Theoretical Investigation on the Substituent Effect of Halogen Atoms at

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Theoretical Investigation on the Substituent Effect of Halogen Atoms at C Position of Adenine: Relative Stability, Vibrational Frequencies, and Raman Spectra of Tautomers 8

Yanli Chen, De-Yin Wu, and Zhong-Qun Tian J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b03604 • Publication Date (Web): 31 May 2016 Downloaded from http://pubs.acs.org on June 7, 2016

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The Journal of Physical Chemistry

Theoretical Investigation on the Substituent Effect of Halogen Atoms at C8 Position of Adenine: Relative Stability, Vibrational Frequencies, and Raman Spectra of Tautomers Yan-Li Chen, De-Yin Wu,* and Zhong-Qun Tian State Key Laboratory of Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemistry, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

ABSTRACT We have theoretically investigated the substituent effect of adenine at the C8 position with a substituent X = H, F, Cl, and Br by using the density functional theory (DFT) at the B3LYP/6-311+G(d, p) level. The aim is to study the substituent effect of halogen atoms on the relative stability, vibrational frequencies, and solvation effect of tautomers. Our calculated results show that for substituted adenine molecules the N9H8X tautomer to be the most stable structure in gas phase at the present theoretical level. Here N9H8X denotes the hydrogen atom binds to the N9 position of imidazole ring and X denotes H, F, Cl, and Br atoms. The influence of the induced attraction of the fluorine substituent is significantly larger than chlorine and bromine

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ones. The halogen substituent effect has a significant influence on changes of vibrational frequencies and Raman intensities.

INTRODUCTION Adenine and its derivatives are the essential component in biological molecules and polymers, such as coenzymes and nucleic acids.1 They work in energy storing, and reaction catalysts, and information transfer as well as medicals.2 The substituent at C8 position of purine can greatly affect the rate of deoxyribosyl transfer to the base and the nature of the nucleoside formation.3 When the substituent is a halogen atom, which has higher electronegativity and electronwithdrawing properties, this causes changes of the electronic properties of the purine ring substantially.4 Such a change in the charge distribution of the nucleobase is expected to influence the acid-base properties of the molecule and possibly change the site of protonation.5 Furthermore, 8-chloroadenine was proved to be a useful biomarker for studying the role of reactive chlorine species during inflammatory processes.6 For example, 8-chloroadenosine is being developed to treat multiple myeloma and leukemia, and Newman et.al. determined the pharmacology of 8-chloroadenosine in rodents through examination of plasma and cellular levels of parent drug and metabolites.7 Besides, the addition of a bromine atom at the adenine C8 position could cause the association constant enhanced.8 When the complex of thymidine and 8bromoadenine was used as substrates, 3-deoxyribonucleoside is the major product initially due to the deoxyribosyl moiety preferentially transferred to the N3 position of the adenine ring, while 9deoxyribonucleoside becomes the major product after long incubation periods.3 However, most of these studies did not provide information about the nucleobase at the molecular level. It is


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important to develop a systematic evaluation of substituted adenine, and shed a light on the chemical and biochemical properties of these nucleosides or nucleotides. Different spectroscopic techniques, containing microwave spectroscopy,9 matrix-isolated spectroscopy,10 double resonance spectroscopy,11 IR spectroscopy,12 NMR spectroscopy,13 and photoelectron spectroscopy,14 have been used to investigate adenine and its derivatives in the isolated molecule state, the solid state, and aqueous solution. But the key problem is how to build the relation between tautomerization and vibrational spectra in experimental and theoretical studies.15-19 A few of theoretical studies have been reported on halogen substituted at the C8 position of adenine, but these studies mainly focused on changes of tautomerism, electronic structures, protonation and deprotonation, as well as the influence of the substituent effect on the hydrogen bonding interaction. Ladik and Bcizó studied the charge distribution of series of substituted adenine at the SCF MO level for understanding the nucleotide base antimetabolitetype possible anti-carcinogenic activity in 1970.20 Then Jorden used the empirical CENDO/2 calculations to investigate the electronic structures of 9-methyladenine in which the C8 substituent is varied through H, Cl, and NH2 groups.21 The relative stability of different conformations of adenosine was investigated due to the protonation at a low ab initio level.22 Recently, density functional theoretical calculations were used to explore the stability of different tautomers and hydrogen bonding pairs of DNA bases, but these studies mainly focused on analyses of the substituent effect on geometries, energies, charge distributions and hydrogen bonding interactions.4, 13, 23-25 Till now, there are only a few studies on theoretical analysis of vibrational spectra of these halogen substituted adenine derivatives.23,

26

The assignment of

observed Raman bands still limited to the optimized structures at the SCF/STO-3G level and the assignment of adenine analogues.26-27


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To fill this gap, we theoretically investigate the effect of halogen substituents at the C8 position on adenine. Figure 1 shows the hydrogen atom H12 of adenine replaced by a fluorine, chlorine or bromine atom. Through density functional theoretical calculations, we determine the relative stability of tautomeric forms of 8-halogen adenine (N9H8X, N3H8X, N7H8X, and N1H8X). Here X denotes H, F, Cl, and Br atoms. Then by using normal mode analysis we further analyze characteristic frequencies and Raman intensities. Finally, we explore the vibrational frequency shift related to the N9−H in-plane bending in the imidazole ring and related aromatic organic compounds, which are closely associated with the hydrogen bonding interaction, and can be considered as an indicator for measuring different environment factors.

Figure 1. Molecular structures of four 8-halogen adenine tautomers. COMPUTATIONAL DETAILS Four low-energy tautomers of 8-halogen adenine with the atomic numbering were shown in Figure 1. The halogen substitution at the C8 position of adenine forms 8-fluoroadenine, 8chloroadenine, and 8-bromoadenine, respectively. Adenine has five nitrogen atoms, which are


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labeled as N1, N3, N7, N9, and N10, respectively. Figure 1 presents four tautomers related to the position of H13 at N atom positions. Density functional theory (DFT) approach28 was used to obtain the optimized structures and vibrational spectra of different tautomers. Hybrid exchange-correlation functional approach B3LYP29-33 is one of the most promising quantum chemical methods for adenine derivatives.16, 34 The basis set for H, C, N, F, Cl, and Br atoms is 6-311+G(d, p),35-36 which includes the polarization function to all of the atoms and the diffusion function to the heavy atoms. So different tautomers of 8-halogen adenine (N9H8X, N3H8X, N7H8X, and N1H8X) were calculated at the B3LYP/6-311+G(d, p) level. All the DFT calculations were performed with the Gaussian 09 program package.37 The vibrational frequencies were calculated to ensure that the optimized equilibrium structures are minima on potential energy surfaces. This theoretical method used has been proven suitable to the investigation of binding interaction, vibrational frequencies, and Raman intensities.38-39 When the solvation effect was considered, the polarizable continuum model (PCM)40 includes a solvent reaction field self-consistent with the solute electrostatic potential. Water was chosen as the solvent with a dielectric constant of 78.3. To investigate the chemical bonding in halogen substituted derivatives, the natural bonding orbital (NBO) analysis41-42 has been used to the optimized geometry at the same theoretical level. To determine the corresponding relationship of different tautomers and vibrational spectra, the vibrational fundamentals were analyzed in details. On the basis of equilibrium geometries and Cartesian force constant matrixes, potential energy distributions (PED) by using the scaled quantum mechanical force field (SQMF) procedure43-44 in Scale 2.0 program,45 are used to do the complete vibrational assignments for vibrational peaks appearing in simulated Raman spectra. The calculated harmonic frequencies were scaled by the factor of 0.981 for below 2000 cm−1 and


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0.967 for above 2000 cm−1.39 The normal mode analysis provides clear physical pictures for understanding the vibrational frequency shift due to the substituent effect at the C8 position of adenine. To provide a deep insight into the Raman spectra, absolute Raman intensities of selected vibration modes were calculated. The absolute Raman intensities were measured by using the differential Raman scattering cross section (DRSCS, ( dσ d Ω )i ),46

( v%0 − v%i ) h  dσ  ( 2π ) Si (1)   = 2 45 8π cv%i 1 − exp ( − hcv%i / k BT )  dΩ  i where, h, c, k B , and T are Planck constant, the speed of light, Boltzmann constant, and Kelvin 4

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temperature, respectively. v%0 and v%i denote the incident light frequency and the vibrational frequency of the ith mode, respectively. The Raman scattering factor (RSF) is 2   dα  2  dγ   Si =  45   + 7   , which is calculated from Gaussian 09 program. The value of RSF   dQi   dQi  

consists of two contributions, the isotropic polarizability derivative, αi′ , and the anisotropic polarizability derivative, γ i′ , of the ith vibrational mode. α ′ and γ ′ are defined as the following expressions,

α′ =

{

1 (α xx′ + α ′yy + α zz′ ) 3

(2)

}

2 2 2 2 1 2 2 α xx′ − α ′yy ) + (α ′yy − α zz′ ) + (α zz′ − α xx′ ) + 6 (α xy′ ) + (α x′z ) + (α ′yz )  (3) (   2 where α ′pq ( p, q = x, y, z ) is the component of the molecular polarizability tensor derivatives

γ ′2 =

along p and q axes. To make a direct comparison with experimental Raman spectra, the simulated Raman spectra were presented in terms of the Lorentzian expansion of the DRSCS magnitudes with a half-height half width about 10 cm−1. The incident wavelength of 785 nm was used here.


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RESULTS AND DISCUSSIONS Relative Stability of 8-Halogen Adenine Tautomers. Table 1 presents the relative energies

∆E, Gibbs free energies ∆G, and dipole moments µ of 8-halogen adenine tautomers in the gas phase and in aqueous solution with the PCM model. The Gibbs free energies were calculated at the 298.15 K under 1 atm. Among four tautomers of adenine, the N9H8H structure is the most stable one in the gas phase or in aqueous solution, which is consistent with previous studies.47-48 The results in Table 1 also show that no matter adenine or the substitutes, the order of relative stabilities of these tautomers is N9H8X > N3H8X > N7H8X > N1H8X in the gas phase. The solvation effect can significantly decrease the relative energy differences of four tautomers.38 Take adenine for example, the energy difference between those in gas phase and in solution decreases from 8.09 to 5.38, 8.30 to 2.55, and 18.68 to 8.44 kcal/mol for N3H8H, N7H8H, and N1H8H with respect to N9H8H, respectively. For adenine, N7H8H becomes more stable than N3H8H under the solvation condition. Thus the stable order is N9H8H > N7H8H > N3H8H > N1H8H. When the solvation effect was considered for 8-fluoroadenine, the relative Gibbs free energies of N9H8F, N3H8F, and N1H8F tautomers decrease to a value less than 2.0 kcal/mol, indicating that they are possibly coexisting in aqueous solution. In the case, N3H8F becomes the most stable tautomer of 8-fluoroadenine. This relative stable order of 8fluoroadenine tautomers is expected to change to N3H8F > N9H8F > N1H8F > N7H8F in aqueous solution. For 8-bromoadenine, our results showed that N9H8Br is the most stable tautomer with the PCM model. While this is different from the previous study, where N3H8Br is predicted to be the most stable tautomer from the single point energy calculated at the B3LYP/Aug-cc-pVTZ level with the B3LYP/6-31(d) optimized structure under the PCM model in dimethyl sulfoxide solvent.13 While for 8-chloroadenine and 8-bromoadenine, the solvation


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effect does not change their relative stability and the N9H8X tautomers are still the most stable ones in aqueous solution. The significant change arises from the large difference in the dipole moments of the four tautomers. The dipole moments listed in Table 1 for four tautomers of 8halogen adenine, also support the relative stability in an ascending order of N9H8X, H3H8X, N7H8X, and N1H8X. Table 1. Relative Energies (∆E, kcal/mol), Gibbs Free Energies (∆G, kcal/mol), and Dipole Moments (µ, Debye) of 8-Halogen Adenine Tautomers Calculated at the B3LYP/6-311+G(d, p) Level in the Gas Phase and in Aqueous Solution with the PCM Model. a N9H8X

N3H8X

N7H8X

N1H8X

Species

X=H

X=F

X = Cl

X = Br a

Gas

PCM

Gas

PCM

Gas

PCM

Gas

PCM

∆E

0

0

8.09

5.38

8.44

0 2.46 2.46 b 0 0 0.81 0 0 1.12 0 0 1.28

0 3.41 3.62 b 0 0 1.42 0 0 1.72 0 0 1.92

8.94 4.14

5.53 5.91

19.46 8.62

8.34 13.22

3.47 4.72 5.88 5.27 5.92 5.86 5.71 6.30 5.86

−0.73 −0.21 8.17 0.76 1.93 8.24 1.12 2.43 8.22

2.55 1.67 b 2.57 10.34 11.45 b 2.36 2.72 9.69 2.67 3.47 9.79 2.73 3.54 9.81

18.68

∆G µ

8.30 7.98 b 9.08 6.97 6.96 b 7.75 8.83 6.50 8.10 8.54 6.48 8.13 8.53 6.43

13.16 14.41 10.07 15.41 15.91 10.14 15.96 16.35 10.15

1.64 0.55 15.13 3.33 4.35 15.27 3.73 4.86 15.28

∆E ∆G µ ∆E ∆G µ ∆E ∆G µ

Relative energies in the gas phase (in aqueous solution with the PCM model) are referred to −467.45139 au (−467.46611 au) of N9H8H, −566.71793 au (−566.73125 au) of N9H8F, −927.07085 au (−927.08369 au) of N9H8Cl, and −3040.99036 au (−3041.00324 au) of N9H8Br, respectively. b Calculated data from ref. 16 Table 2 lists the Boltzmann population ratios of adenine and substituted ones predicted with the PCM model at room temperature. When water was considered as the solvent, adenine will be predominated in the form of N9H8H in aqueous solution, which agrees with previous studies.10, 16, 48

Although the N9H8F tautomer is the main existing form in the gas phase, N3H8F and

N9H8F are the main components of 8-fluoroadenine in aqueous solution. For 8-chloroadenine


8

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and 8-bromoadenine, the N9H8X is the main existing form with a population larger than 95 % at the present theoretical level. Table 2. Boltzmann Population Ratios (%) of 8-Halogen Adenine Tautomers in Aqueous Solution with the PCM Model at 298 K and 1atm. Species

X= H

X= F

X= Cl

X= Br

N9H8X

98.70

35.32

95.96

98.11

N3H8X

0.01

50.47

3.70

1.61

N7H8X

1.29

0.36

0.27

0.25

N1H8X

0.00

13.85

0.06

0.03

Electronic structure. To further investigate the effect of halogen substitutions at C8 position of adenine, we also analyzed changes of electronic structure properties. Figure 2 presents the orbital energy levels and electron density plots of the most stable tautomers N9H8X of four compounds. Some details of optimized structures were provided in Table S1, Figure S1 and Table S2 in Supporting Information. We can summarize the effect of the halogen substitution on the electronic structures as three points. First, the halogen substitution slightly changes the frontier molecular orbital levels. As seen in Figure 2, the substitution of halogen atoms raises the highest occupied molecular orbital (HOMO) π bonding orbital from −6.51 to −6.48 eV, in agreement with the electron-withdrawing ability of halogen atoms. Furthermore, the substitution effect also results in the lowest delocalized π bonding orbital from −12.96 eV in adenine further lowering to −14.55 (F), −13.96 (Cl), and −13.37 eV (Br) in 8-halogen adenine. On the other hand, the halogen substitution causes the lowest unoccupied molecular orbital (LUMO) levels from −0.99 eV in adenine to −0.94, −1.14 and −1.17 eV in N9H8F, N9H8Cl, and N9H8Br, respectively. The second π* anti-bonding orbital (LUMO+1) level of adenine is −0.25 eV. After the halogen substitution, the π* anti-bonding orbital levels decrease to −0.52, −0.48, and −0.47


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eV in N9H8F, N9H8Cl, and N9H8Br (LUMO+2), respectively. Compared with adenine, the C8−X π* anti-bonding orbitals located at 0.61 eV for N9H8F, 0.34 eV for N9H8Cl, and 0.29 eV for N9H8Br. Their energy gaps (ELUMO−HOMO) are larger than 5.3 eV. Among four compounds, the largest orbital energy gap is predicted to be about 5.56 eV in 8-fluoroadenine, as seen in Figure 2. Second, the halogen substitution changes the components of three lone paired orbitals at N1, N3, and N7 positions in the purine ring planar. From Figure 2, the lone paired orbitals are HOMO−1, HOMO−3, and HOMO−5 with the exception of HOMO−7 for N9H8Br. If we take adenine as a reference, the halogen substitute effect decreases the energies of these lone-paired orbitals. The calculated results in Figure 2 indicate that the lone-paired orbitals at N1 and N3 atoms have a large contribution to the HOMO−1 with the high energy while the lone-paired orbital at the N7 atom has a dominant contribution to the lowest lone paired molecular orbital. According to the NBO analysis of N9H8H, the energies of three localized lone paired orbitals are −9.38, −9.83, and −10.55 eV at N1, N3, and N7 atoms, respectively. When the halogen substituted effect was considered, these lone-paired orbitals have an average decrease about 0.3 eV. This can explain the relative stability of different tautomers. Third, now our attention will pay to the p orbitals on halogen atoms directly interacting with the molecular orbitals in the purine ring moiety. This can be considered as two types of molecular orbital interactions. The one is the p orbital parallel to the purine ring interacting with the C8−N7 and C8−N9 bonding orbitals to form a σ* anti-bonding orbital. From Figure 2, the p orbitals locate at −9.67 eV (HOMO−6) and -8.87 eV (HOMO−5) in N9H8Cl and N9H8Br, respectively. While for N9H8F there are two molecular orbitals HOMO−8 (−11.93 eV) and HOMO−9 (−12.43 eV) containing the p orbital of F atom. The other orbital interaction is the π-


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type interaction of the p orbital on halogen atoms perpendicular to the purine ring plane. The π orbitals located at −11.74 eV (HOMO−9) and −11.62 eV (HOMO−9) in N9H8Cl and N9H8Br, respectively, are slightly higher in energy than −11.28 eV (HOMO−7) and −12.77 eV (HOMO−10) in N9H8F. This is consistent with the C8−N7 and C8−N9 bond lengths shorten by the halogen substitution, following the ascending order of F < Cl ≤ Br.


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Figure 2. Molecular orbital energies (eV) and electron cloud plots of low-energy tautomers N9H8X of 8-halogen adenine (X = H, F, Cl, and Br) calculated at the B3LYP/6-311+G(d, p) level in the gas phase. The number shown in the picture of the energy levels is the energy gap (eV) of the HOMO and LUMO levels. Frequencies Analysis and Raman Spectra. For adenine and halogen substituted species, N9H8X is the most stable tautomer in the gas phase. So we first consider the characteristic fundamentals of N9H8X. Figure 3 displays simulated Raman spectra of N9H8X. The calculated frequencies, scaled frequencies, IR intensities, Raman activities, and potential energy distribution (PED) of N9H8X tautomers were collected in Table S3-S5. We discussed the vibrational frequencies separated as three regions here, low (200 − 950 cm−1), middle (950 − 1700 cm−1), and high (3000 − 3600 cm−1) frequency regions. N9H8H. Figure 3a shows the simulated Raman spectrum of N9H8H. In the first frequency region, the strongest Raman peak at 711 cm−1 arises from the ring breathing vibrational mode. Many previous studies focused on the breathing vibrational mode of adenine.49-52 It was noted that the characteristic frequencies in the second region are very useful to provide the fingerprint signals. These intense Raman peaks mainly come from the C−N and C−C stretching vibrations as well as the C−H and N−H in-plane bending vibrations. Among the frequency region, two main characteristic peaks are 1333 cm−1 mainly from the C2−N1 stretching and 1485 cm−1 mainly from the C8−N7 stretching, with the Raman activities about 48 and 77 Å4/amu, respectively. In the observed Raman spectrum, the strong characteristic band at 1333 cm−1 should arise from two strong fundamentals of 1331 and 1338 cm−1 (see Table S3). This is in accordance with the experimental results of polycrystalline adenine that has a strong band at 1333 cm−1 and a broad band at 1483 cm−1.50 N9H8H also has four relatively intense peaks at 1059, 1219, 1243, and


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1388 cm−1, belonging to the C8−N9 stretching, NH2 rocking, C8−H12 in-plane bending, and N9−H in-plane bending, respectively. In the third frequency region, the vibrational frequencies can be attributed clearly to C−H and N−H stretching vibrations according to the vibrational assignment in Table S3.

Figure 3. Simulated Raman spectra of the lowest-energy tautomers N9H8X (X = H, F, Cl, and Br) in the gas phase calculated at the B3LYP/6-311+G(d, p) level. (a) N9H8H, (b) N9H8F, (c) N9H8Cl, (d) N9H8Br. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1.


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N9H8F. Figure 3b presents the simulated Raman spectrum of N9H8F. We can see that the simulated Raman spectrum of N9H8F is very different from that of N9H8H. The ring breathing vibrational frequency displays a large blue shift to 799 cm−1 with PED = 14 from the C−F stretching (see Table S4). In the low frequency region the relatively intense peaks are 228, 389, 488, 598, and 645 cm−1. The fundamentals of 228 and 389 cm−1 can be assigned to the mixture vibrations of the C6−N10 and C−F in-plane bendings. The latter three fundamentals can be attributed to the deformations of the pyrimidine and imidazole rings in terms of Table S4. For the middle frequency region, the rich fingerprint signals presented two very intense peaks at 1233 and 1559 cm−1. They can be attributed to a mixed vibration of the C5−N7 stretching and the −NH2 rocking, and another mixed vibration of the C8−N7 stretching and the −NH2 scissoring, respectively. In the high frequency region, there are four fundamentals predicted at 3068, 3491, 3527, and 3618 cm−1. They can be simply attributed to the C2−H stretching, −NH2 symmetric stretching, the N9−H stretching, and −NH2 asymmetric stretching, respectively. N9H8X (X = Cl and Br). Figure 3c and 3d present the simulated Raman spectra of N9H8Cl and N9H8Br in gas phase. Their simulated Raman spectra are quite similar to each other. In the first frequency region, the ring breathing vibrations are the strongest Raman peaks, which have scaled vibrational frequencies at 753 and 741 cm−1, respectively. It is interesting in the PED distribution with 11 percent from the C8−Cl12 stretching in N9H8Cl (see Table S5). In fact the characteristic C8−Cl12 stretching frequency locates at 407 cm−1 with PED = 40. Except the ring breathing vibration, N9H8Br has only one strong Raman band at 268 cm−1 from the C8−Br12 stretching in the low frequency region. In the second frequency region, the strongest Raman peaks appear at 1481 and 1463 cm−1 for N9H8Cl and N9H8Br, respectively, which can be assigned safely to the C8−N7 stretching with the PED values about 56 and 66, respectively. The secondary intense


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Raman peaks are 1225 and 1317 cm−1 in N9H8Cl and 1223 and 1313 cm−1 in N9H8Br. The former peaks at 1225 and 1223 cm−1 mainly arise from the C5−N7 stretching (PED = 28) and the −NH2 rocking (PED = 24), while the latter ones at 1317 and 1313 cm−1 are mainly from the ring stretchings of pyrimidine. The weak Raman peaks in the region are 1109, 1159, and 1389 cm−1 in N9H8Cl and 1103, 1155, and 1385 cm−1 in N9H8Br. Finally, the characteristic stretching frequency of the pyrimidine ring appears at 1603 cm−1 in N9H8Cl and at 1601 cm−1 in N9H8Br. In the high frequency region, there are four Raman peaks respectively from two C−H and N−H stretching vibrations and two −NH2 stretching ones. By inspecting these four simulated Raman spectra shown in Figure 3, we noted that 8fluoroadenine is significantly different from those of adenine, 8-chloroadenine, and 8bromoadenine. These are consistent with the above analysis of the halogen substituted effect on the geometric structure of adenine. Halogen substituted neighboring effect in imidazole ring. By inspecting the ring breathing vibrational frequencies of N9H8X, we can observe a large blue shift in N9H8X with respect to that in N9H8H. Among three substituents, N9H8F has the largest blue shift about 88 cm−1. Figure 4 further summarizes the vibrational frequency shifts because of the halogen substituent effect at the C8 position. As one can see the trend in Figure 4, both the stretching and in-plane bending vibrational frequencies of C8−X12 have significantly red shifts with the order of H, F, Cl, and Br. For the C8−N7 stretching vibration, only 8-fluoroadenine has a large blue shift. While for the C8−N9 stretching vibration, the characteristic fundamentals appear at 1059 cm−1 in adenine, 1012 and 1436 cm−1 in 8-fluoroadenine, 1109 cm−1 in 8-chloroadenine, and 1103 cm−1 in 8bromoadenine have a great blue shift.


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3500 3000 1500

ν C8-N7 β N9-H13

-1

Raman Shift (cm )

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ν C8-N9

1000

ν ring breathing

500 ν C8-X12 β C8-X12

0 X=H

X=F

X=Cl

X=Br

N9H8X Figure 4. Variation of vibrational frequencies related to selected internal coordinates in N9H8X (X=H, F, Cl, and Br) in the gas phase calculated at the B3LYP/6-311+G(d, p) level. It is very interesting in the significant influence of the halogen substitution on the vibrational modes related to the N9−H deformation. Since the deformation coordinate contributes to two to four fundamentals, this causes a certain difficulty to make a clear assignment for the characteristic frequency of the N9−H bending experimentally and theoretically. In gas phase, for instance, there are 1059, 1243, and 1388 cm−1 in N9H8H, 1183 and 1436 cm−1 in N9H8F, while its contribution delocalizes to three fundamentals at 1109, 1159, 1389 cm−1, and 1103, 1155, 1385 cm−1 for N9H8Cl and N9H8Br, respectively. In previous studies the characteristic frequency of the N9−H in N9H8H bending was proposed to 1061 cm−1 by Mohamed et al.1 or 1451 cm−1 by Hirakawa et al.53 In fact, the bending coordinate simultaneously contributes to three fundamentals at 1076, 1244, and 1396 cm−1 based on normal mode analysis.10, 34 For the 1061 cm−1 fundamental, the vibration is consisted of the C8−N9 stretching with PED = 57 and the N9−H in-plane bending with PED = 31 (see Table S3), indicating the fundamental can be safely


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attributed to the C8−N9 stretching. The N9−H bending also contributes to the 1240 cm−1 fundamental with the PED about 10 and the 1389 cm−1 fundamental with the PED about 28 (see Table S3). We also noted that the N−H deformation is a specific phenomenon in pyrrole,54-56 indole,57-61 imidazole,62-63 and benzimidazole.64 The N−H deformation in pyrrole can contribute to the observed frequencies at 1418, 1127, and 1530 cm−1,54 corresponding to our scaled frequencies at 1422 (PED = 38), 1136 (PED = 29), and 1542 cm−1 (PED = 18), respectively. The N−H deformation in indole can be satisfied to the observed frequencies at 1412, 1276, and 1509 cm−1.57 They agree quite well with our scaled frequencies at 1415 (PED = 26), 1243 (PED = 15), and 1493 cm−1 (PED = 11), respectively. The N−H deformation mainly contributes to the observed fundamentals at 1429 cm−1 in imidazole63 and 1416 cm−1 in benzimidazole,64 corresponding to our unscaled frequencies at 1429 and 1418 cm−1 and scaled frequencies at 1403 (PED = 38) and 1390 cm−1 (PED = 29), respectively. These results showed that the N−H bending vibration contributes two or three fundamentals in analogue compounds. Influence of Solvation Effect on Raman Spectra. Figure 5 shows the simulated Raman spectra of 8-fluoroadenine, and the totally simulated Raman spectrum was estimated on the basis of the Boltzmann distribution in Table 2. Their normal vibrational analyses are listed in Table S6-S7. Compared with the simulated Raman spectrum of N9H8F in the gas phase, the characteristic peaks obviously have changed under the PCM model. Firstly, the distribution of the C8−F12 stretching delocalized to several fundamentals at 644, 800, 1017, and 1544 cm−1 (see Table S6). For N9H8F, the most significant change is the C8−N7 stretching vibration at 1544 cm−1 with a red shift of 15 cm−1 with respect to 1559 cm−1 in the gas phase. The Raman activity of the vibration increases to 213 Å4/amu compared with 49 Å4/amu in the gas phase. The


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fundamentals related to the NH2 rocking were predicted at 988 and 1234 cm−1 with the Raman activities of 18 and 84 Å4/amu, basically the same as 988 and 1233 cm−1 with the Raman activities of 7 and 34 Å4/amu in the gas phase. The C5−N7 stretching frequency still keeps at 1234 cm−1, but its relative Raman intensity obviously decreases. The NH2 scissoring vibrations (1579 and 1601 cm−1) have a red shift of 8 and 20 cm−1 (1587 and 1621 cm−1), respectively. The situation of N3H8F is close to that in the gas phase especially in the low wavenumber region, and the main changes appear in the middle frequency region. Similar to N9H8F, the C8−F12 stretching distributes over 633, 805, 1016, and 1366 cm−1 (see Table S6). The C2−N3 stretching frequency at 1122 cm−1 blue shifts about 7 cm−1, and its Raman activity increases to 37 Å4/amu. In addition, the C8−N9 stretching frequency increases to 1314 cm−1. For example, the C6−N1 stretching peak at 1415 cm−1 has a red shift of 11 cm−1, while its Raman activity increases to 211 Å4/amu from 72 Å4/amu in the gas phase. For N1H8F, the characteristic peaks at 1291 cm−1 and 1593 cm−1 comes from the C5−N7 stretching and the N1−H13 in-plane bending, respectively. The former has a blue shift of 13 cm−1 with the Raman activity about 84 Å4/amu and the latter has a blue shift about 8 cm−1. The C8−F12 stretching contributes to the fundamentals at 635, 807, 1019, and 1373 cm−1 (see Table S7). For the totally simulated Raman spectrum shown in Figure 5d, we can clearly see the main Raman peaks similar to that of N3H8F, with three exception peaks at 1193, 1234, and 1544 cm−1 from N9H8F. The other Raman peaks of N9H8F and N1H8F are only weak shoulder peaks, even to be completely hidden in the overall Raman spectrum. So the contribution from the N1H8F tautomer may be neglected in the observed Raman spectrum.


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Figure 5. Simulated Raman spectra of 8-fluoroadenine calculated at the B3LYP/6-311+G(d, p) level in aqueous solution with the PCM model. (a) N9H8F, (b) N3H8F, (c) N1H8F, (d) totally simulated Raman spectrum of three tautomers according to their Boltzmann distributions. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1. Figure 6 presents simulated Raman spectra of 8-chloroadenine and 8-bromoadenine under the PCM model along with corresponding vibrational analyses in Table S8. The solvation effect causes the largest frequency shifts from 1481 to 1457 cm−1 in N9H8Cl and from 1463 to 1447


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cm−1 in N9H8Br, which related to the C8−N7 stretching. Other characteristic bands in N9H8Cl are 1120, 1167, and 1395 cm−1, which are closely associated with the N9−H in-plane bending vibrations. In N9H8Br, the N9−H in-plane bending contributes to the fundamentals of 1117, 1155, and 1394 cm−1. As seen in Figure 6, besides the vibrational frequency shift, the Raman intensities in the second frequency region are obviously enhanced due to the solvation effect.

Figure 6. Simulated Raman spectra of N9H8X (X = Cl and Br) calculated at the B3LYP/6311+G(d, p) level in aqueous solution with the PCM model. (a) N9H8Cl and (b) N9H8Br. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1. Absolute Raman Intensity. Next we estimated the DRSCS values in these halogen substituents. For adenine, the solvation effect results in the Raman intensity nearly 4-fold larger in aqueous solution than that in the gas phase. The halogen substituents have an enhancement effect up to 6-fold. While their relative intensities in the low frequency range fall due to halogen substituents. Our results showed that the solvation effect obviously influence the relative Raman


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intensity of the ring breathing vibration. These are consistent with our previous studies, such as adenine,38 pyridine,65 and guanine.39 For adenine previous studies estimated the Raman intensities of the ring breathing mode at different excitation wavelengths. The Raman intensity depends on measurement temperature, solvent property, or pH values of aqueous solution.16, 50, 66-67 Here our theoretical results will limit to the temperature at 298.15 K. Compared to other functionals, the B3LYP hybrid functional can predict the simulated Raman spectra of adenine in good agreement with experiments.32, 51 For adenine, the Raman activity of ring breathing mode was predicted about 25 Å4/amu in gas phase and 63 Å4/amu in aqueous solution with the PCM model. The former value can compare with 20.9 and 23.6 Å4/amu predicted at the B3LYP and MP2 levels with the 631G* basis set in gas phase, respectively.1 According to Eq. (1), Figure 7 presents absolute Raman intensities dependent on the excitation wavelengths at static and dynamic polarizability approximations.68-69 The Raman activity about 25 Å4/amu was transformed to the differential scattering cross section about 0.45×10−30 cm2/sr with the incident wavelength of 785 nm. We obtained the DRSCS value of the ring breathing mode about 2.8 × 10−30 cm2 mole−1 sr−1 at 633 nm line, which can compare with 2.9 × 10−30 cm2 mole−1 sr−1 in literature.70 We also inspected the absolute intensity of the strong Raman peak in the middle frequency region changing with excitation wavelengths. The band 1333 cm−1 has been split into two peaks, 1328 and 1341 cm−1, which are attributed to the C2−N1 stretching vibration and C2−H11 in-plane bending vibration with Raman activities of 146 and 114 Å4/amu in aqueous solution, respectively. Thus the total DRSCS value can be estimated to be 1.9 × 10−30 cm2 mole−1 sr−1 at the laser line 785 nm and 5.0× 10−30 cm2 mole−1 sr−1 at the laser line 633 nm.


21

N9H8H N9H8H-PCM NxH8F-PCM N9H8Cl-PCM N9H8Br-PCM N9H8H-pre-PCM

20

-1

-1

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2

15 10

-30

(dσ/dΩ)i (10

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cm mol sr )


5 0 400

500

600

700

800

Incident Wavelength (nm) Figure 7. Dependence of differential Raman scattering cross section on incident wavelengths in visible light with static polarizability approximate. For 8-fluoroadenine the total Raman intensity was calculated according to the tautomer population on the basis of the Boltzmann distribution. The absolute Raman intensities of the ring breathing mode in N9H8X decrease due to the halogen substitution. This agrees with the electron-withdrawing ability of halogen atoms, resulting in the weakest Raman intensity of the ring breathing mode in 8-fluoroadenine due to the largest electronegativity of fluorine among three halogen atoms. Considering the solvation effect, we calculated the Raman activities are 33 Å4/amu at 800 cm−1, 53 Å4/amu at 753 cm−1, and 54 Å4/amu at 740 cm−1 for N9H8F, N9H8Cl, and N9H8Br tautomers with the PCM model, respectively. There are one intense characteristic peaks at 1544 cm−1 in N9H8F and 1415 cm−1 in N3H8F, 1457 cm−1 in N9H8Cl, and 1447 cm−1 in N9H8Br in the second frequency region. The substitution effect decreases the charge density in the pyrimidine ring while increase the charge density distribution in the imidazole ring. This causes an easily polarized imidazole ring and a hardly polarizable pyrimidine ring, that is to say, the halogen substitution causes the electron


22

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flow to the imidazole ring resulting in the enhancement of the vibrational modes in the middle frequency region. Thus our calculated results interpret why the relative Raman intensity changes with the halogen substitution effect and the solvation effect. For these halogen substituents their low-lying excited states possibly affect absolute Raman intensities when the incident photonic energy increases. The first two singlet excited states of N9H8H were predicted at 4.95 and 5.09 eV with the oscillator strengths about 0.2724 and 0.0024, close to experimental data of 4.8 eV.71 The first singlet excited state is higher in energy about 1.85 eV than the photonic energy at 3.10 eV at an excitation wavelength of 400 nm. While for three halogen substituents their first singlet excited states have slightly lower transition energies than that of adenine predicted at the present calculation. For example, there are 4.59 eV for N3H8F, 4.90 eV for N9H8Cl, and 4.84 eV for N9H8Br. The only one experimental transition energy was reported at 4.59 eV for 8-bromoadenine.72 This indicates that in visible light the static polarizability is reliable to describe the absolute Raman intensities of the halogen substituted adenine. CONCLUSIONS This paper has investigated the substituent effect of adenine by a halogen atom at the C8 position on the basis of DFT calculations and normal mode analysis. Our investigation focuses on the relative stability, vibrational frequencies, Raman intensities, and the solvation effect of their low-energy tautomers. These calculated results showed that the most stable tautomer of 8halogen adenine is in the form of N9H8X in the gas phase. The solvation effect significantly changes the relative stability of 8-fluoroadenine in aqueous solution, containing two stable tautomers of N3H8F and N9H8F. We also first present the complete vibrational assignment of all fundamentals of 8-halogen adenine in gas phase and further analyze the vibrational frequency


23


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shift and Raman intensity changes due to the substituent effect and the solvation effect. These results indicate that the change of the relative Raman intensity strongly reflects the charge density redistribution due to the substituent effect and the response on the solvation effect. An interesting N9−H in-plane bending was discussed in details due to its special complexity. The internal coordinate contributes to several fundamentals which are closely associated with the hydrogen bonding interaction in chemical environments. So we compared the case with other analogues, such as pyrrole, indole, imidazole, and benzimidazole. The comparison indicates that the vibrational coupling plays an important role in understanding the relationship of vibrational spectra and molecular structures in different measuring environments. ASSOCIATED CONTENT Supporting Information. The detail optimized geometries and normal modes analysis in the gas phase as well as in aqueous solutions with the PCM model are listed in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Tel: (+86) 592-2189023 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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We are grateful for the financial support of this work by National Natural Science Foundation of China (21321062, 21533006 and 21373712), National Key Basic Research Program of China (No. 2015CB932303), and Funds of State Key Laboratory of Physical Chemistry of Solid Surfaces. REFERENCES (1) Mohamed, T. A.; Shabaan, I. A.; Zoghaib, W. M.; Husband, J.; Farag, R. S.; Alajhaz, A. E.-N. M. A. Tautomerism, Normal Coordinate Analysis, Vibrational Assignments, Calculated IR, Raman and NMR Spectra of Adenine. J. Mol. Struct. 2009, 938, 263-276. (2) Saenger, W., Water and Nucleic Acids. In Principles of Nucleic Acid Structure, Springer: 1984; pp 368-384. (3) Huang, M. C.; Montgomery, J. A.; Thorpe, M. C.; Stewart, E. L.; Secrist Iii, J. A.; Blakley, R. L. Formation of 3-(2′-Deoxyribofuranosyl) and 9-(2′-Deoxyribofuranosyl) Nucleosides of 8-Substituted Purines by Nucleoside Deoxyribosyltransferase. Arch. Biochem. Biophys. 1983, 222, 133-144. (4) Guerra, C. F.; van der Wijst, T.; Bickelhaupt, F. M. Substituent Effects on Hydrogen Bonding in Watson–Crick Base Pairs. A Theoretical Study. Struct. Chem. 2005, 16, 211-221. (5) Major, D. T.; Laxer, A.; Fischer, B. Protonation Studies of Modified Adenine and Adenine Nucleotides by Theoretical Calculations and 15N NMR. J. Org. Chem. 2002, 67, 790802. (6) Whiteman, M.; Jenner, A.; Halliwell, B. 8-Chloroadenine: A Novel Product Formed from Hypochlorous Acid-Induced Damage to Calf Thymus DNA. Biomarkers 1999, 4, 303-310. (7) Gandhi, V.; Chen, W.; Ayres, M.; Rhie, J.; Madden, T.; Newman, R. Plasma and Cellular Pharmacology of 8-Chloro-Adenosine in Mice and Rats. Cancer Chemother Pharmacol 2002, 50, 85-94. (8) Kyogoku, Y.; Lord, R.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc. Natl. Acad. Sci. USA 1967, 57, 250-257. (9) Brown, R. D.; Godfrey, P. D.; McNaughton, D.; Pierlot, A. P. A study of the Major GasPhase Tautomer of Adenine by Microwave Spectroscopy. Chem. Phys. Lett. 1989, 156, 61-63. (10) Nowak, M. J.; Lapinski, L.; Kwiatkowski, J. S.; Leszczyński, J. Molecular Structure and Infrared Spectra of Adenine. Experimental Matrix Isolation and Density Functional Theory Study of Adenine 15N Isotopomers. J. Phys. Chem. 1996, 100, 3527-3534. (11) Plutzer, C.; Kleinermanns, K. Tautomers and Electronic States of Jet-Cooled Adenine Investigated by Double Resonance Spectroscopy. Phys. Chem. Chem. Phys. 2002, 4, 4877-4882. (12) Colarusso, P.; Zhang, K.; Guo, B.; Bernath, P. F. The Infrared Spectra of Uracil, Thymine, and Adenine in the Gas Phase. Chem. Phys. Lett. 1997, 269, 39-48. (13) Laxer, A.; Major, D. T.; Gottlieb, H. E.; Fischer, B. (15N5)-Labeled Adenine Derivatives: Synthesis and Studies of Tautomerism by 15N NMR Spectroscopy and Theoretical Calculations. J. Org. Chem. 2001, 66, 5463-5481.


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Figure Captions Figure 1. Molecular structures of four 8-halogen adenine tautomers. Figure 2. Molecular orbital energies (eV) and electron cloud plots of low-energy tautomers N9H8X of 8-halogen adenine (X = H, F, Cl, and Br) calculated at the B3LYP/6-311+G(d, p) level in the gas phase. The number shown in the picture of the energy levels is the energy gap (eV) of the HOMO and LUMO levels. Figure 3. Simulated Raman spectra of the lowest-energy tautomers N9H8X (X = H, F, Cl, and Br) in the gas phase calculated at the B3LYP/6-311+G(d, p) level. (a) N9H8H, (b) N9H8F, (c) N9H8Cl, (d) N9H8Br. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1. Figure 4. Variation of vibrational frequencies related to selected internal coordinates in N9H8X (X=H, F, Cl, and Br) in the gas phase calculated at the B3LYP/6-311+G(d, p) level. Figure 5. Simulated Raman spectra of 8-fluoroadenine calculated at the B3LYP/6-311+G(d, p) level in aqueous solution with the PCM model. (a) N9H8F, (b) N3H8F, (c) N1H8F, (d) totally simulated Raman spectrum of three tautomers according to their Boltzmann distributions. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1. Figure 6. Simulated Raman spectra of N9H8X (X = Cl and Br) calculated at the B3LYP/6311+G(d, p) level in aqueous solution with the PCM model. (a) N9H8Cl and (b) N9H8Br. The incident wavelength of 785 nm was used here with a Lorentzian line width of 10 cm−1. Figure 7. Dependence of differential Raman scattering cross section on incident wavelengths in visible light with static polarizability approximate. For 8-fluoroadenine the total Raman intensity was calculated according to the tautomer population on the basis of the Boltzmann distribution.


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Theoretical Investigation on the Substituent Effect of Halogen Atoms at

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