Aromaticity and stability going in opposite directions: An energetic, structural, magnetic and electronic study of aminopyrimidines

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Abstract

The relation between molecular energetics and aromaticity was investigated for the interaction between the amino functional group and the nitrogen atoms of the pyridine and pyrimidine rings, using experimental thermodynamic techniques and computational geometries, enthalpies, chemical shifts, atomic charges and the Quantum Theory of Atoms in Molecules. 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were studied by static bomb combustion calorimetry and Knudsen effusion technique. The derived gaseous-phase enthalpies of formation together with the enthalpies of formation of the three isomers of aminopyridine reported in the literature, were compared with the calculated computationally ones and extended to other diamino- and triaminopyrimidine isomers using the MP2/6-311++G(d,p) level of theory.

The results were analyzed in terms of enthalpy of interaction between substituents and, due to the absence of meaningful stereochemical hindrance, strong inductive effects, or intramolecular hydrogen bonds according to QTAIM results, the resonance electron delocalization plays an almost exclusive role in the very exothermic enthalpies obtained. Therefore, this enthalpy of interaction was used as an experimental energetic measure of resonance effects and analyzed in terms of aromaticity. It was found that more conjugation between substituents means less aromaticity according to the magnetic (NICS) and electronic (Shannon) criteria, but more aromaticity according to the geometric (HOMA) criterion.

Highlights

ΔfHmo (cr) of 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were obtained by combustion calorimetry. ► Sublimation thermodynamics of the compounds was studied by Knudsen effusion technique. ► Ab initio computational calculations were performed for mono-, di- and triaminopyrimidine isomers. ► Molecular energetics were correlated with several criteria of aromaticity. ► The influence of intramolecular hydrogen bonds was explored.

Introduction

Aromaticity is the cyclic electron delocalization that provides an additional enthalpic stability to organic compounds [1]. This cyclic electron delocalization is also reflected in the structure, electronic and magnetic behaviour of the molecules. It is difficult to obtain the resonance enthalpy of substituted aromatic rings from acyclic reference compounds, but it is possible to calculate the enthalpy of interaction between substituents from simple isodesmic reactions and correlate it with other aromaticity measures. In this work, the interaction between the amino group and the nitrogen atoms of the pyridine and pyrimidine rings was studied by evaluating energetic, structural and magnetic properties. Since an amino functional group is a σ electron acceptor and π electron donor, and the nitrogen atoms of the ring will behave as σ and π electron acceptors, both will conjugate and increase the stability of the compound. Since there are not any obvious stereochemical effects between the amino group and the nitrogen atoms of the ring and the inductive effect between these two groups is most likely to have a small energetic impact, as both rely on the electronegativity of the same atom, conjugation is expected to be the most important feature of these molecules. It will also be shown that intramolecular hydrogen bonds between the amino group and the nitrogen atoms of the ring [2] do not play an important role on the enthalpic stability of these compounds. The absence of meaningful energetic effects, other than resonance, together with the very exothermic enthalpies of interaction between the amino groups and the nitrogen atoms of the ring observed for these compounds, make aminopyridines and aminopyrimidines ideal molecules to calculate the resonance enthalpy from the isodesmic reactions selected in this work. Moreover, azines in general have interesting aromatic and energetic properties [3], and aminopyrimidines in particular constitute important moieties in current research of drug intermediaries [4], biologically active compounds [5], [6], [7], [8], novel class of electronic polymers [9] and exhibit favourable non-covalent interactions with anions [10], [11] and acid base behaviour to promote enzyme catalysis [12], [13].

In this paper, the enthalpies of formation, in the gaseous phase, of 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine (figure 1) were derived from the results obtained with static bomb combustion calorimetry and Knudsen effusion technique. From the obtained enthalpies of formation for these two compounds and the ones available in the literature for aminopyridine isomers [14], the enthalpy of interaction between substituents was calculated. This parameter was then correlated with the decrease of electron density from the amino donor groups and the increase in electron density of the withdrawing nitrogen atoms of the ring, and a well establish measure of aromaticity, the Nucleus Independent Chemical Shifts (NICS) [15].

The enthalpies of formation of aminopyridine isomers [14], 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were also calculated computationally using MP2 level of theory [16] with the 6-311++G(d,p) basis set. The results were compared with the experimental values. The computational study was extended to the other diamino- and triaminopyrimidine isomers and the results were interpreted in terms of aromaticity according to NICS [15], HOMA [17], [18], and Shannon aromaticity [19].

In the Nucleus Independent Chemical Shifts criterion of aromaticity [15], a virtual chemical shift with the reverse sign is computed at the geometrical centre of the ring or 1 Å above it [20]. The chemical shift obtained is the consequence of electron delocalization in the cyclic ring and, hence, aromaticity. Rings with more negative chemical shifts, caused by enhanced diatropic ring currents, are said to be more aromatic. Lima et al. [21] pointed out a tendency for the more conjugated and stable aminomethylbenzoic acid isomers to be less aromatic according to NICS. This observation will be tested for our system, in which stereochemical hindrance, intramolecular hydrogen bonds, dihedral angles and inductive effects play a less decisive role on the enthalpic stability of the compounds and a dependence between higher stability, due to more extensive π-electron delocalization, and less aromaticity can be obtained. This observation will also be tested for other aromaticity measures (HOMA and Shannon aromaticity) in order to verify if it is a deficiency of the NICS criterion of aromaticity for some type of systems or a marked tendency which can be observed by more than one measure of aromaticity. This study will also contribute understanding to “what extent can aromaticity be defined uniquely” [22] and to identify the regions in which the energetic, geometric, electronic and magnetic descriptors of aromaticity do not have the same tendency.

The Harmonic Oscillator Model of Aromaticity (HOMA) [17], [18] evaluates the effect of electronic delocalization on the geometry of a ring. Benzene is taken as the reference molecule for which aromaticity is optimal. Then two sources for decrease of aromaticity are calculated, the bond length alternation (GEO) and the mean bond length (EN). In benzene, all ring bonds have the same length, but as substitutions are introduced to obtain a heterocyclic ring or a functional benzenic derivative, the bond length alternation may increase, meaning that the deviation of the bond lengths from the mean value increases and the ring becomes less aromatic than benzene. This is the geometric contribution to de-aromatization. On the other hand, as the bonds elongate and became weaker, the aromaticity of the rings also decreases, and this is the energetic contribution to de-aromatization. Majerz and Dziembowska [23], recently, have shown that intramolecular hydrogen bonds, steric effects and π-electron delocalization strongly influences the HOMA values. In this study, besides these effects, it will be shown that symmetry can also have a biased influence on the evaluation of aromaticity by this criterion and, to the best of our knowledge this has not yet been spotted in other studies.

Recently, Noorizadeh and Shakerzadeh [19] introduced a method for measuring aromaticity based on the electronic properties of the ring, using the Shannon definition of entropy [24]. It is based on the probability of the electronic charge distribution and uses the charge density calculated by the Quantum Theory of Atoms in Molecules (QTAIM). Higher values calculated by Shannon aromaticity mean that the ring became less aromatic [19], [25]. This work is one of the first studies to test this observation considering substituent effects. The results will be compared with the energetic properties and aromaticity measured by the magnetic and geometric criteria.

Section snippets

Compounds and purification

The 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were obtained commercially. Further details are presented in table 1. 2,4-Diaminopyrimidine was sublimed twice (p  1 Pa, T  395 K); and 2,4,6-triaminopyrimidine was sublimed once (p  1 Pa, T  440 K), washed twice in boiling ethyl ethanoate and twice in boiling propanone, and, finally, sublimed three times in the same previous conditions, rejecting about 1/5 of the compound corresponding to the less volatile phase.

The purity of the samples of

Computational details

The computational calculations were performed using the Gaussian 03 software package [38]. The geometry optimizations and the fundamental vibrational frequencies calculations were performed using the second-order Møller–Plesset perturbation theory (MP2) [16] with the 6-311++G(d,p) basis set. From the relative stabilities obtained, isodesmic reactions were used to calculate the standard enthalpies of formation of all monoaminopyridine, diaminopyrimidine and triaminopyrimidine isomers, at T = 298.15

Experimental enthalpies of formation

Detailed results of each combustion experiment, for 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine, are presented in tables S2 and S3 of the supporting information, where Δcuo is the standard massic energy of combustion, ΔU is the energy correction to the standard state, derived as recommended by Hubbard et al. for organic compounds containing C, H, N, O [35], and ΔU(IBP) is the internal energy associated with the isothermal bomb process, calculated using the following expression:ΔU(IBP)=-ε

Enthalpies of formation, in the gaseous phase

The experimental standard (p° = 0.1 MPa) molar enthalpies of formation, in the gaseous phase, at T = 298.15 K, of 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine are registered in table 7, and were obtained by combining the values of the standard molar enthalpies of formation in the crystal phase obtained by static bomb calorimetry (table 3) with the values of the standard enthalpy of sublimation derived from the Knudsen effusion technique (table 5).

The standard molar enthalpies of formation, in

Final remarks

The enthalpies of formation obtained in this work for 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were analyzed in terms of conjugation between the amino groups and the nitrogen atoms of the ring. The enthalpy of interaction between substituents for the three aminopyridine isomers, 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine was correlated with conjugation, according the atomic charges of the nitrogen atoms of the amino groups and the charges of the nitrogen atoms of the ring. As

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., I.M.R. and A.F.L.O.M.S. thank FCT and the European Social Fund (ESF) under the Community Support Framework (CSF) for the award of the research grants with references SFRH/BD/62231/2009, SFRH/BD/61915/2009 and SFRH/BPD/41601/2007, respectively.

References (62)

  • J. Bickerton et al.

    J. Chem. Thermodyn.

    (1984)
  • T.M. Krygowski et al.

    Tetrahedron

    (1996)
  • S. Noorizadeh et al.

    Comput. Theoretical Chem.

    (2011)
  • M.A.V. Ribeiro da Silva et al.

    J. Chem. Thermodyn.

    (1984)
  • A.T. Hu et al.

    J. Chem. Thermodyn.

    (1972)
  • M.A.V. Ribeiro da Silva et al.

    J. Chem. Thermyn.

    (2006)
  • R.D. Chirico et al.

    J. Chem. Thermodyn.

    (2010)
  • R.D. Chirico et al.

    J. Chem. Thermodyn.

    (2010)
  • W.V. Steele et al.

    J. Chem. Thermodyn.

    (1989)
  • M.J. van Bommel et al.

    J. Chem. Thermodyn.

    (1988)
  • R.D. Chirico et al.

    J. Chem. Thermodyn.

    (2007)
  • Q. Shi et al.

    J. Chem. Thermodyn.

    (2006)
  • Q. Shi et al.

    Thermochim. Acta

    (2007)
  • M.I. Fernández et al.

    Chem. Phys. Lett.

    (2006)
  • E.N. Baker et al.

    Prog. Biophys. Molec. Biol.

    (1984)
  • I.V. Minkin

    Pure Appl. Chem.

    (1999)
  • D.R. Borst et al.

    J. Phys. Chem. A

    (2002)
  • Y. Wang et al.

    Org. Lett.

    (2010)
  • M. Güllü et al.

    Eur. J. Org. Chem.

    (2010)
  • U. Lucking et al.

    Chem. Med. Chem.

    (2007)
  • A. Marchal et al.

    Eur. J. Org. Chem.

    (2010)
  • T. Kamenecka et al.

    J. Med. Chem.

    (2010)
  • S. Mathieu et al.

    J. Med. Chem.

    (2012)
  • I. Stoll et al.

    Chem. Mater.

    (2010)
  • A. García-Raso et al.

    Crystal Growth Des.

    (2009)
  • W.V. Rossom et al.

    J. Org. Chem.

    (2012)
  • A. Balakrishnan et al.

    J. Am. Chem. Soc.

    (2012)
  • A. Balakrishnan et al.

    J. Am. Chem. Soc.

    (2012)
  • P.V.R. Schleyer et al.

    J. Am. Chem. Soc.

    (1996)
  • C. Møller et al.

    Phys. Rev.

    (1934)
  • T.M. Krygowski

    J. Chem. Inf. Comput. Sci.

    (1993)
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