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The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti-Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti-Trypanosoma properties in vitro and in vivo. The imidazoles showed moderate to strong and specific action against growth of T. congolense. For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti-Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD50 in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives.

Widespread use of commercially available palladium precatalysts is limited by high costs and their synthetic challenges. In this report, series of synthetically affordable, phosphine-free ligands were examined as supports for palladium active centers. 2-(2-Aminoethylamino)ethanol, diethylenetriamine and tris(2-aminoethyl)amine were condensed with sulfonyl chloride reagents in order to obtain flexible, aliphatic amine derivatives with varied steric bulk at the chain ends (ligands 1-Me and 1-tol = RSO2 NH CH2CH2 N(SO2R) CH2CH2Cl; ligands 2-ipr and 2-iprNH = RSO2 NH CH2CH2 NY CH2CH2 O SO2R where Y is H or R; ligands 3-Me, 3-tol and 3-ipr = RSO2 N(CH2CH2 NH SO2R)2; 3-iprNH = HN(CH2CH2 NH SO2R)2; ligands 4-tol and 4-ipr = N(CH2CH2 NH SO2R)3; R = methyl, tolyl or triiso-propyl). Despite the flexibility of the alkyl fragments in these ligands, placement of sterically demanding groups at amine donors enables formation of active species, which supports high turnover frequencies and yields up to 91% within 5 min and at 0.2 mol % palladium loading. Such activity from synthetically simple alkyl ligand frameworks, which are generally not regarded in Pd catalysis, is unprecedented. In situ catalyst generation is favorable for ligands with less than tridentate chelation capacity and presence of poorly chelating secondary NH-amine donor in the central position of the polyamines hinders catalyst performance. However, the preformed tridentate complexes yielded more attractive and living coupling catalyst efficiencies than their corresponding in situ reactions especially when bulkier co-ligand such as pyridine occupies the fourth coordination position (TOF of 5460 h−1 for Pd(4-tol)py and 4800 h−1 for Pd(4-ipr)py). Therefore, mutual steric demands between the tridentate-chelated steric ligands such as 4-tol and 4-ipr, and bulky co-ligand fragments cooperatively aids the generation of active species from assembled precatalyst.

A series of six new, bidentate ligands based on N-(2-(R-sulfonamido)benzyl)R-sulfonamide have been isolated as dianionic or monoanionic chelators via condensation of 2-(aminomethyl)aniline with sulfonyl chloride reagents; R=methyl (1 and 1′), tolyl (2 and 2′), 2,4,6-trimethylphenyl (3), or 2,4,6-triisopropylphenyl (4). Complexes of ligands 2–4 reacted at room temperature with palladium(ii) acetate in the presence of various monodentate N-donor co-ligands to form complexes Pd2(2dmap), Pd2′(OAc.py), Pd3(2acn), Pd3(2py), Pd4(2acn), and Pd4(2py), which were structurally confirmed by three X-ray crystal analyses. Results of catalysis studies in water showed high turnover frequencies and yields of up to 98% within 10min and at 0.2 mol-% palladium catalyst loading. Relative to ligand-free catalysis in the presence of only Pd(OAc)2, the ligand-supported palladium species clearly possess positive catalytic advantage. Furthermore, Suzuki coupling efficiencies by 1:1 ‘Pd(OAc)2+ligand’ yielded notably better outcomes than for the 1:2 ‘Pd(OAc)2+ligand’ insitu catalyst generation, which reveals that coordinative saturation is undesirable. The size of the complementing monodentate co-ligand was observed to influence the catalytic efficiency such that bulkier co-ligands consistently yielded improved turnover frequency values, which leads to the conclusion that steric repulsion between the synthesised ligands and the bulkier co-ligands aided the generation of vacant coordination sites for the more active complexes. Moderate Heck coupling activity was recorded for the complexes and better activities appear to correlate with moderate bulkiness of ligand 3.

A series of new structurally and electronically diversified palladium complexes derived from seven less sterically crowded 2-(4,5-dimethyl-1H-imidazol-2-yl) phenol/2-(4,5-diethyl-1H-imidazol-2-yl) phenol ligands and fourteen 2-(4,5-diphenyl-1H-imidazol-2-yl) phenols/2-(1H-phenanthro[9,10-d]imidazol-2-yl) phenols bearing varying degrees of higher steric bulk have been prepared and characterized. While single crystals grown from precipitated products of complexation reactions confirmed the bis-ligand Pd(N^O)2 coordination, few crystals obtained from reaction filtrates involving the 2-(4,5-diphenyl-1H-imidazol-2-yl) phenols provided evidence for formation of N^O^C chelation species achieved by cyclometallation. Results from structural analyses and catalytic outcomes generally indicate that desirable variables on the ligand frameworks for obtaining superior catalyst activities either provides hemilabile or sterically strained chelation characters, which would both favour generation of monodentate coordination species at the catalysis temperature. In particular, correlation was observed between tendency for cyclometallation in the palladium complexes and poor Suzuki–Miyaura catalytic prospects. Based on hopeful activity obtained for the complex bearing 4-bromo-2-(4,5-dimethyl-1H-imidazol-2-yl) phenol, it was also concluded that sterically bulky ligand is not a necessity for high coupling efficiency, while presence of potentially cyclometallating substituent moieties in the vicinity of the palladium centre may in fact destroy catalytic prospects.

Series of systematically varied 2-(1H-imidazol-2-yl)phenol ligand frameworks, which were synthesized and properly characterized, have been used to investigate favourable ligand characteristics towards in situ formation of active palladium species in Suzuki–Miyaura coupling. Structures of 2-(4,5-diethyl-1H-imidazol-2-yl)-4-nitrophenol (p-N∼de) and 4-(tert-butyl)-2-(4,5-diphenyl-1H-imidazol-2-yl)phenol (p-tBu∼dp) as well as the palladium complex of 2-(4,5-diethyl-1H-imidazol-2-yl)phenol (Pd.de2) were confirmed. Structural analyses show that para-nitro-substituted phenol moieties bear poor oxo-donor atom while the reverse was observed for para-tBu-substituted analogues. Ligand donor strengths were also determined by pKa analysis. Under the same reaction conditions for palladium catalyzed Suzuki–Miyaura coupling in the presence of ‘ligand + palladium(II) acetate’ catalyst system, results show that electronic properties of the ligands are more important than the variation in steric properties. In particular, ligands with strong bidentate chelate coordination potentials acted as poisons while those with monodentate coordination potential proved to be very beneficial towards in situ generation of superior active species. Furthermore, correlation between donor strength pKa data and the trends in catalytic efficiencies as a consequence of ligand presence was studied. Therefore, it was concluded that ligands with strong chelation tendencies adversely impacted in situ palladium catalyst generation efficiency and that there appears to be moderate steric requirement from ligands for optimal catalyst efficiency.

A series of 2-R-6-(aryloxazol-/imidazol-2-yl)pyridine and 2,4-di-tert-butyl-6-(1H-phenanthro[9,10-d]imidazol-/oxazol-2-yl)phenol derivatives were synthesized and characterized using elemental and spectroscopic analyses as well as single-crystal X-ray diffraction analysis. The oxazole derivatives displayed higher photoluminescence efficiencies than their imidazole analogues. The 2-(phenanthro[9,10-d]oxazole/imidazol-2-yl)pyridine derivatives displayed quantum yields approaching unity in non-polar solvents but were quenched in polar solvents. The oxazole analogues produced reversible fluorescence photo-switching between 400 nm and 550 nm regions whilst the imidazole analogues underwent an irreversible photo-induced excimer formation in polar solvents. 1H NMR was used to rationalize the proposed mode of intermolecular interactions between excimers of the 2-(phenanthro[9,10-d]imidazol-2-yl)pyridine derivatives.

A series of new imidazole based heterocycles (5-(4,5-diphenyl-1H-imidazol-2-yl)furan-2-yl)methyl acetate ( Him-dp ), (5-(1H-phenanthro[9,10-d]imidazol-2-yl)furan-2-yl)methyl acetate ( HIm-pt ), (5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)furan-2-yl)methyl acetate ( HIm-phen ), 2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole ( HIm-n ), 1-methyl-2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole ( MeIm-n ), N-(2-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)phenyl)benzamide ( EtIm-ba ) and 2,4-di-tert-butyl-6-(8-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)-1,4-dihydroquinolin-2-yl)phenol ( EtIm-q ) were synthesized and studied for the dependence of their azole donor characteristics on substituent factors by means of experimentally determined ionization constant data (derived as p K a s), spectroscopic analyses and calculated properties of their DFT optimized molecular geometries performed at the B3LYP/6-311 + G * level. Results showed that the lowest donor strength recorded for HIm-pt (p K a = 2.67 ± 0.07) could be traced to the extensive electronic conjugation of the azole π-electrons with 4,5- and 2-substituents. On the other hand, the strongest imidazole donor strength in the series was obtained from EtIm-q (p K a = 4.61 ± 0.04) for which the substituents possessed negligible π-overlap with the azole ring. The experimental results and theoretical calculations lead to conclusions that effective conjugation between the imidazole ring and substituent aromatic groups is accountable for significant withdrawal of charge densities on the imidazole N-donor atom and vice versa. Furthermore, observed donor strengths in the series suggest that electronic inductive effects of the substituents provided lesser impact on donor strength modification of imidazole base and that alkylation of 1-imidazole position did not yield the anticipated push of electron density in favour of the N-donor atom. It is anticipated that the results should promote the understanding of azole-containing bio-macromolecular species and reactions as well as tuning and application of azole functions in molecular science.

Series of 2-R1-6-(1-R2-4,5-diphenyl-1H-imidazol-2-yl)pyridine (R1 = R2 = H, L1; R1 = Me, R2 = H, L2; R1 = H, R2 = Me, L3; R1 = R2 = Me, L4), 2-(6-R1-pyridin-2-yl)-1H-phenanthro[9,10-d]imidazole (R1 = H, L5; R1 = Me, L6) and 2-(pyridin-2-yl)phenanthro[9,10-d]oxazole (L7) were synthesized and used to prepare their corresponding dihalonickel complexes (C1–C9). All organic compounds and nickel complexes were characterized by elemental and spectroscopic analyses. Molecular structures of C1, C4, C5 and C8 were confirmed by the single-crystal X-ray diffraction analysis. The single-crystal X-ray analysis revealed complex C1 as a distorted octahedral geometry, complex C4 as a distorted square pyramidal geometry, complex C5 as a distorted trigonal bipyramidal configuration, and complex C8 as a tetrahedral geometry. Upon activation with methylaluminoxane (MAO), the nickel complexes showed good activity towards norbornene polymerization through main additional and minor ring-opening metathesis. The reaction parameters such as norbornene concentration, reaction temperature and different coordinate environments caused by the ligands affected their catalytic performances.

Fourteen new organic molecules A1–A4, B1–B5, C1–C4 and D and a series of transition metal(II) complexes (Ni1–Ni9 and Pd1–Pd2b) were synthesized and studied in order to characterize the hemilability of 2-(1H-imidazol-2-yl)pyridine and 2-(oxazol-2-yl)pyridine ligands (A1–A4 = 2-R2-6-(4,5-diphenyl-1R1-imidazol-2-yl)pyridines, R1 = H or CH3, R2 = H or CH3; B1–B5 = 1-R2-2-(pyridin-2-yl)-1R1-phenanthro[9,10-d]imidazoles/oxazoles, R1 = H or CH3, R2 = H or CH3; C1–C4 = 2-(6-R2-pyridin-2-yl)-1H-imidazo/oxazo[4,5-f][1,10]phenanthrolines, R2 = H or CH3; D = 2-mesityl-1H-imidazo[4,5-f][1,10]phenanthroline). They were also used to study the substituent effects on the donor strengths as well as the coordination chemistries of the imidazole/oxazole fragments of the hemilabile ligands. All the observed protonation–deprotonation processes found within pH 1–14 media pertain to the imidazole or oxazole rings rather than the pyridyl Lewis bases. The donor characteristics of the imidazole/oxazole ring can be estimated by spectroscopic methods regardless of the presence of other strong N donor fragments. The oxazoles possessed notably lower donor strengths than the imidazoles. The electron-withdrawing influence and capacity to hinder the azole base donor strength of 4,5-azole substituents were found to be in the order phenanthrenyl (B series) > 4,5-diphenyl (A series) > phenanthrolinyl (C series). An X-ray structure of Ni5b gave evidence for solvent induced ligand reconstitution while the structure of Pd2b provided evidence for solvent induced metal–ligand bond disconnection. Interestingly, alkylation of 1H-imidazoles did not necessarily produce the anticipated push of electron density to the donor nitrogen. Furthermore, substituents on the 4,5-carbons of the azole ring were more important for tuning donor strength of the azole base. DFT calculations were employed to investigate the observed trends. It is believed that the information provided on substituent effects and trends in this family of ligands will be useful in the rational design and synthesis of desired azole-containing chelate ligands, tuning of donor properties and application of this family of ligands in inorganic architectural designs, template-directed coordination polymer preparations, mixed-ligand inorganic self-assemblies, etc.

New 2-(1H-imidazol-2-yl)phenols ( L1Et – L8 t BuPt ) bearing a phenolic proton in the vicinity of the imidazole base were prepared and characterized. Experimental studies of the dependence of their protonation/deprotonation equilibrium on substituent identities and intramolecular hydrogen bonding tendencies were carried out using electronic absorption spectroscopy at varying pH values. In order to make comparison, 2-(anthracen-10-yl)-4,5-diphenyl-1H-imidazole ( L9Anthr ) bearing no phenolic proton and 4,5-diphenyl-2-(4,5-diphenyl-1H-imidazol-2-yl)-1H-imidazole ( L10BisIm ) bearing two symmetrical imidazole base fragments were also prepared and experimentally investigated. DFT calculations were carried out to study frontier orbitals of the investigated molecules. While electron-releasing substituents produced increase in protonation–deprotonation p K a s for the hydroxyl group, values for the imidazole base were mainly affected by polarization of the imidazole ring aromaticity across the 2-imidazole carbon and the 4,5-imidazole carbons axis of the imidazole ring. It was concluded that electron-releasing substituents on the phenol ring and/or electron-withdrawing substituents on 4,5-imidazole carbons negatively affects donor strengths/coordination chemistries of 2-(1H-imidazol-2-yl)phenols, and vice versa. Change of substituents on the phenol ring significantly altered the donor strength of the imidazole base. The understanding of p K a variation on account of electronic effects of substituents in this work should aid the understanding of biochemical properties and substituent environments of imidazole-containing biomacromolecules.

A series of hemilabile 2-(imidazol-2-yl)pyridine and 2-(oxazol-2-yl)pyridine palladium ligands are synthesized, characterized, and their catalytic properties in high-temperature Suzuki—Miyaura cross-coupling reactions are investigated.

Eight imidazole-based compounds 4-methyl-2,6-bis(4,5-diphenyl-1H-imidazol-2-yl)phenol ( A-dp), 2-(1H-phenanthro[9,10-d]imidazol-2-yl)phenol ( B-2H), 5-methoxy-2-(1H-phenanthro[9,10-d]imidazol-2-yl)phenol ( B-2H4M), 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol ( C-3H), 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4-methoxyphenol ( C-2H5M), 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-2-methoxyphenol ( C-4H3M), 2-(2-methoxyphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline ( C-2M) and 2-(2,4-dimethoxyphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline ( C-2,4M) were synthesized and characterized by elemental, spectroscopic and X-ray single crystal analyses. Two different crystals of A-dp were grown from ethanol and THF, which revealed that A-dp crystallizes in a monoclinic (P2(1)/c) space group while A-dp·2THF crystallizes in a triclinic (P) space group. A-dp·2THF was devoid of any kind of networks whereas the absence of solvent adducts in the ethanol sample produces 1-dimensional single-stranded helices. Contrary to the reported literature conclusion that 1H-imidazole alkylation should increase the donor strength of the imidazole N-base, protonation–deprotonation equilibrium studies on the compounds suggest that push/pull of electron density on the 2-carbon of the imidazole ring by electron-rich/electron-withdrawing substituents is necessary to influence donor capacity of the N-base electrons. Furthermore, the notable increase in pKa,N: values due to ortho/para-directing methoxy substituents supports the conclusion that electron density push towards the 2-position of the imidazole ring is important for improving N-base donor strengths. DFT calculation results using the B3LYP/6-311+G level of theory were conducted to explore possible theoretical explanations.