Theoretical study on protonated and deprotonated 5-substituted uracil derivatives and their complexes with water

Journal of Molecular Structure 605 (2002) 213±220

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Theoretical study on protonated and deprotonated 5-substituted uracil derivatives and their complexes with water Asit K. Chandra a, Tadafumi Uchimaru a, TheÂreÁse Zeegers-Huyskens b,* a

Department of Physical Chemistry, National Institute of Materials and Chemical Research, Tsukuba, 305 Ibaraki, Japan b Department of Chemistry, University of Leuven, 200F Celestijnenlaan, 3001 Heverlee, Belgium Received 30 April 2001; revised 12 June 2001; accepted 12 June 2001

Abstract The proton af®nity (PA) of the oxygen atoms and the deprotonation enthalpies (DPE) of the NH bonds of 5-substituted uracil derivatives (X ˆ CN, F, Cl, NH2) are computed using the density functional theory (B3LYP) at the 6-31 1 G(d,p) level. The PAs vary from 766 to 875 kJ mol 21 and the DPEs from 1315 to 1442 kJ mol 21. For all the studied uracils, the acidity of the N1H bond is larger than that of the N3H bond and the basicity of the O8 atom is larger than that of the O4 atom. The effect of the intramolecular hydrogen bond in 5-NH2 uracil is discussed. The three stable complexes with one water molecule are the ones in which the oxygen atom of water accepts the acidic NH proton while donating a proton to the carbonyl oxygen of uracils. The intermolecular distances and angles, and the binding energies with water are discussed in terms of the PA and DPE of the atoms or bonds involved in the interaction with one water molecule. q 2002 Elsevier Science B.V. All rights reserved. Keywords: B3LYP-6-31 1 G(d,p) calculations; 5-substituted uracils; Proton af®nities; Deprotonation enthalpies; Water complexes

1. Introduction The speci®c interactions between the purine and pyrimidine bases are one of the cornerstones of molecular biology. These interactions, which underly the transmission of genetic information, are governed in large part by the NH¼O or NH¼N hydrogen bonds between the appropriate bases [1]. These interactions are expected to depend not only on the proton acceptor ability of the O or N atoms but also on the intrinsic acidity of the NH bonds involved in the interaction. The

* Corresponding author. Tel.: 132-16-327477; fax: 132-16327991. E-mail address: [email protected] (T. Zeegers-Huyskens).

basicity of uracil which is the simplest nucleobase has been discussed in several works [2±12]. Only recently have acidity calculations been conducted or measured experimentally [12±16]. In our recent works [10,11], the interaction of uracil and thymine with one water molecule has been discussed in terms of the gas-phase proton af®nity and the deprotonation enthalpy of the atoms or bonds involved in the interaction with water. These studies have been extended to the rare hydroxy-tautomers of uracil [17]. In the present work, theoretical calculations are performed to investigate the effect of substitution in position 5 (X ˆ F, Cl, CN, NH2) on the intrinsic acidity or basicity of uracils and on the structure and energy of their 1:1 adducts with water. Experimental data demonstrate that substitution of ¯uorine for hydrogen alters the chemical reactivity of the ring, although 5-¯uorouracil behaves as uracil

0022-2860/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0022-286 0(01)00760-8

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Table 1 B3LYP/6-31 1 G(d,p) proton af®nities of the oxygen atoms and deprotonation enthalpies of the NH bonds (kJ mol 21) in 5-substituted uracil derivatives (including ZPE energies calculated at the same level) 5-X Uraci

5-CN 5-F 5-Cl 5-H a 5-CH3 a 5-NH2 a b

PA

DPE

O7 (N1 side)

O7 (N3 side)

O8 (N3 side)

O8(C5 side)

N1H

N3H

766.3 798.0 802.4 813.4 830.1 852.6

772.3 802.9 807.5 819.2 835.1 855.7

796.8 816.7 824.5 847.0 854.8 846.5

818.2 838.4 847.1 858.9 865.8 b 875.3

1315.6 1359.2 1367.7 1390.5 1398.0 1402.6

1381.2 1414.7 1417.6 1446.7 1449.3 1442.4

From Ref. [11]. The experimental value of the PA of thymine which corresponds to the PA of the most basic site is 873 kJ mol 21 [33].

with respect to several enzymes [18]. It has also been suggested that 5-halogeno derivatives may adopt rare hydroxy forms easier than the non substituted uracil and therefore can act as a stronger mutagenic agent. However, in IR matrix-isolation study of methyl derivatives of 5-¯uorouracil [19,20], no evidence was found for the appearance of any detectable absorption corresponding to the hydroxy rare tautomers. Theoretical studies have also shown that the dioxo form of 5-F uracil is considerably more stable than the 2-hydroxy-4oxo or 2-oxo-4-hydroxy tautomers [21,22]. The interaction between 5-F uracil and one water molecule has been studied at a low computational level (SCF calculations with the STO-3G basis set) [23]. No theoretical data have been reported other substituted uracil derivatives. 2. Computational methodology The geometry of the isolated uracil derivatives and their corresponding water complexes was fully optimized by the density functional theory using B3LYP exchange correlation functional [24,25] and the 631 1 G(d,p) basis functions. The binding energies were corrected for the basis set superposition errors (BSSE) computed by the counterpoise method [26]. The proton af®nities and deprotonation enthalpies were computed at 298 K, using the same level of theory. As demonstrated in recent works [27±29], the B3LYP/6-31 1 G(d,p) computational level provides results comparable with the MP2 one in

calculating hydrogen bond energies, protonation and deprotonation enthalpies. It is also worth noticing that recent bracketing experiments have provided the gasphase acidities of the N1 and N3 sites of uracil [15]; these measurements are closest (within 4 kJ mol 21) to our predicted B3LYP/6-31 1 G(d,p) values [11], thus validating that computational method and level. The main scope of this work is to compare the acid-base properties of the uracil derivatives; the electron af®nities of the uracil radicals and the bond dissociation energies, not relevant for the discussion, were not considered. Harmonic frequencies were calculated to characterize the stationary points and to evaluate the frequency shifts due to complex formation with water. For the calculation of the zero-point vibrational energy (ZPE), the frequencies were retained unscaled. The Gaussian package [30] was used for all the calculations. 3. Results and discussion In Section 3.1, the intrinsic basicities of the oxygen atoms and the intrinsic acidities of the oxygen atoms of the uracil derivatives are discussed. Section 3.2 deals with the geometries and binding energies of the uracils-water 1:1 adducts. 3.1. Proton af®nities and deprotonation enthalpies of uracil derivatives The in¯uence of the substituents on the properties

A.K. Chandra et al. / Journal of Molecular Structure 605 (2002) 213±220

Fig. 1. B3LYP/6-31 1 G(d,p) optimized geometry of 5-NH2 uracil.

can be discussed in terms of the substituent parameters. The s I parameters associated with polar or inductive effects are CH3 (20.05), F (0.0.51), Cl (0.47), CN (0.52) and NH2 (0.10) while the s R0 parameters related to p-delocalization effects are CH3 (20.10), F (20.34), Cl (20.20), CN(0.14) and NH2 (20.48) [31]. The C2 ˆ O7 and C4 ˆ O8 distances in Ê . They are 5-NH2 uracil are equal to 1.223 and 1.228 A Ê 0.07 and 0.12 A longer than those in 5-CN uracil Ê . The where both distances are equal to 1.216 A Ê, N1C2 distances increases from 1.377 to 1.401 A Ê and the N1C6 distances from 1.392 to 1.363 A on going from 5-NH2 to 5-CN uracil [32]. It is also worth noticing that in 5-NH2 uracil, the sum of the angles around the nitrogen atom of the amino group is 342.68 indicating a marked pyramidalization of the amino group.

Fig. 2. DPE (kJ mol 21) of the N1H bonds (curve A) and of the N3H bonds (curve B) of uracil derivatives as a function of s I 1 s Ro .

215

The proton af®nities of the oxygen atoms and the deprotonation enthalpies of the NH bonds of the uracil derivatives are indicated in Table 1. This Table also contains the corresponding theoretical [11] and experimental [33] values for thymine (X ˆ CH3) useful for the comparison with the present data. In all the investigated uracil derivatives, the acidity of the N1H bond in the gas phase is signi®cantly larger than the one of the N3H bond. These results are in contrast with recent data on the calculated pKa values in water solution [34]. For thymine, uracil and 5-F uracil, the pKa values of the N3 site are lower than for the N1 site. However, for 5-formyluracil and 5NO2 uracil, the solution-phase deprotonation from N1H is more favorable than from N3H. This effect has been explained by a more extensive charge delocalization of the N1 2 species in uracils bearing electro-withdrawing substituents [34]. Further, for all the molecules, the basicity of the O7 atom is markedly lower than the one of the O8 atom. Our results indicate that substitution in position 5 greatly affect the intrinsic acidities and basicities. Substitution of CN by NH2 results in a increase of the PA of the O7 atom by ca. 85 kJ mol 21 and an increase of the DPE of the N1H bond by about the same amount. It is worth noticing that the PA of the O8 atom (N3 side) and the DPE of the N3H bond of 5NH2 uracil is predicted to be lower than in 5-CH3 uracil. This can be attributed to the particular structure of 5-NH2 uracil shown in Fig. 1. As indicated by the Ê and the N9H13O8 short H13¼O8 distance of 2.310 A angle of 105.58, an intramolecular hydrogen bond is present in this molecule. The existence of the bond is also indicated by natural bond orbital analysis (NBO), showing a signi®cant amount of electron transfer from the O8 lone pair orbital to the antibonding orbital of N9H13. As a result, this antibonding orbital has an electron occupancy of 0.012e. The in¯uence of this intramolecular hydrogen bond on PA and DPE can be estimated by the following procedure. As illustrated in Fig. 2, the DPEs of the N1H bonds are correlated to the sum s I 1 s Ro (curve A). An almost parallel curve is obtained for the N3H bond (curve B). Extrapolation of this curve for 5-NH2 uracil gives a DPE value of 1458 kJ mol 21, about 16 kJ mol 21 higher that the calculated value of 1442.4 kJ mol 21. Thus the formation of the intramolecular hydrogen bond

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Fig. 3. Schematic structure of the A, B and C complexes of uracils and water.

results in an increase of the acidity of the adjacent N3H bond by about 16 kJ mol 21. Although the scatter of the points is larger, a similar procedure can be applied to estimate the effect of the intramolecular interaction on the PA of the O8 atom. The formation of the intramolecular hydrogen bond decreases the PA of the lone pair of the O8 atom at the N3 side by about 30 kJ mol 21. The decrease of the PA of the lone pair of the O8 atom at the C5 side is smaller, about 10 kJ mol 21. This is somewhat surprising because this lone pair is involved in the formation of the intramolecular hydrogen bond and, as previously discussed, charge transfer takes place from this lone pair to the N9H13 bond. It is also worth mentioning that the DPEs and the PAs are correlated to each other. Substituents which increase the DPEs of the NH bonds (or decrease their acidity) also increase the basicity of the oxygen carbonyl atoms. This can be expressed by the following polynomials of the second degree where only the PAs of the lone pairs which are relevant for

this work are considered: DPE…N1H† ˆ 26250 1 17:8 PA…O7; N1† 2 0:013 PA 2 …O7; N1†

…1†

…r ˆ 0:9881† DPE…N3H† ˆ 26360 1 18:4 PA…O7; N3† 2 0:019 PA2 …O7; N1†

…2†

…r ˆ 0:9540† DPE…N3H† ˆ 25216114:7 PA…O8; N3† 2 0:0082 PA2 …O8; N3†

…3†

…r ˆ 0:9954† The coef®cient of the linear and non-linear terms of these equations are different but in the three cases, the contribution of the linear term is about 2.2 times

A.K. Chandra et al. / Journal of Molecular Structure 605 (2002) 213±220

217

Table 2 B3LYP/6-31 1 G(d,p) optimized intermolecular distances, intermolecular and dihedral angles (in parentheses) in the 1:1 adducts of 5-substiÊ , angles in degrees) tuted uracils with water (distances in A 5-X uracils

complex A 0

5-CN 5-Cl 5-F 5-H a 5-CH3 a 5-NH2 5-CN 5-F 5-Cl 5-H a 5-CH3 a 5-NH2 a

complex B 0

complex C

0

r((Ow)Hw ¼O) (/OwHw O, /OwHw OC) 2.030 (136.0, 22.6) 2.064 (134.1, 6.0) 1.966 (140.6, 22.0) 1.993 (139.0, 5.2) 1.960 (141.0, 22.0) 1.987 (139.3, 5.0) 1.941 (142.6, 21.7) 1.975 (141.6, 4.9) 1.929 (144.5, 21.6) 1.947 (143.3, 4.4) 1.908 (145.2, 21.3) 1.926 (143.8, 3.8) r((N)H...Ow) (/NHOw, /Hw 0 OwHN) 1.872 (146.6, 28.3) 1.928 (144.7, 9.4) 1.907 (144.5, 27.5) 1.950 (143.8, 8.6) 1.906 (144.7, 27.3) 1.955 (143.6, 8.3) 1.927 (144.3, 27.4) 1.988 (142.6, 7.6) 1.941 (144.3, 26.7) 1.999 (142.2, 7.5) 1.951 (143.0, 26.1) 1.980 (142.4, 7.6)

2.016 (136.6, 26.3) 1.970 (140.1, 25.9) 1.977 (140.1, 25.7) 1.921 (144.0, 25.5) 1.914 (144.8, 25.7) 1.937 (143.3, 25.6) 1.906 (145.7, 22.9) 1.943 (144.0, 22.5) 1.938 (144.7, 22.5) 1.968 (143.0, 22.2) 1.979 (143.0, 22.2) 1.978 (142.7, 22.2)

From Ref. [11].

larger than the one of the quadatric term. This will be useful for the further discussion. Substitution also in¯uences the vibrational frequencies. The n(N1H) and n(N3H) vibrations are predicted at 3656 and 3636 cm 21 in 5-NH2 uracil and at 3610 and 3601 cm 21 in 5-CN uracil. As expected, electron withdrawing substituents increase the frequencies of the n(C ˆ O) vibrations and electron donating substituents decrease these frequencies. The n(C2 ˆ O7) and n(C ˆ O8) vibrations are computed at 1821 and 1789 cm 21, respectively in 5-CN uracil and at 1799 and 1752 cm 21 in 5-NH2 uracil [32]. 3.2. Interaction between the uracil derivatives and one water molecule The B3LYP optimized geometries of the uracils complexed with one water molecule are schematically shown in Fig. 3. As for the uracil-H2O interation, the three stable closed complexes, A, B and C, are the ones in which the oxygen atom of water accepts the acidic NH proton while donating a proton to the carbonyl oxygen of uracils. All the complexes are characterized by the C1 symmetry, the Hw hydrogen atom being out-of-plane of the uracil ring. The OwHw 0 distance which at the present level of theory is equal Ê in free water, is elongated between values to 0.965 A Ê in 5-CN uracil (B) and 0.015 A Ê in 5equal to 0.008 A NH2 uracil (A). The elongation of the NH bonds are

slightly sensitive to the nature of the uracils. In the A complexes, the elongation of the N1H bond varies Ê in 5-CN Ê in 5-NH2 uracil to 0.015 A from 0.012 A uracil. In the C complexes, the elongation of the N3H bond varies within the same limits. The intermolecular distances, the OwHw 0 O and NHOw intermolecular angles and the OwHw 0 OC and Hw 0 OHN dihedral angles are gathered in Table 2. In the 5-NH2 uracil-H2O complex C, the H13¼O8 Ê , the N9H13O8 angle is distance is equal to 2.29 A equal to 105.78 and the sum of the angles around the nitrogen atom of the amino group is 341.98. These results indicate that the distances in the intramolecular hydrogen bond and the pyramidalization of the amino group are not in¯uenced signi®cantly by the formation of the intermolecular one. The intermolecular distances and angles are in¯uenced by the intrinsic acidities or basicities of the host molecules. The OwHw 0 ¼O hydrogen bond becomes more linear when the basicity of the carbonyl oxygen atom increases. For the A complexes, the OwHw 0 O angles increases from 136 to 1458, for the B complexes from 134 to 143.88 and for the C complexes from 136 to 143.38. The NHOw angle appears to be less sensitive to the acidity of the NH bond and increases only slightly, by 2 or 38, when the DPE of the NH bond decreases from 1402 to 1315 kJ mol 21 (A complexes) and from 1442 to 1381 kJ mol 21 (B and C complexes). This may result from the

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for the B and C ones. The equations of these two curves are: for the A complexes r……Ow †H 0 w ¼O† ˆ 10:1 2 0:0187 PA 1 0:11 £ 1024 PA2

…4†

…r ˆ 0:9937† and for the B and C complexes r……Ow †Hw 0 ¼O† ˆ 7:23 2 0:0112 PA 1 5:82 Ê ) as a function of the PA (kJmol 21) of the Fig. 4. r((Ow)Hw 0 ¼Ow) (A corresponding carbonyl oxygen atom. Curve 1 refers to the A complexes and curve 2 to the B and C complexes.

smaller directional character of the O lone pair(s) as compared with the one of the NH bond(s). The data of Table 2 also indicate that the intermolecular distances also depend on the nature of the substituents implanted on the uracil derivatives. The (Ow)Hw 0 ¼O distances vary within the limits of 1.914 Ê and the (N)H¼Ow distances between and 2.064 A Ê . In our previous works [10,11], 1.872 and 1.999 A the intermolecular distances in the uracil and thymine 1:1 water adducts have been discussed in terms of the PAs and DPEs of the bonds or atoms involved in the interaction with water. In Fig. 4, the intermolecular (Ow)Hw 0 ¼O distances are plotted vs. the PA of the corresponding O atoms. This ®gure shows that two distinct curves are obtained for the A complexes and

£ 1026 PA2 …r ˆ 0:9889†

The same intermolecular distances are obtained at lower PAs values for the A than for the B and C complexes. This is obviously due to the fact that the acidity of the N1H bond is higher than the one of the N3H bond. Similarly, the (N)H¼Ow distances are expected to depend mainly on the DPEs of the NH bonds. Fig. 5 indicates that two different lines are obtained: one for the A and B complexes and the other for the C complexes. In this case, the best ®t is obtained for the following linear equations: for the A and B complexes r……N†H¼Ow † ˆ 0:647 1 0:926 £ 1023 DPE …r ˆ 0:9854†

…6†

and for the C complexes r……N†H¼Ow † ˆ 0:427 1 0:107 £ 1022 DPE …r ˆ 0:9876†

Ê ) as a function of the DPE (kJ mol 21) of the Fig. 5. r((N)H¼Ow) (A NH bonds. Curve 1 refers to the C complexes and curve 2 to the A and B complexes.

…5†

…7†

In both the B and C complexes, the water molecule is bonded to the N3H bond of the uracil derivatives. However, the same (N)H¼Ow distances are obtained at larger DPE values for the C complexes than for the B complexes. This can be accounted for by the larger PA of the O4 atom (N3 side) which is involved in the formation of the C complexes. It is, however important to stress that these considerations do not hold within complexes characterized by a given A, B or C structure. For example, for the complexes A, the Ê (N)H¼Ow distance increases from 1.872 to 1.951 A

A.K. Chandra et al. / Journal of Molecular Structure 605 (2002) 213±220 Table 3 B3LYP/6-31 1 G(d,p) binding energies (kJ mol 21) including BSSE corrections for the A, B and C complexes of uracils with one water molecule (the values in parentheses indicate the binding energies with ZPE corrections) 5-X uracil

complex A

complex B

complex C

5-CN 5-F 5-Cl 5-H a 5-CH3 a 5-NH2

243.6 (234.5) 243.1 (234.3) 242.9 (233.4) 242.5 (232.8) 242.4 (232.1) 242.6 (232.9)

233.6 (225.3) 234.4 (225.7) 233.5 (225.1) 233.3(224.5) 233.7 (224.7) 235.6 (226.6)

236.8 (228.3) 235.6 (226.8) 235.6 (226.8) 235.8 (226.7) 235.2 (226.1) 234.0 (225.3)

a

From Ref. [11].

when the DPE of the N1H bond increases from 1316 to 1402 kJ mol 21 (this is as expected) but also increases when the PA of the O7 atom increases (this is rather unexpected). In a previous work on the interaction between uracil, cytosine, adenine and guanine with one water molecule [35], we have shown that the intermolecular distances in the all the closed complexes formed between the NH and carbonyl bonds could be expressed as a function of the difference (DPEÐ 0.37 PA). In this case, the DPE of the different NH bonds and PA of the O atoms of the nucleobases are independant. Owing to the correlations (1), (2) and (3) relating the DPEs and PAs of the different sites of molecules belonging to the same family, such a

Fig. 6. EHB (kJ mol 21) as a function of 1.5 DPEÐPA (kJ mol 21). Curve 1 refers to the 5-H, 5-CH3, 5-F and 5-NH2 uracil-H2O complexes. Curve 2 refers to the 5-Cl uracil-H2O complexes and curve 3 to the 5-CN uracil-H2O complexes.

219

correlation could not be deduced for the present complexes. The binding energies of the uracil derivatives with one water molecule are listed in Table 3. It is worth mentioning that for a given A, B or C structure, these binding energies are rather insensitive to the nature of the substituent implanted in 5position. Their values, including ZPE corrections, vary indeed from 232.1 to 234.5 kJ mol 21 for complexes A, from 224.5 to 226.6 kJ mol 21 for complexes B and from 225.3 to 228.3 kJ mol 21 for complexes C. Thus, for all the complexes between substituted uracils and one water molecule, the binding energies are ordered according to: complexes A . complexes C . complexes B Comparison of the data of Tables 1 and 3 reveals that the most stable hydrogen bond is formed at the lone pair characterized by the lowest PA and at the NH site characterized by the highest acidity. In a previous work [35], we have deduced a correlation between the binding energies of the nucleobases with one water molecule (EHB) and the function (1.5 DPEÐPA). As discussed in our work, this correlation was thought to be valuable only when the intermolecular and dihedral angles in the pseudo-six-membered ring formed between the nucleobase and water are constant or nearly so. For the present complexes, we observe large deviations from this correlation for the three 5-CN uracil-H2O complexes and smaller but signi®cant deviations for the 5-Cl uracil-H2O complexes. This is illustrated in Fig. 6. As discussed above, the intermolecular angles depend on the nature of the substituent. Moreover, the dihedral angles OwHw 0 OC and Hw 0 OwHN increase signi®cantly on going from the 5-NH2-H2O to the 5-CN-H2O complexes. The largest deviation from the planarity of the pseudo-six-membered ring in 5-CN uracil parallels the largest deviation observed in Fig. 6. Although other effects can in¯uence the correlation between hydrogen bond energies and the acidity or basicity of the atoms or groups involved in the interaction, the geometric parameters such as the intermolecular and dihedral angles play a determinant role. These effects have been extensively discussed for open complexes [36] but are less known for cyclic complexes where two hydrogen bonds are formed simultaneously.

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