Palladium-Catalyzed Decarboxylative and Decarbonylative Transformations in the Synthesis of Fine and Commodity Chemicals

Decarboxylation and decarbonylation are important reactions in synthetic organic chemistry, transforming readily available carboxylic acids and their derivatives into various products through loss of carbon dioxide or carbon monoxide. In the past few decades, palladium-catalyzed decarboxylative and decarbonylative reactions experienced tremendous growth due to the excellent catalytic activity of palladium. Development of new reactions in this category for fine and commodity chemical synthesis continues to draw attention from the chemistry community.

The Stoltz laboratory has established a palladium-catalyzed enantioselective decarboxylative allylic alkylation of β-keto esters for the synthesis of α-quaternary ketones since 2005. Recently, we extended this chemistry to lactams due to the ubiquity and importance of nitrogen-containing heterocycles. A wide variety of α-quaternary and tetrasubstituted α-tertiary lactams were obtained in excellent yields and exceptional enantioselectivities using our palladium-catalyzed decarboxylative allylic alkylation chemistry. Enantioenriched α-quaternary carbonyl compounds are versatile building blocks that can be further elaborated to intercept synthetic intermediates en route to many classical natural products. Thus our chemistry enables catalytic asymmetric formal synthesis of these complex molecules.

In addition to fine chemicals, we became interested in commodity chemical synthesis using renewable feedstocks. In collaboration with the Grubbs group, we developed a palladium-catalyzed decarbonylative dehydration reaction that converts abundant and inexpensive fatty acids into value-added linear alpha olefins. The chemistry proceeds under relatively mild conditions, requires very low catalyst loading, tolerates a variety of functional groups, and is easily performed on a large scale. An additional advantage of this chemistry is that it provides access to expensive odd-numbered alpha olefins.

Finally, combining features of both projects, we applied a small-scale decarbonylative dehydration reaction to the synthesis of α-vinyl carbonyl compounds. Direct α-vinylation is challenging, and asymmetric vinylations are rare. Taking advantage of our decarbonylative dehydration chemistry, we were able to transform enantioenriched δ-oxocarboxylic acids into quaternary α-vinyl carbonyl compounds in good yields with complete retention of stereochemistry. Our explorations culminated in the catalytic enantioselective total synthesis of (–)-aspewentin B, a terpenoid natural product featuring a quaternary α-vinyl ketone. Both decarboxylative and decarbonylative chemistries found application in the late stage of the total synthesis.

Programming chemical kinetics: engineering dynamic reaction networks with DNA strand displacement

Over the last century, the silicon revolution has enabled us to build faster, smaller and more sophisticated computers. Today, these computers control phones, cars, satellites, assembly lines, and other electromechanical devices. Just as electrical wiring controls electromechanical devices, living organisms employ "chemical wiring" to make decisions about their environment and control physical processes. Currently, the big difference between these two substrates is that while we have the abstractions, design principles, verification and fabrication techniques in place for programming with silicon, we have no comparable understanding or expertise for programming chemistry.

In this thesis we take a small step towards the goal of learning how to systematically engineer prescribed non-equilibrium dynamical behaviors in chemical systems. We use the formalism of chemical reaction networks (CRNs), combined with mass-action kinetics, as our programming language for specifying dynamical behaviors. Leveraging the tools of nucleic acid nanotechnology (introduced in Chapter 1), we employ synthetic DNA molecules as our molecular architecture and toehold-mediated DNA strand displacement as our reaction primitive.

Abstraction, modular design and systematic fabrication can work only with well-understood and quantitatively characterized tools. Therefore, we embark on a detailed study of the "device physics" of DNA strand displacement (Chapter 2). We present a unified view of strand displacement biophysics and kinetics by studying the process at multiple levels of detail, using an intuitive model of a random walk on a 1-dimensional energy landscape, a secondary structure kinetics model with single base-pair steps, and a coarse-grained molecular model that incorporates three-dimensional geometric and steric effects. Further, we experimentally investigate the thermodynamics of three-way branch migration. Our findings are consistent with previously measured or inferred rates for hybridization, fraying, and branch migration, and provide a biophysical explanation of strand displacement kinetics. Our work paves the way for accurate modeling of strand displacement cascades, which would facilitate the simulation and construction of more complex molecular systems.

In Chapters 3 and 4, we identify and overcome the crucial experimental challenges involved in using our general DNA-based technology for engineering dynamical behaviors in the test tube. In this process, we identify important design rules that inform our choice of molecular motifs and our algorithms for designing and verifying DNA sequences for our molecular implementation. We also develop flexible molecular strategies for "tuning" our reaction rates and stoichiometries in order to compensate for unavoidable non-idealities in the molecular implementation, such as imperfectly synthesized molecules and spurious "leak" pathways that compete with desired pathways.

We successfully implement three distinct autocatalytic reactions, which we then combine into a de novo chemical oscillator. Unlike biological networks, which use sophisticated evolved molecules (like proteins) to realize such behavior, our test tube realization is the first to demonstrate that Watson-Crick base pairing interactions alone suffice for oscillatory dynamics. Since our design pipeline is general and applicable to any CRN, our experimental demonstration of a de novo chemical oscillator could enable the systematic construction of CRNs with other dynamic behaviors.

I. Thermochemistry and reaction kinetics of disolvated protons by ion cyclotron resonance spectroscopy. II. Thermochemical studies of small fluorocarbons by photoionization mass spectrometry

The disolvated proton, H(OH₂)₂⁺ is employed as a chemical reagent in low pressure (˂ 10^-5 torr) investigations by ion cyclotron resonance spectroscopy. Since termolecular reactions are absent at low pressure, disolvated protons are not generally observed. However H(OH₂)₂⁺ is produced in a sequence of bimolecular reactions in mixtures containing H₂O and one of a small number of organohalide precursors. Then a series of hydrated Lewis bases is produced by H₃O⁺ transfer from H(OH₂)₂⁺. In Chapter II, the relative stability of hydrated bases containing heteroatoms of both first and second row elements is determined from the preferred direction of H₃O⁺ transfer between BH(OH₂)⁺ complexes. S and P containing bases are shown to bind H₃O⁺ more weakly than O and N bases with comparable proton affinities. A simple model of hydrogen bonding is proposed to account for these observations.

H⁺ transfer from H(OH₂)₂⁺ to several Lewis bases also occurs at low pressure. In Chapter III the relative importance of H₃O⁺ transfer and H⁺ transfer from H(OH₂)₂⁺ to a series of bases is observed to be a function of base strength. Beginning with CH₃COOH, the weakest base for which H⁺ transfer is observed, the importance of H⁺ transfer increases with increasing proton affinity of the acceptor base. The nature of neutral products formed from H(OH₂)₂⁺ by loss of H⁺ is also considered.

Chapters IV and V deal with thermochemistry of small fluorocarbons determined by photoionization mass spectrometry. The enthalpy of formation of CF₂ is considered in Chapter IV. Photoionization of perfluoropropylene, perfluorocyclopropane, and trifluoromethyl benzene yield onsets for ions formed by loss of a CF₂ neutral fragment. Earlier determinations of ΔH^°_f298 (CF₂) are reinterpreted using updated thermochemical values and compared with results of this study. The heat of formation of neutral perfluorocyclopropane is also derived. Finally, the energetics of interconversion of perfluoropropylene and perfluorocyclopropane are considered for both the neutrals and their molecular ions.

In Chapter V the heats of formation of CF₃⁺ and CF₃I⁺are derived from photoionization of CF₃I. These are considered with respect to ion-molecule reactions observed in CF₃I monitored by the techniques of ion cyclotron resonance spectroscopy. Results obtained in previous experiments are also compared.

I. The rate and mechanism of the vapor-phase reaction between water and parts-per-million concentrations of nitrogen dioxide. II. The rate and mechanism of the air oxidation of parts-per-million concentrations of nitric oxide in the presence of water vapor.

Part I

A study of the thermal reaction of water vapor and parts-per-million concentrations of nitrogen dioxide was carried out at ambient temperature and at atmospheric pressure. Nitric oxide and nitric acid vapor were the principal products. The initial rate of disappearance of nitrogen dioxide was first order with respect to water vapor and second order with respect to nitrogen dioxide. An initial third-order rate constant of 5.5 (± 0.29) x 10⁴ liter² mole^-2 sec^-1 was found at 25˚C. The rate of reaction decreased with increasing temperature. In the temperature range of 25˚C to 50˚C, an activation energy of -978 (± 20) calories was found.

The reaction did not go to completion. From measurements as the reaction approached equilibrium, the free energy of nitric acid vapor was calculated. This value was -18.58 (± 0.04) kilocalories at 25˚C.

The initial rate of reaction was unaffected by the presence of oxygen and was retarded by the presence of nitric oxide. There were no appreciable effects due to the surface of the reactor. Nitric oxide and nitrogen dioxide were monitored by gas chromatography during the reaction.

Part II

The air oxidation of nitric oxide, and the oxidation of nitric oxide in the presence of water vapor, were studied in a glass reactor at ambient temperatures and at atmospheric pressure. The concentration of nitric oxide was less than 100 parts-per-million. The concentration of nitrogen dioxide was monitored by gas chromatography during the reaction.

For the dry oxidation, the third-order rate constant was 1.46 (± 0.03) x 10⁴ liter² mole^-2 sec^-1 at 25˚C. The activation energy, obtained from measurements between 25˚C and 50˚C, was -1.197 (±0.02) kilocalories.

The presence of water vapor during the oxidation caused the formation of nitrous acid vapor when nitric oxide, nitrogen dioxide and water vapor combined. By measuring the difference between the concentrations of nitrogen dioxide during the wet and dry oxidations, the rate of formation of nitrous acid vapor was found. The third-order rate constant for the formation of nitrous acid vapor was equal to 1.5 (± 0.5) x 10⁵ liter² mole^-2 sec^-1 at 40˚C. The reaction rate did not change measurably when the temperature was increased to 50˚C. The formation of nitric acid vapor was prevented by keeping the concentration of nitrogen dioxide low.

Surface effects were appreciable for the wet tests. Below 35˚C, the rate of appearance of nitrogen dioxide increased with increasing surface. Above 40˚C, the effect of surface was small.

Mechanistic studies of a model reaction for enzymatic hydroxylation

A study has been made of the reaction mechanism of a model system for enzymatic hydroxylation. The results of a kinetic study of the hydroxylation of 2-hydroxyazobenzene derivatives by cupric ion and hydrogen peroxide are presented. An investigation of kinetic orders indicates that hydroxylation proceeds by way of a coordinated intermediate complex consisting of cupric ion and the mono anions of 2-hydroxyazobenzene and hydrogen peroxide. Studies with deuterated substrate showed the absence of a primary kinetic isotope effect and no evidence of an NIH shift. The effect of substituents on the formation of intermediate complexes and the overall rate of hydroxylation was studied quantitatively in aqueous solution. The combined results indicate that the hydroxylation step is only slightly influenced by ring substitution. The substituent effect is interpreted in terms of reaction by a radical path or a concerted mechanism in which the formation of ionic intermediates is avoided. The reaction mechanism is discussed as a model for enzymatic hydroxylation.

An investigation of the three-body reaction He^3(He^3, 2p)He^4

Reactions produced by the He³ bombardment of the He³ have been investigated for bombarding energies from 1 to 20 MeV using a tandem Van de Graaff accelerator. Proton spectra from the three-body reaction He³(He³, 2p)He⁴ have been measured with a counter telescope at 13 angles for 9 bombarding energies between 3 and 18 MeV. The results are compared with a model for the reaction which includes a strong p-He⁴ final-state interaction. Alpha-particle spectra have been obtained at 12 and 18 MeV for forward angles with a magnetic spectrometer. These spectra indicate a strongly forward-peaked mechanism involving the ¹S₀ p-p interaction in addition to the p-He⁴ interaction. Measurements of p-He⁴ and p-p coincidence spectra at 10 MeV confirm these features of the reaction mechanism. Deuteron spectra from the reaction of He³(He³, d)pHe³ have been measured at 18 MeV. A triton spectrum from the reaction He³(He³, t)3p at 20 MeV and 4⁰ is interpreted in terms of a sequential decay through an excited state of the alpha particle at 20.0 MeV. No effects are observed which would indicate an interaction in the residual (3p) system. Below 3 MeV the He³(He³, 2p)He⁴ reaction mechanism is observed to be changing and further measurements are suggested in view of the importance of this reaction in stellar interiors.

Depth-sensitive analysis of fluorine on lunar sample surfaces and in carbonaceous chondrites by a nuclear resonant reaction technique

The nuclear resonant reaction ¹⁹F(ρ,αγ)¹⁶O has been used to perform depth-sensitive analyses of fluorine in lunar samples and carbonaceous chondrites. The resonance at 0.83 MeV (center-of-mass) in this reaction is utilized to study fluorine surface films, with particular interest paid to the outer micron of Apollo 15 green glass, Apollo 17 orange glass, and lunar vesicular basalts. These results are distinguished from terrestrial contamination, and are discussed in terms of a volcanic origin for the samples of interest. Measurements of fluorine in carbonaceous chondrites are used to better define the solar system fluorine abundance. A technique for measurement of carbon on solid surfaces with applications to direct quantitative analysis of implanted solar wind carbon in lunar samples is described.

Part I. Coenzyme B12 as a hydroformylation-type catalyst. Part II. Mechanisms of hydrogen transfer in the methylmalonyl coenzyme a mutase reaction

Part I

The mechanism of the hydroformylation reaction was studied. Using cobalt deuterotetracarbonyl and 1-pentene as substrates, the first step in the reaction, addition of cobalt tetracarbonyl to an olefin, was shown to be reversible.

Part II

The role of coenzyme B₁₂ in the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A by methylmalonyl coenzyme A mutase was studied. The reaction was allowed to proceed to partial completion using a mixture of methylmalonyl coenzyme A and 4, 4, 4-tri-²H-methylmalonyl coenzyme A as substrate. The deuterium distribution in the product, succinyl coenzyme A, was shown to best fit a model in which hydrogen is transferred from C-4 of methylmalonyl coenzyme A to C-5’ of the adenosyl moiety of coenzyme B₁₂ in the rate determining step. The three hydrogens at the 5’-adenosyl position of the coenzyme B₁₂ intermediate are then able to become enzymatically equivalent before hydrogen is transferred from the coenzyme B₁₂ intermediate to form succinyl coenzyme A.

Alkylation of ketones with 3-bromomethyl-1,2-benzisothiazoles

The synthesis of 3-bromomethyl-1,2-benzisothiazole and its 5- and 7-methoxy derivatives has been accomplished. In alkylation reactions, these bromides were found to behave much like benzylic bromides; and in this respect they have been used successfully to alkylate strongly basic enolates, thus introducing a latent β-phenylethyl moiety in situations where β-phenylethyl bromide and phenacyl bromide give at best poor yields of alkylated product. In several cases, degradative procedures have been devised to remove the heteroatoms from the benzisothiazoyl system to provide the actual β-phenylethyl fragment; however, no generally applicable degradative method has yet been developed.

An investigation of the reaction negative K¯p → K¯π⁺ at P_(lab) = 2 Gev/c

The reaction K^-p→K^-π⁺n has been studied for incident kaon momenta of 2.0 GeV/c. A sample of 19,881 events was obtained by a measurement of film taken as part of the K-63 experiment in the Berkeley 72 inch bubble chamber.

Based upon our analysis, we have reached four conclusions. (1) The magnitude of the extrapolated Kπ cross section differs by a factor of 2 from the P-wave unitarity prediction and the K⁺n results; this is probably due to absorptive effects. (2) Fits to the moments yield precise values for the Kπ S-wave which agree with other recent statistically accurate experiments. (3) An anomalous peak is present in our backward K^-p→(π+n) K^- u-distribution. (4) We find a non-linear enhancement due to interference similiar to the one found by Bland et al. (Bland 1966).

Part I: Total yield measurements for the ^(21)Ne(α,n)^)(24)Mg reaction. Part II: A study of the ^(12)C(He,p)^(14)N reaction

PART I

The total cross-section for the reaction ²¹Ne(α, n)²⁴Mg has been measured in the energy range 1.49 Mev ≤ E_cm ≤ 2.6 Mev. The cross-section factor, S(O), for this reaction has been determined, by means of an optical model calculation, to be in the range 1.52 x 10¹² mb-Mev to 2.67 x 10¹² mb-Mev, for interaction radii in the range 5.0 fm to 6.6 fm. With S(O) ≈ 2 x 10¹² mb-Mev, the reaction ²¹Ne(α, n)²⁴Mg can produce a large enough neutron flux to be a significant astrophysical source of neutrons.

PART II

The reaction¹²C(³He, p)¹⁴N has been studied over the energy range 12 Mev ≤ E_lab ≤ 18 Mev. Angular distributions of the proton groups leading to the lowest seven levels in ¹⁴N were obtained.

Distorted wave calculations, based on two-nucleon transfer theory, were performed, and were found to be reliable for obtaining the value of the orbital angular momentum transferred. The present work shows that such calculations do not yield unambiguous values for the spectroscopic factors.