Verdazyl radicals are a unique class of stable radicals that have found uses as reporter molecules in biological systems, substrates for molecular-based magnets and mediators in living radical polymerizations. Over the past few years, our laboratory has pioneered the use of verdazyl radicals as substrates in 1,3-dipolar cycloaddition reactions to provide unique small molecule five-membered ring systems containing structural features commonly found in therapeutic agents. As an extension to this work we became interested in seeing whether this chemistry could be applied to the synthesis of macrocyclic scaffolds, in particular cyclophanes. Cyclophanes have been attractive synthetic targets for organic chemists because of their unique structural properties, conformational behaviours and molecular recognition capabilities. Presented in this thesis is the successful demonstration of the extension of the verdazyl chemistry to novel [n]-paracyclophanes. The structural features and conformational biases of these molecules as evidenced by 1H-NMR and X-ray crystallography are highlighted along with molecular recognition studies.

Verdazyl radicals are a unique class of stable radicals that have found uses as reporter molecules in biological systems, substrates for molecular-based magnets and mediators in living radical polymerizations. Over the past few years, our laboratory has pioneered the use of verdazyl radicals as substrates in 1,3-dipolar cycloaddition reactions to provide unique small molecule five-membered ring systems containing structural features commonly found in therapeutic agents. As an extension to this work we became interested in seeing whether this chemistry could be applied to the synthesis of macrocyclic scaffolds, in particular cyclophanes. Cyclophanes have been attractive synthetic targets for organic chemists because of their unique structural properties, conformational behaviours and molecular recognition capabilities. Presented in this thesis is the successful demonstration of the extension of the verdazyl chemistry to novel [n]-paracyclophanes. The structural features and conformational biases of these molecules as evidenced by 1H-NMR and X-ray crystallography are highlighted along with molecular recognition studies.

Coordination compounds involving stable radicals represent a promising avenue toward the design of new magnetic materials. In this respect, a series of new metalverdazyl radical complexes has been prepared and their magnetic properties reported. These systems can be envisioned as model systems designed to help elucidate the fundamental electronic interactions between one paramagnetic metal ion and one verdazyl radical that lead to magnetic exchange. A new chelating verdazyl diradical has also been prepared and fully characterised. The electronic ground state of this diradical species has been established through magnetic and variable temperature electron paramagnetic resonance (VT-EPR) studies. In an effort to expand the metal-radical model systems beyond simple 1:1 metal:radical complexes, this verdazyl diradical was employed as a ligand to prepare a succession of first row transition metal complexes. The magnetic properties of the resulting coordination compounds have been studied in an effort to understand how the nature of the metal-diradical magnetic exchange changes with the metal used. In addition to the wide-spread interest in the magnetic properties of stable organic radicals, there is a growing awareness of the redox properties of this class of compounds. Electrochemical and spectroelectrochemical techniques were utilised to probe the redox properties of a verdazyl diradical and a structurally similar verdazyl monoradical. Coordination compounds involving the redox-inert metal zinc were also prepared and their redox properties investigated. While the addition of zinc to the verdazyl diradical had no significant impact on the magnetic properties of the diradical, there is a distinct difference between the redox properties of the diradical itself and its zinc complex. Coordination to zinc also affected the redox properties of the verdazyl monoradical, although to a lesser extent than what was observed for the diradical. / Graduate / 0485

A series of palladium and platinum complexes of verdazyl radicals were prepared to study the intermolecular magnetic exchange coupling. Reaction of bidentate verdazyl radicals with (RCN)2MCl2 (R = Me or Ph; M = Pd or Pt) yielded square planar (verdazyl)MCl2 complexes. The isolated complexes crystallized in either an infinite 1D array or as loosely associated p-stacked dimer pairs. Molecules stacked with either M–M or M–N(verdazyl) close contacts. Molecules that stacked with a M-M close contact exhibited weak antiferromagnetic coupling. Molecules that stacked with a M– N(verdazyl) close contact had coupling that was an order-of-magnitude weaker, but the type of exchange was also metal dependent. While the palladium complex exhibited weak antiferromagnetic coupling, the exchange in the analogous platinum complex was ferromagnetic. The difference between the two was attributed to increased spin leakage onto the platinum centre relative to palladium. The differing electronic behaviour of the two metals was evident in the data from EPR and UV/vis spectroscopies. Ruthenium complexes of a verdazyl radical were prepared by the reaction of a bidentate verdazyl with Ru(L)2(MeCN)2 (L = acac or hfac). The complexes were isolated in two or more oxidation states and all characterized by FT-IR, UV/vis/NIR, and EPR spectroscopies, and their structures determined by X-ray crystallography. Experimental data was further explained and supported with time-dependant DFT calculations which were performed by Dr. A. B. P. Lever at York University, Toronto, Ontario. When the complex contained an electron-rich metal fragment, Ru(acac)2, noninnocent behaviour was observed. There was a large degree of orbital mixing, so that the spin distribution was approximately 39% metal and 56% ligand. The contrasting complex with the electron-poor fragment, Ru(hfac)2, behaved more innocently, the majority of charge was localized and the spin was ligand-based. Verdazyl-bridged diruthenium complexes were prepared from a bisbidentate verdazyl and Ru(L)2(MeCN)2 (L = acac or hfac) to study the effect of a neutral radical bridge on mixed-valence properties. Structural data from X-ray crystallography, spectroscopic data from EPR, FT-IR, and UV/vis/NIR spectroscopies, and comparison to the mononuclear ruthenium-verdazyl complexes were used to assess the charge distribution in these complexes. The complex in which the verdazyl ligand bridged two electron-rich metal centres exhibited a NIR absorption at approximately 1716 nm. Together, this long wavelength transition and the structural data indicate a delocalized electronic structure, [RuIII−vd–−RuII « RuII−vd•−RuII « RuII−vd–−RuIII]. The EPR spectrum was also consistent with the delocalization of ligand spin onto the ruthenium centres. With the verdazyl bridging two electron-poor Ru(hfac)2 fragments, the spin is ligand-based and best described as RuII−vd•−RuII. Like the analogous mononuclear complexes, the dinuclear complexes were each isolated in their other accessible oxidation states. / Graduate / 0485

This work expands the investigation into the behaviour of verdazyl radicals and N-alkylated tetrazines as ligands. These new ligands were coordinated to various metals as a means of exploring new properties in the metal-verdazyl and metal-tetrazine products. The synthesis of N,N’-diphenyl Kuhn and 6-oxo verdazyl radicals bearing a 2-pyridyl group at the C3 position was accomplished. Palladium(II) dichloride complexes of each of these radicals were prepared in order to study the differences in the structural, electronic, and electrochemical properties compared to corresponding complexes of the previously reported N,N’-dialkyl-6-oxoverdazyl ligands. The N,N’-diphenyl verdazyl ligands are structurally bulkier than their dialkyl counterparts resulting in increased interaction between the ligand and palladium as observed in the solid state. The radical complexes were investigated by EPR and shown to exhibit a small amount of spin density on the palladium atoms with most of the spin density remaining on the ligands. The UV-Visible spectra had a noticeable red-shift in the absorbance maxima of the complexes compared to the free ligands. The electrochemistry of the new palladium-verdazyl complexes showed that there was a positive increase to the reduction and oxidation potentials when compared to the free ligands. An N-benzyl tetrazine and its Ru(hfac)2 complex were synthesized from their corresponding radical species utilizing Mn2(CO)10 to photogenerate benzyl radicals. This method was found to give high yields of the tetrazine and its metal complex. Spectroscopic, structural, and electrochemical properties of the tetrazine and its Ru(hfac)2 complex are reported. These compounds were investigated in regards to the activation energy associated with the homolytic cleavage of the C-N bond in the inert solvent, tert-butylbenzene. The activation energy of C-N bond of the tetrazine was 155 kJmol-1 while its Ru(hfac)2 complex was 138 kJmol-1; this resulted in the rate of dissociation being a factor of ~40 greater for the Ru(hfac)2 complex at 393 K. This work presents the potential of coordination compounds in tuning the properties of molecules associated with the stable free radical polymerization process. / Graduate / 0488 / 0485 / cooper_johnston@hotmail.com

Verdazyl radicals, discovered in 1963, are a family of exceptionally stable radicals defined by their 6-membered ring containing four nitrogen atoms. Verdazyl radicals are highly modular compounds with a large assortment of substitution patterns reported. Their stability and high degree of structural variability has been exploited in the fields of materials, inorganic, polymer and physical chemistry; however their deliberate use as starting materials towards organic synthesis had only been reported in recent years by the Georges lab. In 2008, the Georges group reported a disproportionation reaction that was observed to a occur with 6-oxoverdazyl radicals resulting in azomethine imines capable of undergoing 1,3-dipolar cycloaddition reactions. With this discovery, the door to using verdazyl radicals as substrates towards organic synthesis had been opened. Their utility in synthesis was soon discovered not to be limited to just the cycloadducts their azomethine imine derivatives could generate but also the increasing number of N-heterocycles that could be generated from these cycloadducts via unique rearrangement reactions, a major theme of this thesis. In addition, triphenyl verdazyl radicals, a distinct class of verdazyl radicals, has been shown to react with alkynes by direct radical addition and rearrangement to afford isoquinolines. As part of this thesis, a new synthetic methodology of generating 6-oxoverdazyl radicals is reported that does not rely on the use of phosgene or hydrazines. This new synthesis allows for the expansion of available alkyl substituents possible on N1 and N5 positions of 6-oxoverdazyl radicals, as well as, generation of unsymmetrical examples of 6-oxoverdazyl radicals with non-identical N1 and N5 alkyl substituents. Employing the new 6-oxoverdazyl radicals synthesized via this method, a study on the effects of different alkyl substituents on the disproportionation reaction of 6-oxoverdazyls was undertaken. Lastly, given the assortment of N-heterocyclic molecular scaffolds capable of being synthesised starting from verdazyl radicals as precursors, the applicability of verdazyl radicals in making a diversity oriented synthesis (DOS) based library was explored. In a group effort with other Georges lab members, a small library composed of various classes of verdazyl radical derived compounds was synthesized and non-specifically tested for cytotoxicity against acute myeloid leukemia and multiple myeloma cell lines in collaboration with The Princess Margaret Hospital. One example was shown to effectively kill cancer cells in both these lines in 250 μM concentration pointing out the potential of using verdazyl radical based chemistry in drug discovery.

Verdazyl radicals, discovered in 1963, are a family of exceptionally stable radicals defined by their 6-membered ring containing four nitrogen atoms. Verdazyl radicals are highly modular compounds with a large assortment of substitution patterns reported. Their stability and high degree of structural variability has been exploited in the fields of materials, inorganic, polymer and physical chemistry; however their deliberate use as starting materials towards organic synthesis had only been reported in recent years by the Georges lab. In 2008, the Georges group reported a disproportionation reaction that was observed to a occur with 6-oxoverdazyl radicals resulting in azomethine imines capable of undergoing 1,3-dipolar cycloaddition reactions. With this discovery, the door to using verdazyl radicals as substrates towards organic synthesis had been opened. Their utility in synthesis was soon discovered not to be limited to just the cycloadducts their azomethine imine derivatives could generate but also the increasing number of N-heterocycles that could be generated from these cycloadducts via unique rearrangement reactions, a major theme of this thesis. In addition, triphenyl verdazyl radicals, a distinct class of verdazyl radicals, has been shown to react with alkynes by direct radical addition and rearrangement to afford isoquinolines. As part of this thesis, a new synthetic methodology of generating 6-oxoverdazyl radicals is reported that does not rely on the use of phosgene or hydrazines. This new synthesis allows for the expansion of available alkyl substituents possible on N1 and N5 positions of 6-oxoverdazyl radicals, as well as, generation of unsymmetrical examples of 6-oxoverdazyl radicals with non-identical N1 and N5 alkyl substituents. Employing the new 6-oxoverdazyl radicals synthesized via this method, a study on the effects of different alkyl substituents on the disproportionation reaction of 6-oxoverdazyls was undertaken. Lastly, given the assortment of N-heterocyclic molecular scaffolds capable of being synthesised starting from verdazyl radicals as precursors, the applicability of verdazyl radicals in making a diversity oriented synthesis (DOS) based library was explored. In a group effort with other Georges lab members, a small library composed of various classes of verdazyl radical derived compounds was synthesized and non-specifically tested for cytotoxicity against acute myeloid leukemia and multiple myeloma cell lines in collaboration with The Princess Margaret Hospital. One example was shown to effectively kill cancer cells in both these lines in 250 μM concentration pointing out the potential of using verdazyl radical based chemistry in drug discovery.

The goals of this thesis were to design and synthesize new stable radicals and to study their properties. The attempted synthesis of new stable thioaminyl, verdazyl, and dioxadiazinyl radicals is described. Successfully prepared radicals were characterized by spectroscopic methods. The synthesis of new thioaminyl radicals and diradicals was attempted. Preparation of thioaminyl precursors, the sulfenamides, was accomplished with sulfenyl chlorides and amines. Oxidation with DDQ yielded radicals which decomposed back to the sulfenamides within 1–2 minutes. A bis(sulfenamide) was synthesized using a sulfenyl chloride and an appropriate bis(amine). The structure of the bis(sulfenamide) was confirmed by NMR spectroscopy and x-ray crystallography. Oxidation of the bis(sulfenamide) to the thioaminyl diradical was unsuccessful. New phosphaverdazyl radicals were prepared and studied using EPR spectroscopy. The phosphaverdazyl precursors, the tetrazines, were prepared from the corresponding bis(hydrazides). The tetrazines were oxidized with benzoquinone to yield phosphaverdazyls. The phosphaverdazyls prepared do not share the same level of stability as the parent carbon-based verdazyls; they slowly decompose back to tetrazines. Incorporation of phosphorus into the verdazyl core has several effects on the properties of the radical relative to the parent verdazyl system. Through a combination of EPR and computational studies, it was concluded that the geometry of the verdazyl ring and the electronic nature at phosphorus appear to be sensitive to the nature of the substituents attached to phosphorus. Exocyclic “spin-leakage” was observed for one phosphaverdazyl, which can be rationalized using a spiroconjugative mechanism. The phenomena of spiroconjugation was further explored through the synthesis of a phosphaverdazyl derivative attached to phosphazene in a spirocyclic manner. Synthetic routes to the hitherto unknown dioxadiazinyl system were explored. An intermediate hydroxyamidoxime was synthesized and fully characterized. Cyclization reactions of the hydroxyamidoxime to putative dioxadiazines were carried out using aldehydes and a ketone. The cyclization products could not be unambiguously assigned. The cyclization products can be rationalized as the desired dioxadiazine or the 5-membered oxadiazolidine. One derivative was oxidized to a persistent radical, the EPR of which is consistent with a nitroxide structure. / Graduate

This thesis presents the synthesis, characterization and reactivity of a series of palladium complexes that contain redox-active verdazyl ligands. This work was motivated by the possibility of discovering new and interesting reactivity that may eventually lead to the development of new chemical reactions. A bidentate verdazyl radical ligand that contains an aryl phosphine was synthesized. Reaction of this ligand with (PhCN)2PdCl2 yielded a square planar (verdazyl)PdCl2 complex. Structural and spectroscopic data suggest that this compound consists of a ligand-centered radical coordinated to a Pd(II) center. The radical complex was chemically reduced by one-electron to generate a binuclear chloride-bridged [(verdazyl)PdCl]2 complex. In this reduced complex, both metals were still Pd(II) and the verdazyl ligand was determined to be in its singly reduced, monoanionic charge state. The original radical PdCl2 complex could be regenerated via one-electron oxidation of the reduced complex using PhICl2. The verdazyl ligands in the reduced complex could also be reversibly protonated to generate “leuco” verdazyl complex (verdazyl-H)PdCl2. Reaction of the radical (verdazyl)PdCl2 complex with water triggers a ligand-centered redox disproportionation reaction. A series of bis(verdazyl) palladium complexes were synthesized using a bidentate pyridine-substituted verdazyl ligand. Reaction of two equivalents of radical ligand with (CH3CN)4Pd2+ yielded a (verdazyl)2Pd(solvent)2+ complex (solvent = CH3CN or DMSO). In this complex, one verdazyl radical ligand chelates to palladium and the other binds as a monodentate ligand. Two-electron reduction of this complex generated a (verdazyl)2Pd complex in which two monoanionic verdazyl ligands are bound to a central Pd(II) ion. This reduced complex could also be made via reaction of 0.5 equivalents of Pd(0)2(dba)3 with two equivalents of radical ligand. In this reaction, the metal is oxidized by two electrons and each ligand is reduced by a single electron. Two-electron oxidation of the reduced complex in the presence of DMSO yielded the original bis(radical)complex, (verdazyl)2Pd(DMSO)2+. Chlorination of the reduced complex using one equivalent of PhICl2 (two-electron oxidation) resulted in dissociation of one verdazyl ligand to afford a 1:1 mixture of free verdazyl : (verdazyl)PdCl2, in which both of the verdazyls are neutral radicals. Reaction of the reduced complex with 0.5 equivalents of PhICl2 (one-electron oxidation) yielded a (verdazyl)2PdCl complex that contained a bidentate reduced verdazyl ligand and a monodentate radical ligand. All three of the oxidation reactions described above adhere to ligand-centered redox chemistry. Reaction of the reduced (verdazyl)2Pd complex with excess HCl resulted in protonation of both the anionic verdazyl ring and the pyridyl group to generate a leuco/pyridinium tetrachloropalladate salt, (verdazyl-H2)2(PdCl4). The protonated salt could be converted back to the original (verdazyl)2Pd complex by deprotonation with water. Palladium complexes of a tridentate NNN-chelating verdazyl ligand were prepared and their redox chemistry was explored. Reaction of the radical ligand with (CH3CN)4Pd2+ yielded radical complex (verdazyl)Pd(NCCH3)2+. The tridentate ligand was also prepared in its reduced, leuco form (verdazyl-H). Reaction of the leuco verdazyl with (CH3CN)2PdCl2 generated HCl and a (verdazyl)PdCl complex in which the ligand is in its monoanionic charge state. The reduced (verdazyl)PdCl complex was reacted with AgBF4 to afford (verdazyl)Pd(NCCH3)+ via chloride abstraction; the verdazyl remained in its reduced charge state following the reaction. Both reduced complexes (chloro and acetonitrile) were oxidized by a single electron to afford the corresponding radical complexes. These radical complexes could be reduced by a single electron to regenerate the original reduced complexes. Like the previous two projects, all of the redox chemistry was ligand-centered. The reactivity of these complexes with primary amines was also explored. Reaction of radical complex (verdazyl)Pd(NCCH3)2+ with n-butylamine resulted in one-electron reduction of the verdazyl ligand. We were unable to determine the mechanism of the reaction, but the reactivity that was observed demonstrates the potential for verdazyl-palladium complexes to be used in the design of new radical reactions. / Graduate / 2018-07-17

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.