Chemical Physics 332 (2007) 152161 www.elsevier.

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Structures, stabilities and tautomerizations of uracil and diphosphouracil tautomers

Abraham F. Jalbout
a,*

, B. Trzaskowski b, Y. Xia b, Y. Li b,*, X. Hu b, H. Li b, A. El-Nahas b, Ludwik Adamowicz b

a Institute of Chemistry, National Autonomous University of Mexico, Mexico City NASA Astrobiology Institute, Department of Chemistry, The University of Arizona, Tucson, AZ 85721, USA

Received 27 July 2006; accepted 27 October 2006 Available online 19 November 2006

Abstract A DFT method (B3LYP) and two ab initio methods (MP2 and CCSD(T)) are used to study the stability order and tautomerization processes of all possible uracil and diphosphouracil tautomers. The obtained order of uracil tautomers stability is dierent from the previous computational investigations. Reliable predictions on the stability order and geometrical structures for the diphosphouracil tautomers are presented for the rst time. The dienol tautomers of diphosphouracil are shown to be much more stable than the enolketo and diketo forms, whereas for uracil the diketo form is more favored from the energetical point of view. The comparison of the structures and stability order of the tautomers of the two analogues, allows us to suggest that the interaction between the OH bond and the delocalized p system is crucial for the stabilization of the dienol form of diphosphouracil tautomers. On the other hand, for uracil tautomers only the interaction between the OH bond with the lone pair of the neighboring nitrogen atom plays a major role. Other dierences of intramolecular interactions of the two analogues are attributed to the unique bonding property of the phosphorous atom. The energy barriers of eight rotamerization processes and nine proton transfer processes of both analogues are reported. For both systems rotamerization processes are proved to be far more facile than proton transfer processes, since energy barriers for rotamerizations are only several kcal/mol, while energy barriers for proton transfers are up to 50 kcal/mol. The rotamerizations of diphosphouracil rotamers are easier than that of the uracil rotamers, while the proton transfer barriers of uracil tautomers are lower than that of the diphosphouracil tautomers. All these dierences are the results of dierent molecular properties of the two analogues, and also an evidence dierent intramolecular interactions existed in the two analogues. 2006 Published by Elsevier B.V.
Keywords: Uracil; Diphosphouracil; Ab initio; Tautomers; Theoretical methods

1. Introduction In past years a great eort has been put into the study of properties of uracil and its tautomers. Experimental investigations performed in gas phase, solid state, or in solution indicate that the diketo form is the most stable one [116]. This form may undergo various proton transfer reactions to give the tautomeric forms of uracil. Several experiments

Corresponding authors. E-mail address: ajalbout@u.arizona.edu (A.F. Jalbout).

has been performed to evaluate relative stabilities of some of uracil tautomers as compared with its diketo form. From calorimetric experiments the 2-oxo-4-hydroxy tautomer of uracil was estimated to be 19 6 kcal/mol higher than the energy of the most stable tautomer [17], and Fujii et al. [6,7] found the most stable hydroxy tautomer is approximately 9.5 kcal/mol higher in energy than the diketo form. Theoretical studies give us more information about the stabilities of the tautomers [1841]. In the work of Kryachko and co-workers [42] the stabilities of uracil and its 12 tautomers were comprehensively studied using DFT method, and the geometric structures, the proton

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anities as well as the deprotonation enthalpies were reported. There also have been many studies on the tautomerization processes of uracil [4349]. In a recent report Hu et al. [50] reported a systematical study on the tautomerism of uracil induced by proton transfer. All possible pathways of the proton transfer processes are calculated at the DFT level and discussed in this work. The authors concluded that, in gas phase, longer proton transfer distance corresponds to higher activation energy. In both of these systematical studies on the relative stability of uracil and the barriers of proton-transfer process only the DFT method was used. While it is known that this method gives, in most cases, reliable geometric parameters, it is far from giving very reliable energy values. We believe that high level ab initio methods are necessary to be employed in the case of uracil tautomerization. Such a study may provide a valuable comparison of ab initio and DFT results to estimate the reliability of previous results, or to provide alternative predictions for future investigations. The tautomerization process of uracil includes two different processes [42]. One of them is the proton transfer process, while the other is the rotamerization of the OH group. Former studies on the uracil tautomerizations focused only on the proton transfer process [49,50], and the discussion on the rotamerization process is rare. Thus, one of the aims of the present study is to provide complementary insight into the structure and stability of uracil tautomers as well as their tautomerizations. In this work, one DFT method (B3LYP) and two ab initio methods (MP2, and CCSD(T)) were chosen for the calculations. A comparison between the results obtained from dierent methods allowed us to nd obvious discrepancies in relative energies of the tautomers at dierent level of theories [51], as well as in the stability order of the uracil tautomers. The energy barriers of the tautomerizations are also reported. The proton transfer processes are recalculated at dierent level of theories and the conclusion of previous studies is further conrmed. We have also calculated the energy barriers of the eight rotamerism processes involved in the uracil tautomerizations, which are discussed for the rst time. Although there are numerous works on the uracil and its tautomers, there is no investigation of the phosphorus-containing uracil analogues, diphosphouracils. Inspired by the synthetic works of uracil [52,53], we believe that these analogues of uracil may also be synthesized using similar experimental methods. Similarly to the uracil case the diphosphouracil should also have 13 tautomers. There are many interesting questions on the diphosphouracil tautomers concerning, e.g. their stability order, energy barriers, proton transfer processes, chemical properties. To answer some of the questions using computational studies is another goal of this study. Using the same set of methods as for uracil, we performed theoretical calculations on the tautomers of diphosphouracil as well as its tautomerization processes. The investigation allowed us to predict the geo-

metrical structures as well as the stability order of the diphosphouracil tautomers, as well as discuss the energy barriers of the tautomerization processes. The comparison between uracil and diphosphouracil tautomers allowes us to suggest that there are non-negligible dierences in their structures, and the stability orders of the tautomers of the two analogues are quite dierent. Due to these dierences the energy barriers of analogous tautomerization process of the two systems are also quite dierent. The possible reasons for the dierent properties of the two analogues are also discussed. 2. Computational details All of the calculations were performed using the Gaussian-03 software package [54]. The B3LYP and MP2 methods were used for geometry optimizations and vibrational frequency calculations. Single point energy calculations were done also using CCSD(T) method based on the geometry optimized at the MP2 level of theory. In all calculations the standard 6-31+G** basis set was used. All the minima and transition states were conrmed by frequency analysis. For the notations of the tautomers and rotamers of uracil we use the method employed by Kryachko et al. [42]. The name of the tautomer is derived from the number of the atom connected to a hydrogen atom. Two rotamers of the OH group are dierentiated by subscript 1 or 2, e.g. 1,3-U for uracil, and 3,21-U and 1,21-U are the 2-hydroxy-4-oxo tautomers while their rotamers are 3,22-U and 1,22-U, respectively. For convenience sake the notation of the transition states of some of the tautomerization processes are opposite to those used in Kryachkos paper (e.g. 3,41-U and 3,42-U, which represent the two rotamers of one of the 2-oxo-4Hydroxy tautomers). The notation for diphosphouracil tautomers is identical, but U is replaced by PU to dierentiate them from uracil tautomers. 3. Results and discussion 3.1. The stability order of uracil and diphosphouracil tautomers As shown in Fig. 1, the order of stability of the uracil tautomers is the same when considering relative energy or relative free energy. At B3LYP/6-31+G** level of theory, the most stable tautomer is 1,3-U, followed by 21,3-U, 1,41-U, 21,41-U, 22,41-U, 21,42-U, 22,42-U, 1,42-U, 22,3-U, 1,22-U, 3,42-U, 3,41-U, and 1,21-U. This order is consistent with former studies [30,35,42]. High level ab initio methods give not only considerable dierences in relative energy values, but also change the stability order [51]. Both MP2 and CCSD(T) methods predict that 21,41-U has a lower energy than 1,41-U, what is not in agreement with the B3LYP result. At the MP2 and CCSD(T) levels of theory the stability order of 1,22-U, 22,3-U, and 1,42-U tautomers is

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4 5 3 6 2 1

CCSD(T) MP2 B3LYP

1,3-U 0.0 0.0 (0.0) 0.0 (0.0)

21,3-U 21,41-U 10.2 10.8 10.6 (10.7) 10.9 (11.4) 11.1 (11.0) 12.8 (12.9)

1,41-U 11.6 11.8 (11.9) 12.0 (11.8)

22,41-U 21,42-U 11.9 16.4 12.1 (12.5) 16.7 (16.9) (14.0) 18.3 (18.2) 14.0

22,42-U 16.4 16.7 (16.9) 18.4 (18.3)

1,22-U 18.2 18.7 (18.1) 19.6 (19.1)

22,3-U 18.8 19.3 (18.2) 19.5 (18.7)

3,41-U 1,42-U 21.5 19.0 19.4 (18.9) 21.9 (21.3) 19.2 (18.6) 21.4 (20.7)

3,42-U 24.8 25.2 (23.0) 24.5 (23.3)

1,21-U 28.9 29.7 (28.9) 30.5 (28.6)

Fig. 1. Relative energy (in kcal/mol) of uracil tautomers. Values in parentheses are relative Gibbs energy.

1,22-U > 22,3-U > 1,42-U, while the DFT method indicates these three tautomers have similar energies, and the stability order is completely opposite. Since high level ab initio methods are more reliable in the prediction of energy, we believe the correct order of stability for the uracil tautomers should be (from the most stable to the most unstable): 1,3-U, 21,3-U, 21,41-U, 1,41-U, 22,41-U, 21,42-U, 22,42-U, 1,22-U, 22,3-U, 1,42-U, 3,42-U, 3,41-U, and 1,21-U. The relative energy values for all of the tautomers compared to the value for 1,3-U tautomer are given in Fig. 1. As mentioned above, the energy gaps predicted by dierent methods are also non-identical. In general, the B3LYP method gives the largest energy gaps, while for the CCSD(T) method the energy dierences are the lowest. The discrepancy is particularly large in the case of 21,41-U, 22,41-U, 21,42-U, and 22,42-U tautomers, since the CCSD(T) energy values for these tautomers are 2.0 kcal/mol lower than those for the B3LYP method. The second most stable tautomer 21,3-U, is 11.1 kcal/mol less stable than the 1,3-U tautomer on the B3LYP level. The same dierences calculated at the

MP2 and CCSD(T) levels are 10.6 kcal/mol and 10.2 kcal/ mol, respectively. Compared with experimental value of 9.5 kcal/mol [6,7], the result of CCSD(T) method is the most accurate. A detailed analysis of the geometrical parameters of the tautomers allows us to suggest that there are two factors determining the relative stability of the tautomers. One of them is the repulsion between the neighboring OH and NH or CH groups, while the other one is the attraction between the OH or NH bonds and the lone pair of the neighboring nitrogen or oxygen atoms, as described in former study [42]. The values of the Mulliken partial charges at hydrogen atoms of OH or NH groups are similar, but larger than the values at the hydrogen atom of the CH group (Table 1). As a results, the repulsion between the neighboring OH and NH groups is stronger than the repulsion of the neighboring OH and CH groups (see relative energies of 3,42-U and 3,41-U tautomers). Furthermore, the values of the partial charges makes the structures with neighboring

Table 1 Mulliken atomic charges of uracil tautomersa Hmb 1,3-U 21,3-U 21,41-U 1,41-U 22,41-U 21,42-U 22,42-U 1,22-U 22,3-U 1,42-U 3,41-U 3,42-U 1,21-U
a b

Hnb 0.393 0.392 0.401 0.405 0.397 0.374 0.372 0.418 0.362 0.368 0.398 0.382 0.367

H5 0.214 0.207 0.204 0.212 0.204 0.181 0.181 0.207 0.207 0.189 0.186 0.207 0.207

H6 0.201 0.180 0.177 0.200 0.177 0.177 0.177 0.196 0.180 0.201 0.175 0.177 0.193

O2 0.635 0.568 0.553 0.638 0.554 0.549 0.542 0.582 0.533 0.626 0.615 0.625 0.536

O4 0.602 0.629 0.569 0.554 0.573 0.546 0.535 0.596 0.636 0.512 0.573 0.563 0.578

N1 0.615 0.489 0.455 0.584 0.413 0.410 0.453 0.574 0.450 0.579 0.437 0.443 0.566

N3 0.732 0.694 0.563 0.596 0.591 0.545 0.519 0.562 0.682 0.545 0.697 0.696 0.499

0.382 0.415 0.397 0.378 0.392 0.396 0.395 0.380 0.374 0.379 0.392 0.364 0.353

CCSD(T) results. Hm and Hn mean the proton on m,n-U. For example, for 21,3-U, Hm is the proton on O2 and Hn is the proton on N3.

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OH and NH groups unstable (as in the case of 3,42-U and 1,21-U tautomers). The structures and relative energy values for the diphosphouracil tautomers are given in Fig. 2 (detailed distances and angles values are given in Supplementary material). We can see the structures as well as the stability order are dierent from the uracil case. Furthermore, the values of the Mulliken partial charges carried by the HP and HO groups of the diphosphouracil are also quite dierent from the values obtained for the H-N and HO groups of the uracil (Table 2). Instead of 1,3-PU, the most stable diphosphouracil tautomer is the 21,41-PU. All three computational methods predict that three other tautomers have similar energies, and at CCSD(T) level of theory the rela-

tive energy values for 22,41-PU, 21,42-PU, and 22,42-PU compared to the most stable tautomer are 0.7 kcal/mol, 1.5 kcal/mol, and 1.6 kcal/mol, respectively. These four most stable diphosphouracil tautomers are all dienols, which is dierent from the uracil tautomers, where the diketo 1,3-U system is by far the most stable. It is interesting to notice that the four most stable tautomers of diphosphouracil are all planar structures, while all other tautomers (which are much higher in energy) are all in puckered conformation. In case of uracil all the tautomers are planer. It is reasonable to assume that for the planar dienol forms of phosphouracil tautomers the three p systems involved in the six-membered ring and the lone pairs of

21,41-PU CCSD(T) MP2 B3LYP 0.0 0.0 (0.0) 0.0 (0.0)

22,41-PU 0.7 0.7 (0.6) 0.7 (0.6)

21,42-PU 1.5 1.7 (1.4) 1.8 (1.6)

22,42-PU 1.6 1.8 (1.5) 1.9 (1.7)

1,41-PU 11.4 15.7 (13.9) 10.7 (8.3)

1,3-PU 12.7 18.5 (14.0) 12.1 (6.9)

3,41-PU 13.9 18.3 (16.2) 13.3 (10.7)

1,22-PU 14.0 18.5 (16.5) 14.4 (12.0)

21,3-PU 14.4 18.6 (16.7) 14.1 (11.6)

1,42-PU 14.6 19.0 (16.8) 14.2 (11.4)

3,42-PU 15.4 19.8 (17.3) 14.3 (11.3)

1,21-PU 22,3-PU 17.9 17.5 21.7 (19.0) 22.6 (19.8) 16.7 (13.9) 18.5 (15.5)

Fig. 2. Relative energy (in kcal/mol) of diphosphouracil derivative tautomers. Values in parentheses are relative Gibbs energy.

Table 2 Mulliken atomic charges of diphosphouracil derivative tautomersa Hmb 21,41-PU 22,41-PU 21,42-PU 22,42-PU 1,41-PU 1,3-PU 3,41-PU 1,22-PU 21,3-PU 1,42-PU 3,42-PU 22,3-PU 1,21-PU
a b

Hnb 0.373 0.371 0.367 0.369 0.381 0.004 0.379 0.383 0.009 0.368 0.371 0.017 0.367

H5 0.182 0.181 0.144 0.144 0.192 0.199 0.151 0.195 0.193 0.160 0.184 0.192 0.196

H6 0.186 0.183 0.184 0.181 0.195 0.193 0.185 0.191 0.185 0.195 0.188 0.183 0.194

O2 0.450 0.443 0.449 0.448 0.435 0.427 0.427 0.466 0.458 0.436 0.425 0.445 0.449

O4 0.498 0.496 0.496 0.500 0.471 0.465 0.526 0.471 0.503 0.460 0.506 0.502 0.469

P1 0.300 0.397 0.297 0.398 0.483 0.515 0.278 0.593 0.261 0.485 0.278 0.345 0.519

P3 0.447 0.357 0.545 0.430 0.302 0.487 0.536 0.354 0.565 0.407 0.497 0.489 0.472

0.370 0.367 0.368 0.368 0.028 0.027 0.016 0.034 0.382 0.028 0.037 0.369 0.041

CCSD(T) results. Hm and Hn mean the proton on m,n-PU. For example, for 22,3-PU, Hm is the proton on O2 and Hn is the proton on P3.

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the phosphorous atoms are delocalized, thus the whole molecule is stabilized due to an increased of aromaticity. In these dienol forms the attractive interactions between the OH bonds and the delocalized electron cloud are relatively strong, thus all of the four tautomers of the dienol forms are stable. This can also account for the low relative energies of the 21,42-PU and 22,42-PU tautomers, as compared to the 21,41-PU and 22,41-PU tautomers, respectively. Though in the former two tautomers the orientations of the OH groups at atom C4 do not point to the lone pairs of the phosphorous atoms and there may be unfavorable interactions between the OH and CH groups, they can still gain stability from the attractive interaction between the OH group and the delocalized electron cloud. Because of the unique bonding property of the phosphorous atom [55], the diketo and ketoenol forms of diphosphouracil tautomers are no longer planar. When the P atom is protonated in the diketo and ketoenol forms of tautomers, the lone pair and the three bonded pairs of the P atom(s) are in the tetrahedral geometry, and the six-membered rings are puckered to certain degrees. As a result, the delocalized p system is destroyed ant the relative energies of all the ketoenol and diketo tautomers are much higher. In the puckered ketoenol or diketo forms, the PH bond is out of the six-membered ring, and the attractive interaction between the PH bond and the lone pair of the neighboring O atom is weaker than in the case of uracil tautomers. Despite the weak interaction between the PH bond and the lone pair of the adjacent O atom, there is another factor that can stabilize the ketoenol tautomers. It is the attractive interaction of the OH bond with the lone pair of the phosphorous atom, such as in 1,41-PU tautomer, which is the most stable ketoenol of diphosphouracil. On the other hand, the repulsion interaction between the OH group with neighboring PH or CH bond may destabilize the whole molecule. This is the case in 22,3-PU and 1,21-PU tautomers, which are the least stable systems. All the intramolecular interactions of diphosphouracil tautomers as well as the dierences compared with the uracil tautomers will be further discussed in the description of the tautomerization processes. The dierences in the results for diphosphouracil tautomers obtained using dierent methods are large. MP2 method gives in most cases higher relative energy values, even over 6 kcal/mol higher than those obtained from B3LYP and CCSD(T) calculations. Though the relative energy values predicted by B3LYP and CCSD(T) methods are quite close for all of the tautomers, it is worth noticing that in some cases the CCSD(T) method gives higher relative energies than the B3LYP method (which did not happen in the uracil case). With B3LYP and CCSD(T) methods, 1,41-PU and 1,3-PU tautomers are $10 kcal/ mol higher in energy than the dienol forms. Though the diketo and the ketoenol forms are not as stable as the dienol forms, their energy dierences are not as large as the gaps between the analogous tautomers of uracil. Similarly

to the uracil case, the 1,21-PU is predicted to be the most unstable tautomer. The dierence in the energy between the most stable and unstable system of diphosphouracils is, however, only 17.9 kcal/mol, which is 11 kcal/mol less than for the uracil system. Another dierence between uracil and diphosphouracil systems is the stability order of the tautomers at dierent level of theory. As shown in Fig. 2, the MP2 and CCSD(T) stability order (from stable to unstable) of the diphosphouracil tautomers is 21,41-PU, 22,41-PU, 21,42-PU, 22,42-PU, 1,41-PU, PU, 3,42-PU, 1,22-PU, 21,3-PU, 1,42-PU, 3,41PU, 22,3-PU, and 1,21-PU. The DFT result is slightly different from that. B3LYP calculations indicate the stability order of 1,22-PU, 21,3-PU, and 1,42-PU should be 21,3PU > 1,42-PU > 1,22-PU. The dierence in relative energies for those three tautomers is, however, small for all used levels of theory, and is well within the standard error for those methods. At B3LYP level of theory, the calculated relative free energies of 1,41-PU and 1,3-PU tautomers are 8.3 kcal/ mol and 6.9 kcal/mol, respectively, which indicates 1,3-PU tautomer is more stable than 1,41-U tautomer. MP2 results for the order of the relative free energy are consistent with that of the relative energy. The dipole moments of the uracil and diphosphouracil tautomers are given in Tables 3 and 4, respectively. Former studies indicate the dipole moments of uracil tautomers calculated at MP2/6-31G* level of theory are more accurate than the B3LYP/6-31+G** method [27,33,42,56]. Our results show that when using the 6-31+G** basis set, the dipole moment calculated with MP2 method is slightly higher than that from B3LYP calculation. This result suggests that the calculated dipole moment values are quite sensitive to the basis set used. Compared with available experimental data [14,15], all the predictions overestimate the dipole moment suggesting that indeed the B3LYP method gives more reliable results. As the two tables show, for analogous tautomers of uracil and diphosphouracil the former is predicted to have always a higher dipole moment. For both analogues, the 21,41-U and 21,41-PU tautomers have the lowest dipole moments. The dipole moment of the 1,21-U tautomer is
Table 3 Dipole moments (in Debye) of uracil tautomers B3LYP 1,3-U 21,3-U 21,41-U 1,41-U 22,41-U 21,42-U 22,42-U 1,22-U 22,3-U 1,42-U 3,42-U 3,41-U 1,21-U 4.66 3.41 1.30 5.06 2.49 4.20 3.82 6.72 2.37 7.93 7.46 6.07 9.44 MP2 5.28 3.87 1.65 5.78 2.49 4.76 4.16 7.40 2.48 8.91 8.11 6.45 9.94

A.F. Jalbout et al. / Chemical Physics 332 (2007) 152161 Table 4 Dipole moments (in Debye) of diphosphouracil tautomers B3LYP 1,3-PU 21,3-PU 21,41-PU 1,41-PU 22,41-PU 21,42-PU 22,42-PU 1,22-PU 22,3-PU 1,42-PU 3,42-PU 3,41-PU 1,21-PU 3.26 3.34 0.59 3.69 2.14 3.16 2.66 3.96 1.71 6.05 5.43 4.00 5.98 MP2 3.72 3.47 1.01 4.15 2.12 3.78 3.06 4.33 1.66 6.72 5.72 4.01 6.43 22,41-U ! 22,42-U 3,42-U ! 3,41-U 21,42-U ! 22,42-U 21,41-U ! 22,41-U 21,3-U ! 22,3-U 21,41-U ! 21,42-U 1,22-U ! 1,21-U 1,41-U ! 1,42-U 22,41-U ! 22,3-U 21,42-U ! 1,42-U 21,41-U ! 1,41-U 21,3-U ! 21,41-U 22,42-U ! 3,42-U 22,41-U ! 3,41-U 1,3-U ! 1,41-U 1,3-U ! 21,3-U 1,3-U ! 1,22-U
a b

157

Table 5 Activation energy (in kcal/mol) of uracil tautomerization processes B3LYPa 8.9 4.9 8.6 8.8 9.4 9.8 10.6 11.5 36.1 34.1 33.5 35.6 35.6 38.4 40.8 41.9 47.2 MP2a 8.5 4.6 8.2 8.3 9.2 9.5 10.9 11.5 37.9 36.1 35.6 36.1 37.6 40.0 41.2 42.6 46.6 CCSD (T)b 9.2 4.7 9.0 9.2 9.7 10.3 11.1 12.1 42.8 41.0 40.3 40.7 42.6 45.6 46.3 47.4 51.7

the largest among the uracil tautomers, while for the diphospouracil system the lowest dipole moment can be attributed to the 1,42-PU tautomer. 3.2. The energy barriers and structures of transition states of uracil and diphosphouracil tautomerizations The structures of the transition states for the uracil tautomerization processes obtained at the MP2/6-31+G** level of theory are depicted in Fig. 3 together with selected bond lengths are given. The activation energies for the tautomerizations of uracil are given in Table 5. The energy barriers obtained with B3LYP and MP2 methods are quite similar. On the other hand, CCSD(T) method values are signicantly dierent in all cases, apart from OH group rotamerization processes. The trend of the results from the three methods are quite clear. For the OH group rotamerization processes, all of the activation energies calculated at B3LYP level of theory are slightly higher than those from MP2 calculations. In these processes (except

Gibbs free energy. Relative energy.

for 3,42-U ! 3,41-U), the activation energies from CCSD(T) method are again higher than the relative free energies from B3LYP and MP2 methods. However, for the proton transfer processes (except for 1,3-U ! 1,21-U), the predicted activation energies from B3LYP method are slightly lower (within 2 kcal/mol) than those of MP2. For these processes the dierence between the relative energy from CCSD(T) method and the relative free energies from B3LYP and MP2 is non-negligible, reaching over 5 kcal/ mol. We choose to use the B3LYP energies and MP2 energies for the discussions of rotamerizations of OH group and proton transfer processes, respectively. From Table 5 we can see that the rotamerizations of the OH group are relatively easier than the proton transfer processes, since the

22, (41,42)-U

3, (41,42)-U

(21,22), 42-U
1.396 1.270

(21,22), 41-U

(21,22), 3-U

1.382

1.268

1.377

1.275

21, (41,42)-U
1.381 1.282 1.257 1.392

1, (21,22)-U

1, (41,42)-U
1.336 1.317

22, (3,41)-U

(1,21), 42-U

(1,22), 41-U

1.242 1.411 1.345 1.319

1.346 1.320

21, (3,41)-U

(22,3), 42-U

(22,3), 41-U

1, (3,41)-U

(1,21), 3-U

1, (22,3)-U

Fig. 3. Optimized MP2 structures of the transition states of uracil tautomerization. Selected bond length are shown (values in A). 22, (41, 42)-U means the transition state of 22,41-U ! 22,42-U or 22,42-U ! 22,41-U.

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A.F. Jalbout et al. / Chemical Physics 332 (2007) 152161 Table 6 The relation between the activation energy of uracil tautomerization process and proton transfer distance MP2 (kcal/mol) Transfer distance (A) 1,3-U ! 21,3-U 1,3-U ! 1,41-U 1,3-U ! 1,22-U 21,3-U ! 21,41-U 22,3-U ! 22,41-U 1,41-U ! 21,41-U 1,42-U ! 21,42-U 3,42-U ! 22,42-U 3,41-U ! 22,41-U 42.6 41.2 46.6 36.1 32.2 35.1 34.1 33.2 29.5 0.957 0.955 1.020 0.900 0.833 0.886 0.877 0.876 0.812

activation energies for the former processes are lower. The energy barriers of the rotamerizations of the OH group are relatively low. The lowest activation energy of only 4.9 kcal/mol was attributed to the 3,42-U ! 3,41-U process. The energy barriers of the other seven rotamerization processes are several kcal/mol higher, and the 1,41U ! 1,42-U process has the highest energy barrier of 11.5 kcal/mol. Since all the rotamerizations values are obtained from modeling the transition from the more stable rotamer to the less stable one, the reverse processes are more facile. The energy barriers for proton transfer processes are much higher. For the 21,41-U ! 1,41-U process which has the lowest proton transfer barrier, the activation energy is over 20 kcal/mol higher than that of the 1,41-U ! 1,42-U process, which has the highest rotamerization energy barrier. At MP2/6-31+G** level of theory, the proton transfer barriers for 21,41-U ! 1,41-U, 21,42-U ! 1,42-U, 22,3U ! 22,41-U, 21,3-U ! 21,41-U, 22,42-U ! 3,42-U, 22,41U ! 3,41-U are within the range of 35-40 kcal/mol. For 1,3-U ! 1,41-U, 1,3-U ! 21,3-U, and 1,3-U ! 1,22-U processes the energy barriers are predicted to be even higher: 41.2 kcal/mol, 42.6 kcal/mol, and 46.6 kcal/mol, respectively. Previous DFT studies on the proton transfers of the uracil tautomers indicated that energy barriers of the proton transfer processes is related to the proton transfer distance [50]. This conclusion is further conrmed by the results of our calculations. In Fig. 4, the proton transfer barriers with MP2 method as a function of the proton transfer distances (Table 6) are presented. In all cases the higher proton transfer distance corresponds to the higher activation energy is needed. The structures of the tautomerization transition states of diphosphouracil are given in Fig. 5 while their activation energies are given in Table 7. In the calculations of the OH group rotamerization processes, the barriers calculated

48 46 44 Active energy (kcal/mol) 42 40 38 36 34 32 30 28 0.80 0.85 0.90 0.95 1.00 1.05 Proton transfer distance (angstrom)
Fig. 4. Activation energy of uracil tautomerization as a function of the proton transfer distance. The values are taken from Table 5.

by B3LYP method are the highest, followed by the results of CCSD(T) method. The values for the rotamerization barriers obtained using the MP2 method are the lowest. In this case, however, all the values are very similar with the largest discrepancy being only 1 kcal/mol. Compared with the rotamerization processes of uracil, the energy barriers for most of the analogous processes of the diphosphouracil are lower by 35 kcal/mol. The one exception is the 3,42U ! 3,41-U process. This process has the lowest activation energy among the uracil rotamerizations, and the activation energy of the 3,42-PU ! 3,41-PU process is only slightly lower. This dierence indicates the OH rotamerizations are easier to occur for the diphosphouracil tautomers. The eight dierent rotamerization processes are listed in Table 6 are. Among these processes, the 22,42-PU ! 22,41-PU process has the smallest energy barrier, while the energy barrier of the 1,41-PU ! 1,42-PU process is the highest. In the calculations of proton transfer barriers of the diphosphouracil tautomers, the dierences among the results obtained using the three methods are evident. The barriers predicted by B3LYP method are always the lowest, and except for the processes of 1,3-PU ! 1,21-PU and 1,3PU ! 21,3-PU, the MP2 results are about 3-5 kcal/mol higher than that of the B3LYP. The barriers predicted by CCSD(T) methods are, on the other hand, always the highest. Compared with the tautomerization processes of uracil, the energy barriers of the proton transfer processes of the diphosphouracil tautomers are much higher. The three processes which have the lowest activation energy are 1,3-PU ! 1,22-PU (41.1 kcal/mol), 1,41-PU ! 1,3-PU (41.5 kcal/mol), and 1,3-PU ! 21,3-PU (41.9 kcal/mol). These values are nearly as high as the highest activation energy of the uracil tautomerization processes. For the remaining six processes (22,42-U ! 3,42-U, 21,41-U ! 1,41U, 21,42-U ! 1,42-U, 22,41-U ! 3,41-U, 21,41-U ! 21,3-U, 22,41-U ! 22,3-U), their MP2 activation energies are predicted to be over 50 kcal/mol. The tautomerizations which includes two kinds of processes; one is the rotamerization of the OH group and the other is the proton transfer process. Our results suggest that the phosphouracil rotamers are more likely to undergo the former processes than the uracil rotamers, while the uracil tautomers have lower energy barriers for the latter processes. These dierences can be explained by dierent

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159

22, (41,42)-PU

(21,22), 42-PU

(21,22), 41-PU

3, (41,42)-PU
1.498 1.626

21, (41,42)-PU

1.471

1.638

(21,22), 3-PU
1.495 1.625

1, (21,22)-PU

1, (41,42)-PU

22, (3,41)-PU
1.381 1.690

(1,21), 42-PU

1.728 1.354 1.466 1.643 1.337 1.746

21, (3,41)-PU

(1,22), 41-PU

1, (22,3)-PU

1, (3,41)-PU

(1,21), 3-PU

1.644 1.454

1.643 1.457

(22,3), 42-PU

(22,3), 41-PU

Fig. 5. Optimized MP2 structures of the transition states of diphosphouracil tautomerizations. Selected bond length are shown (values in A). 22, (41, 42)PU means the transition state of 22,41-U ! 22,42-PU or 22,42-U ! 22,41-PU.

Table 7 Activation energy (in kcal/mol) of diphosphouracil tautomerization B3LYPa 22,41-PU ! 22,42-PU 21,42-PU ! 22,42-PU 21,41-PU ! 22,41-PU 3,42-PU ! 3,41-PU 21,41-PU ! 21,42-PU 21,3-PU ! 22,3-PU 1,22-PU ! 1,21-PU 1,41-PU ! 1,42-PU 22,41-PU ! 22,3-PU 21,42-PU ! 1,42-PU 21,41-PU ! 21,3-PU 21,41-PU ! 1,41-PU 1,3-PU ! 1,22-PU 1,41-PU ! 1,3-PU 1,3-PU ! 21,3-PU 22,42-PU ! 3,42-PU 22,41-PU ! 3,41-PU
a b

MP2a 3.5 3.5 3.6 3.8 4.0 5.1 5.5 6.2 53.4 51.3 53.1 50.9 41.1 41.6 41.9 50.8 51.8

CCSD (T)b 3.8 3.9 4.0 4.0 4.4 5.5 5.9 6.9 56.5 54.2 55.7 53.5 44.2 46.3 45.3 53.3 54.5

4.5 4.5 4.6 4.4 5.0 6.0 6.2 7.2 48.2 46.8 47.7 46.3 40.8 38.4 40.3 46.1 47.4

the lone pair of the phosphorous atom (for 1,41-PU and 1,22-PU). In these cases the energy barriers for the OH group rotations are lower. For the proton transfer processes, the stable tautomers of uracil possess strong attractive interaction between the OH bond and the lone electron pair of the nitrogen atom. This interaction can facilitate the migration of the hydrogen atom from the O atom to N atom. On the other hand, for the stable tautomers of diphosphouracil both the interaction of the OH group with lone pair of the neighboring phosphorous atom and interaction of the PH group with the lone pair of the neighboring O atom are supposed to be relatively weak. As a result, neither the migration of the hydrogen atom from the O atom to the P atom nor the reverse process is favorable from the energetical point of view. 4. Conclusion A comprehensive theoretical study on the stability orders as well as the tautomerization processes of uracil and diphosphouracil tautomers has been performed using the B3LYP, MP2 and CCSD(T) methods. Compared to the results obtained from the DFT method, the stability order of the 12 uracil tautomers is reordered at the high level ab initio levels of theory. The structures and stability order of the 12 tautomers of diphosphouracil are predicted for the rst time using these three methods. We have found that the four dienol form diphosphouracil tautomers which have planar structures are much more

Gibbs free energy. Relative energy.

intramolecular interactions of the two analogues. For uracil, the stable rotamers are stabilized by the interaction of the OH bond and the lone pair of the neighboring N atom (except for 3,42-U). This stabilizing interaction makes it more dicult for the OH bond to rotate to other directions. On the other hand, for diphosphouracil systems (except for 3,42-PU), the stable rotamers are stabilized either by the delocalized p systems (for 21,41-PU and 21,42-PU) or by the weak interaction of the OH bond with

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A.F. Jalbout et al. / Chemical Physics 332 (2007) 152161 [5] A. Padva, T.J. ODonnell, P.R. LeBreton, Chem. Phys. Lett. 41 (1976) 278. [6] M. Fujii, T. Tamura, N. Mikami, M. Ito, Chem. Phys. Lett. 126 (1986) 583. [7] Y. Tsuchiya, M. Fujii, M. Ito, J. Phys. Chem. 92 (1988) 1760. [8] B.B. Brady, L.A. Peteanu, D.H. Leavy, Chem. Phys. Lett. 147 (1988) 538. [9] M. Kubota, T. Kobayashi, J. Electron Spectrosc. Relat. Phenom. 82 (1996) 61. [10] D. Shugar, K. Szczepaniak, Int. J. Quantum Chem. 20 (1981) 573. [11] M. Szczesniak, M.J. Nowak, K. Szczepaniak, W.B. Person, D. Shugar, J. Am. Chem. Soc. 105 (1983) 5969. [12] S. Chin, I. Scot, K. Szczepaniak, W.B. Person, J. Am. Chem. Soc. 106 (1984) 3415. [13] Y.D. Radchenko, G.G. Scheina, N.A. Smorygo, Yu. P. Blagoi, J. Mol. Struct. (THEOCHEM) 116 (1984) 387. [14] R.D. Brown, P.D. Godfrey, D. McNaughton, A.P. Pierlot, J. Am. Chem. Soc. 110 (1988) 2329. [15] I. Kulakowska, M. Geller, B. Lesyng, K.L. Wierzchowski, K. Bolewska, Biochim. Biophys. Acta 407 (1975) 420. [16] B.B. Brady, L.A. Peteanu, D.H. Levy, Chem. Phys. Lett. 147 (1981) 538. [17] P. Beak, J.M. White, J. Am. Chem. Soc. 104 (1982) 7073. [18] R. Czerminski, B. Lesying, A. Pohorille, Int. J. Quantum Chem. 16 (1979) 605. [19] T. Zielinski, J. Am. Chem. Soc. 22 (1982) 639. [20] M.J. Scanlan, I.H. Hillier, J. Am. Chem. Soc. 106 (1984) 3737. [21] J.S. Kwiatkowski, T.J. Zielinski, R. Rein, Adv. Quantum Chem. 18 (1986) 85. [22] U.J. Norinder, J. Mol. Struct. (THEOCHEM) 151 (1987) 259. [23] M. Saunders, G.A. Webb, M.S. Tute, J. Chem. Phys. 158 (1987) 69. [24] J.S. Kwiatkowski, R.J. Bartlett, W.B. Person, J. Am. Chem. Soc. 110 (1988) 2353. [25] H. Basch, D.R. Garmer, P.G. Jasien, M. Krauss, W. Stevens, J. Chem. Phys. 163 (1989) 514. [26] A. Les, L. Adamowicz, J. Phys. Chem. 93 (1989) 1649. [27] I.R. Gould, I.H. Hillier, J. Chem. Soc., Perkin Trans. 2 2 (1990) 329. [28] A. Les, L. Adamowicz, J. Phys. Chem. 94 (1990) 7021. [29] P.G. Jasien, G. Fitzgerald, J. Chem. Phys. 93 (1990) 2554. [30] J. Leszczynski, Int. J. Quantum Chem. Quantum Biol. Symp. 18 (1991) 9. [31] A.R. Katritzky, M. Karelson, J. Chem. Soc., Perkin Trans. 2 3 (1991) 1561. [32] J. Leszczynski, J. Phys. Chem. 96 (1992) 1649. [33] D.A. Estrin, L. Paglieri, G. Corongiu, J. Phys. Chem. 98 (1994) 5653. [34] I.R. Gould, N.A. Burton, R.J. Hall, I.H. Hillier, J. Mol. Struct. (THEOCHEM) 331 (1995) 147. [35] L. Paglieri, G. Corongiu, D.A. Estrin, Int. J. Quantum Chem. 56 (1995) 615. [36] M. Monshi, K. Al-Farhan, S. Al-Resayes, A. Ghaith, A.A. Hasanein, Spectrochim. Acta A 53 (1997) 2669. [37] S.X. Tian, C.F. Zhang, Z.J. Zhang, X.J. Chen, K.Z. Xu, Chem. Phys. 242 (1999) 217. [38] M.K. Shukla, J. Leszczynski, J. Phys. Chem. A 106 (2002) 8642. [39] M. Piacenza, S. Grimme, J. Comput. Chem. 25 (2004) 83. [40] R. Zhang, A. Ceulemans, M.T. Nguyen, Mol. Phys. 103 (2005) 983. [41] J.K. Wolken, F. Turecek, J. Am. Soc. Mass Spectrom. 11 (2000) 1065. [42] E. Kryachko, M.T. Nguyen, T. Zeegers-Huyskens, J. Phys. Chem. A 105 (2001) 1288. [43] L. Gorb, J. Leszczynski, J. Am. Chem. Soc. 120 (1998) 5024. [44] J.D. Gu, J. Leszczynski, J. Phys.Chem. A 103 (1999) 577. [45] Z. Smedarchina, W. Siebrand, A. Fernandez-Ramos, L. Gorb, J. Leszczynski, J. Chem. Phys. 112 (2000) 566. [46] L. Gorb, J. Leszczynski, Int. J. Quantum Chem. 70 (1998) 855. [47] J.D. Gu, J. Leszczynski, J. Phys. Chem. A 103 (1999) 2744. [48] L. Gorb, Y. Podolyan, P. Dziekonski, W.A. Sokalski, J. Leszczynski, J. Am. Chem. Soc. 126 (2004) 10119. [49] X. Hu, H. Li, W. Liang, S. Han, J. Phys. Chem. B 108 (2004) 12999.

stable than the diketo and ketoenol forms. By comparisons of the stability of the relative rotamers, we propose the dienol form diphosphouracil tautomers are stabilized by the attractive interaction of the OH bonds with the delocalized p system of the planar structures. On the other hand, the corresponding uracil tautomers are stabilized only by the attractive interaction of the OH bonds with the lone pairs of the neighboring nitrogen atoms. Because of the unique bonding property of P atom and the geometrical features of the diketo and ketoenol form tautomers of phosphouracil, we believe that the interaction of the OH (or PH) bond with the lone pair of the neighboring phosphorous atom (or oxygen atom) is not as strong as the similar interaction that exists in corresponding uracil tautomers. The two processes of the tautomerizations of uracil and phosphouracil tautomers are discussed in details and the activation energies for all these processes are reported. For both uracil or diphosphouracil, computational results show the OH rotamerization processes are much easier to occur than the proton transfer processes. For the OH group rotamerization processes, the energy barriers for the diphosphouracil rotamers are several kcal/mol lower than the rotamerizations of the uracil rotamers. Conversely, for the proton transfer processes the energy barriers for the tautomerizations of the diphosphouracil tautomers are much higher than those of the uracil tautomers. All these dierences are the results of the dierences in structural parameters and intramolecular interactions between the two analogues. Acknowledgements Y. Li and Y. Xia thank the science foundation of Jiangsu province and the Chinese academy of sciences for nancial support. We also thank the reviewers for valuable comments that improved the manuscript. DGSCA and the UNAM are thanked for generous nancial support and computational resources. Appendix A. Supplementary material Detailed MP2/6-31+G(d,p) structures of uracil and diphosphouracil tautomers as well as the transition states for the tautomerization processes. This material is available free of charge via the Internet. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.chemphys.2006.10.026. References
[1] T. Shimanouchi, M. Tsuboi, Y. Kyogoku, Adv. Chem. Phys. 7 (1964) 435. [2] R.C. Lord, G.J. Thomas, Spectrochim. Acta A 23 (1967) 2551. [3] G. Lauer, A. Schafer, A. Schweig, Tetrahedron Lett. 45 (1975) 3939. [4] D. Dougherty, K. Wittel, J. Meeks, S.P. McGlynn, J. Am. Chem. Soc. 98 (1976) 3815.

A.F. Jalbout et al. / Chemical Physics 332 (2007) 152161 [50] X. Hu, H. Li, W. Liang, S. Han, J. Phys. Chem. B 109 (2005) 5935. [51] This result is consistent with the former studies of the four most stable uracil tautomers: M. Piacenza, S. Grimme, J. Comput. Chem. 25 (2004) 83; R.A. Bachorz, J. Rak, M. Gutowski, Phys. Chem. Chem. Phys. 7 (2005) 2116. [52] K. Kobayashi, T. Tsuji, Chem. Lett. (1997) 903. [53] S. Miyakawa, K.-I. Murasawa, K. Kobayashi, A.B. Sawaoka, J. Am. Chem. Soc. 121 (1999) 8144. [54] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y.

161

Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Cliord, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian-03, Revision C.02, Gaussian, Inc., Wallingford, CT, 2004. [55] (a) For the studies on the bonding properties of phosphine and phosphorus-carbon multi-bond systems: J.A. Dobado, H. Martnez Garca, J.M. Molina, M.R. Sundberg, J. Am. Chem. Soc. 120 (1998) 8461; (b) L.L. Lohr, J. Phys. Chem. 88 (1984) 1981; (c) S.T. Howard, J.P. Foreman, P.G. Edwards, Inorg. Chem. 35 (1996) 5805. [56] T.v. Mourik, S.L. Price, D.C. Clary, J. Phys. Chem. A 103 (1999) 1611.