Doctor of Philosophy
Department of Chemistry
Siu, Anna Feng Hua, Synthetic and kinetic studies of π-hydrocarbon iron complexes, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 1995. http://ro.uow.edu.au/theses/1192
In Chapter 1 of this thesis, some important aspects of chiral compounds, especially chiral primary amines, and the methods of preparing these compounds in optically pure form are discussed. Aspects of radiopharmaceutical chemistry that are relevant to the thesis are also introduced.
Chapter 2 describes an investigation into the synthesis of chiral primary amines using [(dienyl)Fe(CO)2L]+ (dienyl = C6H7 , 2-MeOC6H6 or C7H9 and L = CO or PPh3) complexes. Improved methods have been developed for the synthesis of [(dienyl)Fe(CO)2I] and [(dienyl)Fe(CO)2(PPh3)]+ complexes starting from [(dienyl)Fe(CO)3]+. These studies include the synthesis of the complexes [(2- MeOC6H6)Fe(CO)2I] and [(2-MeOC6H6)Fe(CO)2 (PPh3)]+ for the first time. The planned synthetic route to chiral primary amines involved the reaction of [(dienyl)Fe(CO)3]+ cations with ammonia to form novel [(5-amino-diene)Fe(CO)3] adducts possessing planar chirality, followed by condensation reactions with benzaldehyde to yield chiral imine products. Addition of ammonia to [(dienyl)Fe(CO)3]+ complexes gave a mixture of the desired complex [(5-amino-diene)Fe(CO)3] and dimeric adducts [Fe(CO)3(diene)-NH- (diene)Fe(CO)3] and [(CO)3Fe(diene)-NH2-(diene)Fe(CO)3]+, which were characterised by microanalyses and N M R , IR and mass spectroscopic techniques. Treatment of this mixture with benzaldehyde yielded chiral imine compounds. These new imine compounds then subsequently underwent reduction with sodium borohydride or sodium borodeuteride to give chiral amine products. Finally, addition of trifluoroacetic acid to the chiral amine products resulted in the regeneration of the starting dienyl iron cations and simultaneous release of the primary amine products. However, analogous reactions starting with [(dienyl)Fe(CO)2(PPh3)]+ complexes were less satisfactory. This m a y be due to the presence of an electron donating PPh3 ligand which makes the dienyl ring less electrophilic, and therefore nucleophilic attack by ammonia less favorable.
In Chapter 3, a method for the attachment of [(dienyl)Fe(CO)3]+ (dienyl = C6H7 , 2-MeOCeH6 or C7H9) complexes to a polystyrene-support is reported. This procedure involved the initial conversion of the [(dienyl)Fe(CO)3]+ cations to [(dienyl)Fe(CO)2I] complexes, followed by Ag+-catalysed replacement of the iodide ligand with polystyrenesupported PPh3 (with 2 % divinylbenzene cross-linked). Several novel polymer-supported dienyl iron complexes have been produced and characterised by iron analysis and IR and 31P NMR (solution and solid state) spectroscopic techniques. These polymer-supported iron complexes underwent addition reactions at the dienyl ring with various nucleophiles including hydride, tributylphosphine, amines and amino acid esters. Addition of trifluoroacetic acid to these polymer-supported diene adducts regenerated the original polymer-supported dienyl salts.
Chapter 4 describes kinetic and mechanistic studies of the addition of iodide ion to [(dienyl)Fe(CO)3]+ cations as a route to [(dienyl)Fe(CO)2(PPh3)] (dienyl = C6H7, 2- MeOC6H6 or C7H9) and [(dienyl)Fe(CO)2(PPh2-polystyrene] complexes. Detailed IR spectroscopic studies showed that the reactions between the cations and I- depended markedly on the nature of the dienyl ligand. In the case of the C6H7 and 2-MeOCeH6 complexes, the formation of ring adducts [(diene-I)Fe(CO)3] dominated, whereas with the C7H9 substrate carbonyl ligand substitution was the dominant pathway. The reactions in CH3NO2 and acetone also gave acyl iodide adducts [(dienyl)Fe(CO)2(COI)] as minor products; however, in CH3CN this latter type of species was not observed. Another major influence of solvent was the much more rapid reactions observed in acetone compared with CH3NO2 and C H3CN . On the other hand, the nature of the counter cation in the iodide salt reagent has only a very minor effect on the reactions. Detailed kinetic studies of these reactions in various solvents were consistent with the general second order rate law, rate = k[Fe][I-]. In the reactions of [Et4N][I] with [(dienyl)Fe(CO)3]+ and [(2-MeOC6H6)- Fe(CO)3]+, the activation parameters (including negative ΔS ≠ values) and the rate trend C6H7 > 2-MeOC6H6 were in agreement with classical bimolecular nucleophilic attack of I- on the dienyl rings. However, a single electron transfer (SET) mechanism provided an alternative explanation for the various pathways observed in these reactions.
Chapter 5 explores routes to optically active [(diene)Fe(CO)2(PPh3)] and [(dienyl)Fe(CO)2(PPh3)]+ complexes required as precursors for the asymmetric synthesis of chiral primary amines. Novel optically pure dicarbonyl (triphenylphosphine)[(4R)- phenyl-(r' R)-(l'-phenylethyl)-l-aza-l,3-butadiene]iron(0) has been synthesized and fully characterised by X-ray crystallography, microanalysis and IR, NMR and mass spectroscopic techniques. Asymmetric induction was observed when this l-aza-1,3- butadiene iron complex was used as a chiral transfer reagent for the transfer of Fe(CO)2(PPh3) to 1-methoxy-1,3-cyclohexadiene. This route has provided optically active dicarbonyl(triphenylphosphine)-(n4-l-methoxy-l,3-cyclohexadiene)iron for the first time.
Finally, Chapter 6 investigates the possibility using of chiral dienyl iron [(2- MeOC6H6)Fe(CO)3]+ complex to prepare optically active radiopharmaceuticals. An antiinflammatory agent (MK-447) and several of its analogues, including the precursors 2- aminomethyl-4-fert-butylphenol hydrochloride, N-benzyl-(5-tert-butylphenyl-2-hydroxy)- glycine and N-(5-tert-butyl-2-hydroxyphenyl)methylmorpholine have been synthesized and characterised by IR, NMR and mass spectroscopic and uv/visible spectrometric techniques. Radiolabelling of these precursors with iodine-123 yielded n e w radioactive materials with radiochemical purity > 97 %. In vivo biodistribution studies of some of these radiolabeled compounds in rats showed rapid uptake and clearance of radioactivity in the liver and stomach, which indicated fast metabolism of these compounds. Extensive accumulation of radioactivity was also observed in the thyroid and total gastrointestinal tracts. However, the kinetic resolution of the chiral MK-447 analogues could not be successfully achieved.