From 2,4-Dimethoxypyrimidine to 1,3-Dimethyluracil: Isomerization

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From 2,4-Dimethoxypyrimidine to 1,3-Dimethyluracil: Isomerization and Hydrogenation Enthalpies and Noncovalent Interactions Tiago L. P. Galvaõ , Maria D. M. C. Ribeiro da Silva,* and Manuel A. V. Ribeiro da Silva Centro de Investigaçaõ em Química, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre, 687, P-4169-007 Porto, Portugal S Supporting Information *

ABSTRACT: An enthalpic value for the N-methyllactam/O-methyllactim isomerization, in the gaseous phase, is reported in this work for the conversion between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil. For this purpose, the enthalpy of formation of 2,4-dimethoxypyrimidine, in the gaseous phase, was obtained experimentally combining results from combustion calorimetry and Calvet microcalorimetry, and the enthalpy of formation of 1,3-dimethyluracil, in the gaseous phase, reported previously in the literature, is also discussed. The enthalpy of hydrogenation of 1,3dimethyluracil is compared with the enthalpy of hydrogenation of uracil and interpreted in terms of aromaticity, considering the influence of the hyperconjugation and the hindrance of the solvation of the ring by the methyl groups. The enthalpy of sublimation of 2,4-dimethoxypyrimidine was obtained combining Calvet microcalorimetry and differential scanning calorimetry results. This enthalpy is compared with the enthalpy of sublimation of 1,3-dimethyluracil previously reported in the literature and analyzed herein. From the interplay between the experimental results and the theoretical simulation of dimers of these molecules, the influence of stereochemical hindrance on the in-plane intermolecular contacts and aromaticity on the π···π interactions is analyzed.

1. INTRODUCTION 1,3-Dimethyluracil (I, Figure 1) is a prototype for alkylated uracil and, hence, nucleobases, for which its electronic

lactim isomerization, which was shown to happen under certain conditions14 and to play an important role on the synthesis of uracil derivatives.15−17 The tautomeric equilibrium18−25 and structure26−29 of uracil is still a subject of investigation and its dienolic form, 2,4-dihydroxypyrimidine, is not observed in the gaseous phase,26−29 which makes 2,4-dimethoxypyrimidine ideal to mimic certain characteristics of this compound. In a previous study,30 the enthalpy of hydrogenation of uracil was used as an experimental thermodynamic measure of aromaticity, which allowed a more coherent interpretation of the aromaticity of uracil according to other criteria. The degree of aromaticity obtained for uracil was interpreted in terms of the contribution of the more aromatic zwitterionic resonance structures. In this work, the enthalpy of hydrogenation of 1,3dimethyluracil is calculated computationally and the effect of the methyl groups on the stability of the zwitterionic resonance structures will be analyzed. As the zwitterionic resonance structures are more polar than the neutral structure, uracil was found to be more aromatic in the aqueous phase.30 Herein, the effects of solvation on a pyrimidine ring less accessible by the solvent due to the methyl groups will be investigated. The enthalpy of sublimation of 5,6-dihydrouracil30 was found to be lower than that of uracil, which was attributed to more favorable resonance assisted hydrogen bonds of uracil.

Figure 1. Isomerization equilibrium between 1,3-dimethyluracil (I) and 2,4-dimethoxypyrimidine (II).

spectra,1,2 electrophilic properties,3 dimerization,4−6 acidity,7,8 reactivity,9,10 and kinetics of the molecular movements11 have been recently investigated. In this work, the enthalpy of formation, in the gaseous phase, of 2,4-dimethoxypyrimidine (II, Figure 1) was obtained from combustion calorimetry and Calvet microcalorimetry measurements, and, considering the enthalpy of formation of 1,3-dimethyluracil,12,13 the enthalpy of isomerization between both compounds was calculated. This enthalpy of isomerization is compared with another literature value14 and can stand as a reference for the benchmarking of theoretical methods to study the N-methyllactam/O-methyl© XXXX American Chemical Society

Received: April 8, 2014 Revised: June 15, 2014

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dx.doi.org/10.1021/jp503412u | J. Phys. Chem. A XXXX, XXX, XXX−XXX

The Journal of Physical Chemistry A

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difference on the discharge of a capacitor (1400 μF) through a platinum ignition wire (ϕ = 0.05 mm, Goodfellow, mass fraction 0.9999). The cotton thread fuse (empirical formula CH1.686O0.843) has a standard massic energy of combustion assigned to Δcu° = −16 240 J·g−1,42 a value previously confirmed in our Laboratory. Melinex was used as auxiliary in the combustion experiments. The energy corrections for the HNO3 formed were based on ΔfU°m (HNO3, aq, 0.1 mol·dm−3) = −59.7 kJ·mol−1.44 All the necessary weighings for the combustion experiments were made in a Mettler Toledo 245 balance with a sensitivity of ±10−5 g. An estimated pressure coefficient of massic energy, (∂u/∂p)T = −0.2 J·g−1·MPa−1, at T = 298.15 K, was assumed for the studied compounds.45 The standard-state corrections, ΔUΣ, and the heat capacities of the bomb contents, εi and εf, were calculated by the procedure given by Hubbard et al.46 using the enthalpies of solution of CO2 and O2 in pure water reported by Hu et al.47 2.3. Calvet Microcalorimetry. The standard molar enthalpy of vaporization of 2,4-dimethoxypyrimidine was measured by the “vacuum sublimation” drop microcalorimetric technique of Skinner et al.48 using the apparatus described by Santos et al.49 The samples of approximately 5−8 mg contained in a thin glass capillary and a blank reference capillary were simultaneously dropped, at room temperature, in the respective twin calorimetric cells, held at a predefined temperature of 340 K. The thermal corrections for the differences in the mass of both glass capillary tubes and for the different sensibilities of the two calorimetric cells were determined in separated experiments and were minimized, as far as possible, by dropping tubes of near equal mass into each twin calorimeter cell.49 The observed standard molar enthalpy of vaporization, Δg,T l,298.15KH° m, was corrected to T = 298.15 K using the values of ΔT298.15KHm ° (g) calculated computationally at the B3LYP/6311+G(2df,p) level of theory, as described in section 3 (Computational Details). The microcalorimeter was calibrated by measuring the reported standard molar enthalpy of vaporization of undecane (56.58 ± 0.57) kJ·mol−1,50 available commercially from Aldrich Chemical Co. [CAS 1120-21-4]. The calibration constant, k, of the calorimeter was k(T=478 K) = (1.0435 ± 0.0039), the uncertainty quoted being the standard deviation of the mean of six experiments. All the necessary weights were performed on a Mettler CH-8608 analytical balance with a sensitivity of ±(1 × 10−7) g. 2.4. Differential Scanning Calorimetry (DSC). The temperature and standard molar enthalpy of fusion of 2,4dimethoxypyrimidine were measured in a commercial power compensation differential scanning calorimeter, SETARAM DSC 141, using samples of about 8 mg, sealed in aluminum crucibles with a heating rate of 3.3 × 10−2 K·s−1. The temperature and the power scale were calibrated by measuring the temperatures and enthalpies of fusion of the following reference materials,50 available commercially from Aldrich Chemical Co.: o-terphenyl [CAS 84-15-1], benzoic acid [CAS 65-85-0], indium [CAS 7440-74-6], triphenylene [CAS 217-594], tin [CAS 7440-31-5], perylene [CAS 198-55-0], lead [CAS 7439-92-1], and zinc [CAS 7440-66-6]. At least four experiments were performed for each reference material.

Surprisingly, 5,6-dihydrouracil had a higher binding energy for the staked dimer than uracil, which was attributed to C−H···π short contacts.31−33 This conclusion also found support in the fact that cyclohexene has a more favorable π···π stacking dimerization energy than benzene.34 2,4-Dimethoxypyrimidine is a liquid at standard pressure and ambient temperature, whereas 1,3-dimethyluracil is a low-volatile solid.12,13 Since both have very different aromatic properties, by simulating the in-plane and π···π stacking dimers that resemble the crystal structure of 1,3-dimethyluracil,35 we will check if the Bloom and Wheeler findings,36 which correlate lower aromaticity with stronger stacking, can be used to understand the enthalpy of sublimation of 1,3-dimethyluracil12,13 and 2,4-dimethoxypyrimidine obtained in this work.

2. EXPERIMENTAL SECTION 2.1. Compounds and Purity Control. 2,4-Dimethoxypyrimidine [CAS no. 4562-27-0] was obtained commercially from Aldrich Chemical Co. with an accessed minimum purity of 0.97. It was purified by distillation under reduced pressure (p ≈ 1 Pa; T ≈ 298 K), rejecting half of the compound corresponding to the more volatile fraction. The purity of the sample of 2,4-dimethoxypyrimidine used for the calorimetric and effusion measurements was checked by gas−liquid chromatography (Agilent 4890D gas chromatograph HP-5 column, cross-linked, 5% diphenyl and 95% dimethylpolysiloxane) using nitrogen as carrier gas (30 cm3·min−1 flow rate) as being 0.9998, with the following conditions: T(injector) = 543 K; T(detector) = 543 K; T(initial period) = 303 K during 1 min; 5 K·min−1 heating rate; and T(final period) = 523 K during 10 min. The compound was dissolved in methanol for the analysis. The specific density used to calculate the true mass from the apparent mass in air was 1.1501 g·cm−337 and the relative atomic mass was 140.1399 g·mol−1.38 After distillation the compound was stored under dry nitrogen atmosphere. 2.2. Combustion Calorimetry. The standard (p° = 0.1 MPa) massic energy of combustion of 2,4-dimethoxypyrimidine was determined using an isoperibol static bomb calorimeter previously described.39,40 The calorimeter was used with a stainless steel twin-valve bomb (type 1108, Parr Instrument Co.) of internal volume of 0.342 dm3. Calorimeter temperatures were measured with an uncertainty within the bounds of ±10−4 K, at time intervals of 10 s, using a quartz thermometer (Hewlett-Packard HP 2804A) interfaced to a computer programmed to calculate the adiabatic temperature change. In the fore, main, and after periods, 125, 100, and 125 temperature readings were taken, respectively. Data acquisition and control of the calorimeter was performed using the program LABTERMO.41 The calorimetric system was calibrated, according to the procedure suggested by Coops et al.,42 by the combustion of benzoic acid (NIST Standard Reference Material 39j), having a massic energy of combustion, under bomb conditions, of Δcu = −(26 434 ± 3) J·g−1.43 From six calibration experiments, the energy equivalent of the calorimeter obtained was ε(calor) = (15 987.8 ± 0.8) J·K−1 (quoted uncertainty refers to the standard deviation of the mean), for an average mass of water added to the calorimeter of 3119.6 g. The compound was burned enclosed in polyethylene bags, in oxygen, at p = 3.04 MPa, with 1.00 cm3 of deionized water added to the bomb. The value of the standard massic energy of combustion of polyethylene was Δcu° = −(46 282.4 ± 4.8) J·g−1, measured in our laboratory. The electrical energy for the ignition was determined from the change in potential

3. COMPUTATIONAL DETAILS The computational calculations were performed using the Gaussian 09 software package51 for all calculations. The B



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enthalpies, at T = 298.15 K, used for the analysis of the results were calculated using the Complete Basis Set APNO method (CBS-APNO)52 and the Gaussian-3 (G3) composite method.53 To simulate the influence of water, the Polarizable Continuum Model as a self-consistent reaction field was used.54 All molecules used in the calculation of the dimerization energies were optimized using density functional theory (DFT) with the hybrid functional of Truhlar and Zhao (M06-2X)55 and the 6-311++G(d,p) basis set. The geometry optimizations were corrected for basis set superposition error using the counterpoise correction.56,57 In order to estimate the ΔT298.15KHm°(g) needed for the correction of the enthalpic results obtained by Calvet microcalorimetry, all the geometry optimizations and vibrational frequencies calculations were performed using DFT with the hybrid exchange correlation functional (B3LYP)58 with the 6-311+G(2df,p) basis set and using the scale factor for the fundamental frequencies determined by Merrick et al. (0.9938).59

combustion, and the standard molar enthalpy of formation, ΔfHm°(l), in the liquid phase, at T = 298.15 K. The uncertainty assigned to the standard molar energy of combustion corresponds to twice the overall standard deviation of the mean and includes the contributions from the calibration with benzoic acid.60 To derive ΔfHm°(1) from ΔcHm°(1), the following standard molar enthalpies of formation, at T = 298.15 K, were used: ΔfHm°(CO2,g) = −(393.51 ± 0.13) kJ·mol−1,61 ΔfHm°(H2O,l) = −(285.830 ± 0.042) kJ·mol−1.61 4.2. Enthalpy of Vaporization. Table 2 presents the standard molar enthalpy of vaporization obtained by Calvet microcalorimetry. The standard molar enthalpy of vaporization, at T = 298.15 K, was calculated from the value measured at the predefined temperature, T, using ΔT298.15KHm°(g) calculated by computationally at the B3LYP/6-311+G(2df,p) level of theory. The uncertainty of Δg,T 298.15KHm° was calculated as the standard deviation of the mean of six individual experiments and the uncertainty of Δg1Hm°(298.15K) is twice the value derived considering the uncertainty of Δg,T 298.15KHm°, the calibration constant and the reference value for the vaporization of undecane. 4.3. Enthalpy and Entropy of Fusion. The temperature and enthalpy of fusion of 2,4-dimethoxypyrimidine is reported in Table 3, as a mean of four experiments, where the uncertainty quoted is twice the standard deviation of the mean. The standard molar enthalpy of fusion, at T = 298.15 K, was calculated using the following equation:

4. RESULTS 4.1. Experimental Enthalpy of Formation, in the Liquid Phase. Detailed results of each combustion experiment of 2,4-dimethoxypyrimidine are presented in Table S2 of the Supporting Information, where Δcu° is the standard massic energy of combustion, ΔUΣ is the energy correction to the standard state, derived as recommended for organic compounds containing C, H, N, and O,46 and ΔU(IBP) is the internal energy associated with the isothermal bomb process, calculated using the following expression:

Δcrl H(T ) = Δcrl H(Tfus) + Δcrl C °p ,m(T − Tfus)

The calculated standard molar entropy of fusion, at T = 298.15 K, was derived for each compound by using eq 4. All calculated values are listed in Table 3.

ΔU (IBP) = −ε(calor)corr ΔTad + (Ti − 298.15K)εi + (298.15K − Ti − ΔTad)εf + ΔU (ign) (1)

Δcrl S(T ) =

where the adiabatic temperature rise, ΔTad, is the calorimeter temperature change corrected for the heat exchange and work of stirring, and ε(calor)corr = ε(calor) + cp(H2O,l)Δm(H2O,l), where Δm(H2O) is the deviation of the mass of water added to the calorimeter from 3119.6 g. The remaining terms are as previously defined.46 The results refer to the combustion reaction described by the following equation:

+ (11.11 × HBN)

Table 1. Derived Standard (p° = 0.1 MPa) Molar Values for 2,4-Dimethoxypyrimidine, in the Liquid Phase, at T = 298.15 K 3246.4 ± 1.3

3246.4 ± 1.3

258.0 ± 1.5

(5)

where σ is the symmetry number (σ = 1), HBN is the number of hydrogen-bondable H atoms (HBN = 0), and τ is the molecular flexibility number (τ = 1) calculated according to the equation of Dannenfelser and Yalkowsky,63 τ = SP3 + (0.5 × SP2) + 0.5 × (RING − 1), where SP3 and SP2 are the number of independent nonring and nonterminal sp3 and sp2 atoms in the molecule (SP3 = 0 and SP2 = 2), respectively, and RING is the number of single or fused ring systems (RING = 1).

(2)

−ΔfHm°(1)/kJ·mol−1

(4)

Δcr l C p°,m = 33.08 + (2.66τ ) − 19.50 log(σ )

In Table 1 is registered the derived standard (p° = 0.1 MPa) molar energy, Δ c U m °(l), and enthalpy, Δ c H m °(1), of

−ΔcHm°(1)/kJ·mol−1

⎛ T ⎞ Δcrl H(Tfus) + Δcrl C °p ,m ln⎜ ⎟ Tfus ⎝ Tfus ⎠

In both equations, ΔlcrCp,m ° (35.7±13.4) J·K−1·mol−1, estimated by the equation of Wu and Yalkowsky62

C6H8O2 N2(l) + 7O2 (g) → 6CO2 (g) + 4H 2O(l) + N2(g)

−ΔcUm°(1)/kJ·mol−1

(3)

5. DISCUSSION 5.1. Enthalpy of Isomerization. In Table 4 is presented the enthalpy of formation in the gaseous phase for 2,4dimethoxypyrimidine, calculated combining the enthalpy of

Table 2. Standard (p° = 0.1 MPa) Molar Enthalpies Δg1Hm°, of Vaporization, at T = 298.15 K, of 2,4-Dimethoxypyrimidine Obtained by Calvet Microcalorimetry T/K

−1 Δg,T 1,298.15KHm°/kJ·mol

ΔT298.15KHm°(g)/kJ·mol−1

Δg1Hm°(298.15K)/kJ·mol−1

339.6

66.78 ± 0.17

6.50

60.3 ± 1.3

C



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Table 3. Standard (p° = 0.1 MPa) Molar Enthalpy of Fusion, Δ1crHm°, at the Temperature of Fusion, Tfus, and Molar Enthalpy, Δ1crHm°(298.15K), Entropy, Δ1crSm°(298.15K), and Gibbs Energy of Fusion, Δ1crGm°(298.15K), at T = 298.15 K, for 2,4Dimethoxypyrimidine Tfus/K

Δ1crHm°/kJ·mol−1

Δ1crHm°(298.15K)/kJ·mol−1

Δ1crSm°(298.15K)/kJ·mol−1

Δ1crGm°(298.15K)/kJ·mol−1

279.62 ± 0.14

16.64 ± 0.14

17.3 ± 0.3

61.8 ± 1.0

−1.1 ± 0.4

second enthalpy of isomerization, but not with the first. This might be because the first enthalpy of sublimation of 1,3dimethyluracil was determined with a method that combines a Knudsen effusion cell for measuring the equilibrium vapor pressures in a process that usually lasts a few hours67,68 with Calvet microcalorimetry, more suited to measure enthalpies of vaporization or sublimation during a fast nonequilibrium process.48,49 On the other hand, the quartz resonator results have been shown to provide very accurate enthalpies of vaporization and sublimation.69 It should also be noted that Beak and White14 have also obtained an enthalpy of isomerization between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil (ΔisoHm°(g) = −(159 ± 20) kJ·mol−114), based on the heat of isomerization between both compounds, in the liquid phase, and estimates of heats of vaporization. However, the value obtained by Beak and White is not in agreement with the values calculated in this work from experimental enthalpies of formation, nor with the G3 and CBS-APNO computational methods developed for the calculation of high accuracy molecular energies,52,53 even though the trend found by Beak and White14 is the same as the one found in this work. One explanation for this difference might be the estimated enthalpies of vaporization by Beak and White, used to correct the enthalpy of isomerization from the condensed phase to the gaseous phase. In fact, the value estimated by Beak and White for the enthalpy of vaporization of 2,4-dimethoxypyrimidine, (ΔgcrHm° = (48.1 ± 3.5) kJ· mol−114), differs by (12.2 ± 3.7) kJ·mol−1 from the value measured in this work using Calvet microcalorimetry. 5.2. Is 1,3-Dimethylyuracil More or Less Aromatic than Uracil? The Enthalpy of Hydrogenation. In a previous work,30 the enthalpy of hydrogenation of uracil was obtained experimentally and computationally (Figure 3) and interpreted in terms of aromaticity. It was shown30 that the

Table 4. Standard (p° = 0.1 MPa) Molar Enthalpy of Formation, in the Gaseous Phase, at T = 298.15 K, of 2,4Dimethoxypyrimidine compound

ΔfHm°(g)/kJ·mol−1

2,4-dimethoxypyrimidine

−197.7 ± 2.0a

a

Obtained by combining the enthalpy of formation in the liquid phase (Table 1) and the enthalpy of vaporization (Table 2).

formation in the liquid phase (Table 1) and the enthalpy of vaporization (Table 2). The computational methods G3 and CBS-APNO were tested for the relative stabilities between 2,4-dimethoxypyrimidine (Table 4) and 2- and 4-methoxypyridine,64 using the isodesmic reaction (I) presented in Figure 2. It was found that the values of the enthalpies of reaction are in agreement with the experimental values within the associated uncertainty. In Figure 2 is presented the enthalpy of isomerization between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil. In the calculation of this enthalpy of isomerization, two values for the enthalpy of formation, in the gaseous phase, of 1,3dimethyluracil were used: ΔfHm°(g,1) = −(313.6 ± 1.5) kJ· mol−1 and ΔfHm°(g,2) = −(308.8 ± 2.3) kJ·mol−1. Both values share the enthalpy of formation in the crystalline phase obtained from combustion calorimetry results (ΔfHm°(cr) = −(410.5 ± 0.9) kJ·mol−113), but the first was derived from an enthalpy of sublimation determined using a Calvet microcalorimeter with a Knudsen effusion cell65 incorporated to measure vapor pressures (ΔgcrHm°(1) = (96.9 ± 1.2) kJ· mol−113) and, the second, using a quartz resonator to measure the mass loss of vapor from a Knudsen cell66 (ΔgcrHm°(2) = (101.7 ± 2.1) kJ·mol−112). The theoretical methods applied in the study of this reaction (II), G3 and CBS-APNO, are in agreement within the chemical accuracy (4.2 kJ·mol−1) with the

Figure 2. Experimental and computational enthalpies of reaction used to analyze the results: (I) isodesmic reaction and (II) isomerization reaction between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil. Values in kJ·mol−1. D



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Figure 3. Hydrogenation and enthalpies of hydrogenation of uracil (I) and 1,3-dimethyluracil (II), and main zwitterionic resonance structures of uracil (III) and 1,3-dimethyluracil (IV). Values in kJ·mol−1.

uracil, it is possible to verify that 1,3-dimethyluracil is more aromatic than uracil. If the nitrogen atoms of the ring donate the lone pair to the ring, as indicated by the contribution of the zwitterionic resonance structures (Figure 3), the methyl groups in 1,3-dimethyluracil will compensate by the donation of πelectronic density by hyperconjugation and increase the contribution of the more aromatic zwitterionic resonance forms on the overall structure. The zwitterionic resonance structures, being more polar, are expected to play an increased role when the molecule is placed in a more polar field. For this reason, water solvation effects were also studied for uracil,30 considering implicit (Polarizable Continuum Model (PCM) of solvation), explicit (four explicit water molecules interacting with uracil) and hybrid (water as PCM with four explicit water molecules) solvation models. The enthalpy of hydrogenation of uracil was similar for the three solvation models and was in agreement with the value obtained experimentally, from combustion calorimetry results, for the crystalline phase, which is also influenced by polarity and hydrogen bonds. The enthalpy of hydrogenation calculated with the G3 computational method and the PCM model of solvation gives uracil and 1,3-dimethyluracil to be more aromatic in the aqueous phase, in agreement with the increase of contribution of the zwitterionic resonance structures. However, uracil is 12.2 kJ·mol−1 more aromatic in aqueous solution, whereas 1,3-

enthalpy of hydrogenation of uracil allows to truly evaluate aromaticity and distinguish from enthalpic effects resulting from the inner conjugation of the amide moieties, since this conjugation will be present in both reactants and products of the hydrogenation reaction. Taking benzene and hexene as references for a fully aromatic system and a nonaromatic system, respectively, it was possible to obtain the relative aromaticity of uracil as being 30.0%, which indicates a low aromatic character, but energetically important to understand the physical organic properties of uracil. This was justified in terms of the contribution of the zwitterionic resonance forms (Figure 3) to the structure of uracil, which increase its aromaticity. However, as explained for the tautomeric equilibrium of 2-hydroxypyridine/2-pyridinone and 4-hydroxypyrimidine/4(3H)-pyrimidinone, the zwitterionic resonance structures, overall, are thermodynamically disfavored because of the oxygen lone pair repulsion and also because the nitrogen atom of the ring, which usually behaves as σ and π electron withdrawing, would lose its lone pair.70 From several methods tested, only G3 gave results in agreement with experiment;30 thereby, it was used to obtain the enthalpy of hydrogenation of 1,3-dimethyluracil. As the aromaticity of a compound increases, the relative enthalpic stability in comparison with the hydrogenated form also increases, and the reaction of hydrogenation becomes less exothermic. Comparing the G3 enthalpy of hydrogenation of 1,3-dimethyluracil with that of E



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dimethyluracil is only 7.0 kJ·mol−1. Hence, the effect of polarity is more noticeable for the N−H moieties of uracil than for the N−CH3 moieties of 1,3-dimethyluracil. 5.3. Why is 2,4-Dimethoxypyrimidine a Liquid? 2,4Dimethoxypyrimidine is a liquid at standard pressure and ambient temperature, which shows that the intermolecular interactions in the solid are weak enough for the effect of the entropy of fusion to be preponderant. As a consequence, 2,4dimethoxipyrimidine is favored in the solid−liquid equilibrium at T = 298.15 K (negative standard molar Gibbs energy of fusion, Table 3). On the other hand, 1,3-dimethyluracil is a solid. Combining the enthalpy of vaporization obtained by Calvet microcalorimetry (Table 2) and the enthalpy of fusion obtained by DSC (Table 3), and neglecting the influence of the variation of pressure (from the triple point pressure to p° = 0.1 MPa) on enthalpy, it is possible to obtain an enthalpy of sublimation, ΔcrgHm°, of (77.6 ± 1.3) kJ·mol−1 for 2,4dimethoxypyrimidine, which is (24.1 ± 2.5) kJ·mol−1 lower than that of 1,3-dimethyluracil, ΔgcrHm° = (101.7 ± 2.1) kJ· mol−1.12 To understand this difference, the dimers of both compounds with molecules on the same plane or overlapping (π···π stacking dimer) were simulated computationally (Figure 4). The short contacts and relative positions of the molecules in

are stronger than the O−C(H)3···N ones, probably because of stereochemical reasons, which results in intermolecular interaction distances of 302.1 and 324.7 pm, respectively. After optimization, the parallel π···π stacking dimers end up displaced and facing different directions. The lactam forms are known to be less aromatic than the lactim forms,70 yet 1,3dimethylpyrimidine has a stronger binding energy in the stacking dimer than 2,4-dimethoxypyrimidine, which, according to the conclusions of Bloom and Wheeler,36 makes this an example of “taking aromaticity out of aromatic interactions”.

6. FINAL REMARKS In this work is reported an enthalpic value for N-methyllactam/ O-methyllactim isomerization in the gaseous phase. This enthalpy was derived for the reaction of isomerization between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil and can serve as a reference for the benchmarking of theoretical methods to be applied in the study of similar cases of isomerization equilibrium. The enthalpy of formation of 2,4-dimethoxypyrimidine, in the gaseous phase, which allowed the calculation of the enthalpy of isomerization was obtained in this work by combining results from combustion calorimetry and Calvet microcalorimetry. Moreover, the enthalpy of formation of 1,3dimethyluracil in the gaseous phase, reported previously in the literature, was also discussed in this work. Using the enthalpy of hydrogenation of uracil as a reference, it was possible to verify that 1,3-dimethyluracil is more aromatic than uracil according to this criterion. This result was explained in terms of the π-electron donor effect by hyperconjugation of the methyl groups which increase the contribution to the overall structure of the more aromatic zwitterionic resonance forms. However, when the effect of solvation on the enthalpy of hydrogenation of uracil and 1,3-dimethyluracil was analyzed, it was possible to verify that the methyl groups hinder the effect of solvation in aqueous solution. As a result, the higher aromaticity in aqueous solution, due the increase of the overall contribution of the more aromatic zwitterionic resonance forms, is more noticeable in uracil than in 1,3-dimethyluracil. From the experimental enthalpies of sublimation of 1,3dimethyluracil and 2,4-dimethoxypyrimidine, it was possible to verify that 1,3-dimethyluracil has stronger intermolecular interactions in the crystal lattice than 2,4-dimethoxypyrimine. According to the computational dimerization energies, this can be explained in terms of stereochemical hindrance of the inplane intermolecular contacts of 2,4-dimethoxypyrimidine and the more favorable π···π stacking of the molecules of 1,3dimethyluracil, which gives experimental support to the theoretical conclusions of Bloom and Wheeler36 correlating in certain cases less aromaticity with more favorable π···π stacking. From this work, we can conclude that, with the uracil derivatives in the lactam form, everything related to its contribution to the nucleic acids falls into place: they are more stable, form stronger short contacts in the same plane, and have more favorable π···π stacking interactions than the lactim forms.

Figure 4. Dimerization energies of in-plane and π···π stacking dimers of 2,4-dimethoxypyrimidine (upper) and 1,3-dimethyluracil (lower).

the crystal structure of 1,3-dimethyluracil35 were used as the starting points for the optimizations. In the case of the in-plane dimer of 1,3-dimethyluracil, the methyl group in position 1 of the pyrimidine ring was directed toward the carbonyl group in position 2, whereas in the π···π stacking dimer the molecules were parallel to each other. For the short contacts and relative positions of the molecules in the crystal structure of 2,4dimethoxypyrimidine, as it is a liquid at standard pressure and temperature of 298.15 K and, to the best of our knowledge no crystallographic information is available in the literature, the starting points for the optimizations were chosen after a computational screening of different structures, from which the most stable were selected. In the case of the dimer with the molecules in the same plane of 2,4-dimethoxypyrimidine, the methoxy group in position 2 was directed toward the nitrogen atom in position 1, and in the case of the π···π stacking dimer the molecules were also parallel to each other. Both types of dimers have a more favorable binding energy in 1,3dimethyluracil than in 2,4-dimethoxypyrimidine. For the inplane dimers, this means that the N−C(H)3···O short contacts

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ASSOCIATED CONTENT

S Supporting Information *

The supporting information includes detailed data of the effusion orifices of the Knudsen effusion apparatus, parameters used in the calculation of Cp,m ° (cr) according to the group additivity scheme of Domalski and Hearing, all the static bomb combustion calorimetry experiments for 4(3H)-pyrimidinone, F



Article

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computational enthalpies and electronic energies, NICS values, and experimental literature enthalpies of formation. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +351 22 0402 538. Fax: +351 22 0402 659. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Thanks are due to Fundaçaõ para a Ciência e Tecnologia (FCT), Lisbon, Portugal, and to FEDER for financial support ́ to Centro de Investigaçaõ em Quimica, University of Porto (Strategic Project PEst-C/QUI/UI0081/2013). 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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From 2,4-Dimethoxypyrimidine to 1,3-Dimethyluracil: Isomerization

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