Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
The amide protonation of (–)-N-benzoylcytisine in its perchlorate salts
Graphical abstract
Introduction
Amide bonds continue attracting the attention of the chemists, biologists etc. because of their profound importance in living systems; for instance, they determine the interactions of biologically active structures like peptides or proteins. Here we attempt to address the interesting aspect of protonation possibilities of a tertiary amide, taking as an example the certain cytisine derivative containing two such groups, one cyclic – embedded in a six-membered ring, and the other acyclic, connecting the aromatic substituent with the cytisine molecule.
(–)-Cytisine (1, Fig 1) is a naturally occurring quinolizidine alkaloid extracted from seeds of Laburnum anagyroides and other Leguminosae plants. (–)-Cytisine has been used as a smoking cessation aid (Tabex®), and is also a very promising compound for development of new drugs for potential treatment of the central nervous system disorders, particularly Alzheimer’s and Parkinson’s diseases. On the basis of the hitherto studies of certain cytisine derivatives it has been found that introduction of substituents modifying the molecular structure also changes the pharmacological properties of these compounds, that is the affinity and inner activity towards certain subtypes of nACh receptors and the affinity to ganglionic and centric receptors [1], [2], [3]. Moreover, among N-substituted cytisines some compounds with analgesic activities have been found [2], [3], [4]. It is generally accepted that biologically active compounds are usually polyfunctional derivatives whose protonation strongly depends on acid–base properties of individual functional groups, intra- and intermolecular interactions. The calculations in the gas phase and in water (pKa = 6,11 for cytisine) have shown – not surprising – that the oxygen is clearly a more basic site, which is consistent with the results of this study [5], [6].
Upon protonation of quinolizidine and bisquinolizidine compounds their monosalts can be easily formed. The aim of this study is to explain the influence of the structure of N-cytisine derivatives (with additional proton-accepting groups) on the preferred protonation site. The explanation of the hierarchy of protonation sites in cytisine derivatives can help in understanding the mechanisms of binding these molecules to the nAChRs. Up to now, some of the N-substituted cytisines have been docked into a rat and human nAChR models based on the extramolecular domain of a molluscan acetylcholine binding protein and the results agreed with the binding data [7], [8].
In this paper, we are presenting the results of the NMR spectroscopy, DFT calculations, and X-ray studies of the perchlorate salt of N-benzoylcytisine.
Section snippets
Results and discussion
It is obvious that protonation of amides can take place at the oxygen or nitrogen atoms [6]. The calculation of molecular orbitals of strained amides and their N- and O-protonated forms reported by Greenberg indicated that the N-protonated form was favoured over the O-protonated one [10].
However, from the thermodynamical point of view the oxygen atom is much preferred position in this process [9], [11]. Free, unsubstituted cytisine contains three heteroatoms, but only two of them can be
Procedure
N-benzoylcytisine (2) was obtained according to literature [13]: 2 was dissolved in methanol and 60% HClO4 solution in methanol were added to pH = 6.0. A yellow powder of perchlorate salt (2) was precipitated. Recrystalization from ethanol (yield 72%), m.p. 239 °C.; 1H NMR (300 MHz, MeOD-d6, ppm); δ 8.07 (1H, dd, C4H, J = 8.8; 7.4 Hz), phenyl ring: 7,54–7.42 (5H, m, C2′H, C3′H′, C4′H, C5′H, C6′H), 7.18 (1H dd, C3H, J = 7.4; 0.8 Hz); 7.11 (1H, dd, C5H, J = 8.9, 1.3 Hz); 8.81–3.53 (6H, m, C10Hα, C10Hβ, C11Hα,
Conclusions
In conclusion, we present many aspects of protonation possibilities in the perchlorate salt of N-benzoylcytisine, the cation with two tertiary amide moieties, one cyclic, in the six-membered ring A and the other acyclic with a benzoic group. The energy calculations for the isolated cations of (–)-N-benzoylcytisine (DFT level of theory) showed that the lowest energy tautomeric form of the cation had protonated oxygen atom in the six-membered cyclic ring (A), and this form is favoured over the
Acknowledgements
The study was supported by Norway Grants and the National Centre for Research and Development of Poland (NCBiR) as a part of Polish–Norwegian Research Programme: Superior bio-friendly systems for enhanced wood durability. No. Pol-Nor/203119/32; DURAWOOD). This research was also supported in part by PL-Grid infrastructure. The authors wish to express their appreciation to M.Sc. Bożena Wyrzykiewicz for help in NMR experiments.
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