Thermochemical study of dichloromethylpyrimidine isomers

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Highlights

Abstract

The standard (po = 0.1 MPa) molar enthalpies of formation in the condensed phase, ΔfHmo, of 2,4-dichloro-5-methylpyrimidine, 2,4-dichloro-6-methylpyrimidine, 4,6-dichloro-2-methylpyrimidine and 4,6-dichloro-5-methylpyrimidine were derived from the standard molar energies of combustion, ΔcUmo, in oxygen, to yield CO2 (g), N2 (g) and HCl·600H2O (l), at T = 298.15 K, measured by rotating bomb combustion calorimetry. The standard molar enthalpies of vaporization or sublimation, Δcr,lgHmo, for these compounds, at T = 298.15 K were determined by high temperature Calvet microcalorimetry. Combining these values, the following enthalpies of formation in the gas phase, at T = 298.15 K, were then derived: 2,4-dichloro-5-methylpyrimidine, (79.6 ± 4.1) kJ mol−1, 2,4-dichloro-6-methylpyrimidine, (70.5 ± 3.0) kJ mol−1, 4,6-dichloro-2-methylpyrimidine, (68.7 ± 3.3) kJ mol−1, and 4,6-dichloro-5-methylpyrimidine, (78.1 ± 2.5) kJ mol−1. The gas-phase enthalpies of formation were also estimated by G3 theoretical calculations, which were extended to the computation of gas-phase enthalpies of formation of the other dichloromethylpyrimidine isomers, namely, 2,5-dichloro-4-methylpyrimidine, 4,5-dichloro-2-methylpyrimidine and 4,5-dichloro-6-methylpyrimidine, whose experimental study was not performed.

Introduction

Pyrimidine is a six-membered heterocyclic molecule presenting two nitrogen atoms at positions 1 and 3 in the ring, whose great interest is due to the presence of this diazine in many natural and non-natural products, which, frequently, exhibit important biological activities and useful pharmacological applications [1], [2]. As an example, it is possible to refer three types of nucleobases, cytosine, thymine, and uracil, which are pyrimidine derivatives and are also constituents of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).

The literature review indicated that the pyrimidine nucleus is embedded in a large number of alkaloids, in different drugs, antibiotics, antitumor, antimicrobial, cardiovascular, antiparkinsonian agents, [3], [4], [5], [6], [7], [8], [9], [10], and in agrochemicals, fungicides and herbicidal [10], [11], [12]. Pyrimidine skeleton is found in vitamins like thiamine (vitamin B1), riboflavin (vitamin B2) and folic acid (vitamin B9) [10], [13].

Pyrimidine derivatives containing amino and chloro substituents have been used recently in more directed clinical studies: the 5-amino-2,4-dichloropyrimidine has been employed in the synthesis of piperidine-4-yl-aminopyrimidine derivatives, which are HIV-1 reverse transcriptase inhibitors [14]. On the other hand, 2,4-dichloro-5-(2-chloroethyl)pyrimidine was evaluated for cytostatic activity against human malignant tumor cell lines: acute lymphoblastic leukemia, colon carcinoma, breast carcinoma and lung carcinoma [15].

Due to the relevance of the pyrimidine derivatives in such a wide range of applications, the knowledge of their thermodynamic properties is important in order to develop energetic–structure–reactivity relationships and inherent characterization of the chemical behavior of such species. Recently, we have been involved in an extensive research project on the thermodynamic properties of pyrimidines [16], [17], [18], [19], [20], cytosine [21], uracil [22], [23], [24], [25], [26], [27], [28] thiouracil [29], [30] and barbituric acid derivatives [31]. In this context, the present work complements the previous ones and reports the standard (po = 0.1 MPa) molar enthalpies of formation, at T = 298.15 K, of four dichloromethyl substituted pyrimidines: 2,4-dichloro-5-methylpyrimidine, 2,4-dichloro-6-methylpyrimidine, 4,6-dichloro-2-methylpyrimidine and 4,6-dichloro-5-methylpyrimidine. These values were calculated from the standard molar enthalpies of formation, in the crystalline phase, obtained by rotating bomb combustion calorimetry, and from their standard molar enthalpies of sublimation, determined by Calvet microcalorimetry. Additionally, computational thermochemistry was employed to calculate the gas-phase standard molar enthalpies of formation of all the dichlorometylpyrimidine isomers (presented in Fig. 1) using the G3 composite quantum chemical method, together with appropriate isodesmic or homodesmotic reactions.

Section snippets

Compounds and purity control

The compounds, 2,4-dichloro-5-methylpyrimidine, (2,4-dCl-5-MePyr), [CAS 1780-31-0], 2,4-dichloro-6-methylpyrimidine, (2,4-dCl-6-MePyr), [CAS 5424-21-5], 4,6-dichloro-2-methylpyrimidine, (4,6-dCl-2-MePyr), [CAS 1780-26-3] and 4,6-dichloro-5-methylpyrimidine, (4,6-dCl-5-MePyr), [CAS 4316-97-6] were obtained commercially from Aldrich Chemical Co. The liquid 2,4-dichloro-5-methylpyrimidine was purified by repeated distillation under reduced pressure and the crystalline compounds

Computational details

All the theoretical calculations have been performed with the G3 composite method [55]. In this method, the geometries are obtained from second-order perturbation theory [MP2(FU)/6-31G(d)] and the final accurate molecular electronic energy is computed from a proper composition of the energies obtained from a series of very accurate single-point energy calculations at the second-order Moller–Plesset (MP2), fourth-order Moller–Plesset (MP4) and quadratic configuration interaction [QCISD(T)]

Experimental results

Table 2 reports the results for one typical combustion experiment of each studied compound, where Δm(H2O) is the deviation of the mass of water added to the calorimeter from 5222.5 g, the mass assigned to εcal, ΔUΣ is the correction to the standard state and the remaining terms are as previously defined [41], [49], [50]. Detailed values of each combustion experiment performed for each studied compound are given in Tables S1–S4 in the Supporting information.

The values of the internal energy

Computational results and discussion

To achieve highly accurate thermochemical predictions of energies of reactions it is essential to choose an appropriate set of chemical reactions wherein the correlation errors inherent in the calculation of the energies of reactants and products are likely to nearly cancel. Isodesmic reactions, that is, reactions in which the number of any formal type of bond is conserved and only the relationships among the bonds are altered, fit this description. For the dichloromethylpyrimidines we used the

Acknowledgments

Thanks are due to Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal, for the financial support to Project UID/QUI/0081/2013 and to FEDER (COMPETE 2020) for the financial support to Project POCI-01-0145-FEDER-006980 and to Programa Ciência 2008. P. Szterner thanks Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal for the award of the post-doctoral fellowship (SFRH/BPD/33863/2009).

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