From 2-Hydroxypyridine to 4(3H)-Pyrimidinone: Computational Study

Article pubs.acs.org/JPCA

From 2‑Hydroxypyridine to 4(3H)‑Pyrimidinone: Computational Study on the Control of the Tautomeric Equilibrium 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, Porto, Portugal. S Supporting Information *

ABSTRACT: In this work is investigated why the entrance of a nitrogen atom in the ring of cis2-hydroxypyridine and 2-pyridinone, resulting in cis-4-hydroxypyrimidine and 4(3H)pyrimidinone, respectively, shifts the tautomeric equilibrium from the hydroxyl form, in the pyridine derivative, to the ketonic form, in the pyrimidine derivative. The conclusions obtained for these model systems allow us to understand how to control the gaseous-phase keto−enol tautomeric equilibrium in nitrogen heterocyclic rings and justify the tautomeric preference in pyrimidine nucleobases. The experimental and computational energetics of tautomeric equilibrium were interpreted in terms of the aromaticity, intramolecular hydrogen bonds, and electronic delocalization, evaluated using nucleus independent chemical shifts, quantum theory of atoms in molecules, natural bond orbital analysis, and the thermodynamic changes of appropriate reactions.

with experimental values available in the literature.1,2 A comparison with the tautomeric equilibrium between 2hydroxypyridine and 2-pyridinone, a model system for proton transfer reactions13−16 and hydrogen bonding,17−22 will also be discussed, since the hydroxyl form is favored.13 However, the entrance of a nitrogen atom on the para position to the hydroxyl substituent shifts the tautomeric equilibrium to the oxo form1,2 in the equilibrium between 4-hydroxypyrimidine and 4(3H)-pyrimidinone (Figure 1). The results for these two systems are interpreted in terms of computational methods (G3; CBS-APNO; and MP2, SCS-MP2 and CCSD(T), with the cc-pVTZ and the aug-cc-pVTZ basis sets), entropy, aromaticity, possible intramolecular hydrogen bonds, electronic delocalization, and the strength of the N−H bond. The conclusions obtained are used to understand how to control the gaseous-phase keto−enol tautomeric equilibrium in nitrogen rings and justify the tautomeric preference in pyrimidine nucleobases. In order to develop this study, the following theoretical procedures were applied: quantum theory of atoms in molecules (QTAIM),23−25 nucleus independent chemical shifts (NICS),26,27 and natural bond orbital (NBO) analysis.28 This study complements and rationalizes a broad experimental investigation in our research group on the molecular energetics of nucleobases29−35 and other heterocyclic derivatives,36−39 which exist in equilibrium between several tautomeric forms on the gaseous phase.

1. INTRODUCTION 4-Hydroxypyrimidine can exist in tautomeric equilibrium with two ketonic forms,1,2 4(3H)-pyrimidinone and 4(1H)-pyrimidinone, and is a simpler system than the pyrimidine nucleobases cytosine, thymine, and uracil, being present in nature in equilibrium among several conformations and tautomeric forms.3 This compound also constitutes a moiety of pharmacologically relevant4−6 and photophysically active7−9 molecules, and supramolecular polymers.10−12 This study will focus on the understanding of the tautomeric equilibrium of pyrimidine derivatives. The influence of the keto−enol tautomeric equilibrium (Figure 1) on the gaseous-phase structure of 4-hydroxypyrimidine is evaluated by theoretical calculations and compared

Figure 1. Tautomeric equilibrium between 2-hydroxypyridine (I) and 2-pyridinone (II), and between 4-hydroxypyrimidine (III) and 4(3H)pyrimidinone (IV). © 2013 American Chemical Society

Received: October 8, 2013 Revised: November 8, 2013 Published: November 8, 2013 12668

dx.doi.org/10.1021/jp410004x | J. Phys. Chem. A 2013, 117, 12668−12674

The Journal of Physical Chemistry A

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2. COMPUTATIONAL DETAILS The computational calculations were performed using the Gaussian 03 software package.40 All the calculations used for the evaluation and the interpretation of the tautomeric equilibrium using isodesmic reactions were performed with the Gaussian-3 (G3) computational theory.41 The tautomeric equilibria between cis-2-hydroxypyridine and 2-pyridinone, and between cis-4-hydroxypyrimidine and 4(3H)-pyrimidinone, were also evaluated with the following methods: (1) complete basis set APNO method;42 (2) single point energy calculations using second-order Møller−Plesset perturbation theory (MP2);43 (3) spin-component-scaled MP2 (SCS-MP2);44 (4) coupled cluster theory with single, double,45,46 and triple substitutions calculated with perturbation theory (CCSD(T)).47 All the single point energy calculations were effectuated together with the cc-pVTZ and aug-cc-pVTZ basis sets, using the MP2(full)/6-31G(d) geometries and HF/6-31G(d) thermal corrections to Gibbs energies, at 298.15 K, all obtained during the G3 calculations.41 The molecular structure of 2-pyridinone was also optimized in water with the MP2(full)/6-31G(d) computational method, using the polarizable continuum model (PCM) as a selfconsistent reaction field,48 and a single point energy was calculated, in the gaseous phase, for this structure at the SCSMP2/aug-cc-pVTZ level of theory. Natural bond orbital (NBO) analysis28 was performed at the MP2/aug-cc-pVTZ level of theory, using the NBO program (version 3.1).49 The aromaticity of the different molecules was evaluated using nucleus independent chemical shifts (NICS).26,27 The values of the 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. The values of the chemical shifts obtained are a consequence of the electron delocalization in a cyclic ring and, hence, aromaticity. Rings with more negative chemical shifts, caused by enhanced diatropic ring currents, are more aromatic according to this criterion. In this work, the magnetic shieldings were calculated by the standard GIAO procedure,50,51 using density functional theory with the hybrid exchange correlation functional B3LYP52 and the 6311++G(2df,2p) basis set. The optimized geometries during the G3 calculations were used for the computation of the magnetic shieldings. For the NICS at the center of the ring was considered the isotropic value (NICS(0)) and for the NICS above and below the ring was considered the component of the NICS perpendicular to the ring (NICS(+1)ZZ, NICS(−1)ZZ).53 Although the difference between NICS(+1)ZZ and NICS(−1)ZZ is very small, it was considered the mean value of the ZZ component of both chemical shifts (NICS(±1)ZZ). Electron density analysis in the framework of the quantum theory of atoms in molecules was performed using the AIMAll program package.54 In these calculations, the optimized geometries during the G3 calculations, at the MP2(full)/631G(d) level of theory, for cis-2-hydroxypyridine, 2-pyridinone, cis-4-hydroxypyrimidine, and 4(3H)-pyrimidinone, were used. For the study of the influence of the X−H···X angle on the N− H···O and O−H···N hydrogen bonds on these types of systems, single point energies were calculated for these two molecular moieties, at the MP2/aug-cc-pVTZ level of theory, previously to the electron density analysis. Coordinates were generated in order to maintain the O−H and H···N distances of cis-2-hydroxypyridine and the N−H and H···O distances of 2-

pyridinone, considering different X−H···X angles from 60 to 180°.

3. RESULTS AND DISCUSSION In Table 1 are presented the experimental and theoretical Gibbs energies of tautomerization, from cis-2-hydroxypyridine to 2Table 1. Experimental and Theoretical Gibbs Energies of Tautomerization, at T = 298.15 K, from cis-2Hydroxypyridine (I) to 2-Pyridinone (II), and from cis-4Hydroxypyrimidine (III) to 4(3H)-Pyrimidinone (IV) ° (I→II)/kJ ΔrGm mol−1

method experimental

3.213

G3 CBS-APNO MP2/cc-pVTZ MP2/aug-cc-pVTZ SCS-MP2/cc-pVTZ SCS-MP2/aug-cc-pVTZ CCSD(T)/cc-pVTZ CCSD(T)/aug-cc-pVTZ

4.4 4.9 12.5 10.7 6.3 4.6 7.2 5.3

ΔrGm ° (III→IV)/kJ mol−1 −2.01 −2.42 −1.6 −1.7 5.0 3.7 −1.2 −2.4 1.2 −0.3

pyridinone, and from cis-4-hydroxypyrimidine to 4(3H)pyrimidinone (Figure 1). According to experimental gaseous-phase spectroscopic measurements,13 in the 2-hydroxypyridine/2-pyridinone tautomeric equilibrium, the hydroxyl form predominates. This conclusion is supported by all theoretical methods, but G3, CBS-APNO, SCS-MP2/aug-cc-pVTZ, and CCSD(T)/aug-ccpVTZ give results within 2.5 kJ·mol−1. In the case of the tautomeric equilibrium between cis-4-hydroxypyrimidine and 4(3H)-pyrimidinone, instead the ketonic form predominates according to experimental spectroscopic results.1,2 This fact seems to pose an interesting problem for computational chemistry since MP2 with both basis sets and CCSD(T)/ccpVTZ fail to correctly identify the most stable tautomeric form. G3 and CBS-APNO give results in agreement with the experimental ones, as well as SCS-MP2, which performs better than CCSD(T) and MP2 with both basis sets. For this reason, SCS-PM2 seems to be a good compromise between computational cost and accuracy for evaluating the keto−enol tautomeric equilibrium of this type of compound. The entropies of tautomerization from cis-2-hydroxypyridine to 2-pyridinone and from cis-4-hydroxypyrimidine to 4(3H)pyrimidinone are +1.9 and +1.8 J·K−1·mol−1, respectively, according to the values presented in Table S4 of the Supporting Information. Both reactions are entropically favored and the entropies of reaction are nearly the same. As a result, the change in the tautomeric equilibrium when a nitrogen atom enters the cis-2-hydroxypyridine and 2-pyridinone rings should be caused by enthalpic effects. According to NICS(0) and NICS(±1)ZZ values (Table 2), cis-2-hydroxypyridine is more aromatic than cis-4-hydroxypyrimidine, and 2-pyridinone is more aromatic than 4(3H)pyrimidinone. This is a consequence of more extensive conjugation of the hydroxyl and the carbonyl functional groups with the two nitrogen atoms of the pyrimidine ring instead of only one nitrogen of pyridine, which lowers the aromaticity of the ring according to the NICS criterion of aromaticity, as described in previous studies.55−57 12669



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indicates that the second-order perturbation interaction energy, E(2), between the lone pair of electrons of the nitrogen donor atom and the carbonyl acceptor group (nN → σ*(C−O)) decreases from 346.7 kJ·mol−1 in the structure optimized in water to 323.1 kJ·mol−1 in the gaseous-phase structure, but the electronic energy calculated using SCS-MP2/aug-cc-pVTZ is 2.9 kJ·mol−1 higher for the optimized structure in water, as expected by an increase of the contribution of a resonance structure of type B (Figure 3). In order to evaluate the influence of aromaticity on the tautomeric equilibrium, the variation of the NICS values from cis-2-hydroxypyridine to 2-pyridinone and from cis-4-hydroxypyrimidine to 4(3H)-pyrimidinone was calculated. The values presented in Table 3 show that the variation of aromaticity according to NICS(0) and NICS(±1)ZZ is nearly

Table 2. NICS Values Calculated with B3LYP/6-311+ +G(2df,2p) for 2-Hydroxypyridine, 2-Pyridinone, 4Hydroxypyrimidine, and 4(3H)-Pyrimidinone molecule

NICS(0)/ppm

NICS(±1)ZZ/ppm

cis-2-hydroxypyridine 2-pyridinone cis-4-hydroxypyrimidine 4(3H)-pyrimidinone 2-pyridinone (optimized in water)

−6.88 −2.16 −5.81 −0.97 −2.22

−25.22 −11.62 −23.84 −10.27 −11.78

On the other hand, the ketonic forms are also less aromatic than the hydroxyl forms. According to the computational molecular structures obtained, it is possible to notice a decrease of the C−O bond length and an increase of the C−N bond length from cis-2-hydroxypyridine to 2-pyridinone (Figure 2). A

Table 3. Variation of NICS Values from cis-2Hydroxypyridine (I) to 2-Pyridinone (II), and from cis-4Hydroxypyrimidine (III) to 4(3H)-Pyrimidinone (IV) reaction

ΔNICS(0)/ppm

NICS(±1)ZZ/ppm

I → II III → IV

+4.72 +4.84

+13.60 +13.57

the same in both reactions, but a slightly larger difference occurs in ΔNICS(0). As the NICS values at the plane of the ring (NICS(0)) are more affected by σ electronic currents than those 1 Å above and below the ring, this variation can be explained by a stronger inductive effect of the amide moiety of 4(3H)-pyrimidinone, which results in a higher ΔNICS(0) for the reaction of tautomerization. The values of ΔNICS(±1)ZZ show that the formation of the ketonic form has the same effect on the π electronic current in both reactions. Concerning the intramolecular hydrogen bonds, the application of the quantum theory of atoms in molecules reveals the absence of critical points (Figure 4) between the

Figure 2. Molecular structures and C−O and C−N bond distances (Å) for cis-2-hydroxypyridine (I), 2-pyridinone in the gaseous phase (II), and 2-pyridinone in water (II(water)), obtained from MP2(full)/ 6-31G(d) geometry optimizations.

similar pattern can be found comparing the structures of cis-4hydroxypyrimidine and 4(3H)-pyrimidinone. This is consistent with a resonance structure of type A instead of type B (Figure 3), which supports the lower aromaticity of both 2-pyridinone

Figure 3. Resonance structures of 2-pyridinone.

and 4(3H)-pyrimidinone, since in this type of structure only four electrons are available for π delocalization in the ring, instead of six as required by the Hückel rule and allowed by a structure of type B (Figure 3). On the other hand, with a structure of type B, although the aromaticity of the ring is maintained, the nitrogen atom of the ring, which usually behaves as a σ and π electron withdrawing group, is forced to lose its lone pair, and the oxygen of the carbonyl group has three π lone pairs around, which results in higher electronic repulsion. A structure of type C also has three lone pairs around the oxygen but does not compensate with more aromaticity (Figure 3), according to the Hückel rule. To confirm these explanations, the geometry of 2-pyridinone was reoptimized in water using the PCM model (considering the same conformation and tautomeric form of the gaseous phase), since the higher polarity considered in this calculation is likely to increase the contribution of a structure of type B or C. As a result, when comparing with the optimized structure of 2pyridinone in the gaseous phase (Figure 2), the length of the C−O bond increases, the C−N bond decreases, NICS values (Table 2) give a higher aromaticity, and the NBO analysis

Figure 4. Critical points detected by the AIMAll program for 2pyridinone (1), 4(3H)-pyrimidinone (2), and N−H···O moieties with N−H and H···O distances of 2-pyridinone and N−H···O angle of 90° (3) and 122.5° (4).

hydrogen of N−H and the oxygen of CO in 2-pyridinone and 4(3H)-pyrimidinone, which means that no intramolecular hydrogen bonds exist in these molecules. This is in agreement with the geometric rule of Baker and Hubbard58 used to identify hydrogen bonds. According to Baker and Hubbard, the distance between the hydrogen and the oxygen (N−H···OC) should be less than 2.5 Å, the distance between the nitrogen and the oxygen (H−N···OC) should be less than 3.5 Å, and the angle (θ) between the N−H and the oxygen should be at least 120°. From the data collected in Table 4 for 2-pyridinone and 4(3H)-pyrimidinone it is possible to verify that, although 12670



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enthalpy of tautomerization from cis-3-hydroxypyridazine to 3(2H)-pyrazidinone presented in Figure 6. In this case, the

Table 4. Interatomic Distances and Angles (MP2(full)/631G(d) Optimized Geometries) of the Amide Moiety of 2Pyridinone and 4(3H)-Pyrimidinone molecule

d(H···O)/Å

d(N···O)/Å

ϕ(N−H···O)/deg

2-pyridinone 4(3H)-pyrimidinone

2.439 2.474

2.290 2.296

69.5 68.0

the interatomic distances could indicate an intramolecular hydrogen bond, the N−H···O angle (nearly 70°) is clearly unfavorable. The influence of the N−H···O angle on the intramolecular hydrogen bond still poses an interesting problem for molecular mechanics.59 Coordinates were generated in order to maintain the N−H and H···O distances of 2-pyridinone, but considering N−H···O angles from 60 to 180°. The application of the quantum theory of atoms in molecules identified the minimal angle for an intramolecular hydrogen bond for these geometrical conditions to be between 122 and 122.5°. For 122.5° or wider angles, a bond critical point is obtained between the hydrogen and the oxygen (Figure 4). For smaller angles no bond critical point is detected between the hydrogen and the oxygen, and instead a bond critical point is obtained between the nitrogen and the oxygen, which means that for smaller angles the electronic clouds of the more electronegative atoms interact too much with each other, making it impossible for a bond path to exist between the hydrogen and the oxygen. To test the influence of the electron withdrawing effects of the nitrogen in position 1 of 4(3H)-pyrimidinone on the amide moiety, the bond dissociation enthalpy of the N−H bond of this molecule was compared with the same parameter of 2pyridinone, according to reaction II represented in Figure 5.

Figure 6. Enthalpy of tautomerization (in kJ·mol−1) calculated using G3 computational theory, from cis-3-hydroxypyridazine (I) to 3(2H)pyridazinone (II), from cis-4-hydroxypyrimidine (III) to 4(3H)pyrimidinone (IV), from cis-2-hydroxypyrazine (V) to 2(1H)pyrazinone (VI), and from 2-hydroxypyrimidine (VII) to 2pyrimidinone (VIII).

ketonic form is more favored than in the case of the tautomeric equilibrium between 4-hydroxypyrimidine and 4(3H)-pyrimidinone, and the N−H bond of 3(2H)-pyrazidinone has an even higher dissociation enthalpy than 2-pyridinone (Figure 5). In the cases of the equilibrium between cis-2-hydroxypyrazine and 2(1H)-pyrazinone, and between 2-hydroxypyrimidine and 2pyrimidinone, the hydroxyl form is favored (Figure 6) and the N−H bond has a lower dissociation enthalpy than in 2pyridinone (reactions III and IV of Figure 5, respectively). Recently, a correlation between the leaving group ability and acidity for hydroxypyridine and pyridinone derivatives was obtained,16 and it was analyzed in terms of resonance delocalization and tautomeric preference. In this study, the homolytic cleavage of the N−H bond shows that it is possible to favor the ketonic form in keto−enol tautomeric equilibria of pyridine derivatives by withdrawing electronic density from the nitrogen of the amide moiety. In the equilibrium between 2-hydroxypyrimidine and 2pyrimidinone the hydroxyl form is favored, which is in agreement with the fact that cytosine also exists predominantly under this form,60−64 whereas thymine and uracil exist predominantly under the ketonic form.3,60,64,65 The tautomeric preference in thymine and uracil can be explained by the fact that in the equilibrium between cis-4-hydroxypyrimidine and 4(3H)-pyrimidinone the ketonic form predominates. If a carbonyl group is assumed for position 4 of thymine and uracil, this means that the nitrogen atom in position 3 of thymine and uracil is no longer a π electron withdrawing group and cannot conjugate with the hydroxyl group in position 2. From the NBO analysis of 2-hydroxy-4(3H)-pyrimidinone, it was possible to verify that the lone pair of electrons of the nitrogen donor atom in position 3 only interacts with the carbonyl group in position 4 (nN3 → σ*(C4−O4) = 403.9 kJ· mol−1) and does not interact at all with the hydroxyl group in position 2. Instead, the NBO analysis of uracil revealed that the lone pair of electrons of the nitrogen atom in position 3 donates to both carbonyl groups in positions 2 (nN3 → σ*(C2− O2)) and 4 (nN3 → σ*(C4−O4)), with interaction energies of 355.5 and 285.3 kJ·mol−1, respectively. Furthermore, the two lone pairs of electrons of the hydroxyl donor group of 2hydroxy-4(3H)-pyrimidinone have a second-order perturbation

Figure 5. Reactions representing the difference between the enthalpy of dissociation (in kJ·mol−1) of the N−H bond in 3(2H)-pyrazidinone (reaction I), 4(3H)-pyrimidinone (reaction II), 2(1H)-pyrazinone (reaction III), and 2-pyrimidinone (reaction IV) and the N−H bond in 2-pyridinone.

The enthalpy for reaction II was +38.0 kJ·mol−1 obtained from G3 calculations. This result shows that the N−H bond is stronger in 4(3H)-pyrimidinone than in 2-pyridinone. The influence of the nitrogen atom relative to the amide moiety was evaluated by the enthalpy of tautomerization of various isomers of 4-hydroxypyrimidine and 4(3H)-pyrimidinone, respectively. When a nitrogen atom enters the ortho position of the nitrogen of the amide moiety, it favors the ketonic form, according to the 12671



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interaction energy, E(2), with the nitrogen acceptor atom in position 1 (nO2 → σ*(C2−N1)) of 262.6 kJ·mol−1, but with the nitrogen in position 3 (nO2 → σ*(C2−N3)) of only 5.2 kJ· mol−1.

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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4. FINAL REMARKS This paper addresses a question arising from data reported in the literature: why does the entrance of a nitrogen atom in the rings of cis-2-hydroxypyridine and 2-pyridinone, to give cis-4hydroxypyrimidine and 4(3H)-pyrimidinone, respectively, shift the tautomeric equilibrium from the hydroxyl form to the ketonic form? In this problem several computational methods were used to calculate the Gibbs energy of tautomerization and to compare with spectroscopic literature data. G3 and CBS-APNO gave results in agreement with experiment, as well as SCS-MP2, which performed better than CCSD(T) with the cc-pVTZ and aug-cc-pVTZ basis sets. However, it is important to notice that without the experimental literature data it would be very difficult to choose an appropriate computational method to calculate the tautomeric equilibrium analyzed in this work. The aromaticity, possible intramolecular hydrogen bonds, and electronic effects concerning the two reactions of tautomerization and, particularly, 2-pyridinone and 4(3H)-pyrimidinone, were explored. The hydroxyl forms were found to be more aromatic according to NICS values, and this was justified in terms of resonance structures. It is concluded that, for the ketonic form to maintain the aromaticity undisturbed, an enthalpic cost due to other electronic effects is associated. No intramolecular hydrogen bonds were found according to the quantum theory of atoms in molecules, in these molecules, due to a low N−H···O angle. By comparing the bond distances, atomic charges, and the difference between N−H bond dissociations, the electrostatics were found to be more favorable in the amide moiety of 4(3H)-pyrimidinone than in 2pyridinone. The N−H bond dissociation was correlated with the tautomeric preference in several hydroxydiazines, and the tautomeric preference between 4-hydroxypyrimidine and 4(3H)-pyrimidinone was used to explain the tautomerism of uracil.

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ASSOCIATED CONTENT

S Supporting Information *

Gibbs energies, enthalpies, electronic energies, NICS values, entropies, critical point properties, and Cartesian coordinates from the optimized structures obtained in this work. This material is available free of charge via the Internet at http:// pubs.acs.org.

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REFERENCES

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 the 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. thank FCT and the European Social 12672



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