The amide protonation of (–)-N-benzoylcytisine in its perchlorate salts

doi:10.1016/j.saa.2014.02.192

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Volume 129, 14 August 2014, Pages 1-6

https://doi.org/10.1016/j.saa.2014.02.192 Get rights and content

Highlights

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The new salts of (–)-N-benzoylcytisine were characterized by spectroscopic methods.
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The energy calculations for tautomeric forms of the salts is presented.
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The structures were established by crystallographic analysis.
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In crystal, the protonation is on oxygen atom at cyclic amide, not at benzoic moiety.
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N-benzoylcytisinium salts protonation is at the oxygen atom instead nitrogen atom.

Abstract

The ¹³C NMR spectrum of (–)-N-benzoylcytisine perchlorate does not show a double set of signals typical of amide compounds, although this effect has been observed for the other diamine derivatives of cytisine. This observation means that in solution there must be the state of equilibrium between two forms of the cation with the protonated amide groups. DFT calculations have indeed indicated two preferred tautomeric forms with protonated oxygen atoms of amide groups. In the solid state however, according to X-ray analysis of perchlorate and perchlorate hydrate of N-benzoylcytisine the oxygen atom of the amide group in the six-membered ring A is preferred protonation site as compared with the oxygen in benzoic moiety. (–)-N-benzoylcytisine salt is the first compound from among the known derivatives of quinolizidine alkaloids that are not N-oxides, in which in solid state only the oxygen atom at cyclic amide is protonated instead of nitrogen atom or oxygen in benzoic moiety.

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 (pK_a = 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, C4 single bond H, 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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Molecular structure and spectroscopic studies of (−)-cytisine salt with (+)-tartaric acid
2024, Journal of Molecular Structure
Why the tartrate salt of (−)-cytisine? Just because tartrate anion belongs to the group of anions that are the most often used as active pharmaceutical ingredients (APIs) of category I, according to the Orange Book, and it has been already established as a safe counterion. The salt formation is the most common and effective way for modulating physical properties of drugs and increasing solubility of potential drugs. Formation of an appropriate salt can improve the overall therapeutic and pharmaceutical effects of active pharmaceutical ingredients (APIs) in this case (−)-cytisine. The main purpose of this study was to determine the structural properties of a new cytisine salt. Cytisine is natural alkaloid and a well-known smoking cessation medication because it acts as a partial nicotinic acetylcholine receptor agonist. Because solid-state form of active pharmaceutical ingredients (APIs) can be critical for design and development of a new pharmaceutical formulation, therefore, the new salt of (−)-cytisine with L-(+)-tartaric acid was characterized using structural and spectroscopic methods: single crystal X-ray diffraction, FT-IR, ¹H NMR, ¹³C NMR. The crystal structure is stabilized by a number of OH···⁻OOC, N⁺−H···⁻OOC and OH···O hydrogen bonds, in addition to van der Waals interactions. The semi-tartrate anions are joined by the strong OH⋯O hydrogen bond with an O⋯O distance of 2.502(4) Å into chains linked by one water molecule, while the other water molecule acts as a bridge between chains of the semi-tartrate anions.
Weak interactions in the structures of newly synthesized (–)-cytisine amino acid derivatives
2021, Crystals
Crystallization of Anhydrous Proton from Acidic Aqueous Solution with Diamide Building Block
2019, Crystal Growth and Design
Different cationic forms of (â€“)-cytisine in the crystal structures of its simple inorganic salts
2018, Acta Crystallographica Section C: Structural Chemistry

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The amide protonation of (–)-N-benzoylcytisine in its perchlorate salts

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Procedure

Conclusions

Acknowledgements

Farmaco

Neuropharmacology

Neuropharmacology

Bioorg. Med. Chem. Lett.

Pol. J. Chem.

J. Chem. Phys.

Neuroreport

Br. J. Pharmacol.

Int. J. Mol. Sci.

J. Med. Chem.

CrystEngComm

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Nature

Angew. Chem. Int. Ed.