Computational, Synthetic, and Spectroscopic Investigations of PTA and Derivatives Towards Drug Development and Rare Earth Metal Extraction from Aqueous Media
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Authors
Cournoyer, Travis
Issue Date
2017
Type
Dissertation
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Keywords
Cancer Therapy , Mineral Extraction , PTA , RAPTA , Rare Earth
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Abstract
The synthesis of novel upper-rim PTA-amides, where PTA is 1,3,5-triaza-7-phosphaadamantane, was attempted through several synthetic routes including those utilizing both amine and carboxylic acid-based PTA starting materials. Nitrogen-carbon amide bond formation was attempted between upper-rim PTA-enamines and nitrogen-protected amino acids with the coupling agent 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide (HBTU) and diisopropylethylamine (DIPEA). The upper-rim benzylamide of PTA was prepared by nucleophilic attack of methyl-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]-decane-6-carboxylate (PTA-CO2Me) by benzylamine, facilitated by sodium methoxide in THF. Hydrochloride salts of butylamine and benzylamine as well as methyl ester-protected amino acids histidine and glycine were coupled to lithium 1,3,5-triaza-7-phosphaadamantane-6-carboxylate (PTA-CO2Li) with the assistance of HBTU and DIPEA in DMF. These upper-rim PTA amides were characterized with both NMR spectroscopy and Fourier-Transform Infrared Spectroscopy (FT-IR) and selectivity as high as 100% was observed when the reaction was conducted with alkyl and aryl substrates.The oxidation of upper-rim PTA enamines was optimized and the isomerization kinetics of one derivative PTA=C[C5H2(OMe)3]NH2 were investigated with time-resolved 31P{1H} NMR at variable temperatures. Equilibrium constants of 0.871, 0.866, and 0.897 were determined for the isomerization at 25 ºC, 35 ºC, and 45 ºC, respectively. Rate constants for conversion of the E isomer to the Z isomer were found to be 1.42 x 10-2, 2.52 x 10-2, and 5.27 x 10-2 at the same temperatures as well, respectively.The coordination modes of PTA were investigated with Density Functional Theory (DFT) to elucidate the location of electron density around the nucleophilic phosphorus and nitrogen atoms of the phosphine. It was found that most of the electron density of the Highest Occupied Molecular Orbital (HOMO) is centered around a nitrogen atom, which potentially explains the observed borane substitution behavior that has been referenced in previous publications, at least in part. The coordination modes of several metal-PTA and metal-O=PTA complexes were also investigated with nickel and Ln3+, respectively, where Ln3+ is La, Ce, Eu, Sm, and Yb. Characterization with 31P{1H} NMR spectroscopy (solid state and solution state), single-crystal X-ray diffraction, and FT-IR suggests that the nickel-PTA complexes are phosphorus-bound, as opposed to nitrogen-bound as was previously eluded to in the literature. Characterization of lanthanide complexes with O=PTA reveal oxygen-coordination is the exclusive coordination mode between the phosphine oxide and the metals.The pH-dependent precipitation of lanthanides from aqueous media with the use of lithium 1,3,5-triaza-7-phosphaadamantane-6-carboxylate (PTA-CO2Li) was investigated and optimized. The pKa of [PTA-CO2-][H+] was experimentally determined to be 6.1 ± 0.2 through an NMR titration, and relative energy calculations comparing the different isomers of the ligand suggest that protonation of the 3-nitrogen yields the most stable structure and the carboxylic acid is the least stable. The pKa of [PTA-(CO2)2-][H+] was experimentally determined to be 6.09 ± 0.52 through an NMR titration as well. Reaction conditions required to precipitate lanthanides (La3+, Gd3+, and Yb3+) from aqueous media with [PTA-CO2-][H+] via hydrothermal treatment were investigated and optimized. It was found that the precipitation of lanthanides form aqueous media is most efficient when the initial reaction pH lies close to 4 and the phosphine to lanthanide ratio exceeds 3:1. Finally, dilution of these precipitates in acidic media with chloride salts followed by basification with sodium hydroxide to pH > 10 yields the lanthanide hydroxides, which can be calcined to yield lanthanide oxides in a more carbon-neutral manner than the lanthanide oxalates which are currently being utilized in the industry to precipitate lanthanides from aqueous media.
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