Reactions of small molecules facilitated by metal-acceptor interactions

The role of metal-acceptor interactions arising from M–BR3 and M–PR3 bonding is discussed with respect to reactions between first-row transition metals and N2, H2, and CO. Thermally robust, S = 1/2 (TPB)Co(H2) and (TPB)Co(N2) complexes (TPB = tris(2- (diisopropylphosphino)phenyl)borane) are described and the energetics of N2 and H2 binding are measured. The H2 and N2 ligands are bound more weakly in the (TPB)Co complexes than in related (SiP3)M(L) complexes (SiP3 = tris(2- (diisopropylphosphino)phenyl)silyl). Comparisons within and between these two ligand platforms allow for the factors that affect N2 (and H2) binding and activation to be delineated. The characterization and reactivity of (DPB)Fe complexes (DPB = bis(2- (diisopropylphosphino)phenyl)phenylborane) in the context of N2 functionalization and E–H bond addition (E = H, C, N, Si) are described. This platform allows for the one-pot transformation of free N2 to an Fe hydrazido(-) complex via an Fe aminoimide intermediate. The principles learned from the N2 chemistry using (DPB)Fe are applied to CO reduction on the same system. The preparation of (DPB)Fe(CO)2 is described as well as its reductive functionalization to generate an unprecedented Fe dicarbyne. The bonding in this highly covalent complex is discussed in detail. Initial studies of the reactivity of the Fe dicarbyne reveal that a CO-derived olefin is released upon hydrogenation. Alternative approaches to uncovering unusual reactivity using metal- acceptor interactions are described in Chapters 5 and 6, including initial studies on a new π-accepting tridentate diphosphinosulfinyl ligand and strategies for designing ligands that undergo site-selective metallation to generate heterobimetallic complexes.

The intramolecular Buchner reaction of α-diazo-β-ketonitriles : development and application to the total synthesis of (+)-Salvileucalin B

Since its discovery in 1896, the Buchner reaction has fascinated chemists for more than a century. The highly reactive nature of the carbene intermediates allows for facile dearomatization of stable aromatic rings, and provides access to a diverse array of cyclopropane and seven-membered ring architectures. The power inherent in this transformation has been exploited in the context of a natural product total synthesis and methodology studies.

The total synthesis work details efforts employed in the enantioselective total synthesis of (+)-salvileucalin B. The fully-substituted cyclopropane within the core of the molecule arises from an unprecedented intramolecular Buchner reaction involving a highly functionalized arene and an α-diazo-β-ketonitrile. An unusual retro-Claisen rearrangement of a complex late-stage intermediate was discovered on route to the natural product.

The unique reactivity of α-diazo-β-ketonitriles toward arene cyclopropanation was then investigated in a broader methodological study. This specific di-substituted diazo moiety possesses hitherto unreported selectivity in intramolecular Buchner reactions. This technology was enables the preparation of highly functionalized norcaradienes and cyclopropanes, which themselves undergo various ring opening transformations to afford complex polycyclic structures.

Finally, an enantioselective variant of the intramolecular Buchner reaction is described. Various chiral copper and dirhodium catalysts afforded moderate stereoinduction in the cyclization event.

Reactivity of titanocene methylidene with metal halides, alkene sulfides, and alkene oxides

Titanocene metallacyclobutanes show a wide variety of reactivites with organic and inorganic reagents. Their reactions include methylene transfer to organic carbonyls, formation of enolates, electron transfer from activated alkyl chlorides, olefin metathesis, ring opening polymerization. Recently, preparations of heterobinuclear µ-methylene complexes were reported. In this thesis, mechanistic, synthetic, and structural studies of the heterobinuclear µ-methylene complexes will be described. Also, the reaction of titanocene methylidene trimethylphosphine complex with alkene sulfide and styrene sulfide will be presented.

Heterobinuclear µ-methylene-µ-methyl complexes C_(p2)Ti(µ-CH_2)( µ-CH_3)M(1,5-COD) have been prepared (M = Rh, Ir). X-ray crystallography showed that the methyl group of the complex was bonded to the rhodium and bridges to the titanium through an agostic bond. The ^(1)H,^(13)CNMR, IR spectra along with partial deuteration studies supported the structure in both solution and solid state. Activation of the agostic bond is demonstrated by the equilibration of the µ-CH_3 and µ-CH_2 groups. A nonlinear Arrhenius plot, an unusually large kinetic isotope effect (24(5)), and a large negative activation entropy (-64(3)eu) can be explained by the quantum-mechanical tunneling. Calculated rate constants with Bell-type barrier fitted well with the observed one. This equilibration was best explained by a 4e-4c mechanism (or σ bond metathesis) with the character of quantum-mechanical tunneling.

Heterobinuclear µ-methylene-µ-phenyl complexes were synthesized. Structural study of C_(p2)Ti(µ-CH_(2))(µ-p-Me_(2)NC_(6)H_(4))Rh(l,5-COD) showed that the two metal atoms are bridged by the methylene carbon and the ipso carbon of the p-N,N-dimethylarninophenyl group. The analogous structure of C_(p2))Ti(µ-CH_(2))(µ-o-MeOC_(6)H_(4))Rh(1,5-COD) has been verified by the differential NOE. The aromaticity of the phenyl group observed by ^(1)H NMR, was confirmed by the comparison of the C-C bond lengths in the crystallographic structure. The unusual downfield shifts of the ipso carbon in the ^(13)C NMR are assumed to be an indication of the interaction between the ipso carbon and electron-deficient titanium.

Titanium-platinum heterobinuclear µ-methylene complexes C_(p2)Ti(µ-CH_(2))(µ -X)Pt(Me)(PM_(2)Ph) have been prepared (X= Cl, Me). Structural studies indicate the following:(1) the Ti-CH2 bond possesses residual double bond character, (2) there is a dative Pt→Ti interaction which may be regarded as a π back donation from the platinum atom to the 'Ti=CH_(2)'' group, and (3) the µ-CH_3 group is bound to the titanium atom through a three-center, two-electron agostic bond.

Titanocene (η^(2)-thioformaldehyde)•PMe_3 was prepared from C_(p2)Ti=CH_(2)•PMe_3 and sulfur-containing organic compounds (e.g. alkene sulfide, triphenylphosphine sulfide) including elemental sulfur. Mechanistic studies utilizing trans-styrene sulfide-d_1 suggested the stepwise reaction to explain equimolar mixture of trans- and cis-styrene-d_1 as by-products. The product reacted with methyl iodide to produce cationic titanocene (η_(2)-thiomethoxymethyl) complex. Complexes having less coordinating anion like BF_4 or BPh_4 could be obtained through metathesis. Together with structural analyses, the further reactivities of the complexes have been explored.

The complex C_(p2)TiOCH_(2)CH(Ph)CH_2 was prepared from the compound C_(p2)Ti=CH_(2)-PMe_3 and styrene oxide. The product was characterized with ^(1)H-^(1)H correlated 2-dimensional NMR, selective decoupling of ^(1)H NMR, and differential NOE. Stereospecificity of deuterium in the product was lost when trans-styrene oxide-d_1 was allowed to react. Relative rates of the reaction were measured with varying substituents on the phenyl ring. Better linearity (r = -0.98, p^(+) = -0.79) was observed with σ_(p)^(+)than σ(r = -0.87, p = -1.26). The small magnitude of p^+ value and stereospecificity loss during the formation of product were best explained by the generation of biradicals, but partial generation of charge cannot be excluded. Carbonylation of the product followed by exposure to iodine yields the corresponding β-phenyl γ-lactone.

Signal transduction with hybridization chain reactions

Some of the most exciting developments in the field of nucleic acid engineering include the utilization of synthetic nucleic acid molecular devices as gene regulators, as disease marker detectors, and most recently, as therapeutic agents. The common thread between these technologies is their reliance on the detection of specific nucleic acid input markers to generate some desirable output, such as a change in the copy number of an mRNA (for gene regulation), a change in the emitted light intensity (for some diagnostics), and a change in cell state within an organism (for therapeutics). The research presented in this thesis likewise focuses on engineering molecular tools that detect specific nucleic acid inputs, and respond with useful outputs.

Four contributions to the field of nucleic acid engineering are presented: (1) the construction of a single nucleotide polymorphism (SNP) detector based on the mechanism of hybridization chain reaction (HCR); (2) the utilization of a single-stranded oligonucleotide molecular Scavenger as a means of enhancing HCR selectivity; (3) the implementation of Quenched HCR, a technique that facilitates transduction of a nucleic acid chemical input into an optical (light) output, and (4) the engineering of conditional probes that function as sequence transducers, receiving target signal as input and providing a sequence of choice as output. These programmable molecular systems are conceptually well-suited for performing wash-free, highly selective rapid genotyping and expression profiling in vitro, in situ, and potentially in living cells.

Ultrafast transient ring-shaped population grating

We demonstrate an ultrafast transient, ring-shaped population grating induced by an ultrashort hollow Gaussian laser bullet by solving the three-dimensional full-wave Maxwell-Bloch equations. Through adjusting the beam waist and the area of the pulse, we can control the number of lines and the period of the grating. Based on this coherent control scheme, a door to produce gratings with complex transverse structure is opened.

Sequence specific complexation of b DNA at sites containing g,c base pairs

A series of eight related analogs of distamycin A has been synthesized. Footprinting and affinity cleaving reveal that only two of the analogs, pyridine-2- car box amide-netropsin (2-Py N) and 1-methylimidazole-2-carboxamide-netrops in (2-ImN), bind to DNA with a specificity different from that of the parent compound. A new class of sites, represented by a TGACT sequence, is a strong site for 2-PyN binding, and the major recognition site for 2-ImN on DNA. Both compounds recognize the G•C bp specifically, although A's and T's in the site may be interchanged without penalty. Additional A•T bp outside the binding site increase the binding affinity. The compounds bind in the minor groove of the DNA sequence, but protect both grooves from dimethylsulfate. The binding evidence suggests that 2-PyN or 2-ImN binding induces a DNA conformational change.

In order to understand this sequence specific complexation better, the Ackers quantitative footprinting method for measuring individual site affinity constants has been extended to small molecules. MPE•Fe(II) cleavage reactions over a 10^5 range of free ligand concentrations are analyzed by gel electrophoresis. The decrease in cleavage is calculated by densitometry of a gel autoradiogram. The apparent fraction of DNA bound is then calculated from the amount of cleavage protection. The data is fitted to a theoretical curve using non-linear least squares techniques. Affinity constants at four individual sites are determined simultaneously. The distamycin A analog binds solely at A•T rich sites. Affinities range from 10^(6)- 10^(7)M^(-1) The data for parent compound D fit closely to a monomeric binding curve. 2-PyN binds both A•T sites and the TGTCA site with an apparent affinity constant of 10^(5) M^(-1). 2-ImN binds A•T sites with affinities less than 5 x 10^(4) M^(-1). The affinity of 2-ImN for the TGTCA site does not change significantly from the 2-PyN value. At the TGTCA site, the experimental data fit a dimeric binding curve better than a monomeric curve. Both 2-PyN and 2-ImN have substantially lower DNA affinities than closely related compounds.

In order to probe the requirements of this new binding site, fourteen other derivatives have been synthesized and tested. All compounds that recognize the TGTCA site have a heterocyclic aromatic nitrogen ortho to the N or C-terminal amide of the netropsin subunit. Specificity is strongly affected by the overall length of the small molecule. Only compounds that consist of at least three aromatic rings linked by amides exhibit TGTCA site binding. Specificity is only weakly altered by substitution on the pyridine ring, which correlates best with steric factors. A model is proposed for TGTCA site binding that has as its key feature hydrogen bonding to both G's by the small molecule. The specificity is determined by the sequence dependence of the distance between G's.

One derivative of 2-PyN exhibits pH dependent sequence specificity. At low pH, 4-dimethylaminopyridine-2-carboxamide-netropsin binds tightly to A•T sites. At high pH, 4-Me_(2)NPyN binds most tightly to the TGTCA site. In aqueous solution, this compound protonates at the pyridine nitrogen at pH 6. Thus presence of the protonated form correlates with A•T specificity.

The binding site of a class of eukaryotic transcriptional activators typified by yeast protein GCN4 and the mammalian oncogene Jun contains a strong 2-ImN binding site. Specificity requirements for the protein and small molecule are similar. GCN4 and 2-lmN bind simultaneously to the same binding site. GCN4 alters the cleavage pattern of 2-ImN-EDTA derivative at only one of its binding sites. The details of the interaction suggest that GCN4 alters the conformation of an AAAAAAA sequence adjacent to its binding site. The presence of a yeast counterpart to Jun partially blocks 2-lmN binding. The differences do not appear to be caused by direct interactions between 2-lmN and the proteins, but by induced conformational changes in the DNA protein complex. It is likely that the observed differences in complexation are involved in the varying sequence specificity of these proteins.

Studies of molecular bonding, interactions and decomposition reactions on the (001) surface of ruthenium

The interactions of N₂, formic acid and acetone on the Ru(001) surface are studied using thermal desorption mass spectrometry (TDMS), electron energy loss spectroscopy (EELS), and computer modeling.

Low energy electron diffraction (LEED), EELS and TDMS were used to study chemisorption of N₂ on Ru(001). Adsorption at 75 K produces two desorption states. Adsorption at 95 K fills only the higher energy desorption state and produces a (√3 x √3)R30° LEED pattern. EEL spectra indicate both desorption states are populated by N₂ molecules bonded "on-top" of Ru atoms.

Monte Carlo simulation results are presented on Ru(001) using a kinetic lattice gas model with precursor mediated adsorption, desorption and migration. The model gives good agreement with experimental data. The island growth rate was computed using the same model and is well fit by R(t)^m - R(t₀)^m = At, with m approximately 8. The island size was determined from the width of the superlattice diffraction feature.

The techniques, algorithms and computer programs used for simulations are documented. Coordinate schemes for indexing sites on a 2-D hexagonal lattice, programs for simulation of adsorption and desorption, techniques for analysis of ordering, and computer graphics routines are discussed.

The adsorption of formic acid on Ru(001) has been studied by EELS and TDMS. Large exposures produce a molecular multilayer species. A monodentate formate, bidentate formate, and a hydroxyl species are stable intermediates in formic acid decomposition. The monodentate formate species is converted to the bidentate species by heating. Formic acid decomposition products are CO₂, CO, H₂, H₂O and oxygen adatoms. The ratio of desorbed CO with respect to CO₂ increases both with slower heating rates and with lower coverages.

The existence of two different forms of adsorbed acetone, side-on, bonded through the oxygen and acyl carbon, and end-on, bonded through the oxygen, have been verified by EELS. On Pt(111), only the end-on species is observed. On dean Ru(001) and p(2 x 2)O precovered Ru(001), both forms coexist. The side-on species is dominant on clean Ru(001), while O stabilizes the end-on form. The end-on form desorbs molecularly. Bonding geometry stability is explained by surface Lewis acidity and by comparison to organometallic coordination complexes.

Reactions of oxygen containing ligands in the coordination sphere of permethylhafnocene and permethyltantalocene

A series of terl-butylperoxide complexes of hafnium, Cp*₂Hf(R)(OOCMe₃) (Cp* = ((η⁵-C₅Me₅); R = Cl, H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂CH₂CH₃, CH₂CHMe₂, CH=CHCMe₃, C₆H₅, meta-C₆H₃(CH₂)2) and Cp*(η⁵-C₅(CH₃)₄CH₂CH₂CH₂)Hf(OOCMe₃), has been synthesized. One example has been structurally characterized, Cp*₂Hf(OOCMe₃)CH₂CH₃ crystallizes in space group P2₁/c, with a = 19.890(7)Å, b = 8.746(4)Å, c = 17.532(6)Å, β = 124.987(24)°, V = 2498(2)ų, Z = 4 and R_F = 0.054 (2222 reflections, I > 0). Despite the coordinative unsaturation of the hafnium center, the terl-butylperoxide ligand is coordinated in a mono-dentate ligand. The mode of decomposition of these species is highly dependent on the substituent R. For R = H, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂CH₂CH₃, CH₂CHMe₂ a clean first order conversion to Cp*₂Hf(OCMe₃)(OR) is observed (for R CH₂CH₃, ΔHǂ = 19.6 kcal•mol^-1, ΔSǂ = -13 e.u.). These results are discussed in terms of a two step mechanism involving η²-coordination of the terl-butylperoxide ligand. Homolytic O-O bond cleavage is observed upon heating of Cp*₂Hf(OOCMe₃) R (R = C₆H₆, meta-C₆H₃(CH₃)₂). In the presence of excess 9,10-dihydroanthracene thermolysis of Cp*₂Hf(OOCMe₃)C₆H₆ cleanly affords Cp*₂Hf(C₆H₆)OH and HOCMe₃ (ΔHǂ = 22.6 kcal•mol^-1, ΔSǂ = -9 e.u.). The O-O bond strength in these complexes is thus estimated to be 22 kcal•mol^-1.

Cp*₂Ta(CH₂)H, Cp*₂Ta(CHC₆H₅)H, Cp*₂Ta(C₆H₄)H, Cp*₂Ta(CH₂=CH₂)H and Cp*₂Ta(CH₂=CHMe)H react, presumably through Cp*₂Ta-R intermediates, with H₂O to give Cp*₂Ta(O)H and alkane. Cp*₂Ta(O)H was structurally characterized: space group P2₁/n, a= 13.073(3)Å, b = 19.337(4)Å, c = 16.002(3)Å, β = 108.66(2)°, V = 3832(1)ų, Z = 8 and R_F = 0.0672 (6730 reflections). Reaction of terlbutylhydroperoxide with these same starting materials ultimately yields Cp*₂Ta(O)R and HOCMe₃. Cp*₂Ta(CH₂=CHR)OH species are proposed as intermediates in the olefin hydride reactions. Cp*₂Ta(O₂)R species can be generated from the reaction of the same starting materials and O₂. Lewis acids have been shown to promote oxygen insertion in these complexes.

Synthetic, kinetic and mechanistic studies in early transition metal systems. I. α- and β-hydrogen elimination reactions in derivatives of permethyltitanocene, -zirconocene, and -hafnocene. II. The reactions of aluminum alkyls with derivatives of permethylniobocene

The thermal decomposition of Cp*Ti(CH_3)_2 (Cp*≡ ƞ^5-C_5Me_5) toluene solution follows cleanly first-order kinetics and produces a single titanium product Cp*(C_5Me_4CH_2)Ti(CH_3) concurrent with the evolution of one equivalent of methane. Labeling studies using Cp*_2Ti- (CD_3)_2 and (Cp*-d_(15))_2Ti(CH_3)_2 show the decomposition to be intramolecular and the methane to be produced by the coupling of a methyl group with a hydrogen from the other TiCH_3 group. Activation parameters, ΔH^‡ and ΔS^‡, and kinetic deuterium isotope effects have been measured. The alternative decomposition pathways of α-hydrogen abstraction and a-hydrogen elimination, both leading to a titanium-methylidene intermediate, are discussed.

The insertion of unactivated acetylenes into the metal-hydride bonds of Cp*_2MH_2 (M = Zr, Hf) proceeds rapidly at low temperature to form monoand/ or bisinsertion products, dependent upon the steric bulk of the acetylene substituents. Cp*_2M(H)(C(Me)=CHMe), Cp*_2M(H)(CH=CHCMe_3), Cp*_2M(H)-(CH=CHPh), Cp*_2M(CH=CHPh)_2, Cp*_2M(CH=CHCH_3)_2 and Cp*_2Zr- (CH=CHCH_2CH_3)_2 have been isolated and characterized. To extend the study of unsaturated-carbon ligands, Cp*_2M(C≡CCH_3)_2 have been prepared by treating Cp*_2MCl_2 with LiC≡CCH_3. The reactivity of many of these complexes with carbon monoxide and dihydrogen is surveyed. The mono(2- butenyl) complexes Cp*_2M(H)(C(Me)=CHMe) rearrange at room temperature, forming the crotyl-hydride species Cp*_2M(H)(ƞ^3-C_4H_7). The bis(propenyl) and bis(l-butenyl) zirconium complexes Cp*_2Zr(CH=CHR)_2 (R = CH_3, CH_2CH_3) also rearrange, forming zirconacyclopentenes. Labeling studies, reaction chemistry, and kinetic measurements, including deuterium isotope effects, demonstrate that the unusual 6-hydrogen elimination from an sp^2-hybridized carbon is the first step in these latter rearrangements but is not observed in the former. Details of these mechanisms and the differences in reactivity of the zirconium and hafnium complexes are discussed.

The reactions of hydride- and alkyl-carbonyl derivatives of permethylniobocene with equimolar amounts of trialkylaluminum reagents occur rapidly producing the carbonyl adducts Cp*_2Nb(R)(COAlR'_3) (R = H, CH_3, CH_2CH_3, CH_2CH_2Ph, C(Me)=CHMe; R' = Me, Et). The hydride adduct Cp*_2NbH_3•AlEt_3 has also been formed. In solution, each of these compounds exists in equilibrium with the uncomplexed species. The formation constants for Cp*_2Nb(H)(COA1R'_R) have been measured. They indicate the steric bulk of the Cp* ligands plays a deciding factor in the isolation of the first example of an aluminum Lewis acid bound to a carbonyl-oxygen in preference to a metalhydride. Reactions of Cp*_2Nb(H)CO with other Lewis acids and of the one:one adducts with H_2, CO and C_2H_4 are also discussed.

Cp*_2Nb(H)(C_2H_4) also reacts with equimolar amounts of trialkylaluminum reagents, forming a one:one complex that ^1H NMR spectroscopy indicates contains a Nb-CH_2CH_2-Al bridge. This adduct also exists in equilibrium with the uncomplexed species in solution. The formation constant for Cp*_2N+/b(H)(CH_2CH_2ĀlEt_3) has been measured. Reactions of Cp*_2Nb(H)(C_2H_4) with other Lewis acids and the reactions of Cp*_2N+b(H)- (CH_2CH_2ĀlEt_3) with CO and C_2H_4 are described, as are the reactions of Cp_*2Nb(H)(CH_2=CHR) (R = Me, Ph), Cp*_2Nb(H)(CH_3C≡CCH_3) and Cp*_2Ti-(C_2H_4) with AlEt_3.

Theory of ozone isotopic effects and various electron transfer reactions

Three separate topics, each stimulated by experiments, are treated theoretically in this dessertation: isotopic effects of ozone, electron transfer at interfaces, and intramolecular directional electron transfer in a supramolecular system.

The strange mass-independent isotope effect for the enrichment of ozone, which has been a puzzle in the literature for some 20 years, and the equally puzzling unconventional strong mass-dependent effect of individual reaction rate constants are studied as different aspects of a symmetry-driven behavior. A statistical (RRKM-based) theory with a hindered-rotor transition state is used. The individual rate constant ratios of recombination reactions at low pressures are calculated using the theory involving (1) small deviation from the statistical density of states for symmetric isotopomers, and (2) weak collisions for deactivation of the vibrationally excited ozone molecules. The weak collision and partitioning among exit channels play major roles in producing the large unconventional isotope effect in "unscrambled" systems. The enrichment studies reflect instead the non-statistical effect in "scrambled" systems. The theoretical results of low-pressure ozone enrichments and individual rate constant ratios obtained from these calculations are consistent with the corresponding experimental results. The isotopic exchange rate constant for the reaction ^(16)O + ^(18)O ^(18)O→+ ^(16)O ^(18)O + ^(18)O provides information on the nature of a variationally determined hindered-rotor transition state using experimental data at 130 K and 300 K. Pressure effects on the recombination rate constant, on the individual rate constant ratios and on the enrichments are also investigated. The theoretical results are consistent with the experimental data. The temperature dependence of the enrichment and rate constant ratios is also discussed, and experimental tests are suggested. The desirability of a more accurate potential energy surface for ozone in the transition state region is also noted.

Electron transfer reactions at semiconductor /liquid interfaces are studied using a tight-binding model for the semiconductors. The slab method and a z-transform method are employed in obtaining the tight-binding electronic structures of semiconductors having surfaces. The maximum electron transfer rate constants at Si/viologen^(2-/+) and InP /Me_(2)Fc^(+/O) interfaces are computed using the tight-binding type calculations for the solid and the extended-Huckel for the coupling to the redox agent at the interface. These electron transfer reactions are also studied using a free electron model for the semiconductor and the redox molecule, where Bardeen's method is adapted to calculate the coupling matrix element between the molecular and semiconductor electronic states. The calculated results for maximum rate constant of the electron transfer from the semiconductor bulk states are compared with the experimentally measured values of Lewis and coworkers, and are in reasonable agreement, without adjusting parameters. In the case of InP /liquid interface, the unusual current vs applied potential behavior is additionally interpreted, in part, by the presence of surface states.

Photoinduced electron transfer reactions in small supramolecular systems, such as 4-aminonaphthalimide compounds, are interesting in that there are, in principle, two alternative pathways (directions) for the electron transfer. The electron transfer, however, is unidirectional, as deduced from pH-dependent fluorescence quenching studies on different compounds. The role of electronic coupling matrix element and the charges in protonation are considered to explain the directionality of the electron transfer and other various results. A related mechanism is proposed to interpret the fluorescence behavior of similar molecules as fluorescent sensors of metal ions.

Reactions of platinum(II) complexes with dioxygen: progress toward alkane functionalization

Whereas stoichiometric activation of C-H bonds by complexes of transition metals is becoming increasingly common, selective functionalization of alkanes remains a formidable challenge in organometallic chemistry. The recent advances in catalytic alkane functionalization by transition-metal complexes are summarized in Chapter I.

The studies of the displacement of pentafluoropyridine in [(tmeda)Pt(CH_3)(NC_5F_5)][BAr^f_4] (1) with γ- tetrafluoropicoline, a very poor nucleophile, are reported in Chapter II. The ligand substitution occurs by a dissociative interchange mechanism. This result implies that dissociative loss of pentafluoropyridine is the rate-limiting step in the C-H activation reactions of 1.

Oxidation of dimethylplatinum(II) complexes (N-N)Pt(CH_3)_2 (N-N = tmeda(1), α-diimines) by dioxygen is described in Chapter III. Mechanistic studies suggest a two-step mechanism. First, a hydroperoxoplatinum(IV) complex is formed in a reaction between (N-N)Pt(CH_3)_2 and dioxygen. Next, the hydroperoxy complex reacts with a second equivalent of (N-N)Pt(CH_3)_2 to afford the final product, (N-N)Pt(OH)(OCH_3)(CH_3)_2. The hydroperoxy intermediate, (tmeda)Pt(OOH)(OCH_3)(CH_3)_2 (2), was isolated and characterized. The reactivity of 2 with several dime thylplatinum(II) complexes is reported.

The studies described in Chapter IV are directed toward the development of a platinum(II)-catalyzed oxidative alkane dehydrogenation. Stoichiometric conversion of alkanes (cyclohexane, ethane) to olefins (cyclohexene, ethylene) is achieved by C-H activation with [(N-N)Pt(CH_3)(CF_3CH_2OH)]BF_4 (1, N-N is N,N'-bis(3,5-di-t- butylphenyl)-1,4-diazabutadiene) which results in the formation of olefin hydride complexes. The first step in the C-H activation reaction is formation of a platinum(II) alkyl which undergoes β-hydrogen elimination to afford the olefin hydride complex. The cationic ethylplatinum(II) intermediate can be generated in situ by treating diethylplatinum(II) compounds with acids. Treatment of (phen)PtEt_2 with [H(OEt_2)_2]Bar^f_4 at low temperatures resulted in the formation of a mixture of [(phen)PtEt(OEt_2)]Bar^f_4 (8) and [(phen)Pt(C_2H_4)H] Bar^f_4 (7). The cationic olefin complexes are unreactive toward dioxygen or hydrogen peroxide. Since the success of the overall catalytic cycle depends on our ability to oxidize the olefin hydride complexes, a series of neutral olefin complexes of platinum(II) with monoanionic ligands (derivatives of pyrrole-2-carboxyaldehyde N-aryl imines) was prepared. Unfortunately, these are also stable to oxidation.

A unified strategy to ent-kauranoid natural products : total syntheses of (–)-maoecrystal Z, (–)-trichorabdal A, and (–)-longikaurin E

The diterpenoid constituents of the Isodon plants have attracted reasearchers interested in both their chemical structures and biological properties for more than a half-century. In recent years, the isolations of new members displaying previously unprecedented ring systems and highly selective biological properties have piqued interest from the synthetic community in this class of natural products.

Reported herein is the first total synthesis of such a recently isolated diterpenoid, (–)-maoecrystal Z. The principal transformations implemented in this synthesis include two highly diastereoselective radical cyclization reactions: a Sm^(II)-mediated reductive cascade cyclization, which forms two rings and establishes four new stereocenters in a single step, and a Ti^(III)-mediated reductive epoxide-acrylate coupling that yields a functionalized spirolactone product, which forms a core bicycle of maoecrystal Z.

The preparation of two additional ent-kauranoid natural products, (–)-trichorabdal A and (–)-longikaurin E, is also described from a derivative of this key spirolactone. These syntheses are additionally enabled by the palladium-mediated oxidative cyclization reaction of a silyl ketene acetal precursor that is used to install the bridgehead all-carbon quaternary stereocenter and bicyclo[3.2.1]octane present in each natural product. These studies have established a synthetic relationship among three architecturally distinct ent-kaurane diterpenoids and have forged a path for the preparation of interesting unnatural ent-kauranoid structural analogs for more thorough biological study.

The theory of long distance electron transfer reactions

The rate of electron transport between distant sites was studied. The rate depends crucially on the chemical details of the donor, acceptor, and surrounding medium. These reactions involve electron tunneling through the intervening medium and are, therefore, profoundly influenced by the geometry and energetics of the intervening molecules. The dependence of rate on distance was considered for several rigid donor-acceptor "linkers" of experimental importance. Interpretation of existing experiments and predictions for new experiments were made.

The electronic and nuclear motion in molecules is correlated. A Born-Oppenheimer separation is usually employed in quantum chemistry to separate this motion. Long distance electron transfer rate calculations require the total donor wave function when the electron is very far from its binding nuclei. The Born-Oppenheimer wave functions at large electronic distance are shown to be qualitatively wrong. A model which correctly treats the coupling was proposed. The distance and energy dependence of the electron transfer rate was determined for such a model.

Mechanistic studies of reactions at the single-molecule level using microfluidics with applications in molecular diagnostics

Motivated by needs in molecular diagnostics and advances in microfabrication, researchers started to seek help from microfluidic technology, as it provides approaches to achieve high throughput, high sensitivity, and high resolution. One strategy applied in microfluidics to fulfill such requirements is to convert continuous analog signal into digitalized signal. One most commonly used example for this conversion is digital PCR, where by counting the number of reacted compartments (triggered by the presence of the target entity) out of the total number of compartments, one could use Poisson statistics to calculate the amount of input target.

However, there are still problems to be solved and assumptions to be validated before the technology is widely employed. In this dissertation, the digital quantification strategy has been examined from two angles: efficiency and robustness. The former is a critical factor for ensuring the accuracy of absolute quantification methods, and the latter is the premise for such technology to be practically implemented in diagnosis beyond the laboratory. The two angles are further framed into a “fate” and “rate” determination scheme, where the influence of different parameters is attributed to fate determination step or rate determination step. In this discussion, microfluidic platforms have been used to understand reaction mechanism at single molecule level. Although the discussion raises more challenges for digital assay development, it brings the problem to the attention of the scientific community for the first time.

This dissertation also contributes towards developing POC test in limited resource settings. On one hand, it adds ease of access to the tests by incorporating massively producible, low cost plastic material and by integrating new features that allow instant result acquisition and result feedback. On the other hand, it explores new isothermal chemistry and new strategies to address important global health concerns such as cyctatin C quantification, HIV/HCV detection and treatment monitoring as well as HCV genotyping.

Z-selective olefin metathesis using chelating ruthenium alkylidene catalysts

Publications about olefin metathesis will generally discuss how the discovery and development of well-defined catalysts to carry out this unique transformation have revolutionized many fields, from natural product and materials chemistry, to green chemistry and biology. However, until recently, an entire manifestation of this methodology had been inaccessible. Except for a few select examples, metathesis catalysts favor the thermodynamic trans- or E-olefin products in cross metathesis (CM), macrocyclic ring closing metathesis (mRCM), ring opening metathesis polymerization (ROMP), and many other types of reactions. Judicious choice of substrates had allowed for the direct synthesis of cis- or Z-olefins or species that could be converted upon further reaction, however the catalyst controlled synthesis of Z-olefins was not possible until very recently.

Research into the structure and stability of metallacyclobutane intermediates has led to the proposal of models to impart Z-selectivity in metathesis reactions. Having the ability to influence the orientation of metallacyclobutane substituents to cause productive formation of Z- double bonds using steric and electronic effects was highly desired. The first successful realization of this concept was by Schrock and Hoveyda et al. who synthesized monoaryloxide pyrolidine (MAP) complexes of tungsten and molybdenum that promoted Z-selective CM. The Z-selectivity of these catalysts was attributed to the difference in the size of the two axial ligands. This size difference influences the orientation of the substituents on the forming/incipient metallacyclobutane intermediate to a cis-geometry and leads to productive formation of Z-olefins. These catalysts have shown great utility in the synthesis of complicated natural product precursors and stereoregular polymers. More recently, ruthenium catalysts capable of promoting Z-selective metathesis have been reported by our group and others. This thesis will discuss the development of ruthenium-based NHC chelated Z-selective catalysts, studies probing their unique metathesis mechanism, and synthetic applications that have been investigated thus far.

Chapter 1 will focus on studies into the stability of NHC chelated complexes and the synthesis of new and improved stable chelating architectures. Chapter 2 will discuss applications of the highly active and Z-selective developed in Chapter 1, including the formation of lepidopteran female sex pheromones using olefin cross metathesis and highly Z- and highly E-macrocycles using macrocyclic ring closing metathesis and Z-selective ethenolysis. Chapter 3 will explore studies into the unique mechanism of olefin metathesis reactions catalyzed by these NHC chelated, highly Z-selective catalysts, explaining observed trends by investigating the stability of relevant, substituted metallacyclobutane intermediates.