthermore, palladium complex III, bearing a para-xylyl linked bis-NHC ligand, was made by transmetallation from both a silver and mercury complex. This is the first reported NHC-palladium complex of a para-xylyl linked bis-NHC ligand. A new redox transmetallation method for NHC ligand transfer, using a mercury complex, is presented. A palladium complex was made via redox transmetallation using a mercury complex of an ortho-NHC-cyclophane. A ruthenium(II)-NHC complex, IV containing an ortho-cyclophane ligand has been prepared via silver transmetallation and in situ complexation methods. In the transmetallation route, a silver complex of an ortho-cyclophane was treated with RuCl2(PPh3)3 to form IV. This complex represents the first example of a ruthenium complex bearing an NHC-cyclophane ligand, v and is also the first example of a metal complex derived from an imidazolium-linked cyclophane where the arene unit of the cyclophane is also involved in bonding to the metal centre.

The ability to generate chiral building blocks is of paramount importance to organic chemists. This problem presents itself most notably at the interface of chemistry and biology, where molecules of only a single enantiomer can induce function to many biological systems. In this context, recent developments in the field of organocatalysis, most notably the employment of chiral N-heterocyclic carbenes (NHCs) have shown much promise. Our group has recently shown that one possible chiral NHC catalyzed Stetter cyclization product of a conjugated triene, a highly functionalized cyclopentenone, contains both a chiral center and an adjacent conjugated diene. This structure can be easily elaborated to a bicyclic structural motif present in some biologically active natural products from the ginkgolide family, and is difficult to access by other means. The synthesis of novel vinyl stannanes and other coupling substrates involved in the development of the aforementioned reaction discovery are described in this report.

This research work includes three parts, with the first section describing the synthesis and applications of neutral 3-coordinate aluminum complexes. As demonstrated in this part, aluminum complexes in a 3-coordinate geometry can be formed only with a ring size greater than or equal to a 6-member ring when supported by diamido ligands. It is found that 1,2-diamido ligands designed for 5-member ring formations can accommodate the formation of only 4-coordinate dinuclear species, which show no activity when used as a single component catalyst in the ring-opening polymerization (ROP) of cyclic esters under specified reaction conditions. Three-coordinate neutral (1,4-diamido)AlMe complexes are successfully synthesized, revealing a higher activity in the ROP of cyclic esters than the existing 6-member analogues under the same reaction conditions. A detailed discussion of the structure-reactivity relationship of Al catalysts in the ROP of cyclic esters is presented. The second part of this thesis project consists of investigations into the applications of 1,4-diamido ligands for the formation of 3-coordinate NHP (N-heterocyclic phosphine) and 2-coordinate NHP+ cations (phosphenium cations). These novel NHP species are the first to be shown in a 7-member ring supported by 1,4-diamido ligands. Various N-substituents in the 1,4-diamido ligands are examined for the formation of a cyclic structure based on their steric hindrance. It is found that a Dipp (2,6-diisopropylphenyl) group is unable to allow for the formation of a 7-member NHP due to its excessive steric bulk. The less bulky mesityl (2,4,6-trimethylphenyl) group at the N-positions in the ligands leads to successful formation of these novel NHPs and NHP+ species. Furthermore, an investigation is carried out to explore their π-accepting property by means of 31P NMR studies. The NHP and NHP+ species synthesized in this project show chemical shifts downfield relative to the existing 5- and 6-member analogues in 31P NMR experiments, suggesting a high potential of 7-member NHPs to be used as π-acceptor ligands. The second section also examined the resulting NHPs and NHP+ species for coordinating to various metals. The last part of this research work is dedicated to presenting the first example of chelating 3–triNHC (tri-N-heterocyclic carbene) ligands that allow for the formation of (triNHC)Pd(II) complexes in a meridional fashion, wherein the triNHC ligand coordinates to the metal center in a pseudo-meridional fashion. Novel [(triNHC)MePdX]X (X = Cl or acetate) complexes are successfully synthesized, and they display extraordinary stability against air and heat. Low activities of the resulting complexes are found in promoting C-C coupling reactions, possibly due to the low solubility of the resulting complexes in organic solvents. Various attempts to change the N-substituents to groups other than methyls are conducted to improve the solubility of the complexes in organic solvents for higher activities in C-C coupling reactions. The results from these attempted modifications to these complexes are discussed in detail. All complexes are characterized by standard spectral methods such as mass spectrometry, X-ray crystallography, elemental analysis, 1H NMR, 13C NMR and 31P NMR spectroscopy.