My supervisor Dr. A Soares for the encouragement, advice, guidance and support throughout this project, without you this thesis would never have become a reality. My colleagues from the School of Chemistry for creating the good atmosphere; especially Bongiwe (fellow student) for the encouragement, enthusiasm and moral support. Both cases resulted in the yield of the same imidazo[1,5-a]pyridyl compounds. ii) The second route was the development on the first route for those imine intermediates that could not be isolated and only hydrochloric acid catalysts were used.
In both the first and second routes, paraformaldehyde was used for the ring-closing step of the reaction. The latter route for the formation of imidazo[1,5-a]pyridyl compounds did not involve the use of the paraformaldehyde reagent. Appropriate routes were followed depending on the nature of the target products and the reaction yields were moderate to excellent.
INTRODUCTION
- Definition of microbes as problematic organisms
- Silver nitrate as solution to microbial damages
- Silver complexes as solution to problematic microbes
- Mode of action of silver complexes
- Uses of quaternary ammonium compounds
- Historical background of quaternary ammonium compounds
- Mode of action for quaternary ammonium compounds
- Research objectives
20th century, it was realized that silver nitrate can be irritating, which led to the discovery of the use of colloidal silver solutions. There are different ways of the mechanism of action of the silver ions that have been proposed by different researchers, depending on the study done, but are not well understood. On the same side, silver cations also affect the respiratory electron transport chain, thus depriving the cell of the energy currency, ATP.
It was discovered that, although silver sulfadiazine and silver nitrate were observed to kill bacteria quickly, their effectiveness did not last long, leading to reinfection of the wounds. Quaternary ammonium compounds are considered one of the most important and powerful antimicrobial agents due to their ability to react with the cytoplasmic membrane of bacteria leading to the loss of permeability properties of the membrane. In sufficient concentrations, QACs with ATP inhibit synthetic process and respiration process, and can result in membrane leakage and release of the cellular constituents resulting in cell death.4 Quaternary ammonium compounds that have antimicrobial properties are reported to have properties closely related to surfactants.
MICROORGANISMS AND ANTIMICROBIALS
Definition of micro-organisms
Change in the drug target for antibiotic action: mutations in the target, production of alternative targets or protection of the target. This is where the microorganism produces a drug-inactivating enzyme that destroys the drug's ability to kill the microorganism. Altered access: change in the bacterial outer membrane, which makes it difficult for a drug to bind to the outside of the microorganism.
Microorganisms can also acquire resistance to an antibiotic drug to which it was previously sensitive. This may be due to the results of these mechanisms as a result of genetic mutations, acquisition of resistance genes from the other microorganisms via gene transfer and combination of both events.4 There has been an ongoing effort towards the synthesis of new antibiotics and the development on the modification of existing drugs for to solve this problem.
ANTIBIOTICS (ANTIMICROBIALS)
- β-Lactam Antibiotics
In this chapter we will look at some of the antibiotics mentioned above; their chemical structures and mode of action. β-Lactam antibiotics alter this cross-linked peptidoglycan network in their binding sites (see Scheme 2.2) and inhibit the enzymes involved in the synthesis of this composite cell wall structure. Most antibiotics that target bacterial peptidoglycan biosynthesis are derived from natural products produced by microorganisms.17 Glycopeptide antibiotics (including vancomycin and teicoplanin) are active on the cell wall and inhibit the final steps of the peptidoglycan biosynthesis pathway.
The resonance of the nitrogen electrons (shown in scheme 2.3) around or to the carbene carbon is the main key for the stabilization of N-heterocyclic carbenes.23 These types of N-heterocyclic carbenes are imidazolium compounds that have their unique reactivity, stability, function and properties. Despite the fact that the free N-heterocyclic carbenes are stable due to the resonance of their structure, they are also stable in their complex form. The lone pair of electrons of the carbene carbon is stabilized by the inductive effect of the adjacent nitrogen atoms.
REVIEW FOR THE SYNTHESIS OF IMIDAZOLES
- Introduction
- Non- pyridyl fused imidazoles
- Synthesis of imidazo[1,2-a]pyridine system (3.2)
- Synthesis of imidazo[1,5-a]pyridine (3.3)
- System 2
- Synthesis of quaternary imidazo[1,5-a]pyridine
These compounds have a wide range of reported applications, such as antimycobacterial,5 antitumor,6 corticotropin-releasing hormone receptor antagonist,7 cyclin-dependent kinase inhibitors,8 xanthine oxidase inhibitors,9 anticonvulsants,10 and antiviral agents.11 They also appear in cofactors and nucleic acids, which play a key role in modulating protein function and signal transduction.12 There are many other non-pyridyl imidazole derivatives (3.1) with different R substituents and their chemical synthetic pathways are completely different. This procedure enables the formation of various imidazolium compounds with a substitution pattern, such as various 1,3-diaryl-substituted imidazoles.18 However, there is a large drop in the overall yield of the reaction for the formation of imidazolium salts by this route because its rate number is quite high. The final step was dehydration of the intermediate with acetic anhydride and removal of acetic acid in the presence of hydrochloric acid in toluene at 90 °C to give the product (3.4).
Treatment of 2,2'-pyridyl and benzaldehyde with ammonium acetate in the presence of acetic acid was carried out at 118 °C and was optimized to 41% when the ratio of pyridyl, aldehyde and ammonium acetate is 1:1:8. In this section, we considered two kinds of synthesis that have been reported in the literature that allow the formation of imidazo[1,2-a]pyridine (3.2). The final step was the ring closure of 3.8b to form imidazo[1,5-a]pyridine (3.8) in the presence of phosphorus oxychloride (POCl3).
Shibahara and co-workers46 described the oxidative condensation-cyclization of an aldehyde (3.14a) and aryl-2-pyridylmethylamine (3.14b) in the presence of elemental sulfur. The reaction yield was optimized to 86 % by heating the reaction to 80 °C in DMF in the presence of sodium carbonate (Na2CO3). Methyl picolinate was first converted to the corresponding picolinamides (3.17b) and then cyclized to the required products in the presence of phosphorus oxychloride (POCl3).
Van Leusen's imidazole synthesis involved the use of the corresponding aldehyde (3.18a) containing vinylog bromide and its condensation with an amine containing a double bond to give an imine which was treated with tosylmethyl isocyanides (TolO2SCH2NC) in the presence of base . Katrizky and Qiu synthesized imidazo[1,5-a]pyridine by addition of 2-pyridinecarboxaldehyde (3.19a) and benzotriazole with 2-oxazolidinone (3.19b) to give the Mannich adduct (3.19c), which was further reacted with aliphatic cyanides at 60 °C. °C in the presence of TiCl4 to give 3.19. The second (route B) was carried out by cyclization of formamide (3.21b) in the presence of phosphorus oxychloride (POCl3) to give the N-alkyl/aryl imidazo[1.5-a]pyridinium salt (3.21).
The second step involving the cyclization of the imine was achieved by treating the imine (3.23a) with paraformaldehyde in the presence of hydrochloric acid in toluene.
RESULTS AND DISCUSSION
Synthesis of the imidazo[1,5-a]pyridinium compounds
- Synthesis of imines, the intermediates (4.2)
- Reaction of pyridine-2-aldehyde (4.5) with ortho, meta and para substituted anilines (4.1b-i)
- Synthesis of the imidazole pyridinium compounds (4.3) (for R 3 is electron donating group)
- The use of POCl 3 as a catalyst (refer to route b in scheme 4.1)
- The use of HCl as a catalyst (refer to route c in scheme 4.1)
- Synthesis of 5-substituted imidazolium compounds (4.4) (via route e)
Completion of the reaction was confirmed by the disappearance of the strong carbonyl peak extending at 1708 cm-1 in the IR spectrum shown in Figure 4.3. Surprisingly, H-5 was shifted further downfield than H-4 due to the anisotropic effect caused by the N=C bond on H-5, as shown in Figure 4.2. A comparative study of the aromatic region of various imine intermediates, as shown in Table 4.1, shows that there is no significant change in the chemical shift of the aromatic protons.
However, a comparative study of the chemical shifts of the different imminium protons, CH1=N, is shown in Table 4.2. The disappearance of an aldehyde C-H stretching band at 2730 cm-1 in the infrared spectrum confirmed the success of the reaction. The infrared spectrum also showed the stretching frequencies of various functional groups such as C=N (shown in Table 4.3), C-N and those of the aromatic region.
The oxygen of the hydroxyl group withdraws electrons, as shown in Scheme 4.5. Some of the failed reactions were the reaction of pyridine-2-carbaldehyde (4.5) with aniline derivatives (4.1i-m), shown in Figure 4.8. The change in the stretching frequencies from the infrared spectra of the functional group C=N is recorded in table 4.4.
However, the rest of the substituents had more than a threefold change in wavenumber, as shown in column 4 of Table 4.4. Using HCl6,8 catalyst for the same reactions instead of POCl3 resulted in a good improvement in reaction yield, by at least 6%, as shown in Table 4.5. The purpose of adding the catalyst was to activate the carbonyl carbon for nucleophilic attack with nitrogen's lone pair of electrons (as shown in Scheme 4.7).
Synthesis of the imidazolium compounds (4.3) via route d as in scheme 4.1, where R3 is an electron-withdrawing group. The synthesis of the imidazolium compounds (4.3) via route d was successful as described above with good yields in the range of 67-73. Various analogues of the imidazolium compounds (4.3i-k) with different electron-withdrawing substituents on their benzene ring (as shown in Figure 4.12) were synthesized following this method.
CONCLUSIONS
FUTURE WORK
EXPERIMENTAL
- Instrumentation and General Experimental conditions
Flash column chromatography was performed using Merck Kieselgel 60 placed in a glass column (5 cm diameter). The amount of silica (Merck Kieselgel 60) can be varied depending on the amount of sample and the impurities. The crude product was placed on top of the column and allowed to adsorb to the silica on top of the column.
Preparative scaled thin layer chromatography (TLC) was performed using Merck Kieselgel 60254 which was coated on 20 x 20 cm glass plates. Silica gel (200 g) was homogeneously suspended in 500 ml of water to prepare TLC with a thickness of 2 mm (silica gel). Visualization of the TLC plates was achieved using iodine tank and/or fluorescence upon exposure to short wavelength ultraviolet light (254 nm).
The volatile solvents were removed in vacuo to give a dark yellow semi-solid which was then purified on a silica gel column and then on the TLC plate to give the desired product (4.3a). Pyridyl[1,5-a]-4-(p-nitro)phenylimidazolium chloride (4.3i) was obtained following procedure "A" (refluxed for 12 h, 4-nitroanaline as starting material).
