Mannich reaction derived novel boron complexes with amine-bis(phenolate) ligands: Synthesis, spectroscopy and in vitro/in silico biological studies
Graphical Abstract
Introduction
Boron-based organic synthesis, such as amine-bis(phenolate) boron complexes wherein the boron is coordinated to an organic amine-bis(phenolate) ligand, maybe become one of the most popular research areas due to their interesting properties and unique coordination chemistry of boron which allows preparation of multifunctional novel organic compounds. Because they offer potential advantages such as unique electronic and photo physical properties, enhanced flexibility and solution process ability at low cost, boron complexes continue to attract great interest in applications ranging from Lewis-acidic character [1] to pharmaceutical industry [2], [3], [4], catalysis [5], [6], [7], [8] and biological imaging [9] etc. However, this area is still in its infancy and the design and preparation of different boron complexes are challenging tasks. This is mostly due to the labile nature of ligands attached to the tetra-coordinated boron atom that makes it configurationally unstable. Accordingly, the choice of the nature of boron's ligands is crucial [10]. Also, the recent time interest for tetra-coordinated boron complexes comes from the fact that they are easily available, stable and, more importantly, are quite resistant to dissociation compared with tri-coordinate boron compounds [11], [12], [13]. Therefore, we think that choosing amine-bis (phenolate) groups as ligand will remove some restrictions in the boron area and will be important research topics.
The use of chelating tetra dentate amine-bis(phenolate) ligands have recently played an increasingly important role in transition-metal catalyst design and modelling of metalloenzyme active-sites. During several years we have studied the different behavior exhibited by these ligands, mainly due to the potential reduction capacity showed by the chemical group which leads to a great variety of coordination patterns [14]. Other than these, amine-bis(phenolate) ligands which is a chelating tetra dentate has been an attractive subject in combination with various metals such as Fe, Co, Rh, Zr, and Cr and these metal complexes have been acted as catalysts for cross-coupling of alkyl halides [15], [16], [17], [18], [19], 1-hexene polymerization [20], hydrogenation of ketones [17] and CO2 conversion [21]. To the best of our knowledge, the synthesis and applications in different fields of amine-bis(phenolate) boron complexes are very rare. In this context, we think that amine-bis(phenolate) boron complexes coordinated with various boronic acids will be used in many new application areas today and will be an important new class of boron compounds.
Boronic acids are a class of compounds that have received considerably more attention in recent years because of the unique reactivity they confer upon complexation with diols [22]. A boronic acid is a trivalent boron-containing compound that has two hydroxyls and one alkyl or aryl functional groups. The functional group bonded to boron determines the reactivity of boronic acid [23,24]. Differently in this study, we preferred amine-bis(phenolate) ligands instead of diols for coordinated with boronic acids. Additionally, these new boron compounds are 1:1 Lewis type intramolecular noncovalent B←N coordination bonds formed from boronic esters and amine-bis(phenolate) ligands, of which the former are derived from arylboronic acids and catechol derivatives.
Molecular oxygen, one of the main sources of free radicals, is a stable radical, it is also a necessary compound for life and cell function. Cells produce oxygen-centered radicals with various physiological processes. Reactive oxygen species (ROS) are among the most important of these endogenously occurring species [25]. Free radicals having a single unpaired electron in their outer orbitals have a very reactive property [26,27]. When produced in foods or biological tissues, these species, which are generally harmful to humans, react easily with macromolecules such as lipids, carbohydrates, protein and nucleic acids, producing different radical and non-radical species [25,28]. The radicals, which cause lipid peroxidation, DNA damage and protein oxidation, are known to play an important role in the formation of many neurodegenerative diseases such as Alzheimer's disease [29,30]. It has been reported that ß-amyloid, which is associated with Alzheimer's disease, also produces free radicals. ß-amyloid interacts with vascular endothelial cells, producing superoxide radicals and oxidizing agents that cause lipid peroxidation. This suggests that ß-amyloid plays a role in the production of free radicals and the formation of Alzheimer's disease [31]. There is a significant relationship between the increase of beta amyloids and the acetylcholinesterase (AChE), which hydrolyzes the neurotransmitter acetylcholine involved in cholinergic metabolism [32]. In previous studies, it has been reported that ß-amyloid increases with increasing AChE activity. This shows that AChE can indirectly contribute to the formation of free radicals. Therefore, the synthesis of new compounds with both radical scavenging and AChE inhibitory properties is important.
Continuing this research, our groups are interested in all aspects of boron chemistry, including the synthesis, characterization, catalysis and pharmaceutical chemistry of different organic ligands for boron coordination. In this paper, we present the formation of newly synthesized amine-bis(phenolate) ligands (L1 and L2) and their four-coordinated boron complexes [L1B(1-5)] and [L2B(1-5)] for in silico and in vitro biological evaluation. For this purpose, the inhibition effects of the synthesized compounds on AChE activity and their radical scavenging activities were scanned.
Section snippets
Synthesis and characterization
Initially, we have prepared two O, N, O-tridentate amine-bis(phenolate) ligands (L1 and L2) through a Mannich reaction utilizing two equivalents of phenol derivatives (2,4-Di-tert-butylphenol or 4-tert-butylphenol), two equivalents of formaldehyde and a single equivalent of 2-Aminoethyl diphenylborinate as primary amine in ethanol/water under reflux temperature with a yield in the range 58-56% (Scheme 1). Further condensation of amine-bis(phenolate) ligands (L1 and L2), with various boronic
Conclusion
In this work, we report a new synthesized amine-bis(phenolate) ligands (L1 and L2) and their (B←N) and (B-O) units containing four-coordinated boron complexes [L1B(1-5)] and [L2B(1-5)] which could be alternative therapeutic agents to increase the antioxidant capacity of the cells. The newly synthesized amine-bis(phenolate) ligands (L1 and L2) and their boron complexes [L1B(1-5)] and [L2B(1-5)] were characterized by 1H and 13C NMR, FT-IR, UV-Vis spectroscopy and LC-MS/MS spectrometry, and
General Considerations
All organic solvents and starting materials used for the synthesis of the amine-bis(phenolate) ligands (L1 and L2) and their corresponding amine-bis(phenolate) boron complexes [L1B(1-5)] and [L2B(1-5)] were commercially available and used without any additional purification. All liquids were distilled according to the usual procedures and stored over 4 Å molecular sieves for a week and distilled before use. All boron complexes reactions were performed in a pure Argon atmosphere using standard
Declaration of Competing Interest
None.
Acknowledgements
This work was supported by the Research Fund of Harran University (grant number 20011) and the Research Fund of Anadolu University (grant number 1610S681).
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