Asymmetric α-alkylation reactions
- Authors: Klein, Rosalyn
- Date: 2000
- Subjects: Asymmetric synthesis , Alkylation , Chemical reactions
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4405 , http://hdl.handle.net/10962/d1006710 , Asymmetric synthesis , Alkylation , Chemical reactions
- Description: A novel camphor-derived hydroxy ketal 138 has been developed as a crural auxiliary, and used to prepare a series of six carboxylic esters of increasing steric bulk. The α-benzylation of this series of esters was achieved with diastereoselectivities of 59 - 83% d. e. and in 39 - 48% material yield. These results compared very favourably with those obtained in earlier studies using a regioisomeric analogue as the chiral auxiliary. Computer.modelling studies of the putative enolate intermediate has provided some insight into the possible mode of electrophilic attack at the α-carbon and the roles of the ketal protecting group and the lithium cation in these asymmetric transformations. In a related investigation, based on earlier work, a camphor-derived imino lactone has provided convenient access to α-alkyl α-amino acids, the imino lactone serving as a masked glycine equivalent. Using straight chain primary alkyl iodides [RI; R = Me, Et, Pr, Bu, CH₃(CH₂)₄ and CH₃(CH₄)₅], alkylation of the potassium enolate of the camphor-derived imino lactone was effected with 54 - 89% d.e. and in 54 - 87% material yield. Four novel alkylated derivatives were synthesised using isopropyl iodide, sec-butyl iodide and allyl iodide, the latter reagent resulting in both the monoallylated and diallylated products. While very good diastereoselectivities were achieved (83 - 88% d. e.) in these reactions, the material yields from reaction with the secondary alkyl iodides were low (31- 35%) due, presumably, to their decreased electrophilicity. Computer modelling studies of the enolate were carried out and support the hypothesis of endo attack by the electrophile on the enolate intermediate. These studies also indicate the possibility of coordination of the postassium cation to the endocyclic ester oxygen, thus effectively anchoring the bulky cation away from the reaction site.
- Full Text:
- Date Issued: 2000
- Authors: Klein, Rosalyn
- Date: 2000
- Subjects: Asymmetric synthesis , Alkylation , Chemical reactions
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4405 , http://hdl.handle.net/10962/d1006710 , Asymmetric synthesis , Alkylation , Chemical reactions
- Description: A novel camphor-derived hydroxy ketal 138 has been developed as a crural auxiliary, and used to prepare a series of six carboxylic esters of increasing steric bulk. The α-benzylation of this series of esters was achieved with diastereoselectivities of 59 - 83% d. e. and in 39 - 48% material yield. These results compared very favourably with those obtained in earlier studies using a regioisomeric analogue as the chiral auxiliary. Computer.modelling studies of the putative enolate intermediate has provided some insight into the possible mode of electrophilic attack at the α-carbon and the roles of the ketal protecting group and the lithium cation in these asymmetric transformations. In a related investigation, based on earlier work, a camphor-derived imino lactone has provided convenient access to α-alkyl α-amino acids, the imino lactone serving as a masked glycine equivalent. Using straight chain primary alkyl iodides [RI; R = Me, Et, Pr, Bu, CH₃(CH₂)₄ and CH₃(CH₄)₅], alkylation of the potassium enolate of the camphor-derived imino lactone was effected with 54 - 89% d.e. and in 54 - 87% material yield. Four novel alkylated derivatives were synthesised using isopropyl iodide, sec-butyl iodide and allyl iodide, the latter reagent resulting in both the monoallylated and diallylated products. While very good diastereoselectivities were achieved (83 - 88% d. e.) in these reactions, the material yields from reaction with the secondary alkyl iodides were low (31- 35%) due, presumably, to their decreased electrophilicity. Computer modelling studies of the enolate were carried out and support the hypothesis of endo attack by the electrophile on the enolate intermediate. These studies also indicate the possibility of coordination of the postassium cation to the endocyclic ester oxygen, thus effectively anchoring the bulky cation away from the reaction site.
- Full Text:
- Date Issued: 2000
Stability of prochlorperazine in solution and in the solid-state
- Authors: Antunes, Edith Martins
- Date: 2000
- Subjects: Phenothiazine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4536 , http://hdl.handle.net/10962/d1016399
- Description: Prochlorperazine, a member of the piperazine subclass of phenothiazines, widely used as an anti-emetic, is susceptible to oxidation to sulfoxides. These are main metabolites and degradants of all phenothiazines which are found to be inactive at the dopamine receptors. Prochlorperazine causes photosensitivity effects in patients attributed to dechlorination at C2 with the release of HCI (Huang and Sands, 1967; Nejmeh and Pilpel, 1978; Moore and Tamat, 1980). The aim of this study is to investigate the thermal and photostability of prochlorperazine edisylate and mesylate salts in the solid state and in solution. Prochlorperazine is available as a fine chemical and in a variety of dosage forms, including injectables and tablets. According to ICH guidelines, any degradants greater than 0.1 % are required to be isolated and identified. In order to assess the photostability of the two salts, an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection, quantitation and ruggedness. Sulfoxides were synthesised for use as standards in the rate studies according to the well-known hydrogen peroxide method (Owens et al., 1989). The rate of prochlorperazine degradation in solution under various light sources (254 nm UV light, diffuse light and sunlight) was studied. The light sources used abovF were quantified using potassium ferrioxalate as a chemical actinometer). The photodegradation rate was found to be greater in ampoules sealed under nitrogen than air, but the thermal degradation was faster in ampoules sealed with air than those purged with nitrogen. Amber ampoules retarded the rate of degradation under all photolytic conditions. This is a vital consideration for the packaging and storage of prochlorperazine in injectables. Degradation was found to occur mainly by first-order kinetics and the degradation rate decreased in the following order: sunlight » UV light 254 nm > fluorescent I diffuse light. Solid state samples, however, were found to be relatively stable to the various light / heat conditions over a 6 month period when compared to prochlorperazine solutions, but still considerably unstable. Thus both storage and packaging is a vital consideration for prochlorperazine injectables. The thermal behaviour of mixtures of prochlorperazine with standard excipients, was assessed for potential interactions, using differential scanning calorimetry. For most of the excipients (magnesium stearate, stearic acid, Explotab®, AC-Di-Sol®, Encompress® and Ludipress®, lactose and Starch 1500®) disappearance or broadening of the melting endotherm of the drug indicated interactions. Lubritab®, however, was the only 'inert' excipient tested. Liquid chromatography - mass spectrometry (LC-MS) was used to determine the nature of the degradation products. The major degradation pathways included dechlorination and demethylation of the parent drug, as well as sulfoxidation and Noxidation. Prochlorperazine underwent dechlorination and sulfoxidation with subsequent photosubstitution to yield the 2-hydroxy derivative. The solid state photostudies showed the formation of dealkylated, oxidised and hydroxylated products, sulfoxides and dimers. Since N-demethylation, N-oxidation, sulfoxidation and aromatic hydroxylation are reported to occur in the in vitro metabolism of perazine derivatives, it does appear that there is some relationship between metabolites and photoproducts (Breyer, 1974). This study has been successful in providing understanding of the photolytic and thermal degradation pathways of prochlorperazine.
- Full Text:
- Date Issued: 2000
- Authors: Antunes, Edith Martins
- Date: 2000
- Subjects: Phenothiazine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4536 , http://hdl.handle.net/10962/d1016399
- Description: Prochlorperazine, a member of the piperazine subclass of phenothiazines, widely used as an anti-emetic, is susceptible to oxidation to sulfoxides. These are main metabolites and degradants of all phenothiazines which are found to be inactive at the dopamine receptors. Prochlorperazine causes photosensitivity effects in patients attributed to dechlorination at C2 with the release of HCI (Huang and Sands, 1967; Nejmeh and Pilpel, 1978; Moore and Tamat, 1980). The aim of this study is to investigate the thermal and photostability of prochlorperazine edisylate and mesylate salts in the solid state and in solution. Prochlorperazine is available as a fine chemical and in a variety of dosage forms, including injectables and tablets. According to ICH guidelines, any degradants greater than 0.1 % are required to be isolated and identified. In order to assess the photostability of the two salts, an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection, quantitation and ruggedness. Sulfoxides were synthesised for use as standards in the rate studies according to the well-known hydrogen peroxide method (Owens et al., 1989). The rate of prochlorperazine degradation in solution under various light sources (254 nm UV light, diffuse light and sunlight) was studied. The light sources used abovF were quantified using potassium ferrioxalate as a chemical actinometer). The photodegradation rate was found to be greater in ampoules sealed under nitrogen than air, but the thermal degradation was faster in ampoules sealed with air than those purged with nitrogen. Amber ampoules retarded the rate of degradation under all photolytic conditions. This is a vital consideration for the packaging and storage of prochlorperazine in injectables. Degradation was found to occur mainly by first-order kinetics and the degradation rate decreased in the following order: sunlight » UV light 254 nm > fluorescent I diffuse light. Solid state samples, however, were found to be relatively stable to the various light / heat conditions over a 6 month period when compared to prochlorperazine solutions, but still considerably unstable. Thus both storage and packaging is a vital consideration for prochlorperazine injectables. The thermal behaviour of mixtures of prochlorperazine with standard excipients, was assessed for potential interactions, using differential scanning calorimetry. For most of the excipients (magnesium stearate, stearic acid, Explotab®, AC-Di-Sol®, Encompress® and Ludipress®, lactose and Starch 1500®) disappearance or broadening of the melting endotherm of the drug indicated interactions. Lubritab®, however, was the only 'inert' excipient tested. Liquid chromatography - mass spectrometry (LC-MS) was used to determine the nature of the degradation products. The major degradation pathways included dechlorination and demethylation of the parent drug, as well as sulfoxidation and Noxidation. Prochlorperazine underwent dechlorination and sulfoxidation with subsequent photosubstitution to yield the 2-hydroxy derivative. The solid state photostudies showed the formation of dealkylated, oxidised and hydroxylated products, sulfoxides and dimers. Since N-demethylation, N-oxidation, sulfoxidation and aromatic hydroxylation are reported to occur in the in vitro metabolism of perazine derivatives, it does appear that there is some relationship between metabolites and photoproducts (Breyer, 1974). This study has been successful in providing understanding of the photolytic and thermal degradation pathways of prochlorperazine.
- Full Text:
- Date Issued: 2000
The solubility enhancement and the stability assessment of rifampicin, isoniazid and pyrazinamide in aqueous media
- Authors: Chen, Yu-Jen
- Date: 2000
- Subjects: Gel permeation chromatography , Rifampin , Isoniazid , Pyridazines
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4346 , http://hdl.handle.net/10962/d1005009 , Gel permeation chromatography , Rifampin , Isoniazid , Pyridazines
- Description: Tuberculosis (TB) is a highly contagious disease caused by the bacterium known as Mycobacterium tuberculosis which is widely spread in South Africa, especially in the rural areas of the Western Province. Rifampicin, isoniazid and pyrazinamide are the three most effective drugs against this organism. However, most of the current commercial anti-TB formulations are inconvenient to administrate. This results in patient non-compliance which has increased with incomplete tuberculosis treatment and further has intensified the mortality rate. The matter is especially severe amongst the paediatric and geriatric patients. Therefore, creating a "user-friendly" but non-alcoholic liquid formulation should improve the whole situation. The key to a successful formulation relies on sufficient concentrations of the drugs within the formulation together with acceptable stability of these drugs. Therefore, during the pre-formulation stage, the solubility and stability studies of rifampicin, isoniazid and pyrazinamide are to be conducted. Rifampicin, isoniazid and pyrazinamide were fully characterized and identified by means of spectroscopic and thermal techniques. A HPLC method for simultaneous analysis of the three drugs was developed and validated. This HPLC method was employed for all the solubility and stability assessments. Unbuffered HPLC water of pH value 7.01 was chosen as the aqueous solvent. This was decided after the stability of rifampicin, isoniazid and pyrazinamide was studied at a pH range of 2 to 10. The solubility and the stability studies of rifampicin, isoniazid, pyrazinamide, rifampicin with isoniazid, rifampicin with pyrazinamide, isoniazid with pyrazinamide and rifampicin combined with both isoniazid and pyrazinamide were performed in the presence of various agents. These agents can be categorized into three groups: the surfactants (poloxamer 188, poloxamer 407 and sorbitol) which could increase the intrinsic solubility or the drugs by altering the surface tensions of the aqueous solution medium, the suspending agents (carbopol 934 and carbopol 974P) which could enable the amount of dosage required to be homogeneously suspended in the formulation without considering the low intrinsic solubility factor of the drugs, and the complexing agents (ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin and -cyclodextrin) which could initiated the inclusion complex between the host cyclodextrin and the drugs, thus further enhance the solubility of the drugs . The stability assessments were performed after 7-days stability trail with the HPLC method developed. Each drug/combination of drugs were stored in closed ampoules and subjected to 25, 40 and 60° C with or without nitrogen flushing while in the presence of the above mentioned agents. While assessing the solubility/stability of the drugs in the presence of the above mentioned surfactants, the phase-solubility curves indicate that both rifampicin and pyrazinamide fail to achieve the desired concentration. Moreover, the stability-time plots clearly indicate that these surfactants fail to enhance the general stabilities of the drugs. When the stabilizing effects of the above mentioned suspending agents were investigated, it was found that although the desired concentration could be easily accomplished by suspending the drug in the aqueous carbopol solutions, the stabilities of the different drug combinations were still below the regulatory level. Cyclodextrins are well known to form inclusion complexes with less polar drug molecules. The inclusion complexation could enhance both the solubility and the stability of the included drug molecules. The computer force field generated models of the cyclodextrin-drug were used to predict the complexation sites. The results indicated the all the inclusion complexation between the drugs and the cyclodextrins were favourable, but do not necessary protect the potential degradation sites of the drugs. The stability results confirmed the above findings as the cyclodextrins did not enhance the stability of the drugs. Various drug-drug interaction pathways were also predicted from the experimental observations which clearly indicated the stability reductions of these drugs in combination. This leads to the conclusion that a liquid formulation combining rifampicin, isoniazid and pyrazinamide should not initiate the use of aqueous solutions as the protic ions of the solution are able to initiate the degradation of these drugs.
- Full Text:
- Date Issued: 2000
- Authors: Chen, Yu-Jen
- Date: 2000
- Subjects: Gel permeation chromatography , Rifampin , Isoniazid , Pyridazines
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4346 , http://hdl.handle.net/10962/d1005009 , Gel permeation chromatography , Rifampin , Isoniazid , Pyridazines
- Description: Tuberculosis (TB) is a highly contagious disease caused by the bacterium known as Mycobacterium tuberculosis which is widely spread in South Africa, especially in the rural areas of the Western Province. Rifampicin, isoniazid and pyrazinamide are the three most effective drugs against this organism. However, most of the current commercial anti-TB formulations are inconvenient to administrate. This results in patient non-compliance which has increased with incomplete tuberculosis treatment and further has intensified the mortality rate. The matter is especially severe amongst the paediatric and geriatric patients. Therefore, creating a "user-friendly" but non-alcoholic liquid formulation should improve the whole situation. The key to a successful formulation relies on sufficient concentrations of the drugs within the formulation together with acceptable stability of these drugs. Therefore, during the pre-formulation stage, the solubility and stability studies of rifampicin, isoniazid and pyrazinamide are to be conducted. Rifampicin, isoniazid and pyrazinamide were fully characterized and identified by means of spectroscopic and thermal techniques. A HPLC method for simultaneous analysis of the three drugs was developed and validated. This HPLC method was employed for all the solubility and stability assessments. Unbuffered HPLC water of pH value 7.01 was chosen as the aqueous solvent. This was decided after the stability of rifampicin, isoniazid and pyrazinamide was studied at a pH range of 2 to 10. The solubility and the stability studies of rifampicin, isoniazid, pyrazinamide, rifampicin with isoniazid, rifampicin with pyrazinamide, isoniazid with pyrazinamide and rifampicin combined with both isoniazid and pyrazinamide were performed in the presence of various agents. These agents can be categorized into three groups: the surfactants (poloxamer 188, poloxamer 407 and sorbitol) which could increase the intrinsic solubility or the drugs by altering the surface tensions of the aqueous solution medium, the suspending agents (carbopol 934 and carbopol 974P) which could enable the amount of dosage required to be homogeneously suspended in the formulation without considering the low intrinsic solubility factor of the drugs, and the complexing agents (ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin and -cyclodextrin) which could initiated the inclusion complex between the host cyclodextrin and the drugs, thus further enhance the solubility of the drugs . The stability assessments were performed after 7-days stability trail with the HPLC method developed. Each drug/combination of drugs were stored in closed ampoules and subjected to 25, 40 and 60° C with or without nitrogen flushing while in the presence of the above mentioned agents. While assessing the solubility/stability of the drugs in the presence of the above mentioned surfactants, the phase-solubility curves indicate that both rifampicin and pyrazinamide fail to achieve the desired concentration. Moreover, the stability-time plots clearly indicate that these surfactants fail to enhance the general stabilities of the drugs. When the stabilizing effects of the above mentioned suspending agents were investigated, it was found that although the desired concentration could be easily accomplished by suspending the drug in the aqueous carbopol solutions, the stabilities of the different drug combinations were still below the regulatory level. Cyclodextrins are well known to form inclusion complexes with less polar drug molecules. The inclusion complexation could enhance both the solubility and the stability of the included drug molecules. The computer force field generated models of the cyclodextrin-drug were used to predict the complexation sites. The results indicated the all the inclusion complexation between the drugs and the cyclodextrins were favourable, but do not necessary protect the potential degradation sites of the drugs. The stability results confirmed the above findings as the cyclodextrins did not enhance the stability of the drugs. Various drug-drug interaction pathways were also predicted from the experimental observations which clearly indicated the stability reductions of these drugs in combination. This leads to the conclusion that a liquid formulation combining rifampicin, isoniazid and pyrazinamide should not initiate the use of aqueous solutions as the protic ions of the solution are able to initiate the degradation of these drugs.
- Full Text:
- Date Issued: 2000
Design, synthesis and characterization of novel rhenium(V) and technetium(V) complexes as potential radiopharmaceuticals
- Authors: Hlabela, Patrick Simon
- Date: 2001
- Subjects: Radiopharmaceuticals , Rhenium , Technetium
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4306 , http://hdl.handle.net/10962/d1004964 , Radiopharmaceuticals , Rhenium , Technetium
- Description: A number of bidentate N, N-diethyl-N' -(R ')benzoylthiourea ligands (where R' = H,CH₃,CI,OCH₃ and N0₂) have been synthesized, as well as the three Re(V) precursor complexes, ReOCl₃(PPh₃)₂,[ReO₂(py)₄]CI and [n-Bu₄N] [ReOCI₄J. The reaction of N,N-diethyl-N'-benzoylthiourea (LH) with these three metal precursor complexes in methanol in the presence of a base gave a novel mixed-ligand complex bis(N,N-diethyl-N'-benzoylthioureato)methoxyoxorhenium(V), [ReO(L)₂(OMe)] (1). In the absence of a base and under an inert atmosphere, the reaction between [n-Bu₄N][ReOCI₄] and LH yielded bis(N,N-diethyl-N'-benzoylthioureato)chlorooxorhenium(V), [ReO(L)₂CI] (lb). The reaction of LH with [ReO₂(py)₄]CI in ethanol and iso-propanol in the presence of sodium acetate gave the novel mixed ligand complexes bis(N,N-diethyl-N'benzoylthioureato) ethoxyoxorhenium(V), [ReO(L)₂(OEt)] (6) and bis(N,N-diethyl-N'benzoylthioureato)(iso-propoxy)oxorhenium(V), [ReO(L)₂(OiPr)] (7), respectively. An oxygen bridged dirhenium complex, [(L)₂0Re-O-ReO(L)₂] (15) was obtained when the reaction was carried out in acetonitrile. A series of mixed ligand Re(V)-oxo complexes using N, N-diethyl-Nʾ-(R' )benzoylthiourea (LR'),N,N-morpholino-N' -(R')benzoylthiourea (morph-LR') and 8-(N-(R')benzoylthiocarbamoyl)-1,4-dioxa-8-azaspiro[4.5]decane ligands (spiro-LR') (where R' = H,CH₃,CI, OCH₃ and N0₂) ((1)(14) have been prepared by the reaction of [ReO₂(py)₄]CI and the ligand in the presence of sodium acetate in methanol. The solution state chemistry of these complexes has shown that complexes(1)-(14) (with the exception of (1b)) undergo dimerization in solution to give complex (15) in the presence of water. Preliminary ¹H NMR kinetics studies of the dimerization of (1), (6) and (7) to (15) have shown that the rate of dimerization decreases in the order (7) > (6) > (1). The rate of dimerization has also been compared for complexes (1), [ReO(morph-L)₂(OMe)] (8) and [ReO(spiro-L)₂(OMe)] (13) and the rate of dimerization was found to be fastest for (13). The crystal structures of (1), [ReO(LN0₂)₂(OMe)] (4), (6) and (15) have been determined. The Re(V)-oxo complexes (1), (4) and (6) have a slightly distorted octahedral geometry with the two acylthiourea ligands binding in a cis arrangement in the equatorial plane of the octahedron. The alkoxy and oxo ligands occupy the axial positions and are situated trans to each other. The crystal and molecular structure of complex (15), consist of two slightly distorted octahedral [ReO(L)₂] moieties bridged by an oxygen atom with a Re-O-Re bond angle of 175.2(2)°. The preliminary studies done in the present study have indicated that the complexation chemistry of technetium(V) with the N,N-diethyl-benzoylthiourea is different to that of rhenium (V). The reaction between [n-BuN₄][TcOCl₄] and N,N-diethyl-N'-benzoylthiourea yielded the square pyramidal cationic complex [TcO(L)₂]Cl. By contrast the octahedral methoxy complex [ReO(L )₂( OMe)] was obtained when the analogous Re(V)-oxo precursor, [n-Bu₄N] [ReOCI₄], was reacted with N,N-diethyl-N'-benzoylthiourea under the same reaction conditions.
- Full Text:
- Date Issued: 2001
- Authors: Hlabela, Patrick Simon
- Date: 2001
- Subjects: Radiopharmaceuticals , Rhenium , Technetium
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4306 , http://hdl.handle.net/10962/d1004964 , Radiopharmaceuticals , Rhenium , Technetium
- Description: A number of bidentate N, N-diethyl-N' -(R ')benzoylthiourea ligands (where R' = H,CH₃,CI,OCH₃ and N0₂) have been synthesized, as well as the three Re(V) precursor complexes, ReOCl₃(PPh₃)₂,[ReO₂(py)₄]CI and [n-Bu₄N] [ReOCI₄J. The reaction of N,N-diethyl-N'-benzoylthiourea (LH) with these three metal precursor complexes in methanol in the presence of a base gave a novel mixed-ligand complex bis(N,N-diethyl-N'-benzoylthioureato)methoxyoxorhenium(V), [ReO(L)₂(OMe)] (1). In the absence of a base and under an inert atmosphere, the reaction between [n-Bu₄N][ReOCI₄] and LH yielded bis(N,N-diethyl-N'-benzoylthioureato)chlorooxorhenium(V), [ReO(L)₂CI] (lb). The reaction of LH with [ReO₂(py)₄]CI in ethanol and iso-propanol in the presence of sodium acetate gave the novel mixed ligand complexes bis(N,N-diethyl-N'benzoylthioureato) ethoxyoxorhenium(V), [ReO(L)₂(OEt)] (6) and bis(N,N-diethyl-N'benzoylthioureato)(iso-propoxy)oxorhenium(V), [ReO(L)₂(OiPr)] (7), respectively. An oxygen bridged dirhenium complex, [(L)₂0Re-O-ReO(L)₂] (15) was obtained when the reaction was carried out in acetonitrile. A series of mixed ligand Re(V)-oxo complexes using N, N-diethyl-Nʾ-(R' )benzoylthiourea (LR'),N,N-morpholino-N' -(R')benzoylthiourea (morph-LR') and 8-(N-(R')benzoylthiocarbamoyl)-1,4-dioxa-8-azaspiro[4.5]decane ligands (spiro-LR') (where R' = H,CH₃,CI, OCH₃ and N0₂) ((1)(14) have been prepared by the reaction of [ReO₂(py)₄]CI and the ligand in the presence of sodium acetate in methanol. The solution state chemistry of these complexes has shown that complexes(1)-(14) (with the exception of (1b)) undergo dimerization in solution to give complex (15) in the presence of water. Preliminary ¹H NMR kinetics studies of the dimerization of (1), (6) and (7) to (15) have shown that the rate of dimerization decreases in the order (7) > (6) > (1). The rate of dimerization has also been compared for complexes (1), [ReO(morph-L)₂(OMe)] (8) and [ReO(spiro-L)₂(OMe)] (13) and the rate of dimerization was found to be fastest for (13). The crystal structures of (1), [ReO(LN0₂)₂(OMe)] (4), (6) and (15) have been determined. The Re(V)-oxo complexes (1), (4) and (6) have a slightly distorted octahedral geometry with the two acylthiourea ligands binding in a cis arrangement in the equatorial plane of the octahedron. The alkoxy and oxo ligands occupy the axial positions and are situated trans to each other. The crystal and molecular structure of complex (15), consist of two slightly distorted octahedral [ReO(L)₂] moieties bridged by an oxygen atom with a Re-O-Re bond angle of 175.2(2)°. The preliminary studies done in the present study have indicated that the complexation chemistry of technetium(V) with the N,N-diethyl-benzoylthiourea is different to that of rhenium (V). The reaction between [n-BuN₄][TcOCl₄] and N,N-diethyl-N'-benzoylthiourea yielded the square pyramidal cationic complex [TcO(L)₂]Cl. By contrast the octahedral methoxy complex [ReO(L )₂( OMe)] was obtained when the analogous Re(V)-oxo precursor, [n-Bu₄N] [ReOCI₄], was reacted with N,N-diethyl-N'-benzoylthiourea under the same reaction conditions.
- Full Text:
- Date Issued: 2001
Novel approaches to the synthesis of quinoline derivatives
- Authors: Klaas, Phindile Jonathan
- Date: 2001 , 2013-04-26
- Subjects: Quinoline--Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4299 , http://hdl.handle.net/10962/d1004751 , Quinoline--Synthesis
- Description: The investigation has been concerned with the application of the Baylis-Hillman methodology to the synthesis of quinoline derivatives. An extensive range of novel Baylis-Hillman products has been prepared, typically in moderate to excellent yields, by condensing 2-nitrobenzaldehyde derivatives with various vinyl ketones and acrylic esters in the presence of diazabicyclo[2.2.2]octane (DABCO). Reduction of the nitro group in the Baylis-Hillman products was effected by catalytic hydrogenation in ethanol using a 10% palladium-on-carbon catalyst to afford quinoline, quinoline-N-oxide and quinolone derivatives. In all cases, it is apparent that cyclisation involves exclusive attack of nucleophilic nitrogen at the carbonyl centre, with acrylic ester derivatives affording quinolones and vinyl ketone derivatives affording quinolines and the corresponding quinoline-N-oxides. No products arising from a conjugate addition pathway were observed. The use of stannous chloride as an alternative reagent to effect reductive cyclisation of the Baylis-Hillman products has been explored, and found to favour the formation of 1,2- dihydroquinoline derivatives, with cyclisation occurring via a conjugate addition pathway. Isolation of the products, following work-up of the stannous chloride reactions, however, presented some difficulty. All compounds were characterised by spectroscopic (NMR and IR) and, where appropriate, elemental (high-resolution MS) analysis. Interconversion of the quinoline and quinoline-N-oxide derivatives has been explored and finally achieved in quantitative yields. Reduction of 2,3-dimethylquinoline-N-oxide to the corresponding quinoline was effected using phosphorus tribromide in DMF, and the reverse transformation with meta-chloroperbenzoic acid (MCPBA) in CHCl₃. Application of these methods to mixtures of 2,3-dimethylquinoline and its N-oxide has afforded, selectively, either the quinoline derivative or the corresponding N-oxide. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
- Authors: Klaas, Phindile Jonathan
- Date: 2001 , 2013-04-26
- Subjects: Quinoline--Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4299 , http://hdl.handle.net/10962/d1004751 , Quinoline--Synthesis
- Description: The investigation has been concerned with the application of the Baylis-Hillman methodology to the synthesis of quinoline derivatives. An extensive range of novel Baylis-Hillman products has been prepared, typically in moderate to excellent yields, by condensing 2-nitrobenzaldehyde derivatives with various vinyl ketones and acrylic esters in the presence of diazabicyclo[2.2.2]octane (DABCO). Reduction of the nitro group in the Baylis-Hillman products was effected by catalytic hydrogenation in ethanol using a 10% palladium-on-carbon catalyst to afford quinoline, quinoline-N-oxide and quinolone derivatives. In all cases, it is apparent that cyclisation involves exclusive attack of nucleophilic nitrogen at the carbonyl centre, with acrylic ester derivatives affording quinolones and vinyl ketone derivatives affording quinolines and the corresponding quinoline-N-oxides. No products arising from a conjugate addition pathway were observed. The use of stannous chloride as an alternative reagent to effect reductive cyclisation of the Baylis-Hillman products has been explored, and found to favour the formation of 1,2- dihydroquinoline derivatives, with cyclisation occurring via a conjugate addition pathway. Isolation of the products, following work-up of the stannous chloride reactions, however, presented some difficulty. All compounds were characterised by spectroscopic (NMR and IR) and, where appropriate, elemental (high-resolution MS) analysis. Interconversion of the quinoline and quinoline-N-oxide derivatives has been explored and finally achieved in quantitative yields. Reduction of 2,3-dimethylquinoline-N-oxide to the corresponding quinoline was effected using phosphorus tribromide in DMF, and the reverse transformation with meta-chloroperbenzoic acid (MCPBA) in CHCl₃. Application of these methods to mixtures of 2,3-dimethylquinoline and its N-oxide has afforded, selectively, either the quinoline derivative or the corresponding N-oxide. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
Photosensitizing properties of non-transition metal porphyrazines towards the generation of singlet oxygen
- Seotsanyana-Mokhosi, Itumeleng
- Authors: Seotsanyana-Mokhosi, Itumeleng
- Date: 2001 , 2013-05-02
- Subjects: Phthalocyanines , Photosensitization, Biological , Active oxygen -- Physiological effect , Photosensitizing compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4395 , http://hdl.handle.net/10962/d1006086 , Phthalocyanines , Photosensitization, Biological , Active oxygen -- Physiological effect , Photosensitizing compounds
- Description: Metallophthalocyanine complexes containing non-transition metals are very useful as sensitizers for photodynamic therapy, a cure for cancer that is based on visible light activation of tumour localized photo sensitizers. Excited sensitizers generate singlet oxygen as the main hyperactive species that destroy the tumour. Water soluble sensitizers are sought after for the convenience of delivery into the body. Thus, phthalocyanine (pc), tetrapyridinoporphyrazines (tppa) and tetramethyltetrapyridinoporphyrazines (tmtppa) with non-transition central metal atoms of Ge, Si, Sn and Zn were studied. First was the synthesis of these complexes, followed by their characterisation. The characterisation involved the use of ultraviolet and visible absorption spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, electrochemical properties and elemental analysis. Photochemical properties of the complexes were then investigated. Photolysis of these macrocycles showed two processes; -reduction of the dye and photobleaching, which leads to the disintegration of the conjugated chromophore structure of the dye. Photobleaching is the reductive quenching of the excited state of the sensitizers. The intensity of the quenching decreased progressively from tmtppa, tppa to pc metal complexes with photobleaching quantum yields, 6.6 x 10.5⁻¹, 1.8 x 10.5⁻¹ and 5.4 x 10⁻⁶ for Zntmtppa, Zntppa and Znpc, respectively. Efficiency of singlet oxygen sensitization is solvent dependent with very different values obtained for the same compound in different solvents, for example, 0.25 and 0.38 were observed as singlet oxygen quantum yields for Gepc complex in DMSO and DMF respectively. In DMSO the efficiency of ¹O₂ generation decrease considerably from pc to tppa and finally tmtppa. In water Getmtppa exhibits much higher singlet oxygen quantum yield, hence promising to be effective as a sensitizer for photodynamic therapy.
- Full Text:
- Date Issued: 2001
- Authors: Seotsanyana-Mokhosi, Itumeleng
- Date: 2001 , 2013-05-02
- Subjects: Phthalocyanines , Photosensitization, Biological , Active oxygen -- Physiological effect , Photosensitizing compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4395 , http://hdl.handle.net/10962/d1006086 , Phthalocyanines , Photosensitization, Biological , Active oxygen -- Physiological effect , Photosensitizing compounds
- Description: Metallophthalocyanine complexes containing non-transition metals are very useful as sensitizers for photodynamic therapy, a cure for cancer that is based on visible light activation of tumour localized photo sensitizers. Excited sensitizers generate singlet oxygen as the main hyperactive species that destroy the tumour. Water soluble sensitizers are sought after for the convenience of delivery into the body. Thus, phthalocyanine (pc), tetrapyridinoporphyrazines (tppa) and tetramethyltetrapyridinoporphyrazines (tmtppa) with non-transition central metal atoms of Ge, Si, Sn and Zn were studied. First was the synthesis of these complexes, followed by their characterisation. The characterisation involved the use of ultraviolet and visible absorption spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, electrochemical properties and elemental analysis. Photochemical properties of the complexes were then investigated. Photolysis of these macrocycles showed two processes; -reduction of the dye and photobleaching, which leads to the disintegration of the conjugated chromophore structure of the dye. Photobleaching is the reductive quenching of the excited state of the sensitizers. The intensity of the quenching decreased progressively from tmtppa, tppa to pc metal complexes with photobleaching quantum yields, 6.6 x 10.5⁻¹, 1.8 x 10.5⁻¹ and 5.4 x 10⁻⁶ for Zntmtppa, Zntppa and Znpc, respectively. Efficiency of singlet oxygen sensitization is solvent dependent with very different values obtained for the same compound in different solvents, for example, 0.25 and 0.38 were observed as singlet oxygen quantum yields for Gepc complex in DMSO and DMF respectively. In DMSO the efficiency of ¹O₂ generation decrease considerably from pc to tppa and finally tmtppa. In water Getmtppa exhibits much higher singlet oxygen quantum yield, hence promising to be effective as a sensitizer for photodynamic therapy.
- Full Text:
- Date Issued: 2001
Alkane oxidation using metallophthalocyanine as homogeneous catalysts
- Authors: Grootboom, Natasha Denise
- Date: 2002
- Subjects: Oxidation , Alkanes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4449 , http://hdl.handle.net/10962/d1007794
- Description: Iron polychlorophthalocyanine (FePc(Cl)₁₆) and tetrasulfophthalocyanine ([M¹¹TSPc]⁴) complexes of iron, cobalt and manganese are employed as catalysts for the oxidation of cyclohexane using tert-butyl hydroperoxide (TBHP), chloroperoxybenzoic acid (CPBA) and hydrogen peroxide as oxidants. Catalysis using the FePc(Cl)₁₆ was performed in a dimethylformamide:dichloromethane (3 :7) solvent mixture. For the [Fe¹¹TSPc]⁴⁻, [Co¹¹TSPc]⁻ and [Mn¹¹TSPc]⁴⁻catalysts, a water:methanol (1:9) mixture was employed. The products of the catalysis are cyclohexanone, cyclohexanol and cyclohexanediol. The relative percentage yields, percentage selectivity and overall percentage conversion of the products depended on types of oxidant, or catalyst, concentrations of substrate or catalysts and temperature. TBHP was found to be the best oxidant since minimal destruction of the catalyst and higher selectivity in the products were observed when this oxidant was employed. Of the four catalysts investigated [Fe¹¹TSPc]⁴⁻ yielded the highest overall percentage conversion of 20%.The mechanism of the oxidation of cyclohexane in the presence of the FePc(Cl)₁₆ and [M¹¹TSPc]⁴⁻ involves the oxidation of these catalysts, forming an Fe(IlI) phthalocyanine species as an intermediate. Electrocatalysis using [Co¹¹TSPc]⁴⁻ as catalyst, employed an aqueous pH 7 buffer medium for electro-oxidation of 4-pentenoic acid. An enone is suggested as the only oxidation product of 4-pentenoic acid. No degradation of [Co¹¹TSPc]⁴⁻ was observed during the electrocatalytic process. In this process water was used as a source of oxygen therefore eliminating the production of by products from oxidant as in the case of TBHP and CPBA. This system was studied In an attempt to set up conditions for alkane electrocatalytic oxidation.
- Full Text:
- Date Issued: 2002
- Authors: Grootboom, Natasha Denise
- Date: 2002
- Subjects: Oxidation , Alkanes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4449 , http://hdl.handle.net/10962/d1007794
- Description: Iron polychlorophthalocyanine (FePc(Cl)₁₆) and tetrasulfophthalocyanine ([M¹¹TSPc]⁴) complexes of iron, cobalt and manganese are employed as catalysts for the oxidation of cyclohexane using tert-butyl hydroperoxide (TBHP), chloroperoxybenzoic acid (CPBA) and hydrogen peroxide as oxidants. Catalysis using the FePc(Cl)₁₆ was performed in a dimethylformamide:dichloromethane (3 :7) solvent mixture. For the [Fe¹¹TSPc]⁴⁻, [Co¹¹TSPc]⁻ and [Mn¹¹TSPc]⁴⁻catalysts, a water:methanol (1:9) mixture was employed. The products of the catalysis are cyclohexanone, cyclohexanol and cyclohexanediol. The relative percentage yields, percentage selectivity and overall percentage conversion of the products depended on types of oxidant, or catalyst, concentrations of substrate or catalysts and temperature. TBHP was found to be the best oxidant since minimal destruction of the catalyst and higher selectivity in the products were observed when this oxidant was employed. Of the four catalysts investigated [Fe¹¹TSPc]⁴⁻ yielded the highest overall percentage conversion of 20%.The mechanism of the oxidation of cyclohexane in the presence of the FePc(Cl)₁₆ and [M¹¹TSPc]⁴⁻ involves the oxidation of these catalysts, forming an Fe(IlI) phthalocyanine species as an intermediate. Electrocatalysis using [Co¹¹TSPc]⁴⁻ as catalyst, employed an aqueous pH 7 buffer medium for electro-oxidation of 4-pentenoic acid. An enone is suggested as the only oxidation product of 4-pentenoic acid. No degradation of [Co¹¹TSPc]⁴⁻ was observed during the electrocatalytic process. In this process water was used as a source of oxygen therefore eliminating the production of by products from oxidant as in the case of TBHP and CPBA. This system was studied In an attempt to set up conditions for alkane electrocatalytic oxidation.
- Full Text:
- Date Issued: 2002
Development of nickel-selective molecularly imprinted polymers
- Tshikhudo, Tshinyadzo Robert
- Authors: Tshikhudo, Tshinyadzo Robert
- Date: 2002 , 2013-07-25
- Subjects: Imprinted polymers , Imprinted polymers -- Synthesis , Molecular imprinting , Nickel , Nickel -- Metallurgy
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4292 , http://hdl.handle.net/10962/d1004449 , Imprinted polymers , Imprinted polymers -- Synthesis , Molecular imprinting , Nickel , Nickel -- Metallurgy
- Description: A series of eight novel bidentate ligands, designed for use in the construction of nickel-selective molecularly imprinted polymers (MIP's), have been prepared. The synthetic pathway was established by retrosynthetic analysis of the target molecules to the readily available precursors, pyridine-2-carbaldehyde (or 6-methylpyridine-2-carbaldehyde) and ethyl bromoacetate. The ligands were designed to contain an allyl group for co-polymerisation and amine and pyridyl nitrogen donors, located to permit the formation of 5-membered nickel chelates. The eight novel ligands and their respective precursors were characterized by elemental (high-resolution MS) and spectroscopic (IR and ¹H and ¹³C NMR) analysis. High resolution electron-impact mass spectrometry has also been used, together with B/E linked scan data, to explore the fragmentation patterns of selected ligands. The various nickel(ll) complexes were analyzed using spectroscopic techniques and, in some cases, elemental analysis; computer modelling has also been used to explore conformational effects and complex stability. Numerous MIP's, containing nickel(II) complexes of the bidentate ligands, have been prepared, using ethylene glycol dimethylacrylate (EGDMA) as the cross-linker, azobis(isobutyronitrile) (AlBN) as the polymerization initiator and MeOH as the porogenic solvent. The template nickel(II) ions were leached out with conc. HCI, and the nickel(II) selectivity [in the presence of Fe(Ill)] of the nickel-imprinted polymers was examined by ICP-MS analysis. The ICP-MS data indicate that the MIP's examined exhibit extremely high selectivity for nickel over iron. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
- Authors: Tshikhudo, Tshinyadzo Robert
- Date: 2002 , 2013-07-25
- Subjects: Imprinted polymers , Imprinted polymers -- Synthesis , Molecular imprinting , Nickel , Nickel -- Metallurgy
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4292 , http://hdl.handle.net/10962/d1004449 , Imprinted polymers , Imprinted polymers -- Synthesis , Molecular imprinting , Nickel , Nickel -- Metallurgy
- Description: A series of eight novel bidentate ligands, designed for use in the construction of nickel-selective molecularly imprinted polymers (MIP's), have been prepared. The synthetic pathway was established by retrosynthetic analysis of the target molecules to the readily available precursors, pyridine-2-carbaldehyde (or 6-methylpyridine-2-carbaldehyde) and ethyl bromoacetate. The ligands were designed to contain an allyl group for co-polymerisation and amine and pyridyl nitrogen donors, located to permit the formation of 5-membered nickel chelates. The eight novel ligands and their respective precursors were characterized by elemental (high-resolution MS) and spectroscopic (IR and ¹H and ¹³C NMR) analysis. High resolution electron-impact mass spectrometry has also been used, together with B/E linked scan data, to explore the fragmentation patterns of selected ligands. The various nickel(ll) complexes were analyzed using spectroscopic techniques and, in some cases, elemental analysis; computer modelling has also been used to explore conformational effects and complex stability. Numerous MIP's, containing nickel(II) complexes of the bidentate ligands, have been prepared, using ethylene glycol dimethylacrylate (EGDMA) as the cross-linker, azobis(isobutyronitrile) (AlBN) as the polymerization initiator and MeOH as the porogenic solvent. The template nickel(II) ions were leached out with conc. HCI, and the nickel(II) selectivity [in the presence of Fe(Ill)] of the nickel-imprinted polymers was examined by ICP-MS analysis. The ICP-MS data indicate that the MIP's examined exhibit extremely high selectivity for nickel over iron. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
Synthetic approaches to marine labdane diterpenes
- Authors: Wisch, Gregory Albert
- Date: 2002 , 2013-05-10
- Subjects: Diterpenes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4289 , http://hdl.handle.net/10962/d1003131 , Diterpenes
- Description: The work presented in this thesis describes the synthesis of labd-13-en-8ß, 15-diol (46) a stable reduced derivative of an unstable marine natural product aldehyde [8ß-hydroxylabd-13E-en-15-al (6)] isolated by Cimino, et al. from the skin of a Notaspidean mollusc Pleurobranchaea meckelii. The rationale for the synthesis was to provide sufficient 46 for eventual mild oxidation to 6 and investigation of the biological activity of this latter compound. (-)-Sclareol (32), a common diterpene synthetic precursor, was the starting point for the ten step synthesis of 46 described in this thesis. A search of the literature revealed that only one non stereospecific synthesis of 46 had been previously reported. To provide the necessary background to the synthetic component of this thesis, both the occurrence of labdane and ent-labdane in the marine environment and the use of sclareol in the synthesis of marine natural products, was reviewed. The initial step in the synthesis of 46 was the potassium permanganate oxidation of sclareol to give a bisnorlabdane ketone. Reduction of this ketone with lithium aluminium hydride produced a mixture of diols which, through t-butyldimethysilyl triflate protection, afforded a quantitative route to protecting the C-13 ketone in an effort to prevent unwanted intramolecular cyclization reactions. Dehydration of the tertiary alcohol moiety at C-8 with phosphorous oxychloride yielded the Δ⁸·¹⁵ exocyclic alkene required for the next oxidation step. Ozonolysis succeeded in producing the desired C-8 ketone after much deliberation and research into alternative oxidation strategies. Methyl lithium methylation quantitatively afforded the desired a-methyl substitution at C-8, identified at the onset as the key step in the synthesis. Tetra-butylarnmonium fluoride deprotection yielded the 8ß,13-dihydoxylated product, which was in turn subjected to a Swern oxidition to give the desired 8ß-hydroxy-bisnorlabda-13-one. A modified Horner-Wadsworth-Emmons reaction allowed for elaboration at C-13 to yield a to Δ¹³ olefin with a terminal C-15 ethyl ester. Diisobutylaluminium hydride reduction of the ester produced the desired labd-13-en-8ß, 15-diol (46) in a low overall yield of 3.4%. Although opportunities for optimization of at least three steps in the synthesis exist, time constraints prevented both optimization of these steps and an investigation of the oxidation of 46 to 6. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
- Authors: Wisch, Gregory Albert
- Date: 2002 , 2013-05-10
- Subjects: Diterpenes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4289 , http://hdl.handle.net/10962/d1003131 , Diterpenes
- Description: The work presented in this thesis describes the synthesis of labd-13-en-8ß, 15-diol (46) a stable reduced derivative of an unstable marine natural product aldehyde [8ß-hydroxylabd-13E-en-15-al (6)] isolated by Cimino, et al. from the skin of a Notaspidean mollusc Pleurobranchaea meckelii. The rationale for the synthesis was to provide sufficient 46 for eventual mild oxidation to 6 and investigation of the biological activity of this latter compound. (-)-Sclareol (32), a common diterpene synthetic precursor, was the starting point for the ten step synthesis of 46 described in this thesis. A search of the literature revealed that only one non stereospecific synthesis of 46 had been previously reported. To provide the necessary background to the synthetic component of this thesis, both the occurrence of labdane and ent-labdane in the marine environment and the use of sclareol in the synthesis of marine natural products, was reviewed. The initial step in the synthesis of 46 was the potassium permanganate oxidation of sclareol to give a bisnorlabdane ketone. Reduction of this ketone with lithium aluminium hydride produced a mixture of diols which, through t-butyldimethysilyl triflate protection, afforded a quantitative route to protecting the C-13 ketone in an effort to prevent unwanted intramolecular cyclization reactions. Dehydration of the tertiary alcohol moiety at C-8 with phosphorous oxychloride yielded the Δ⁸·¹⁵ exocyclic alkene required for the next oxidation step. Ozonolysis succeeded in producing the desired C-8 ketone after much deliberation and research into alternative oxidation strategies. Methyl lithium methylation quantitatively afforded the desired a-methyl substitution at C-8, identified at the onset as the key step in the synthesis. Tetra-butylarnmonium fluoride deprotection yielded the 8ß,13-dihydoxylated product, which was in turn subjected to a Swern oxidition to give the desired 8ß-hydroxy-bisnorlabda-13-one. A modified Horner-Wadsworth-Emmons reaction allowed for elaboration at C-13 to yield a to Δ¹³ olefin with a terminal C-15 ethyl ester. Diisobutylaluminium hydride reduction of the ester produced the desired labd-13-en-8ß, 15-diol (46) in a low overall yield of 3.4%. Although opportunities for optimization of at least three steps in the synthesis exist, time constraints prevented both optimization of these steps and an investigation of the oxidation of 46 to 6. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
Thermal and photostability studies of furosemide and its cyclodextrin mixtures
- Authors: Melane, Babalwa Blossom
- Date: 2002 , 2013-05-16
- Subjects: Furosemide , Furosemide -- Stability
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4440 , http://hdl.handle.net/10962/d1007625 , Furosemide , Furosemide -- Stability
- Description: Furosemide (Lasix®), abbreviated as FR and also known as frusemide, is a drug used for renal problems and treatment of cardiac edema. Various polymorphic forms of furosemide, dependent upon the method of preparation and thermal treatment, have been reported. The main thermal decomposition product of furosemide has been identified as saluamine. The dissolution properties of furosemide have also been reported to be improved by complexation with beta-cyclodextrin. Photostabilities of the different crystal forms have been studied. Differential scanning calorimetry (DSC) and thermogravimetry (TG) have been used to examine the thermal behaviour of furosemide itself and of its physical and kneaded mixtures with betacyclodextrin (BCD) and gamma-cyclodextrin (GCD). There is strong evidence from DSC that complex formation between FR and GCD occurs. This is supported by IR and XRD data. Decreases in the intensity and broadening of the characteristic carbonyl (1660 cm'l) and amine (1588 cm⁻¹) bands in the kneaded mixture, compared to the physical mixture, were observed with IR. X-ray diffraction results for the 1:3 molar ratio FR/GCD kneaded mixture showed a halo diffraction pattern characteristic. of an amorphous solid and did not resemble patterns from the drug, or the gamma, cyclodextrin, or the physical mixture. Photostability studies have been conducted on solid furosemide and its mixtures with GCD or BCD. An HPLC method was developed to determine the amount of drug remaining after exposure and the presence of any degradants. Results indicated that about 10% degradation of the drug occurred during exposure for 16 hours at 550 W/m², with the appearance of polar degradants. Although IR and DSC results for the 1:3 molar ratio FR/GCD kneaded mixture showed a probable strong interaction between FR and GCD, the photostability of FR was decreased. The 1 :3 molar ratio FR/BCD kneaded mixture showed less photo-degradation than the 1:3 molar ratio FR/GCD mixture under similar conditions, suggesting that inclusion of the drug molecule (FR) is different in the two cyclodextrins.
- Full Text:
- Date Issued: 2002
- Authors: Melane, Babalwa Blossom
- Date: 2002 , 2013-05-16
- Subjects: Furosemide , Furosemide -- Stability
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4440 , http://hdl.handle.net/10962/d1007625 , Furosemide , Furosemide -- Stability
- Description: Furosemide (Lasix®), abbreviated as FR and also known as frusemide, is a drug used for renal problems and treatment of cardiac edema. Various polymorphic forms of furosemide, dependent upon the method of preparation and thermal treatment, have been reported. The main thermal decomposition product of furosemide has been identified as saluamine. The dissolution properties of furosemide have also been reported to be improved by complexation with beta-cyclodextrin. Photostabilities of the different crystal forms have been studied. Differential scanning calorimetry (DSC) and thermogravimetry (TG) have been used to examine the thermal behaviour of furosemide itself and of its physical and kneaded mixtures with betacyclodextrin (BCD) and gamma-cyclodextrin (GCD). There is strong evidence from DSC that complex formation between FR and GCD occurs. This is supported by IR and XRD data. Decreases in the intensity and broadening of the characteristic carbonyl (1660 cm'l) and amine (1588 cm⁻¹) bands in the kneaded mixture, compared to the physical mixture, were observed with IR. X-ray diffraction results for the 1:3 molar ratio FR/GCD kneaded mixture showed a halo diffraction pattern characteristic. of an amorphous solid and did not resemble patterns from the drug, or the gamma, cyclodextrin, or the physical mixture. Photostability studies have been conducted on solid furosemide and its mixtures with GCD or BCD. An HPLC method was developed to determine the amount of drug remaining after exposure and the presence of any degradants. Results indicated that about 10% degradation of the drug occurred during exposure for 16 hours at 550 W/m², with the appearance of polar degradants. Although IR and DSC results for the 1:3 molar ratio FR/GCD kneaded mixture showed a probable strong interaction between FR and GCD, the photostability of FR was decreased. The 1 :3 molar ratio FR/BCD kneaded mixture showed less photo-degradation than the 1:3 molar ratio FR/GCD mixture under similar conditions, suggesting that inclusion of the drug molecule (FR) is different in the two cyclodextrins.
- Full Text:
- Date Issued: 2002
Cyclodepsipeptides from a Kenyan marine cyanobacterium
- Authors: Dzeha, Thomas Mwambire
- Date: 2003
- Subjects: Cyanobacteria , Stereochemistry , Natural products -- Kenya
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4303 , http://hdl.handle.net/10962/d1004961 , Cyanobacteria , Stereochemistry , Natural products -- Kenya
- Description: An examination of an organic extract of the cyanobacterium Lyngbya majuscula collected from Wasini Island off the southern Kenyan coast led to the isolation of the known cyclodepsipeptide antanapeptin A (7), recently isolated from a Madagascan collection of L. majuscula, and a new bioactive cyclodepsipeptide, homodolastatin 16 (42). Although L. majuscula is a common, pantropical cyanobacterium this study represents the first investigation of the natural product chemistry of a Kenyan population of L. majuscula. The structures of the two cyclodepsipeptides were determined from 2D NMR and mass spectrometry data. The L- stereochemistry of the proline, valine, and N-methylphenylalanine amino acids in 7 and the L – proline configuration in 42, was confirmed by Marfey’s HPLC method. Chiral GC was used to determine the absolute stereochemistry of the hydroxyisovaleric acid moiety in 7 and 42, the lactate residue in 42 and tentatively propose an L-stereochemistry for the Nmethylisoleucine amino acid in 42. Homodolastatin 16, a higher homologue of the potential anti-cancer agent, dolastatin 16, exhibited moderate activity against two oesophageal cancer cell lines.
- Full Text:
- Date Issued: 2003
- Authors: Dzeha, Thomas Mwambire
- Date: 2003
- Subjects: Cyanobacteria , Stereochemistry , Natural products -- Kenya
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4303 , http://hdl.handle.net/10962/d1004961 , Cyanobacteria , Stereochemistry , Natural products -- Kenya
- Description: An examination of an organic extract of the cyanobacterium Lyngbya majuscula collected from Wasini Island off the southern Kenyan coast led to the isolation of the known cyclodepsipeptide antanapeptin A (7), recently isolated from a Madagascan collection of L. majuscula, and a new bioactive cyclodepsipeptide, homodolastatin 16 (42). Although L. majuscula is a common, pantropical cyanobacterium this study represents the first investigation of the natural product chemistry of a Kenyan population of L. majuscula. The structures of the two cyclodepsipeptides were determined from 2D NMR and mass spectrometry data. The L- stereochemistry of the proline, valine, and N-methylphenylalanine amino acids in 7 and the L – proline configuration in 42, was confirmed by Marfey’s HPLC method. Chiral GC was used to determine the absolute stereochemistry of the hydroxyisovaleric acid moiety in 7 and 42, the lactate residue in 42 and tentatively propose an L-stereochemistry for the Nmethylisoleucine amino acid in 42. Homodolastatin 16, a higher homologue of the potential anti-cancer agent, dolastatin 16, exhibited moderate activity against two oesophageal cancer cell lines.
- Full Text:
- Date Issued: 2003
Synthesis of zinc phthalocyanine derivatives for possible use in photodynamic therapy
- Authors: Matlaba, Pulane Maseleka
- Date: 2003
- Subjects: Photochemotherapy , Electrochemistry , Phthalocyanines , Zinc
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4374 , http://hdl.handle.net/10962/d1005039 , Photochemotherapy , Electrochemistry , Phthalocyanines , Zinc
- Description: The synthesis of symmetrically and unsymmetrically substituted zinc phthalocyanines (ZnPc) derivatives is done according to reported procedures. The unsymmetrical ZnPc derivatives are synthesized by ring expansion of sub-phthalocyanine complexes. Ring substitution is effected with tert-butyl phenol, naphthol, and hydroxybenzoic acid. Comparison of the redox potentials for the complexes substituted with varying numbers of tert-butyl phenol: 1, 2, 3, 6 and 8 show that the complex with the highest number of substituents are more difficult to oxidize and easier to reduce. Water soluble sulphonated ZnPc (ZnPcSn) was prepared. The possibility of using axial ligation to increase the solubility and the photochemical activity of sulphotnated ZnPc in aqueous solutions was investigated. Pyridine, aminopyridyl and bipyridyl were used as axial ligands. When bipyridyl was used as the axial ligand, solubility of the ZnPcSn increased, shown by the increase in the Q-band of the monomer species in solution and the singlet oxygen quantum yields was relatively higher than that of the unligated ZnPcSn. The singlet oxygen quantum yields by the various complexes in DMF using diphenylisobenzofuran as a chemical quencher for organic solvent were determined. Singlet oxygen quantum yields for the unsymmetrically ring substituted complexes range from 0.22 to 0.68. Photobleaching quantum yields are in the order of 10-5, which means that the complexes are relatively photostable.
- Full Text:
- Date Issued: 2003
- Authors: Matlaba, Pulane Maseleka
- Date: 2003
- Subjects: Photochemotherapy , Electrochemistry , Phthalocyanines , Zinc
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4374 , http://hdl.handle.net/10962/d1005039 , Photochemotherapy , Electrochemistry , Phthalocyanines , Zinc
- Description: The synthesis of symmetrically and unsymmetrically substituted zinc phthalocyanines (ZnPc) derivatives is done according to reported procedures. The unsymmetrical ZnPc derivatives are synthesized by ring expansion of sub-phthalocyanine complexes. Ring substitution is effected with tert-butyl phenol, naphthol, and hydroxybenzoic acid. Comparison of the redox potentials for the complexes substituted with varying numbers of tert-butyl phenol: 1, 2, 3, 6 and 8 show that the complex with the highest number of substituents are more difficult to oxidize and easier to reduce. Water soluble sulphonated ZnPc (ZnPcSn) was prepared. The possibility of using axial ligation to increase the solubility and the photochemical activity of sulphotnated ZnPc in aqueous solutions was investigated. Pyridine, aminopyridyl and bipyridyl were used as axial ligands. When bipyridyl was used as the axial ligand, solubility of the ZnPcSn increased, shown by the increase in the Q-band of the monomer species in solution and the singlet oxygen quantum yields was relatively higher than that of the unligated ZnPcSn. The singlet oxygen quantum yields by the various complexes in DMF using diphenylisobenzofuran as a chemical quencher for organic solvent were determined. Singlet oxygen quantum yields for the unsymmetrically ring substituted complexes range from 0.22 to 0.68. Photobleaching quantum yields are in the order of 10-5, which means that the complexes are relatively photostable.
- Full Text:
- Date Issued: 2003
Thermal and photostability studies of triprolidine hydrochloride and its mixtures with cyclodextrin and glucose
- Authors: Ndlebe, Vuyelwa Jacqueline
- Date: 2004
- Subjects: Antihistamines , Glucose , Cyclodextrins
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4387 , http://hdl.handle.net/10962/d1005052 , Antihistamines , Glucose , Cyclodextrins
- Description: Triprolidine hydrochloride (C₁₉H₂₂N₂.HCl.H₂O) (TPH) is a well-known antihistamine drug. It melts between 118°C and 122°C and the amount of water present is 4.5 mass percent. TPH is reported as being photosensitive and must be stored in sealed, light-tight containers. The thermal stabilities of TPH and of 1:1 molar and 1:1 mass ratio physical mixtures of TPH with beta-cyclodextrin (BCD) and with glucose have been examined using DSC, TG and TG-FTIR, complemented by X-ray powder diffraction (XRD) and infrared spectroscopic (IR) studies. Thermal studies of the solid TPH/BCD mixtures indicated that interaction between the components occurs and it is possible that the TPH molecule may be least partially accommodated in the cavity of the BCD host molecule. XRD results support this indication of inclusion. The results for mixtures of TPH/glucose also suggest that there is interaction between the two components. The results of molecular modelling suggest that TPH is most likely to be accommodated in the BCD cavity as a neutral triprolidine molecule with the toluene portion of the molecule entering first. There is also an indication that the Z-isomer should be accommodated slightly more readily than the E-isomer. Photostability studies were done by irradiating thin layers of solid samples of TPH and its mixtures for various times at 40°C using an Atlas Sun test CPS lamp operating at 550 W h m⁻². An analytical method using HPLC was developed and validated to determine the amounts of any photodegradants. DSC, TG, FTIR, XRD and IR were also used examine the irradiated samples. XRD results showed that changes in the TPH crystal structure occurred during irradiation and that these changes increased with the time of irradiation. Irradiation for 20 hours with UV or exposure to sunlight showed the presence of degradants. The results obtained illustrate the general stability of TPH, especially in the solid state. Although the potential for isomerization to the pharmaceutically inactive Z-isomer exists, this transformation would require extreme light conditions. The study has also shown TPH to be compatible with both glucose and BCD, which are potential excipients both in solid and liquid dosage forms. The presents of these excipients in dosage forms will thus not adversely affect the stability and the therapeutic efficacy of TPH. . An analytical method using HPLC was developed and validated to determine the amounts of any photodegradants. DSC, TG, FTIR, XRD and IR were also used examine the irradiated samples. XRD results showed that changes in the TPH crystal structure occurred during irradiation and that these changes increased with the time of irradiation. Irradiation for 20 hours with UV or exposure to sunlight showed the presence of degradants.
- Full Text:
- Date Issued: 2004
- Authors: Ndlebe, Vuyelwa Jacqueline
- Date: 2004
- Subjects: Antihistamines , Glucose , Cyclodextrins
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4387 , http://hdl.handle.net/10962/d1005052 , Antihistamines , Glucose , Cyclodextrins
- Description: Triprolidine hydrochloride (C₁₉H₂₂N₂.HCl.H₂O) (TPH) is a well-known antihistamine drug. It melts between 118°C and 122°C and the amount of water present is 4.5 mass percent. TPH is reported as being photosensitive and must be stored in sealed, light-tight containers. The thermal stabilities of TPH and of 1:1 molar and 1:1 mass ratio physical mixtures of TPH with beta-cyclodextrin (BCD) and with glucose have been examined using DSC, TG and TG-FTIR, complemented by X-ray powder diffraction (XRD) and infrared spectroscopic (IR) studies. Thermal studies of the solid TPH/BCD mixtures indicated that interaction between the components occurs and it is possible that the TPH molecule may be least partially accommodated in the cavity of the BCD host molecule. XRD results support this indication of inclusion. The results for mixtures of TPH/glucose also suggest that there is interaction between the two components. The results of molecular modelling suggest that TPH is most likely to be accommodated in the BCD cavity as a neutral triprolidine molecule with the toluene portion of the molecule entering first. There is also an indication that the Z-isomer should be accommodated slightly more readily than the E-isomer. Photostability studies were done by irradiating thin layers of solid samples of TPH and its mixtures for various times at 40°C using an Atlas Sun test CPS lamp operating at 550 W h m⁻². An analytical method using HPLC was developed and validated to determine the amounts of any photodegradants. DSC, TG, FTIR, XRD and IR were also used examine the irradiated samples. XRD results showed that changes in the TPH crystal structure occurred during irradiation and that these changes increased with the time of irradiation. Irradiation for 20 hours with UV or exposure to sunlight showed the presence of degradants. The results obtained illustrate the general stability of TPH, especially in the solid state. Although the potential for isomerization to the pharmaceutically inactive Z-isomer exists, this transformation would require extreme light conditions. The study has also shown TPH to be compatible with both glucose and BCD, which are potential excipients both in solid and liquid dosage forms. The presents of these excipients in dosage forms will thus not adversely affect the stability and the therapeutic efficacy of TPH. . An analytical method using HPLC was developed and validated to determine the amounts of any photodegradants. DSC, TG, FTIR, XRD and IR were also used examine the irradiated samples. XRD results showed that changes in the TPH crystal structure occurred during irradiation and that these changes increased with the time of irradiation. Irradiation for 20 hours with UV or exposure to sunlight showed the presence of degradants.
- Full Text:
- Date Issued: 2004
Bioactive 4-methoxypyrrolic natural products from two South African marine invertebrates
- Authors: Rapson, Trevor Douglas
- Date: 2005
- Subjects: Natural products -- South Africa , Marine invertebrates -- South Africa , Bryozoa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4412 , http://hdl.handle.net/10962/d1006766 , Natural products -- South Africa , Marine invertebrates -- South Africa , Bryozoa
- Description: This thesis presents an investigation of the 4-methoxypyrrolic constituents of two South African marine invertebrates, the nudibranch Tambja capensis and the bryozoan Bugula dentata. Three known compounds tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15) were isolated during this investigation. All three compounds were shown to be active against oesophageal cancer in accordance with the general anticancer and immunosuppressive properties observed for 4-methoxypyrrolic natural products. Tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15), together with tambjamine K (21) and L (22) (previously isolated in our laboratory) were used as standards to quantitatively assess the presence of these tambjamines in T. capensis and B. dentata collected from three different sites along the South African coast. This study confirmed that B. dentata is the source of the 4-methoxypyrrolic natural products sequestered by T. capensis and eliminated the closely related bryozoan B. neritina as a source of these metabolites. The paucity of tambjamine L (21) and K (22) obtained in previous investigations of the sequestered chemistry of T. capensis prompted an attempt at the development of synthetic methodology that could be used to synthesize tambjamines in sufficient yield for in depth bioactivity studies. In order to by pass the extensively reported problems associated with the synthesis of this group of compound 3-methoxy-2-formylpyrrole (47), readily accessible from 3-methoxypyridine N-oxide (48), was used as the starting material in a singlet oxygen induced 2,2’ bipyrrole coupling reaction. Although 47 proved unreactive in this coupling reaction, when the N-Boc protected analogue of 47 was used, and the reaction worked up in the dark, the novel methyl 4-aza-5-oxo-6,6-di-(2-pyrrolyl)-2(Z)-hexenoate (57) was obtained in low yield. The physical properties of tambjamine (E) (13) and the tetrapyrrole (15) were investigated to further the understanding of the proposed oxidative DNA cleavage mechanism and to determine the potential of the 4-methoxypyrrolic natural products as photodynamic therapy agents.
- Full Text:
- Date Issued: 2005
- Authors: Rapson, Trevor Douglas
- Date: 2005
- Subjects: Natural products -- South Africa , Marine invertebrates -- South Africa , Bryozoa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4412 , http://hdl.handle.net/10962/d1006766 , Natural products -- South Africa , Marine invertebrates -- South Africa , Bryozoa
- Description: This thesis presents an investigation of the 4-methoxypyrrolic constituents of two South African marine invertebrates, the nudibranch Tambja capensis and the bryozoan Bugula dentata. Three known compounds tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15) were isolated during this investigation. All three compounds were shown to be active against oesophageal cancer in accordance with the general anticancer and immunosuppressive properties observed for 4-methoxypyrrolic natural products. Tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15), together with tambjamine K (21) and L (22) (previously isolated in our laboratory) were used as standards to quantitatively assess the presence of these tambjamines in T. capensis and B. dentata collected from three different sites along the South African coast. This study confirmed that B. dentata is the source of the 4-methoxypyrrolic natural products sequestered by T. capensis and eliminated the closely related bryozoan B. neritina as a source of these metabolites. The paucity of tambjamine L (21) and K (22) obtained in previous investigations of the sequestered chemistry of T. capensis prompted an attempt at the development of synthetic methodology that could be used to synthesize tambjamines in sufficient yield for in depth bioactivity studies. In order to by pass the extensively reported problems associated with the synthesis of this group of compound 3-methoxy-2-formylpyrrole (47), readily accessible from 3-methoxypyridine N-oxide (48), was used as the starting material in a singlet oxygen induced 2,2’ bipyrrole coupling reaction. Although 47 proved unreactive in this coupling reaction, when the N-Boc protected analogue of 47 was used, and the reaction worked up in the dark, the novel methyl 4-aza-5-oxo-6,6-di-(2-pyrrolyl)-2(Z)-hexenoate (57) was obtained in low yield. The physical properties of tambjamine (E) (13) and the tetrapyrrole (15) were investigated to further the understanding of the proposed oxidative DNA cleavage mechanism and to determine the potential of the 4-methoxypyrrolic natural products as photodynamic therapy agents.
- Full Text:
- Date Issued: 2005
Synthesis, photochemical and photophysical properties of phthalocyanine derivatives
- Authors: Maqanda, Weziwe Theorine
- Date: 2005 , 2013-06-18
- Subjects: Photochemotherapy , Phthalocyanines , Zinc , Magnesium
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4436 , http://hdl.handle.net/10962/d1007472 , Photochemotherapy , Phthalocyanines , Zinc , Magnesium
- Description: Substituted zinc and magnesium phthalocyanine and porphyrazine derivatives were synthesized according to the reported procedures. The magnesium and zinc phthalocyanine and porphyrazine derivatives were synthesized by ring enlargement of subphthalocyanine and statistical condensation of the two phthalonitrile derivatives. Characterization of the complexes involved the use of infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet and visible spectroscopy, and Maldi-TOF spectroscopy (for selected compounds) and elemental analysis. Photochemical and photophysical properties of the complexes in non-aqueous solution was then investigated. Photobleaching quantum yields are in order of 10⁻⁵ indicating their relative photostability. Complexes containing more electron-donating substituents were more easily oxidized. For complexes 66 and 69 (as these complexes have the same number of substituents but differ in the metal center) photobleaching quantum yield for the ZincPc complex 69 was slightly less than that of the MgPc complex 66. Singlet oxygen quantum yields of the various complexes in DMSO using diphenylisobenzofuran (DPBF) as a quencher in organic solvents were determined. Singlet oxygen quantum yields of the complexes range from 0.23 to 0.67. High values of Φ[subscript]Δ ZnPc complexes was observed compared to the corresponding MgPc, complexes. This was evidenced by complexes 66 and 69 with Φ[subscript]Δ values of Φ[subscript]Δ = 0.26 and 0.40, respectively. Varying number of phenoxy substituents, complex 71 gave significantly large value of Φ[subscript]Δ compared to 70 (that is, the presence of more electron-donating substituted group, gave higher singlet oxygen quantum yields (0 .67 and 0.25 for 71 and 70 repectively). The triplet quantum yields and triplet lifetimes were determined by laser flash photolysis for selected compounds. The triplet quantum yields increase as the number of substituents increases e.g 68 > 67 > 66. Comparing porphyrazine complexes (63, 64 and 65), 63 with benzene attached to the ring, has higher triplet state lifetime (420 μs) compared to 64 and 65 containing long alkyl chain and tertbutyl substituents, 350 and 360 μs,respectively). The observed Φ[subscript]f values for 68 and 63 were quiet suprising, since low values are observed compared to the rest of the complexes (e.g 0.03 and 0.02 respectively). Although these values seem so low, they are sufficient for fluorescence imaging applications. The Φ[subscript]f values for the complexes under study are within the range reported for complexes currently used for PDT. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2005
- Authors: Maqanda, Weziwe Theorine
- Date: 2005 , 2013-06-18
- Subjects: Photochemotherapy , Phthalocyanines , Zinc , Magnesium
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4436 , http://hdl.handle.net/10962/d1007472 , Photochemotherapy , Phthalocyanines , Zinc , Magnesium
- Description: Substituted zinc and magnesium phthalocyanine and porphyrazine derivatives were synthesized according to the reported procedures. The magnesium and zinc phthalocyanine and porphyrazine derivatives were synthesized by ring enlargement of subphthalocyanine and statistical condensation of the two phthalonitrile derivatives. Characterization of the complexes involved the use of infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet and visible spectroscopy, and Maldi-TOF spectroscopy (for selected compounds) and elemental analysis. Photochemical and photophysical properties of the complexes in non-aqueous solution was then investigated. Photobleaching quantum yields are in order of 10⁻⁵ indicating their relative photostability. Complexes containing more electron-donating substituents were more easily oxidized. For complexes 66 and 69 (as these complexes have the same number of substituents but differ in the metal center) photobleaching quantum yield for the ZincPc complex 69 was slightly less than that of the MgPc complex 66. Singlet oxygen quantum yields of the various complexes in DMSO using diphenylisobenzofuran (DPBF) as a quencher in organic solvents were determined. Singlet oxygen quantum yields of the complexes range from 0.23 to 0.67. High values of Φ[subscript]Δ ZnPc complexes was observed compared to the corresponding MgPc, complexes. This was evidenced by complexes 66 and 69 with Φ[subscript]Δ values of Φ[subscript]Δ = 0.26 and 0.40, respectively. Varying number of phenoxy substituents, complex 71 gave significantly large value of Φ[subscript]Δ compared to 70 (that is, the presence of more electron-donating substituted group, gave higher singlet oxygen quantum yields (0 .67 and 0.25 for 71 and 70 repectively). The triplet quantum yields and triplet lifetimes were determined by laser flash photolysis for selected compounds. The triplet quantum yields increase as the number of substituents increases e.g 68 > 67 > 66. Comparing porphyrazine complexes (63, 64 and 65), 63 with benzene attached to the ring, has higher triplet state lifetime (420 μs) compared to 64 and 65 containing long alkyl chain and tertbutyl substituents, 350 and 360 μs,respectively). The observed Φ[subscript]f values for 68 and 63 were quiet suprising, since low values are observed compared to the rest of the complexes (e.g 0.03 and 0.02 respectively). Although these values seem so low, they are sufficient for fluorescence imaging applications. The Φ[subscript]f values for the complexes under study are within the range reported for complexes currently used for PDT. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2005
Application of the Baylis-Hillman reaction in the preparation of quinoline derivatives
- Authors: Pakade, Vusumzi Emmanuel
- Date: 2006 , 2013-06-11
- Subjects: Heterocyclic compounds -- Derivatives , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4442 , http://hdl.handle.net/10962/d1007669 , Heterocyclic compounds -- Derivatives , Quinoline
- Description: The reaction of various 2-nitrobenzaldehyde derivatives with methyl vinyl ketone (MVK) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) has afforded the Baylis-Hillman adducts in moderate to good yield. Dissolution of the catalyst in the solvent before the addition of the aldehyde was observed to improve the yield. Reduction of the Baylis-Hillman adducts was effected by catalytic hydrogenation using a 10% palladium-on- carbon catalyst in ethanol to give quinoline and quinoline-N-oxide derivatives and, in some cases, acyclic reduction products. All products were characterised using NMR and, where appropriate, HRMS methods. Selected quinoline-N-oxides were successfully converted to their corresponding quinoline derivatives using phosphorus tribromide (PBr₃) and DMF as solvent. Conjugate addition of the benzylamine and piperidine nucleophiles to the Baylis-Hillman adducts was also investigated but proved problematic, with one of the substrates undergoing a retro-Baylis-Hillman reaction to afford the aldehyde in ca. 40% yield, but seemingly only traces of the required product. Perkin-type coupling of two 2-methylquinolines with benzaldehyde was successfully effected to afford the desired styrylquinoline derivatives confirming the potential of the Baylis-Hillman approach to the construction of the analogues of known HIV-1 integrase inhibitors. Three ¹³C NMR chemical shift prediction programmes, viz., Chem Window, neural network and HOSE (hierarchically ordered spherical description of environment) methods were applied to selected representative compounds prepared in the project. The results from the three programmes correlated reasonably well with the experimental carbon-13 chemical shift data for each of the selected compounds.
- Full Text:
- Date Issued: 2006
- Authors: Pakade, Vusumzi Emmanuel
- Date: 2006 , 2013-06-11
- Subjects: Heterocyclic compounds -- Derivatives , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4442 , http://hdl.handle.net/10962/d1007669 , Heterocyclic compounds -- Derivatives , Quinoline
- Description: The reaction of various 2-nitrobenzaldehyde derivatives with methyl vinyl ketone (MVK) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) has afforded the Baylis-Hillman adducts in moderate to good yield. Dissolution of the catalyst in the solvent before the addition of the aldehyde was observed to improve the yield. Reduction of the Baylis-Hillman adducts was effected by catalytic hydrogenation using a 10% palladium-on- carbon catalyst in ethanol to give quinoline and quinoline-N-oxide derivatives and, in some cases, acyclic reduction products. All products were characterised using NMR and, where appropriate, HRMS methods. Selected quinoline-N-oxides were successfully converted to their corresponding quinoline derivatives using phosphorus tribromide (PBr₃) and DMF as solvent. Conjugate addition of the benzylamine and piperidine nucleophiles to the Baylis-Hillman adducts was also investigated but proved problematic, with one of the substrates undergoing a retro-Baylis-Hillman reaction to afford the aldehyde in ca. 40% yield, but seemingly only traces of the required product. Perkin-type coupling of two 2-methylquinolines with benzaldehyde was successfully effected to afford the desired styrylquinoline derivatives confirming the potential of the Baylis-Hillman approach to the construction of the analogues of known HIV-1 integrase inhibitors. Three ¹³C NMR chemical shift prediction programmes, viz., Chem Window, neural network and HOSE (hierarchically ordered spherical description of environment) methods were applied to selected representative compounds prepared in the project. The results from the three programmes correlated reasonably well with the experimental carbon-13 chemical shift data for each of the selected compounds.
- Full Text:
- Date Issued: 2006
Substituted phthalocyanines development and self-assembled monolayer sensor studies
- Authors: Matemadombo, Fungisai
- Date: 2006
- Subjects: Phthalocyanines , Monomolecular films , Electrochemistry , Spectrum analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4364 , http://hdl.handle.net/10962/d1005029 , Phthalocyanines , Monomolecular films , Electrochemistry , Spectrum analysis
- Description: Zinc, cobalt and iron phenylthio substituted phthalocyanines have been synthesized and characterized. Cyclic and square wave voltammetry in dimethylformamide containing tetrabutylammonium perchlorate revealed five and six redox processes respectively for the cobalt and iron phenylthio substituted phthalocyanines. These complexes are easier to reduce compared to the corresponding unsubstituted MPc and to butylthio substituted derivatives. Spectroelectrochemistry (in dimethylformamide containing tetrabutylammonium perchlorate) was employed to assign the cyclic voltammetry peaks, and gave spectra characteristic of Fe(I)Pc for reduction of iron phenylthio substituted phthalocyanine and Co(I)Pc for the reduction of cobalt phenylthio substituted phthalocyanine. The spectrum of the former is particularly of importance since such species have not received much attention in literature. Cobalt and iron phenylthio substituted phthalocyanines have been deposited on Au electrode surfaces through the self assembled monolayer (SAM) technique. The so formed layers were studied using voltammetric techniques. These SAMs blocked a number of Faradic processes and electrocatalyzed the oxidation of L-cysteine. Amine substituted cobalt phthalocyanine (CoTAPc) was deposited on gold surfaces by using an interconnecting SAM of mercaptopropionic acid or dithiobis(N-succinimidyl propionate) through the creation of an amide. Reductive and oxidative desorption of the SAMs limit the useful potential window. The SAM-CoTAPc layers show electrocatalytic activities towards oxygen reduction through the Co(I) central metal ion. Both SAMs were highly stable and hence will be interesting tools for further research in surface modification and sensor development.
- Full Text:
- Date Issued: 2006
- Authors: Matemadombo, Fungisai
- Date: 2006
- Subjects: Phthalocyanines , Monomolecular films , Electrochemistry , Spectrum analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4364 , http://hdl.handle.net/10962/d1005029 , Phthalocyanines , Monomolecular films , Electrochemistry , Spectrum analysis
- Description: Zinc, cobalt and iron phenylthio substituted phthalocyanines have been synthesized and characterized. Cyclic and square wave voltammetry in dimethylformamide containing tetrabutylammonium perchlorate revealed five and six redox processes respectively for the cobalt and iron phenylthio substituted phthalocyanines. These complexes are easier to reduce compared to the corresponding unsubstituted MPc and to butylthio substituted derivatives. Spectroelectrochemistry (in dimethylformamide containing tetrabutylammonium perchlorate) was employed to assign the cyclic voltammetry peaks, and gave spectra characteristic of Fe(I)Pc for reduction of iron phenylthio substituted phthalocyanine and Co(I)Pc for the reduction of cobalt phenylthio substituted phthalocyanine. The spectrum of the former is particularly of importance since such species have not received much attention in literature. Cobalt and iron phenylthio substituted phthalocyanines have been deposited on Au electrode surfaces through the self assembled monolayer (SAM) technique. The so formed layers were studied using voltammetric techniques. These SAMs blocked a number of Faradic processes and electrocatalyzed the oxidation of L-cysteine. Amine substituted cobalt phthalocyanine (CoTAPc) was deposited on gold surfaces by using an interconnecting SAM of mercaptopropionic acid or dithiobis(N-succinimidyl propionate) through the creation of an amide. Reductive and oxidative desorption of the SAMs limit the useful potential window. The SAM-CoTAPc layers show electrocatalytic activities towards oxygen reduction through the Co(I) central metal ion. Both SAMs were highly stable and hence will be interesting tools for further research in surface modification and sensor development.
- Full Text:
- Date Issued: 2006
Studies towards the development of novel multidentate ligands
- Authors: Magqi, Nceba
- Date: 2007
- Subjects: Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4358 , http://hdl.handle.net/10962/d1005023 , Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Description: In this study, attention has been given to the design and synthesis of novel multidentate ligands for use in the construction of ruthenium-based metathesis catalysts, and their chelating potential has been explored by computer modelling at the Density Functional Theory (DFT) level. Both Kemp’s triacid (1,3,5-trimethyl-1,3,5-cyclohexanetricarboxylic acid) and D-(+)-camphor have been investigated as molecular scaffolds for the development of such ligands. However selective elaboration of the functional groups in Kemp’s triacid proved difficult to achieve, and the research has focused on the development of camphor derivatives. The synthesis of the camphor-based ligands has involved C-8 functionalisation and ring-opening of the bicyclic system to afford tridentate products. The formation of 9-iodocamphorquinone bis(ethylene ketal) together with the desired product, the 8-iodo isomer, has been confirmed by single crystal X-ray analysis of both compounds. Formation of the 9-iodo analogue has provided new insights into the intramolecular rearrangement of camphor skeleton, and the mechanistic implications have been assessed by coset analysis. Attempts to effect nucleophilic displacement of the 8-halogeno groups by nucleophilic donor moieties proved unexpectedly difficult and, coupled with the susceptibility of the carbonyl groups to nucleophilic attack, has led to the formation of novel tricyclic products, viz., 1,6-dimethyl-3-(2-pyridylamino)-4-oxatricyclo[4.3.0.0[superscript 3,7]]-2-nonanone and 6,7-dimethyl-3-(2-pyridylamino)-4-oxatricyclo -[4.3.0.0[superscript 3,7]]-2-nonanone. However the diphenylphosphine group was successfully introduced at C-8 and oxidative ring-opening of the camphor skeleton has afforded the tridentate ligands, 2-(diphenylphosphinoylmethyl)-1,2-dimethyl-1,3-cyclopentanedicarboxylic acid and 2-(diphenylphosphinoylmethyl)-1,3-bis(hydroxymethyl)1,2-dimethylcyclopentane. One- and two-dimensional NMR and, where appropriate, high-resolution MS methods have been used to characterise the products. Three [superscript 13]C NMR chemical shift prediction programmes, viz., ChemWindow and the MODGRAPH neural network and HOSE (Hierachially Ordered Spherical description of Environment), have been applied to representative compounds to assess their efficacy. While the predicted shifts correlated reasonably well with the experimental data, they proved to be insufficiently accurate to differentiate the isomeric systems examined.
- Full Text:
- Date Issued: 2007
- Authors: Magqi, Nceba
- Date: 2007
- Subjects: Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4358 , http://hdl.handle.net/10962/d1005023 , Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Description: In this study, attention has been given to the design and synthesis of novel multidentate ligands for use in the construction of ruthenium-based metathesis catalysts, and their chelating potential has been explored by computer modelling at the Density Functional Theory (DFT) level. Both Kemp’s triacid (1,3,5-trimethyl-1,3,5-cyclohexanetricarboxylic acid) and D-(+)-camphor have been investigated as molecular scaffolds for the development of such ligands. However selective elaboration of the functional groups in Kemp’s triacid proved difficult to achieve, and the research has focused on the development of camphor derivatives. The synthesis of the camphor-based ligands has involved C-8 functionalisation and ring-opening of the bicyclic system to afford tridentate products. The formation of 9-iodocamphorquinone bis(ethylene ketal) together with the desired product, the 8-iodo isomer, has been confirmed by single crystal X-ray analysis of both compounds. Formation of the 9-iodo analogue has provided new insights into the intramolecular rearrangement of camphor skeleton, and the mechanistic implications have been assessed by coset analysis. Attempts to effect nucleophilic displacement of the 8-halogeno groups by nucleophilic donor moieties proved unexpectedly difficult and, coupled with the susceptibility of the carbonyl groups to nucleophilic attack, has led to the formation of novel tricyclic products, viz., 1,6-dimethyl-3-(2-pyridylamino)-4-oxatricyclo[4.3.0.0[superscript 3,7]]-2-nonanone and 6,7-dimethyl-3-(2-pyridylamino)-4-oxatricyclo -[4.3.0.0[superscript 3,7]]-2-nonanone. However the diphenylphosphine group was successfully introduced at C-8 and oxidative ring-opening of the camphor skeleton has afforded the tridentate ligands, 2-(diphenylphosphinoylmethyl)-1,2-dimethyl-1,3-cyclopentanedicarboxylic acid and 2-(diphenylphosphinoylmethyl)-1,3-bis(hydroxymethyl)1,2-dimethylcyclopentane. One- and two-dimensional NMR and, where appropriate, high-resolution MS methods have been used to characterise the products. Three [superscript 13]C NMR chemical shift prediction programmes, viz., ChemWindow and the MODGRAPH neural network and HOSE (Hierachially Ordered Spherical description of Environment), have been applied to representative compounds to assess their efficacy. While the predicted shifts correlated reasonably well with the experimental data, they proved to be insufficiently accurate to differentiate the isomeric systems examined.
- Full Text:
- Date Issued: 2007
Study of metallophthalocyanines attached onto pre-modified gold surfaces
- Authors: Mashazi, Philani Nkosinathi
- Date: 2007
- Subjects: Phthalocyanines , Electrochemistry , Electrodes, Enzyme , Glucose -- Measurement
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4361 , http://hdl.handle.net/10962/d1005026 , Phthalocyanines , Electrochemistry , Electrodes, Enzyme , Glucose -- Measurement
- Description: Tetra-carboxy acid chloride phthalocyanine complexes of cobalt, iron and manganese were synthesized and characterized using spectroscopic and electrochemical techniques. These complexes were fabricated as thin films on gold electrode following a covalent immobilization and self-assembling methods. Surface electrochemical and spectroscopic characterization showed that these complexes are surface-confined species. The characterization using spectroscopic and electrochemical methods confirmed the formation of thiol and MPc SAMs on gold electrode. The electrocatalytic behaviour of the SAM modified gold electrodes was studied for the detection of L-cysteine and hydrogen peroxide. The limits of detection (LoD) for Lcysteine were of the orders of 10[superscript -7] mol.L[superscript -1] for all the MPc complexes studied and the LoD for hydrogen peroxide at cobalt phthalocyanine modified gold electrode was of the orders of 10[superscript -7]mol.L[superscript -1] for both electrocatalytic oxidation and reduction. The modification process for gold electrodes was reproducible and showed good stability, if stored in pH 4 phosphate buffer solutions and can be used over a long period of time. The cobalt phthalocyanine modified gold electrode was also investigated for the fabrication of glucose oxidase (GOx)-based biosensor and as an electron mediator between the enzyme and gold electrode. The behaviour of the enzyme modified gold electrode towards the detection of glucose was studied and the results gave a limit of detection of the orders of 10[superscript -6] mol.L[superscript -1] with low binding constant (4.8 mM) of enzyme (GOx) to substrate (glucose) referred to as Michaelis-Menten constant. The practical applications, i.e. the real sample analysis and interference studies, for the enzyme modified gold electrodes were investigated. These studies showed that the enzyme electrode is valuable and can be used for glucose detection.
- Full Text:
- Date Issued: 2007
- Authors: Mashazi, Philani Nkosinathi
- Date: 2007
- Subjects: Phthalocyanines , Electrochemistry , Electrodes, Enzyme , Glucose -- Measurement
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4361 , http://hdl.handle.net/10962/d1005026 , Phthalocyanines , Electrochemistry , Electrodes, Enzyme , Glucose -- Measurement
- Description: Tetra-carboxy acid chloride phthalocyanine complexes of cobalt, iron and manganese were synthesized and characterized using spectroscopic and electrochemical techniques. These complexes were fabricated as thin films on gold electrode following a covalent immobilization and self-assembling methods. Surface electrochemical and spectroscopic characterization showed that these complexes are surface-confined species. The characterization using spectroscopic and electrochemical methods confirmed the formation of thiol and MPc SAMs on gold electrode. The electrocatalytic behaviour of the SAM modified gold electrodes was studied for the detection of L-cysteine and hydrogen peroxide. The limits of detection (LoD) for Lcysteine were of the orders of 10[superscript -7] mol.L[superscript -1] for all the MPc complexes studied and the LoD for hydrogen peroxide at cobalt phthalocyanine modified gold electrode was of the orders of 10[superscript -7]mol.L[superscript -1] for both electrocatalytic oxidation and reduction. The modification process for gold electrodes was reproducible and showed good stability, if stored in pH 4 phosphate buffer solutions and can be used over a long period of time. The cobalt phthalocyanine modified gold electrode was also investigated for the fabrication of glucose oxidase (GOx)-based biosensor and as an electron mediator between the enzyme and gold electrode. The behaviour of the enzyme modified gold electrode towards the detection of glucose was studied and the results gave a limit of detection of the orders of 10[superscript -6] mol.L[superscript -1] with low binding constant (4.8 mM) of enzyme (GOx) to substrate (glucose) referred to as Michaelis-Menten constant. The practical applications, i.e. the real sample analysis and interference studies, for the enzyme modified gold electrodes were investigated. These studies showed that the enzyme electrode is valuable and can be used for glucose detection.
- Full Text:
- Date Issued: 2007
Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2007
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2007