Energetics of aminomethylpyrimidines: An examination of the aromaticity of nitrogen heteromonocyclic derivatives

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Highlights

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    Vapour pressure study of three aminomethylpyrimidines by Knudsen effusion technique.

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    Enthalpies of formation of three aminomethylpyrimidines by combustion calorimetry. • NICS, HOMA, Shannon analysis used as aromaticity criteria for three aminomethylpyrimidines.

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    QTAIMs properties, HOMO–LUMO gap, hardness, Kekulé mode and UV–Vis spectra are analyzed.

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    Benzene, pyridine and pyrimidine are taken as references for the aromaticity analysis.

Abstract

The standard (po = 0.1 MPa) molar enthalpies of formation, in the gaseous phase, at the reference temperature of 298.15 K, of 2-amino-4-methylpyrimidine ((98.1 ± 1.6) kJ · mol−1), 2-amino-4,6-dimethylpyrimidine ((55.9 ± 1.8) kJ · mol−1) and 4-amino-2,6-dimethylpyrimidine ((60.1 ± 1.8) kJ · mol−1) were calculated from the enthalpies of formation, in the crystalline phase, and enthalpies of sublimation, derived, respectively, from static bomb combustion calorimetry and Knudsen effusion technique results. In order to quantify the resonance effects arising from the substitution on the pyrimidine ring, hypothetical isodesmic reactions were used to analyze the experimental gaseous-phase enthalpies of formation. The aromaticity of benzene, pyridine, pyrimidine and the substituted pyrimidines was investigated in terms of magnetic (NICS), geometric (HOMA), electronic (Shannon aromaticity, QTAIMs ring critical point properties and HOMO–LUMO gap), reactive (hardness), vibrational (Kekulé mode) and spectroscopic (UV–Vis) properties.

Introduction

The resonance enthalpy provided by the delocalized electrons in substituted heterocyclic molecules, in comparison to hypothetical localized structures, is difficult to obtain [1]. In this work the enthalpy of interaction between the amino and methyl substituents and the nitrogen heteroatoms, in positions 1,3 of a hexagonal ring, is derived from simple isodesmic reactions and correlated with other aromaticity indices. Since the amino and methyl functional group are π electron donors, by mesomeric effect and hyperconjugation, respectively, and the nitrogen atoms of the ring behave as π electron acceptors, those functional groups will conjugate with the heteroatoms of the pyrimidine ring and increase the stability of the compound. This electronic delocalization resulted in very negative enthalpies of interaction between the amino and methyl groups and the nitrogen atoms of the ring, which make these ideal molecules to calculate the resonance enthalpy due to the interaction of substituents. Moreover, aminopyrimidines and methylpyrimidines constitute important structures in current research of drug intermediaries [2], nuclecobases [3], [4], [5] and biologically active compounds [6], [7] and are used in the synthesis of chelating agents [8], [9], luminescent compounds [10], [11] and electronic polymers [12]. These pyrimidine derivatives also exhibit favourable non-covalent interactions with anions [13], [14] and proteins [15], [16], and they have acid base behaviour that promotes enzyme catalysis [17], [18].

In this paper, the enthalpies of formation, in the gaseous phase, of 2-amino-4-methylpyrimidine, 2-amino-4,6-dimethylpyrimidine and 4-amino-2,6-dimethylpyrimidine (figure 1) were derived from the enthalpies of formation, in the crystalline phase, and enthalpies of sublimation, obtained with static bomb combustion calorimetry and Knudsen effusion technique, respectively. From the values of the gaseous enthalpies of formation of these three compounds and from those previously studied, 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine (figure 1) [19], the enthalpy of interaction between substituents was calculated, and analysed in terms of the Nucleus Independent Chemical Shifts (NICS) [20], [21], Harmonic Oscilator Model of Aromaticity (HOMA) [22], [23], [24], [25], Shannon aromaticity [26], Quantum Theory of Atoms in Molecules (QTAIM) [27] ring critical point (RCP) properties [28], [29], [30], the highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO) energy gaps [31], chemical hardness [32], Kekulé mode [33], [34] and UV–Vis electronic transitions [35], [36], [37]. Benzene, pyridine and pyrimidine are taken as a reference [38] in order to evaluate the sensibility of the different aromaticity measurements.

Section snippets

Compounds and purity control

The 2-amino-4-methylpyrimidine, 2-amino-4,6-dimethylpyrimidine and 4-amino-2,6-dimethylpyrimidine were obtained from Alfa Aesar. The 2-amino-4-methylpyrimidine was sublimed three times (p ≈ 1 Pa, T ≈ 313 K), 2-amino-4,6-dimethylpyrimidine was sublimed three times (p ≈ 1 Pa, T ≈ 353 K) rejecting a small amount of the more volatile phase in each sublimation, and 4-amino-2,6-dimethylpyrimidine was sublimed twice (p ≈ 1 Pa, T ≈ 368 K). Due to its hygroscopicity, after sublimation, the 2-amino-4-methylpyrimidine and

Computational Details

The computational calculations were performed using the Gaussian 03 software package [64]. All calculations used in the evaluation of the relative stabilities of the compounds, ionization energies and electronic affinities were performed with the Gaussian-3 (G3) composite method [65]. The ionization energies and electronic affinities obtained in this work, at T = 298.15 K, with G3, used for calculating the chemical hardness of a molecule ((Ionization energy – electronic affinity)/2 [32]), are

Experimental enthalpy of formation, in the crystalline phase

Detailed results of each combustion experiment are presented in tables S3–S5 of the Supplementary information, where Δcuo is the standard massic energy of combustion, ΔU∑ is the energy correction to the standard state, derived as recommended for organic compounds containing C H N and O [60], and ΔU(IBP) is the internal energy associated with the isothermal bomb process, calculated using expression (3).ΔU(IBP)=-ε(calor)corr.·ΔTad+(Ti-298.15K)·εi+(298.15K-Ti-ΔTad)·εf+ΔU(ign).

The adiabatic

Experimental and computational relative enthalpic stabilities

The values of the experimental enthalpy of formation, in the gaseous phase, for 2-amino-4-methylpyrimidine, 2-amino-4,6-dimethylpyrimidine and 4-amino-2,6-dimethylpyrimidine, derived from the experimental results, are presented in table 7.

In order to verify the internal consistency of the results, the experimental relative enthalpic stabilities of the compounds were compared with those calculated computationally, using G3 theory and the reactions I, II and III presented in scheme 1. Reactions I

Final remarks

Considering the NICS, Shannon aromaticity, QTAIḾs electronic density and Laplacian of the electronic density of the ring critical points, HOMO–LUMO energy gap, chemical hardness and UV–Vis π → π∗ wavelength transitions, there seems to be a real differentiation in the aromaticity of benzene, pyridine and pyrimidine. This decrease of aromaticity from benzene to pyrimidine finds support in literature [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], according to the values of

Acknowledgments

Thanks are due to Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal and to FEDER for financial support to Centro de Investigação em Química, University of Porto. T.L.P.G. thanks FCT and the European Social Fund (ESF) under the Community Support Framework (CSF) for the award of the research grant with reference SFRH/BD/62231/2009.

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