Is Uracil Aromatic? The Enthalpies of Hydrogenation in the Gaseous

Article pubs.acs.org/JPCA

Is Uracil Aromatic? The Enthalpies of Hydrogenation in the Gaseous and Crystalline Phases, and in Aqueous Solution, as Tools to Obtain an Answer Tiago L. P. Galvaõ , Inês M. Rocha, 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, Portugal S Supporting Information *

ABSTRACT: The enthalpy of hydrogenation of uracil was derived from the experimental enthalpies of formation, in the gaseous phase, of uracil and 5,6dihydrouracil, in order to analyze its aromaticity. The enthalpy of formation of 5,6dihydrouracil was obtained from combustion calorimetry, Knudsen effusion technique and Calvet microcalorimetry results. High-level computational methods were tested for the enthalpy of hydrogenation of uracil, but only with G3 was possible to obtain results in agreement with the experimental ones. It was found that uracil possesses 30.0% of aromatic character in the gaseous phase. Using both implicit, explicit, and hybrid solvation methods, it was possible to obtain a reference value for the enthalpy of hydrogenation of uracil in the aqueous solution and the effect of polarity and hydrogen bonds on the aromaticity of uracil was analyzed. The value of the hydrogenation enthalpy of uracil in aqueous solution was compared with the experimental value in the crystal phase, also dominated by polarity and hydrogen bonds, derived from combustion calorimetry results. The supramolecular effects on the crystal lattice were explored by the computational simulation of π−π staking dimers and hydrogen bonded dimers.

1. INTRODUCTION Is uracil aromatic? Some textbooks describe uracil, which exists predominantly under the ketonic form,1−6 as being aromatic,7,8 others as being nonaromatic9 but compensated with the stronger bonds of the two amide moieties (D(CO) = (178.8 ± 0.2) kJ·mol−1 and D(N−H) = (107.6 ± 0.1) kJ·mol−1 10), when comparing to the enolic forms (D(C−O) = (112.4 ± 0.6) kJ·mol−1 and D(O−H) = (90 ± 3) kJ·mol−1 10).11 The structure of uracil (Figure 1) suggests a nonaromatic

relevance of the zwitterionic resonance structures from pyrimidine to uracil, according to natural resonance theory.14 Cyransky et al.15 used a geometric criterion of aromaticity, the Harmonic Oscillator Model of Aromaticity,16,17 and obtained a value that lies right between nonaromatic and the aromaticity of benzene, which is in agreement with the importance of the zwitterionic resonance structures. In this study, the enthalpy of hydrogenation will be used as an experimental thermodynamic measure of the aromaticity. The enthalpy of formation, in the gaseous phase, of 5,6dihydrouracil was determined experimentally using results from static bomb combustion calorimetry, Knudsen effusion, and Calvet microcalorimetry, and the enthalpy of hydrogenation of uracil was calculated and compared with other reference molecules. Enthalpies of hydrogenation have played a fundamental role as an experimental probe for solving chemical problems dealing with aromaticity, conjugation, strain energies, and the relative stabilities of molecules.18−20 Besides the quintessential example of the resonance energy of benzene, there are recent examples in which the enthalpy of hydrogenation has given further insight into questions such as the aromaticity of a model cyclohexatriene,21 acenaphthylene and pyracylene,22 N,N-dihydrodiazaacenes,23,24 and 1,2-azaborines;25 the conjugation of polyynes26−30 and disulfide

Figure 1. Representation of the structure of uracil (I) and other resonance contributing structures (II−IV).

compound with two π electrons on the ring, but the contribution of the zwitterionic resonance structures of the type II−IV (Figure 1) would increase the π-electron delocalization of uracil. Sun and Nicklaus12 have also concluded that uracil is nonaromatic according to the most widely used magnetic criterion of aromaticity, the Nucleus Independent Chemical Shifts (NICS),13 but demonstrated the increased © 2013 American Chemical Society

Received: May 20, 2013 Revised: June 20, 2013 Published: June 24, 2013 5826

dx.doi.org/10.1021/jp404938u | J. Phys. Chem. A 2013, 117, 5826−5836

The Journal of Physical Chemistry A

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bonds;31 the strain energies of alkenes, alkynes, and allenes;32 and the relative stabilities of carbenes.33,34 The hydrogenation of uracil, in particular, also plays a fundamental role in the catabolism of pyrimidines35−37 and the derivatives of 5,6dihydrouracil are important compounds in cancer research.38−40 Moreover, in recent years, the energetic properties of pyrimidine41−43 and uracil44−48 derivatives, as well as other related compounds such as cytosine49 and barbituric acid derivatives,50−52 have gained particular interest within the thermochemical community. For this reason, the experimental enthalpy of formation of 5,6-dihydrouracil, in the gaseous phase, obtained in this work and the derived enthalpy of hydrogenation of uracil, will give further insight into the energetic properties of uracil and can also be used as a benchmark for computational studies in other research areas. The enthalpy obtained for the hydrogenation of uracil will be used to test several theoretical methods widely used in thermochemical studies (B3LYP with a large and flexible enough basis set 6-311+G(2df,p), and three composite methods, G3, G3MP2, and CBS-APNO). The computations will be extended to the aqueous solution, where the zwitterionic resonance forms are expected to play a more important role and, hence, influence the aromaticity of uracil. Other authors have investigated the role of solvation on the physical− chemical properties of uracil such as hydrogen bond patterns,53−57 tautomeric equilibrium,58,59 charge transfer,60 electron affinities,61−63 acidity,64,65 and electronic spectra.66 In this work, implicit, explicit, and hybrid solvation methods will be used to evaluate the influence of polarity effects and hydrogen bonds on the aromaticity of uracil. The dimerization of uracil through the π−π staking of molecules67−74 and hydrogen bonds67,73 is a topic of considerable interest, as it is fundamental for the stability and function of DNA and RNA. Thereby, the influence of these effects on the enthalpies of sublimation of uracil and 5,6-dihydrouracil will be explored herein.

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, 100, 100, and 100 temperature readings were taken, respectively. Data acquisition and control of the calorimeter were performed using the program LABTERMO.79 The calorimetric system was calibrated, according to the procedure suggested by Coops et al.,80 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−1.81 From eight calibration experiments, the energy equivalent of the calorimeter obtained was ε(calor) = (15 995.3 ± 2.0) 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. Both compounds were burned in the pellet form enclosed in Melinex bags, in oxygen, at p = 3.04 MPa, with 1.00 cm3 of deionized water added to the bomb. The electrical energy for the ignition was determined from the change in potential 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−1,80 a value previously confirmed in our Laboratory. Melinex was used as auxiliary in the combustion experiments. The energy of combustion of the Melinex, ΔU(Melinex), was calculated using Δcu° (Melinex) = (22 902 ± 5) J·g−1.82 The mass of Melinex used in each experiment was corrected for the mass fraction of water (0.0032) and the mass of carbon dioxide produced from it was calculated using the factor previously reported.82 The energy corrections for the HNO3 formed were based on ΔfU°m(HNO3, aq, 0.1 mol·dm−3) = −59.7 kJ·mol−1.83 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.84 The standard state corrections, ΔU∑, and the heat capacities of the bomb contents, εi and εf, were calculated by the procedure given by Hubbard et al.85 using the enthalpies of solution of CO2 and O2 in pure water reported by Hu et al.86 2.3. Knudsen Effusion Measurements. The vapor pressures of 5,6-dihydrouracil, in the range of 0.1−1.0 Pa, were measured, at several temperatures, by the Knudsen effusion technique. The apparatus and experimental procedure described by Ribeiro da Silva et al.87 was used. This apparatus enables the simultaneous operation of nine effusion cells, at three different temperatures. Determining the mass Δm sublimed from the effusion cell during a time period t, by weighing the cell to ±0.01 mg on a Mettler AE 163 balance, before and after the measurement, it was possible to calculate the vapor pressure p, at the temperature T, using the Knudsen eq 1. Ao is the area of the effusion orifice, R is the gas constant (R = 8.314 472 J·K−1·mol−1), M is the molar mass of the effusion vapor, and wo is the Clausing probability factor, which can be calculated using the eq 2, where l is the thickness of the effusion orifice and ϕ is its diameter. The areas and Clausing factors of the effusion orifices, in the platinum foil of 0.0125 mm thickness, are presented in the Supporting Information, table S1.

2. EXPERIMENTAL SECTION 2.1. Compounds and Purity Control. 5,6-Dihydrouracil [CAS number: 4562−27−0] was obtained commercially from Alfa Aesar with an accessed minimum purity of 0.99. It was purified by washing in boiling methanol and two sublimations under reduced pressure (p ≈ 1 Pa; T ≈ 423 K). The purity of the sample of 5,6-dihydrouracil 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% dimethyl-polysiloxane) using nitrogen as carrier gas (30 cm3·min−1 flow rate), as being 0.9997, with the following conditions: T(injector) = 523 K; T(detector) = 523 K; T(initial period) = 323 K during 1 min; 10 K·min−1 heating rate; and T(final period) = 513 K during 10 min. The compound was dissolved in dimethylformamide for the analysis. The specific density used to calculate the true mass from the apparent mass in air was 1.575 g·cm−3 75 and the relative atomic mass was 114.1026 g·mol−1.76 Due to its hygroscopicity, after sublimation, the compound was handled under a dry nitrogen atmosphere. 2.2. Combustion Calorimetry Measurements. The standard (p° = 0.1 MPa) massic energy of combustion of 5,6-dihydrouracil was determined using an isoperibol static bomb calorimeter previously described.77,78 The calorimeter was used with a stainless steel twin valve bomb (type 1108, Parr Instrument Company) of internal volume of 0.342 dm3. 5827


The Journal of Physical Chemistry A p=

Δm ⎛⎜ 2πRT ⎞⎟1/2 · A◦w◦t ⎝ M ⎠

−1 ⎡ 3l ⎤ w◦ = ⎢1 + ⎥ ⎣ 4ϕ ⎦

Article

GEO is the dearomatization due to bond length alternation, Ropt is the optimal length for a specific bond (HOMA:17 1.388 Å for CC bonds and 1.334 Å for CN bonds ; HOMED:100 1.394 Å for CC bonds and 1.334 Å for CN bonds; HOMEHD:101 1.387 Å for CC bonds and 1.339 Å for CN bonds), Rav is the average bond length, Ri is the bond length of the optimized structure at the MP2(Full)/6-31G(d) level of theory, n is the number of bonds taken into account, and α is a normalization constant (HOMA:17 257.7 for α(CC) and 93.52 for α(CN); HOMED:100 88.09 for α(CC) and 91.60 for α(CN); HOMEHD:101 78.6 for α(CC) and 87.4 for α(CN)).

(1)

(2)

2.4. Calvet Microcalorimetry. The standard molar enthalpy of sublimation of 5,6-dihydrouracil was also measured by the “vacuum sublimation” drop microcalorimetric technique of Skinner et al.88 using the apparatus described by Santos et al.89 The samples of approximately 5−8 mg contained in a thin glass capillary and a blank reference capillary were simultaneously dropped, at room temperature, into the respective twin calorimetric cells, held at a predefined temperature of 478 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.88,89 The observed standard molar enthalpy of sublimation, Δg,T ° , was corrected to T = 298.15 K using the values cr,298.15KHm 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 in situ for these measurements using the reported standard molar enthalpy of sublimation of anthracene (101.4 ± 0.4) kJ·mol−1,87 available commercially from Aldrich Chemical Co. [CAS 120−12−7]. The calibration constant, k, of the calorimeter was k (T = 477.9 K) = (0.9968 ± 0.0037), the uncertainty quoted being the standard deviation of the mean of ten experiments. All the necessary weights were measured on a Mettler CH-8608 analytical balance with a sensitivity of ±(1 × 10−7) g.

HOMA, HOMED, HOMEHD = 1 − EN − GEO = 1 − α(R opt − R av)2 − α ·Σ[R av − R i]2 /n

(3)

Electron density analysis in the framework of the Quantum Theory of Atoms in Molecules was performed using the AIMAll program package,102 from the optimized structures during the G3 calculations. From these results it was possible to calculate the Para Delocalization Index (PDI),103 using the average of the delocalization indexes, δ, of atoms in the para position in a six-membered ring: PDI =

δ(1, 4) + δ(2, 5) + δ(3, 6) 3

(4)

In order to estimate the gaseous-phase molar heat capacity at constant pressure (p° = 0.1 MPa), at T = 298.15 K, needed for the temperature correction of the thermodynamic properties obtained by Knudsen effusion and ΔT298.15KH°m (g) needed for the correction of the enthalpic results obtained by Calvet microcalorimetry, all the geometry optimizations and vibrational frequency calculations were performed using density functional theory (DFT) with the hybrid exchange correlation functional (B3LYP)91 with the 6-311+G(2df,p) basis set and using scale factors for the fundamental frequencies determined by Merrick et al. (0.9686 for the calorific capacity and 0.9938 for the enthalpy corrections).104

3. COMPUTATIONAL DETAILS The computational calculations were performed using the Gaussian 03 software package.90 The hydrogenation of uracil was evaluated using geometries and frequencies calculated with B3LYP91 together with the 6-311+G(2df,p) basis set and three composite methods: Complete Basis Set APNO method (CBSAPNO),92 Gaussian-3 (G3),93 and Gaussian-3 with MP2 single point energies for basis set extrapolation (G3(MP2)).94 To simulate the influence of water, the Polarizable Continuum Model (PCM) as a self-consistent reaction field95 was used with G3. G3(MP2) was also used to simulate the dimers of 5,6dihydrouracil and uracil. The aromaticity of the different molecules was evaluated using the Nucleus Independent Chemical Shifts (NICS).13,96 The values of the total magnetic shieldings were calculated for ghost atoms placed on the geometric center of the ring and 1 Å above and below the center of the ring, by the GIAO procedure,97,98 for the MP2(Full)/6-31G(d) optimized geometries during the G3 calculations, using density functional theory with the hybrid exchange correlation functional B3LYP91 and the 6-311++G(2df,2p) basis set. Besides the isotropic value (NICS(0), NICS(+1)), the component of the NICS perpendicular to the ring (NICS(0)zz, NICS(+ 1)zz) was also considered.99 The HOMA, HOMED, and HOMEHD indices, also used to obtain the aromaticity of uracil, were calculated according to eq 3,16,17 where EN is the dearomatization due to bond energy,

4. RESULTS 4.1. Experimental Enthalpy of Formation, in the Crystalline Phase. Detailed results of each combustion experiment of 5,6-dihydrouracil are presented in Table S3 of the Supporting Information, where Δcu° 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,85 and ΔU(IBP) is the internal energy associated with the isothermal bomb process, calculated using expression 5, 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.85 ΔU (IBP) = −ε(calor)corr. ·ΔTad + (Ti − 298.15K) ·εi + (298.15K − Ti − ΔTad) ·εf + ΔU (ign) (5)

The results refer to the combustion reaction described by eq 6. 5828



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3 (Computational Details) and an uncertainty of 4.0 was assigned.

C4 H6O2 N2(cr) + 4.5O2 (g) → 4CO2 (g) + 3H 2O(l) + N2(g)

(6)

Δcrg Hm° (298.15 K) = Δcrg Hm° (⟨T ⟩) + Δcrg C p°,m

The derived standard (p° = 0.1 MPa) molar energy, ΔcU°m(cr), and enthalpy, ΔcH°m(cr), of combustion, and the standard molar enthalpy of formation, ΔcHm° (cr), in the crystalline phase, at T = 298.15 K, are reported in table 1.

·(298.15 K − ⟨T ⟩) −1

The Cp,m ° (cr) = (136.4 ± 8.0) J·K ·mol was calculated from the group additivity scheme of Domalski and Hearing,107 as presented in the Supporting Information. Due to the absence of the C°p,m [CONH-(CB)2, cr] parameter in the Domalski and Hearing Group Additivity Scheme the value of 46.30 J·K−1·mol−1 was evaluated in this work by fitting existing group values to the experimental data reported in table S2 of the Supporting Information and using the Solver software from Microsoft Excel included in the Microsoft Office 2007 software package. Table S2 contains the experimental values for the standard molar heat capacities of a series of cyclic amides, as well as the calculated heat capacities and the difference between the experimental108−111 and calculated values. The differences between experimental and calculated heat capacity values for the compounds presented in Table S2, except for 5,6dimethyluracil, do not exceed 8 J·K−1·mol−1, which is the uncertainty suggested by Domalski and Hearing for their scheme. This fact provides enough confidence in the use of the estimated value for the C°p,m [CONH-(CB)2, cr] parameter. Table 3 reports the standard molar enthalpy of sublimation obtained by Calvet microcalorimetry. The standard molar

Table 1. Derived Standard (p° = 0.1 MPa) Molar Values of 5,6-Dihydrouracil, in the Condensed Phase, at T = 298.15 K (ΔcU°m(cr))/(kJ·mol−1)

(ΔcH°m(cr))/(kJ·mol−1)

(ΔfH°m(cr))/(kJ·mol−1)

−1940.1 ± 1.2

−1938.9 ± 1.2

−492.6 ± 1.3

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.105 To derive ΔfH°m(cr) from Δc Hm° (cr), the following standard molar enthalpies of formation, at T = 298.15 K, were used: ΔfHm ° (CO2, g) = −(393.51 ± 0.13) kJ·mol−1,106 ΔfH°m(H2O, l) = −(285.830 ± 0.042) kJ·mol−1.106 4.2. Enthalpy of Sublimation. The integrated form of the Clausius−Clapeyron equation, ln(p/Pa) = a − b (1/(T/K)), where a is a constant and b = ΔgcrH°m(⟨T⟩)/R, was used to derive the standard molar enthalpies of sublimation, at the mean temperature of the experimental temperature range, ΔgcrHm ° (⟨T⟩). The experimental results of the vapor pressure measurements obtained by the Knudsen effusion technique for each cell together with the residuals of the Clausius−Clapeyron equation, derived from least-squares adjustment are presented in Table S4 of the Supporting Information. Table S5 reports results, for each orifice and for the global treatment of all the (p, T) points obtained for 5,6-dihydrouracil, the parameters of the Clausius−Clapeyron equation together with the mean temperature, ⟨T⟩, the equilibrium pressure at the mean temperature, p(⟨T⟩), the standard molar enthalpy of sublimation at the mean temperature, ΔgcrH°m(⟨T⟩), and the molar entropy of sublimation at the mean temperature and equilibrium pressure, ΔgcrSm(⟨T⟩,p(⟨T⟩)). The molar entropy of sublimation, at equilibrium conditions, ΔgcrSm(⟨T⟩,p(⟨T⟩)), was calculated as ΔgcrSm(⟨T⟩,p(⟨T⟩)) = ΔgcrSm(⟨T⟩)/⟨T⟩. The calculated enthalpy and entropy of sublimation obtained for the smaller orifice are slightly larger than the same parameters obtained with the medium and larger orifices. For this reason, the enthalpy of sublimation of 5,6-dihydrouracil was also determined by Calvet microcalorimetry. Table 2 registers the standard molar enthalpy, entropy and Gibbs energy of sublimation, and vapor pressure, calculated at T = 298.15 K, obtained by Knudsen effusion. The sublimation enthalpies, at T = 298.15 K, were derived using relation 7, where ΔgcrCp,m ° = −(19.5 ± 8.9) J·K−1·mol−1. The C°p,m (g) = (116.9 ± 4.0) J·K−1·mol−1, was calculated at the B3LYP/6-311+G(2df,p) level of theory as described in section

Table 3. Standard (p° = 0.1 MPa) Molar Enthalpies,ΔgcrHm °, of Sublimation, at T = 298.15 K, of 5,6-Dihydrouracil Obtained by Calvet Microcalorimetry

° )/ (ΔgcrSm (J·K−1·mol−1)

° )/ (ΔgcrGm (kJ·mol−1)

p/Pa

116.0 ± 1.2

191.6 ± 3.3

58.9 ± 1.6

(4.8 ± 3.1)·10−6

T/K

(Δg,T cr,298.15KH° m)/ (kJ·mol−1)

(ΔT298.15KH°m)/ (kJ·mol−1)

(ΔgcrH°m(298.15K))/ (kJ·mol−1)

477.9

140.5 ± 0.6

26.1

114.4 ± 1.6

enthalpy of sublimation, at T = 298.15 K, was calculated from the value measured at the predefined temperature, T, using ΔT298.15kH°m (g) calculated by computationally at the B3LYP/6311+G(2df,p) level of theory. The uncertainty of Δg,T cr,298.15kH° m was calculated as the standard deviation of the mean of eight individual experiments and the uncertainty of ΔgcrHm ° (298.15K) is twice the value derived considering the uncertainty of Δg,T cr,298.15kH° m, the calibration constant and the reference value for enthalpy of sublimation of anthracene. The value of the standard molar enthalpy of sublimation, at T = 298.15 K, derived from the results of Calvet microcalorimetry, presented in Table 3, is in good agreement with the value derived from vapor pressure measurements presented in Table 2. 4.3. Computational Calculations. Calculated enthalpies, at T = 298.15 K, of uracil and 5,6-dihydrouracil with different methods and in different chemical environments, used during the discussion of the results, are presented in Table S6 of the Supporting Information. Cartesian coordinates of the optimized structures during the G3 and G3MP2 calculations, at the MP2(Full)/6-31G(d) level of theory, are also reported in the Supporting Information. QTAIM results for the PDI aromaticity criteria, obtained using AIMAll, are also given in Table S8 of the Supporting Information.

Table 2. Values of the Standard (po = 0.1 MPa) Molar Enthalpies,ΔgcrHm ° , Entropies, ΔgcrSm ° , and Gibbs Energies ΔgcrG°m, of Sublimation of 5,6-Dihydrouracil, at T = 298.15 K (ΔgcrHm ° )/ (kJ·mol−1)

(7) −1

5. DISCUSSION 5.1. Experimental and Computational Enthalpies of Hydrogenation. The enthalpy of formation of 5,6-dihydrour5829



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acil, in the gaseous phase, presented in Table 4, was obtained combining the enthalpy of formation, in the crystalline phase, Table 4. Standard (p° = 0.1 MPa) Molar Enthalpies of Formation of 5,6-Dihydrouracil, in Both Crystalline and Gaseous Phases, and Standard Molar Enthalpies of Sublimation, at T = 298.15 K (ΔfH°m(cr))/(kJ·mol−1)

(ΔgcrH°m)/(kJ·mol−1)

(ΔfH°m)(g)/(kJ·mol−1)

−492.6 ± 1.3

115.4 ± 1.0

−377.2 ± 1.6

a

a

Weighted mean of the values determined by Knudsen effusion technique (Table 2) and Calvet microcalorimetry (Table 3).

obtained in this work from combustion calorimetry results, and the enthalpy of sublimation obtained as the weighted mean of the values obtained from Knudsen effusion vapor pressure measurements and Calvet microcalorimetry. In Table 5 is presented the enthalpy of hydrogenation of uracil (Figure 2) calculated from the enthalpies of formation, in Table 5. Standard (p° = 0.1 MPa) Molar Enthalpy of Hydrogenation of Uracil, in the Gaseous Phase, at T = 298.15 K method Experimental B3LYP/6-311+G(2df,p) CBS-APNO G3MP2 G3 a

(ΔhydHm ° (g))/(kJ·mol−1) −75.7 −59.3 −80.0 −70.8 −75.8

± 3.0 (−16.4)a (+4.3)a (−4.9)a (+0.1)a

Figure 2. Reactions and experimental and computational standard (po = 0.1 MPa) molar enthalpies of hydrogenation of benzene, uracil, cyclohexene, ethene, and pentalene, in the gaseous phase, at T = 298.15 K. For uracil the computed values for the aqueous solution are also presented. All values in kJ·mol−1.

Difference between the experimental and computational value.

the gaseous phase, of 5,6-dihydrouracil and uracil. The enthalpy of formation, in the gaseous phase, of uracil used in this work was the one selected recently by Dorofeeva and Vogt (ΔfHm ° (g) = −(301.5 ± 2.5) kJ·mol−1 112), after revision of the available experimental data.113−117 The enthalpy of hydrogenation of uracil was computed using three widely used methods to obtain thermochemical properties: B3LYP, G3MP2, G3, and CBS-APNO. B3LYP was used with a large and flexible enough basis set 6-311+G(2df,p), but it performed poorly, underestimating the exothermicity of the reaction by 16.4 kJ·mol−1. G3MP2 underestimates the exothermicity of the reaction by 4.9 kJ·mol−1, a value outside the experimental uncertainty (3.0 kJ·mol−1). G3 gives a result in excellent agreement with experiment, which supports the use of MP4 single point energies for the basis set extrapolation for this reaction, instead of MP2 as in G3MP2. CBS-APNO, the more expensive computational method applied in this work and the more accurate method of the Complete Basis Set (CBS) family of methods created by Petersson and co-workers, which includes computationally an expensive QCISD(T)/6-311+ +G(2df,p) single point energy calculation, overestimates the exothermicity of the reaction by 4.3 kJ·mol−1, outside the experimental uncertainty (3.0 kJ·mol−1). The G3 method was also tested for the enthalpy of hydrogenation of benzene (3), cyclohexene (4), and ethene (5) (the enthalpies of formation, in the gaseous phase, of the compounds used in the calculation are presented in Table S7 of the Supporting Information) and the results, presented Figure 2, are in good agreement with those obtained experimentally. As a result, whenever possible, the G3 method will be used throughout this work. The enthalpy for the reaction describing

the hydrogenation of uracil to give 5,6-dihydro-2,4-dihydroxypyrimidine (2), the enolic form of 5,6-dihydrouracil, was also calculated using G3 theory. By comparison of the experimental enthalpy of hydrogenation derived in this work and that calculated for this reaction, it is possible to confirm that not only uracil, but also 5,6-dihydrouracil exists mainly under the ketonic form in the gaseous phase. 5.2. The Aromaticity of Uracil from the Hydrogenation Enthalpy. In Figure 2 are presented the hydrogenation reactions of benzene (3), uracil (1), hexane (4), ethene (5), and pentalene (6), and the corresponding experimental and computational standard molar enthalpies of hydrogenation. Comparing the hydrogenation enthalpy of uracil with benzene, cyclohexene, and ethene allows an indirect measure of the enthalpic stabilization produced due to aromaticity. As the aromaticity of a compound decreases, the relative enthalpic stability in comparison with the hydrogenated form also decreases, and the reaction of hydrogenation becomes less endothermic or more exothermic. For an antiaromatic compound such as pentalene the hydrogenation enthalpy, calculated with the G3 method, would be lower than the hydrogenation enthalpy of cyclohexene, which can be taken as a reference for a nonaromatic cyclic compound or ethene without any type of electronic delocalization. With benzene and cyclohexene as references for a fully aromatic system and a nonaromatic system, respectively, it is possible to calculate the relative aromaticity of uracil (in %) as 5830



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Table 6. NICS Values and Relative Aromaticity of Uracil Considering Benzene as the Fully Aromatic System and Cyclohexene as the Nonaromatic System molecule

(NICS(0))/(ppm)

Benzene Uracil Cyclohexene

−7.80 −0.53 −0.03

(NICS(0)zz)/(ppm)

(NICS(+1))/(ppm)

−15.70 −7.80 15.22 −1.30 22.10 1.26 relative aromaticity of uracil/% 18.2 28.3

6.4

Δhyd Hm° (uracil) − Δhyd Hm° (nonaromatic) Δhyd Hm° (fully aromatic) − Δhyd Hm° (nonaromatic)

(NICS(+1)zz)/(ppm) −29.77 −2.28 2.56 15.0

placed in a more polar field. For this reason, water solvation effects will be studied in the next section, considering both implicit and explicit and hybrid models. 5.3. Solvation: Effect of Polarity and Hydrogen Bonds on the Aromaticity of Uracil. The enthalpy of hydrogenation of uracil in the aqueous solution was computed using G3 theory, with the PCM model, being less exothermic than in the gaseous phase. The result, presented in Figure 2 (1), suggests that uracil is 12.3 kJ·mol−1 more aromatic in aqueous solution than in the gaseous phase, considering the difference between both computed values at the G3 level of theory. The geometry of uracil, presented in Figure 3, also confirms this

× 100 (8)

According to the experimental values of hydrogenation of the compounds presented in Figure 2, it is possible to calculate the relative aromaticity of uracil as being 30.0%. This can be due to the contribution of the zwitterionic resonance forms, presented in Figure 1, to the structure of uracil, which increase its aromaticity. Applying the previous procedure to NICS and PDI values, presented in Table 6, it is possible to verify the energetic conclusions using the magnetic and electronic criteria of aromaticity. The absolute NICS values lack consistency, as uracil can have a small degree aromaticity (NICS(+1) and NICS(+1)zz), no aromaticity (NICS(0)) or can even be considered antiaromatic (NICS(0)zz). However, the relative NICS values consider uracil to have a relative aromaticity between 6.4% and 28.3%, which can be considered in qualitative agreement with the relative aromaticity calculated from the enthalpy of hydrogenation depending of the NICS index used. The PDI values (Table 7) give a relative aromaticity of 10.9%, which also considers uracil to have some degree of aromaticity. Table 7. PDI Values and Relative Aromaticity of Uracil Considering Benzene as the Fully Aromatic System and Cyclohexene As the Nonaromatic System molecule

PDI/au

Benzene Uracil Cyclohexene

0.0994 0.0223 0.0129 relative aromaticity of uracil/% 10.9

Using HOMA to access the aromaticity of uracil (Table 8), it is also possible to conclude that it has some aromatic character,

Figure 3. Most relevant bond lengths and HOMA values for uracil in different chemical environments. Bond lengths in Å.

Table 8. Values of Geometric Dearomatization (GEO), Energetic Dearomatization (EN), and total HOMA, HOMED, and HOMEHD Aromaticity Indexes for Uracil HOMA

HOMED

HOMEHD

0.414

0.641

0.681

increase of aromaticity in aqueous solution, according to the HOMA values. As can be noticed by the geometric features of uracil calculated with PCM to simulate the aqueous solution, the C1−N2 and N3−C4 ring bonds decrease and both C−O bonds increase as expected by the increase of the contribution of the more polar and aromatic zwitterionic structural forms, as presented in Figure 1. To verify the results obtained with the PCM model, four explicit water molecules were also added to the same relative positions of both uracil and 5,6-dihydrouracil. These molecules were placed considering the most stable conformation of previous literature studies.53,64 According to the conformational analysis of Bachrach and Dzierlenga,64 four

although the more recent parametrizations HOMED and HOMEHD seem to overestimate the aromaticity of uracil when comparing with the enthalpy of hydrogenation, NICS and PDI. The zwitterionic resonance structures II, III, and IV, presented in Figure 1, are more polar than the neutral form I, and, as a result, should be favored when the molecule is 5831



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−49.6 kJ·mol−1 for uracil and −41.9 kJ·mol−1 for 5,6dihydrouracil, computed at the G3MP2 level of theory. For hydrogen bonded dimers of the type II the dimerization enthalpy is −49.5 kJ·mol−1 for uracil and −40.9 kJ·mol−1 for 5,6-dihydrouracil. Together, both types of dimers give 16.3 kJ·mol−1 of stronger hydrogen bonds for uracil in comparison with 5,6-dihydrouracil which explains the larger sublimation enthalpy of uracil. The geometric features of the dimers indicates that uracil becomes more aromatic according to the HOMA values, but also that the hydrogen bonds are shorter in uracil [dimer I (N−H···O) = 1.863 Å; dimer II (N−H···O) = 1.855 Å; dimer II (C−H···O) = 2.197 Å] than in 5,6dihydrouracil [dimer I (N−H···O) = 1.910 Å; dimer II (N− H···O) = 1.933 Å; dimer II (C−H···O) = 2.213 Å], which is a case of resonance assisted hydrogen bonds.11,120,121 In order to verify the influence of the π−π stacking interactions, the enthalpies of dimerization of pairs of stacked uracil and 5,6-dihydrouracil molecules were computed and the result was −40.6 kJ·mol−1 for uracil and −42.6 kJ·mol−1 for 5,6dihydrouracil. Although aromatic molecules generally stack better than the saturated equivalents, as found by Grimme122 for naphthalene and larger polycyclic aromatic hydrocarbons, the results obtained for uracil and 5,6-dihydrouracil are in agreement with the dimerization of benzene which is 2.0 kJ·mol−1 weaker at the B2PLYP-D/QZV3P level of theory122 than cyclohexene. Although the less aromatic molecule has a stronger binding, which according to the conclusions of Bloom and Wheeler can be an example of taking the aromaticity out of aromatic interactions,123 this can also be a result of C−H···π short contacts124−126 in 5,6-dihydrouracil.

water molecules should be enough, since with a number of water molecules beyond this, the extra water molecule interacts only with other water molecules and do not form any extra hydrogen bonds with uracil. As a result, the effect on the enthalpy of hydrogenation of a higher number of explicit water molecules should be negligible. The enthalpies of hydrogenation obtained (1, Figure 2) with the four explicit water molecules and the hybrid model (PCM model together with four explicit water molecules) are similar to the results obtained with the implicit solvation model (PCM) only. A closer inspection of the geometric features of the structure of uracil using the explicit model of solvation, in comparison with the implicit model, reveals that the molecule indeed becomes more aromatic, according to HOMA (Figure 3), but this effect is not noticed in the enthalpy of hydrogenation, since it is intrinsic to the amide moieties and should have a similar effect in uracil and 5,6-dihydrouracil. The result obtained for the aqueous solution using the three solvation models (implicit: −63.5 kJ·mol−1; explicit: −65.1; and hybrid: −66.8 kJ·mol−1) is also similar to the enthalpy of hydrogenation in another phase, also dominated by polarity effects and hydrogen bonds, the crystal phase (−(63.0 ± 1.4) kJ·mol−1), calculated from the standard molar enthalpy of formation in the crystalline phase of uracil (−(429.6 ± 0.6) kJ·mol−1 113) and 5,6-dihydrouracil obtained in this work (Table 1), and considering a negligible heat of sublimation for hydrogen at standard pressure and T = 298.15 K (the agreement between enthalpies of hydrogenation determined in the condensed phase and calculated computationally for the gaseous phase, indicate that this is a valid approximation and is often used18,21,22,25,29). The agreement between experimental and G3 enthalpies of hydrogenation, in the gaseous phase, and the consistency between the enthalpies of hydrogenation using three solvation models with the experimental enthalpy of hydrogenation in the crystalline phase, suggests that the enthalpies of hydrogenation in aqueous solution for uracil, computed in this work, can also be considered reference values for other work. The most relevant features of the crystalline phase and its effects on the structural, electronic, and energetic properties of uracil will be analyzed in detail in the next section. 5.4. Crystal Lattice: Stacking and Hydrogen Bonds. The experimental standard molar enthalpy of sublimation of a compound is a measure of the heat necessary to transform 1 mol of a solid at a standard pressure into an ideal gas at the same pressure. This enthalpy value accounts the change in translational, rotational, vibrational, and intermolecular enthalpies and the stability of the molecules themselves from the crystalline phase to the gaseous phase. The crystal lattice of uracil and 5,6-dihydrouracil is established by π−π stacking of the molecules and hydrogen bonds when they are in the same plane.75,118,119 The enthalpy of sublimation of uracil112 is 12.4 kJ·mol−1 larger than the enthalpy of sublimation of 5,6dihydrouracil reported in this work. The comparison of the enthalpy of dimerization of pairs of uracil and 5,6-dihydrouracil molecules in the same plane held together by two N−H···O hydrogen bonds can help clarify if there is a difference in the hydrogen bonds of both compounds or if they produce a difference in the aromaticity of the ring. Hydrogen bonded dimers of the type I and II (Figure 3) were built with short contacts similar to those found in the crystal lattice of both compounds.75,118,119 For hydrogen bonded dimers of the type I the dimerization enthalpy is

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FINAL REMARKS From the enthalpy of hydrogenation of uracil, derived from the enthalpy of formation, in the gaseous phase, of 5,6dihydrouracil, obtained in this work, and uracil, it was possible to conclude that the zwitterionic resonance forms play an important role in the structure and aromaticity of uracil, which becomes increasingly important in highly polar environments and in the presence of intermolecular hydrogen bonds, such as in the aqueous or crystalline phases. Moreover, polarity seems to play a more important role than hydrogen bonds in the aromaticity of uracil, whereas hydrogen bonds seem to affect the inner conjugation within the amide moieties more. The crystalline phase is affected by resonance assisted hydrogen bonds, which favor the hydrogen bonds in uracil, but 5,6dihidrouracil stacks better than uracil.

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ASSOCIATED CONTENT

S Supporting Information *

Detailed data of the effusion orifices of the Knudsen effusion apparatus, calculation of the calorific capacities in the crystalline phase, all the results from static bomb combustion calorimetry and Knudsen effusion experiments, enthalpies calculated computationally, Cartesian coordinates of optimized structures and QTAIM results. 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 address: [email protected] (M.D.M.C. Ribeiro da Silva). 5832



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Notes

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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 European Social Fund for ́ financial support to Centro de Investigaçaõ em Quimica, University of Porto (strategic project PEst-C/QUI/UI0081/ 2011). T.L.P.G. and I.M.R. 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 and SFRH/BD/61915/2009.

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Is Uracil Aromatic? The Enthalpies of Hydrogenation in the Gaseous

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