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Proceeding Paper

An Optimised Method to Synthesise N5O2 Aminophenols †

by
Paula Oreiro-Martínez
1,*,
Julio Corredoira-Vázquez
1,2,
Jesús Sanmartín-Matalobos
1,3 and
Matilde Fondo
1
1
Departamento de Química Inorgánica, Facultade de Química, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
2
Phantom-g, CICECO—Aveiro Institute of Materials, Department of Physics, University of Aveiro, 3810-193 Aveiro, Portugal
3
Institute of Materials (iMATUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
*
Author to whom correspondence should be addressed.
Presented at the 27th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-27), 15–30 November 2023; Available online: https://ecsoc-27.sciforum.net/.
Chem. Proc. 2023, 14(1), 17; https://doi.org/10.3390/ecsoc-27-16145
Published: 15 November 2023

Abstract

:
Aminophenol compounds are usually employed in coordination chemistry due to their versatility to form metal complexes. Heptadentate N5O2 aminophenol ligands can lead to the formation of lanthanoid complexes with pentagonal bypiramidal (pbp) geometry, which are very interesting in the field of molecular magnetism. In this communication, we report an optimised method for obtaining two similar N5O2 aminophenols named 2-((((6-(((5-hydroxy-2-R-benzyl)(pyridin-2-ylmethyl)amino)methyl)pyridin-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)-4-R-phenol (R = methyl or methoxy), which significantly improves the few examples of synthesis of this type of compound reported in the literature.

1. Introduction

Aminophenols are di- or polydentate Lewis bases that can coordinate to a variety of metal ions in different ways, which makes them very valuable ligands in coordination chemistry. Besides, some coordination compounds with this kind of ligand also possess interesting biological, luminescent, and/or catalytic properties [1,2,3]. In addition, the number of donor atoms in the aminophenols and their rigidity can be modulated to try to form metal complexes with a predetermined geometry. This is a very attractive field for the development of molecule magnets [4], since, as the theory of Rinehart and Long [5] showed, the magnetic anisotropy of lanthanoid complexes can be modulated by their geometry. In this context, heptadentate N5O2 aminophenol ligands can be good candidates for the obtention of lanthanoid complexes of oblate ions with pentagonal bypiramidal (pbp) geometry and, accordingly, increased easy axis anisotropy.
In spite of these advantages, the number of N5O2 acyclic aminophenol donors previously described is very scarce [6,7,8,9], and the methods of obtaining them are usually quite time-consuming, leading to several by-products that impurify the target organic derivative, which must be separated by chromatographic techniques. This generally entails long separation times and very low yields, in the best of cases. Therefore, the search for alternative methods of isolating these polydentate Lewis bases, which enhance reaction times and facilitate the separation of the species formed, is a field of interest in coordination chemistry. With these considerations in mind, in this work, we describe an optimised method for obtaining two similar N5O2 aminophenols, which significantly improves the few examples of synthesis of this type of compound reported in the literature.

2. Materials and Methods

2.1. Materials and General Methods

All chemical reagents were purchased from commercial sources and used as received without further purification. 1H NMR spectra of H2LMe and H2LOMe were recorded on a Varian Inova 400 spectrometer, using CDCl3 as solvent.

2.2. Synthesis

The synthesis of H2LR ligands (R = Me or OMe) described herein requires the obtaining of the N5 precursor 2,6- bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine from 2-[(tosylamino)methyl]pyridine and 2,6 bis(bromomethyl)pyridine, as detailed in the literature [10].
The syntheses of both H2LR compounds are exemplified by the isolation of H2LMe, as shown below.
H2LMe: To a solution of 2,6 bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine (0.216 g, 0.677 mmol) in toluene (5 mL) and water (10 mL), 4-methylphenol (0.195 g, 1.800 mmol) and formaldehyde (135 μL, 1.800 mmol) were added, and the mixture was refluxed for 24 h. Then, it was extracted with dichloromethane (4 × 50 mL), the organic phases were combined, and the solution was dried with anhydrous magnesium sulphate. The magnesium sulphate was removed, and the solution was concentrated to dryness to obtain a brown oil that was washed with water to remove the excess 4-methylphenol. Yield: 190 mg (50%). MW: 559.70 g/mol. 1H NMR (400 MHz, CDCl3, δ in ppm): 2.23 (s, 6H, H18); 3.75 (s, 4H, H11); 3.86 (s, 8H, H4 and H5); 6.78 (d, J = 8.1 Hz, 2H, H14 or H15), 6.85 (s, 2H, H17), 6.96 (d, 2H, J = 8.1 Hz, H14 or H15), 7.12–7.17 (m, 2H, H9), 7.22 (d, J = 7.7 Hz, 2H, H2 or H7); 7.30 (d, J = 7.8 Hz, 2H, H2 or H7); 7.53 (t, J = 7.7 Hz, 1H, H1); 7.61 (t, J = 7.7 Hz, 2H, H8); 8.56 (d, J = 4.6 Hz, 2H, H10); 10.61 (s, 2H, OH).
H2LOMe: quantity of 2,6 bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine (0.232 g, 0.727 mmol), 4-methoxyphenol (0.242 g, 1.933 mmol), and formaldehyde (145 μL, 1.933 mmol). Yield: 174 mg (40%). MW: 591.68 g/mol. 1H NMR (400 MHz, CDCl3, δ in ppm): 3.73 (s, 6H, H18); 3.76 (s, 4H, H11); 3.87 (s, 8H, H4 and H5); 6.63 (d, J = 3.0 Hz, 2H, H17), 6.73 (dd, J1 = 8.7 Hz, J2 = 3.0 Hz, 2H, H15), 6.81 (d, 2H, J = 8.7 Hz, H14), 7.12–7.16 (m, 2H, H9), 7.23 (d, J = 7.7 Hz, 2H, H2 or H7); 7.30 (d, J = 7.8 Hz, 2H, H2 or H7); 7.54 (t, J = 7.7 Hz, 1H, H1); 7.59 (t, J = 7.7 Hz, 2H, H8), 8.56 (d, J = 4.9 Hz, 2H, H10); 10.40 (s, 2H, OH).

3. Results and Discussion

3.1. Synthesis of the Aminophenols

The method described herein for the isolation of the N5O2 acyclic aminophenols completely differs from the previously reported one [6,7,8,9] not only in the purification method but also in the reactants employed. Thus, in the reported method, the precursor R-2-(((pyridin-2-ylmethyl)amino)-methyl)phenol is initially synthesised, and then it reacts with 2,6-bis(bromomethyl)pyridine, as shown in Scheme 1, followed by columm chromatography for purifying the product.
In our case study, the precursor is the N5 (2,6-bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine) amine, which was isolated as described in the literature [10] (Scheme 2) from commercially available reagents.
The reaction of this precursor with formaldehyde and 4-methylphenol or 4-methoxyphenol led to the isolation of H2LMe or H2LOMe, respectively (Scheme 3).
In this synthesis, a significant excess of R-phenol and formaldehyde is necessary for the correct addition of the R-phenol onto the amine nitrogen atoms. After the reflux time has elapsed, the mixture is extracted with CH2Cl2, and the organic phase is dried and concentrated to dryness. The aminophenol is the only product formed in this reaction, but it is contaminated with the excess R-phenol. This latter is removed by washing with water, thus obtaining two pure, different brown products.

3.2. Characterisation of the Aminophenols

Both compounds were characterised by 1H NMR spectroscopy in CDCl3 (Figure 1 and Figure 2).
From these spectra, the following is noted:
  • The presence of two singlets in the region 3.5–4 ppm that integrate to 12 protons in total, indicating the existence of six CH2 groups and agreeing with the addition of the phenolic arms at the N5 precursor.
  • The presence of nine signals in the aromatic region, which globally integrate to 17 protons, in agreement with the five aromatic rings, and, therefore, with the correct addition of the R-phenol to the N5 precursor.
  • The presence of a singlet at 10 ppm (2H) and a second singlet at 2.3 ppm (6H) for H2LMe and at 3.73 for H2LOMe (6H), assigned to the hydroxyl and CH3 groups, respectively, also indicates the successful binding of the R-phenol to the precursor.
These NMR spectra also confirm that this way of synthesis leads to H2LR ligands with high purity, as there are no additional signals. Thus, it is noteworthy that no peak corresponding to free R-phenol is observed, which shows that water washing is a very efficient method to separate the ligand and excess R-phenol and is much faster and less polluting than the column chromatography carried out in the synthesis of this ligand previously described.

4. Conclusions

This work reports an alternative and optimised method to synthesise N5O2 aminophenols, avoiding chromatography to purify the final product.

Author Contributions

Conceptualization, M.F., P.O.-M. and J.C.-V.; methodology, P.O.-M. and J.C.-V.; investigation, M.F., P.O.-M. and J.C.-V.; writing—original draft preparation, P.O.-M. and M.F.; supervision, M.F. and J.S.-M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing does not apply to this article.

Acknowledgments

P. Oreiro-Martínez acknowledges Fundación Segundo Gil Dávila for her predoctoral fellowship, and J. Corredoira-Vázquez acknowledges Xunta de Galicia for his postdoctoral fellowship (ED481B-2022-068).

Conflicts of Interest

The authors declare no conflict of interest.

References

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Scheme 1. Synthesis of N5O2 aminophenols by reported methods [6,7,8,9].
Scheme 1. Synthesis of N5O2 aminophenols by reported methods [6,7,8,9].
Chemproc 14 00017 sch001
Scheme 2. Synthesis of 2,6 bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine [10].
Scheme 2. Synthesis of 2,6 bis{[(pyrid-2-ylmethyl)amino]methyl}-pyridine [10].
Chemproc 14 00017 sch002
Scheme 3. Synthesis of H2LR (R = Me or OMe) by a new method reported herein.
Scheme 3. Synthesis of H2LR (R = Me or OMe) by a new method reported herein.
Chemproc 14 00017 sch003
Figure 1. 1H NMR spectrum of H2LMe in CDCl3 between 6.7 and 8.6 ppm. Inset: spectrum between 2.0 and 4.0 ppm.
Figure 1. 1H NMR spectrum of H2LMe in CDCl3 between 6.7 and 8.6 ppm. Inset: spectrum between 2.0 and 4.0 ppm.
Chemproc 14 00017 g001
Figure 2. 1H NMR spectrum of H2LOMe in CDCl3 between 6.6 and 8.6 ppm. Inset: spectrum between 3.5 and 4.1 ppm.
Figure 2. 1H NMR spectrum of H2LOMe in CDCl3 between 6.6 and 8.6 ppm. Inset: spectrum between 3.5 and 4.1 ppm.
Chemproc 14 00017 g002
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MDPI and ACS Style

Oreiro-Martínez, P.; Corredoira-Vázquez, J.; Sanmartín-Matalobos, J.; Fondo, M. An Optimised Method to Synthesise N5O2 Aminophenols. Chem. Proc. 2023, 14, 17. https://doi.org/10.3390/ecsoc-27-16145

AMA Style

Oreiro-Martínez P, Corredoira-Vázquez J, Sanmartín-Matalobos J, Fondo M. An Optimised Method to Synthesise N5O2 Aminophenols. Chemistry Proceedings. 2023; 14(1):17. https://doi.org/10.3390/ecsoc-27-16145

Chicago/Turabian Style

Oreiro-Martínez, Paula, Julio Corredoira-Vázquez, Jesús Sanmartín-Matalobos, and Matilde Fondo. 2023. "An Optimised Method to Synthesise N5O2 Aminophenols" Chemistry Proceedings 14, no. 1: 17. https://doi.org/10.3390/ecsoc-27-16145

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