UV and Resonance Raman Spectroscopic and Theoretical Studies on

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A: Kinetics, Dynamics, Photochemistry, and Excited States

UV and Resonance Raman Spectroscopic and Theoretical Studies on the Solvent-Dependent Ground and Excited State Thione # Thiol Tautomerization of 4,6-Dimethyl-2-Mercaptopyrimidine (DMMP) Xin Liu, Xin Wei, Haiqiang Zhou, Shuang Meng, Jiadan Xue, Xuming Zheng, and Yanying Zhao J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b04525 • Publication Date (Web): 11 Jun 2018 Downloaded from http://pubs.acs.org on June 18, 2018

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The Journal of Physical Chemistry

UV and Resonance Raman Spectroscopic and Theoretical Studies on the Solvent-Dependent Ground and Excited State Thione → Thiol Tautomerization of 4,6-Dimethyl-2Mercaptopyrimidine (DMMP) Xin Liuξ˭, Xin Weiξ˭, Haiqiang Zhouξ˭, Shuang Mengξ, Yanying Zhaoξ#*, Jiadan Xueξ#, Xuming Zhengξ# ξ

#

Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China

Engineering Research Center for Eco-dyeing and Finishing of Textiles, Key Laboratory of

Advanced Textiles Materials and Manufacture Technology, Ministry of Education, Zhejiang SciTech University, Hangzhou 310018, China

Abstract

The vibrational spectra of 4,6-dimethyl-2-mercaptopyrimidine (DMMP) in acetonitrile, methanol, and water were assigned by resonance Raman spectroscopy through a combination of Fourier-transform Infrared spectroscopy (FT-IR), FT-Raman UV-Vis spectroscopy, and density functional theoretical (DFT) calculations. The FT-Raman spectra show that the neat solid DMMP is formed as a dimer due to intermolecular hydrogen bonding. In methanol and water, however, the majority of the Raman spectra were assigned to the vibrational modes of 1 ACS Paragon Plus Environment

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DMMP(solvent)n (n = 1–4) clusters containing NH···O hydrogen bonds. The intermolecular NH···O hydrogen bond interactions, which are key constituents of the stable DMMP thione structure, revealed significant structural differences in acetonitrile, methanol, and water. In addition, UV-induced hydrogen transfer isomeric reactions between the thione and thiol forms of DMMP were detected in water and acetonitrile. DFT calculations indicate that the observed thione → thiol tautomerization should occur easily in lower excited states in acetonitrile and water.

˭

Xin Liu, Xin Wei, and Haiqiang Zhou contributed equally to this work.

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1. Introduction

Pyrimidine and its derivatives are of great significance to both chemists and biologists as they are present in a large variety of nucleic acid medicines. As such, naturally occurring compounds containing the pyrimidine moiety continue to attract the attention of biologists and pharmaceutical scientists who wish to measure their activities, especially since pyrimidine derivatives tend to exhibit antiviral, antibacterial, antitumor, and anti-thyroidal activities.1–4 Furthermore, mercaptopyrimidine derivatives exhibit a wide range of structures through their coordination as both S and N mono- and poly-dentate ligands to either a single metal center (as a chelating ligand) or several metal centers (as a bridging ligand), so they are used extensively as antirust agents.5–8 Understanding the tautomerism of mercaptopyrimidine derivatives is also of importance in synthetic chemistry, medicinal chemistry, and biochemistry, as such derivatives exhibit tautomeric equilibria between their thiol (C-SH) and thione (C=S) forms through facile hydrogen transfer. In this context, both the environment and the physical state of these molecules largely determine their predominant form.9 X-ray diffraction studies have confirmed that the thione dimer is formed via hydrogen bonds in the solid state.10–12 Rocha et al. systematically reported the ground-state proton transfer reaction between 2-pyrimidinethiol and 2(1H)pyrimidinethione in different environments.12 In this case, two distinct mechanisms were considered, namely a direct intramolecular transfer and a water-assisted mechanism. In the gas phase, intramolecular transfer leads to a large energy barrier that passes through a three-center transition state. The solvent effect was found to be sizable, and it was found to be considerably more important in the water-assisted mechanism, namely, in the solvent field of solute–solvent 3 ACS Paragon Plus Environment


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interactions.13 Notably, the assistance of a single water molecule for proton transfer decreases the energy barrier by half; in solution, these calculated activation barriers are 32.0 and 14.8 kcal/mol,14 respectively. Thus, the barrier for hydrogen transfer between 2-pyrimidinethiol and 2(1H)-pyrimidinethione in the ground state generally exceeds 30 kcal/mol, indicating that tautomerization is challenging in the ground state.13,15 However, with the aid of a few water molecules the transition state energies for some similar compounds have been reported to decrease sharply to almost half for direct proton transfer in the ground state, due to the role of hydrogen bonding in both the thione–thiol tautomerization reaction and molecular dynamics.16–18 Recently, the solvent-assisted excited-state intra- and/or intermolecular proton transfer (ESIPT) mechanism has received growing attention because of its crucial role in the activity of photoacids and photobases,19–21 including photo-sensitive proteins22–25 and metal complexes.26 Interestingly, it has also been considered among some of the primary factors enabling the evolution of life due to its role in nucleic acid base photochemistry.27–29 In addition, photoinduced proton transfer, which is commonly accompanied by a pronounced redistribution of electron density, results in large shifts in the Stokes emission, giving rise to the possibility of bioluminescence color tuning and selective molecular photoswitching and information storage.30–35

In the case of 4,6-dimethyl-2-mercaptopyrimidine (DMMP), a typical mercaptopyrimidine, its two tautomeric thione (NH) and thiol (SH) forms may persist in different environments, where the former contains a C=S double bond (1) and the latter bears an endocyclic C=N double bond and an S-H moiety (2), as shown in Scheme 1. Fierro et al.36 confirmed by Fouriertransform infrared (FT-IR) spectroscopy that the thione form was dominant in the solid state and 4 ACS Paragon Plus Environment

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demonstrated the importance of solvent polarity in controlling the tautomeric thiol–thione equilibrium of DMMP. Ultraviolet (UV) and nuclear magnetic resonance (NMR) experiments showed that the thione structure dominates in polar solvents (e.g., methanol and dimethyl sulfoxide), whereas the thiol structure dominates in apolar media. The potential of combining spectroscopic experiments with advanced computational density functional theory (DFT) calculations for the identification and characterization of the tautomeric equilibrium of DMMP in solution were also demonstrated. In this context, similar nitrogen/sulfur-containing heterocyclic molecules, such as 2-hydroxypyridine (2HP),37,

38

2-pyridone (2PY),39,

40

2-

mercaptopyridine,36, 41 and thioacetamide and its thiol tautomer42 have attracted growing interest because of their importance in both organic chemistry and biochemistry.43–44 Furthermore, in the context of hydrogen bonding and the solvent effect, Han et al. carried out theoretical investigations using 4H-1-benzopyrane-4-thione and thiocoumarin in methanol45, 46 and found that C=S···H-O intermolecular hydrogen bonding decreases the energy gap between the S2 and S1 states, thereby strengthening the extent of internal conversion (IC) from S2 to S1. Moreover, ultrafast vibrational spectroscopy has been employed as a key technique in the investigation of charge and/or proton transfer chemical reactions.47–50 On this basis, the present study has focused on the solvent-dependent excited-state hydrogen transfer photoisomerization reaction of DMMP using UV resonance Raman spectroscopy and time-dependent density functional theory (TDDFT) calculations. The vibrational spectra of DMMP are assigned in different solvents and the excited-state structural dynamics are proposed based on the type of hydrogen bonding in the DMMP-H2O cluster in protic solvents. Overall, it is expected that this study will promote the study of sulfur-substituted pyrimidines. 5 ACS Paragon Plus Environment


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(a) (b)

(c)

(d)

Scheme 1. Monomer and dimer structures of DMMP: (a) thiol; (b) thione; (c) thiol dimer; (d) thione dimer

2. Experimental and computational methods


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DMMP (99%, J&K Scientific, China) was employed without further purification. Solutions of DMMP of various concentrations (i.e., 2.0×10−3 to 5.0×10−3 mol/L) were prepared using HPLC grade acetonitrile (99.9%, Tedia, USA), methanol (99.9%, Spectrum, USA), and deionized water.

FT-Raman and FT-IR spectra were obtained using FT-Raman (Thermo Nicolet 960, Thermo Fisher Nicolet, USA) and FT-IR (Thermo Nicolet Avatar 370, Thermo Fisher Nicolet, USA) spectrometers with a resolution of 2 cm−1. The UV absorption spectra were measured using a UV-visible spectrometer (UV-2501PC, Shimadzu, Japan). As the resonance Raman experimental method and apparatus have been described elsewhere,51,52 only a brief description is provided here. Briefly, the harmonics of a nanosecond Nd: YAG laser and their hydrogen Raman-shifted laser lines were used to generate the 273.9 nm excitation wavelengths utilized in the resonance Raman experiments. The excitation laser beam used a ~100 µJ pulse energy, which was loosely focused on a 0.5–1.0 mm-diameter spot of the flowing sample. The Raman shifts of the resonance Raman spectra were calibrated using the known vibrational frequencies of the solvents (i.e., acetonitrile, methanol, and water).

The experimental results were confirmed at the B3LYP/6-311++G(3df,p) level of theory using the Gaussian suite of programs,53 and the normal mode analysis of DMMP was carried out using the VEDA program.54 The noncovalent interactions, that is, the hydrogen bonding characteristics, were visualized by the Multiwfn program based on the electron densities and their reduced gradient densities (RGD).55



3. Results and Discussion

3.1 UV spectra, electronic transitions, and vibrational spectra of DMMP

We initially collected the UV spectra of DMMP in apolar (cyclohexane, n-heptane, nhexane and n-heptane) and polar (water, methanol, ethanol and acetonitrile ) solvents, as shown in Figures 1 and S1; the excitation wavelengths for the resonance Raman experiments are also labeled in Figure 1. Three obvious bands are observed in polar solvents. In water, the experimental UV spectrum for DMMP exhibits three absorption bands with maxima at approximately 330 (f = 0.087, ε = 3.866×103 L·mol−1·cm−1), 275 (f = 0.2988, ε = 1.805×104 L·mol−1·cm−1), and 220 nm (f = 0.187, ε = 1.017×104 L·mol−1·cm−1), which are otherwise known as the A-, B-, and C-bands, respectively. In acetonitrile, the A- and B-band absorptions were red-shifted relative to those observed in water by ~30 and 12 nm, respectively. However, in apolar solvents, two distinguishable bands are observed. In cyclohexane, the maximum band absorption was blue-shifted to 237 nm relative to that in polar solvents, which is consistent with previous experiments.10,

36

Thus, we tentatively assigned the thione form of

DMMP in polar solvents and its thiol form in apolar solvents. 273.9 nm CH3 CN H O

0.8

2

CH3 OH C6 H12

0.6

Absorption

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.4

0.2

0.0

200

250

300

3 50

400

Wavelength/nm


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Figure 1. UV absorption spectra of DMMP in c-C6H12, CH3CN, CH3OH, and H2O.

Next, TD-DFT calculations were performed to assign the various absorption spectra. Specifically, the B3LYP/6-311++G(3df,p) level of theory was used to predict the electronic transition energies and their corresponding orbitals, as shown in Table 1. The calculated results for the two tautomeric structures of DMMP clearly indicate that the thiol structure is lower in energy than the thione structure in the gas phase; however, the reverse is true when the calculations were performed using the PCM solvation method in water, acetonitrile, and methanol. Within the calculated spectral region for singlet transitions, Table 1 shows that the two calculated transitions of the thiol structure exhibit allowed electronic absorptions at 273 and 239 nm in cyclohexane, giving the largest oscillator strengths observed (i.e., f = 0.0420 and 0.3796, respectively). These results are in good agreement with the two intense absorption bands observed experimentally in cyclohexane at 270 and 237 nm for DMMP, which correspond to π→π* electronic transitions. TD-DFT calculations using the PCM solvation method predict that, in water, the thione form has three key absorption bands at 333, 276, and 220 nm with corresponding oscillator strengths of 0.0746, 0.4183, and 0.1610, respectively. These results agree with the experimentally observed bands for DMMP in H2O at 330, 275, and 220 nm, with respective oscillator strengths of 0.087, 0.2988, and 0.187. These three maximum absorption bands can be attributed to the πH→πL*, πH→πL+1*, and πH-3→πL* transitions, respectively. Based on these results, we conclude that the thiol structure dominates in apolar solvents (i.e.,



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cyclohexane) whereas the thione structure dominates in polar solvents. Again, these observations agree with previously reported literature spectra and assignments.7-9

Table 1. Wavenumber difference (∆) between contiguous vibrational mode from FT-Raman experiment and computational frequencies at B3LYP/6-311++G(3df, p) for mono- and dimer DMMP. Wavenumber difference (∆)/ cm-1

∆17-18

∆16-17

∆15-16

FT-Raman

25

29

94

Monomer

27

79

67

Dimer

34

41

75

To further confirm the predominant tautomeric form of DMMP in the solid state and to assign its vibrational spectra, FT-Raman and resonance Raman experiments were carried out. The results suggest that the 273.9 nm excitation wavelength used to obtain the experimental resonance Raman spectrum of DMMP resonated with the B-band absorptions of DMMP in polar solvents. Figure 2 shows the FT-Raman and FT-IR spectra of DMMP in the solid state, in addition to the calculated Raman activities of the most stable monomeric and dimeric thione forms. The thiol form of DMMP is calculated to be 5.3 and 0.1 kcal/mol lower in energy than the thione structure in the gas phase and in cyclohexane, respectively. In addition, the optimized thione dimer was 2.5 and 5.1 kcal/mol lower in energy than the thiol dimer in these two phases, as shown in Table S1.


1722 1626

1493 1572

1190 1223 1238

1323 1362 1386 1440

1172

1034

874 897 953

982

854

737

538 592

ν12

Thione dimer

ν7

ν8

ν15

ν17 ν18

ν20 ν34

ν21

ν38 ν37 ν36 ν23

ν24

ν16

1171 1196 1225

987 1033

848 877 889 952

737

592

1319 1379 1388 1473 1477 1494 1570 1616

563

463

ν27 ν25

(b)

(c)

1000

ν9

ν19

500

ν14

ν13 ν10ν11

Thione monomer

ν26

ν28

(a)

FT-Raman

472 532

172 187 231

247

463

FT-IR

ν29

Raman Activity

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Raman Intensity Absorbance

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1500

(d)

2000

Wavenumber/cm-1

Figure 2. Experimental (a) FT-IR and (b) FT-Raman spectra of DMMP in solid and the calculated Raman spectra of most stable (c) di- and (d) monomer DMMP at B3LYP/6311++G(3df, p) level.

On the basis of infrared spectroscopy, it was previously reported that the thione tautomer was the dominant form of DMMP7,

9

in the solid state, where it formed a dimeric structure through

NH···S hydrogen bonds. As shown in Figure 2(b), several strong bands at ~247, 463, 563, and 987 cm−1 exhibit strong Raman intensity patterns in the 100−2000 cm−1 region, while bands of 11 ACS Paragon Plus Environment


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medium intensity were observed at 532, 952, 1171, 1196, 1225, 1319, 1379, 1388, and 1570 cm−1. In contrast, the bands at 848, 877, 889, and 1618 cm−1 were weak compared with the other vibrational modes. In particular, the bands observed at 1437, 1477, and 1494 cm−1 correspond to calculated dimeric bands at 1479, 1492 and 1506 cm−1; clearly, they do not correlate well with the single calculated band at 1474 cm−1 for the thione monomer form. Thus, despite the similar spectra observed for the monomeric and dimeric thione forms of DMMP shown in Figures 1(c) and 1(d), their calculated spectra at the B3LYP/6-311++G(3df,p) level of theory indicate that the experimental spectra correspond with the dimeric form. The observed bands at 1171(ν18), 1196 (ν17), 1225 (ν16), and 1319 (ν15) cm−1 correspond to the 1177, 1211, 1262, and 1337 cm−1 bands for the thione dimer; by comparison, the monomeric bands would be observed at 1150, 1177, 1256, and 1323 cm−1. Table 2 shows the wavenumber differences (∆) between the contiguous vibrational modes. Compared with the experimental values, the predicted value for ∆ν16−17 is too large for the monomer, whereas ∆ν15−16 is too small. Thus, the calculated ∆ν7−8, ∆ν12−15, ∆ν15−16, ∆ν16−17, and ∆ν17−18 bands are 48, 154, 94, 29, and 25 cm−1, respectively, which correlate with the experimental values of 50, 159, 75, 41, and 34 cm−1. Consequently, the solid-state form of DMMP should be assigned to the thione dimer with NH···S bonds.17, 56,57

Table 2. Experimental and calculated singlet electronic transition energies at B3LYP-TD/6311++G(3df, p) on the optimized ground state geometry of DMMP, and the corresponding orbitals and oscillator strengths with the electronic transition character. States

Orbitals(coefficient)

Electronic

Transition

Oscillator 12

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transition

Energy(nm) Calc.

Expt.

strength(f) Calc.

Expt.

DMMP-thiol in cyclohexane S1(A'')

36→38(0.70523)

nN→πL*

276

S2(A')

37→38(0.69445)

πH→πL*

273

S3(A'')

36→39(0.70353)

nN→πL+1*

252

S4(A')

37→39(0.69532)

πH→πL+1*

239

37→40(0.41975)

πH→Ryd1

37→41(0.48866)

πH→Ryd2

S5(A'')

0.0049 270

0.0000 237

226

36:nN

37:πH

38:πL*

0.0420

0.3796 0.0049

39:πL+1* 40:Ryd1 41:Ryd2

DMMP-thione in CH3CN S1(A'')

36→38(0.6866)

nH-1→πL*

380

S2(A')

37→38(0.6940)

πH→πL*

354

S3(A'')

36→39(0.6849)

nH-1→πL+1*

316

S4(A')

37→39(0.6856)

πH→πL+1*

276

S5(A'')

35→38(0.7042)

πH-2→πL*

274

0.0006

S6(A”)

37→40(0.6835)

πH→Ryd1

239

0.0275

S7(A’)

36→40(0.6659)

nH-1→Ryd1

237

0.0468

S8(A”)

35→39(0.7017)

nN→πL+1*

230

0.0054

S9(A”)

37→41(0.6279)

πH→Ryd2

213

0.0016

S10(A’)

36→42(0.5037)

nH-1→Ryd3

211

0.0099

S11(A”)

37→42(0.6031)

πH→Ryd3

210

0.0241

S12(A)

34→38(0.6016)

πH-3→πL*

209

0.0164

S13(A’)

36→41(0.6536)

nH-1→Ryd2

208

0.0002 361

0.0747

0.071

0.0001 288

220

0.4213

0.2049

0.29

0.103 13



34:πH-3

35:nN 36:n H-1 37:πH

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38:πL* 39:πL+1* 40: Ryd1 41: Ryd2

42: Ryd3

DMMP-thione in H2O S1(A'')

36→38(0.68648)

ns→πL*

378.50

S2(A')

37→38(0.69387)

πH→πL*

352.52

S3(A'')

36→39(0.68484)

ns→πL+1*

314.38

S4(A')

37→39(0.68565)

πH→πL+1*

275.45

S5(A'')

35→38(0.70423)

nN→πL*

272.95

0.0006

S6(A'')

37→40(0.68318)

πH→Ryd1

238.18

0.0285

S7(A')

36→40(0.66551)

ns→Ryd1

236.41

0.0476

S8(A'')

35→39(0.70149)

nN→πL+1*

229.80

0.0056

S9(A'')

37→41(0.62053)

πH→Ryd2

212.19

0.0022

S10(A')

36→42(0.51030)

ns→Ryd3

211.03

0.0064

S11(A'')

37→42(0.59024)

πH→Ryd3

209.74

0.0239

S12(A')

36→41(0.57643)

ns→Ryd2

208.77

0.0587

S13(A')

34→38(0.53419)

πH-3→πL*

208.17

34: πH-3

35:nN

0.0002 333

0.0746

0.0870

0.0001 276

220

0.4183

0.2988

0.1610

36:nS 37:πH 38:πL* 39:πL+1* 40: Ryd1 41: Ryd2 42: Ryd3

3.2 Resonance Raman spectra and excited-state structural dynamics of DMMP

Figure 3 shows the 273.9 nm resonance Raman spectra of DMMP in a range of solvents. It is immediately apparent that these spectra differ from those of the solid. In particular, strong bands at 556, 893, 1019, 1187, 1231, and 1622 cm−1 dominate in water, while in methanol and 14 ACS Paragon Plus Environment

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acetonitrile, strong bands were observed at 555, 892, 1016, 1178, 1228, and 1618 cm−1 and at 553, 890, 1017, 1166, 1218, and 1611 cm−1, respectively. In the 1500–1700 cm−1 region, intense bands were also observed at 1571 cm−1 in water and 1573 cm−1 in methanol. In contrast, the analogous band in acetonitrile (1560 cm−1) was particularly weak. Furthermore, the intense band observed at 1166 cm−1 in acetonitrile was observed as a weak band in both methanol (1178 cm−1) and water (1187 cm−1). Moreover, the weak band at 1231 cm−1 observed in water became slightly stronger in both acetonitrile (1218 cm−1) and methanol (1228 cm−1), while in the 1300– 1400 cm−1 region, the resolvable 1309, 1335, and 1366 cm−1 peaks observed in acetonitrile were not clearly resolved in methanol due to peak overlap and poor separation. Additionally, the 1560 and 1611 cm−1 bands observed in acetonitrile were both blue-shifted by 11 cm−1 in water, and the intense bands at 553, 890, and 1017 cm−1 were blue-shifted slightly to 556, 893, and 1019 cm−1. These results indicate that the varying peak intensities and their corresponding wavenumbers are affected by differences in both the solvent polarity and the extent of intermolecular hydrogen bonding.


400

600

800

1000

1200

1400

1911

1781

1611 1600

1800

1919

ν9 1794

#

1187 1231

ν9

1327 1342 1371 1389 1456 1486 1571 1622

893

ν11 ν9

1019

556

DMMP in H O 2

1913

1016

*

1785

892

555

DMMP in MeOH

1560

1309 1366 1335 1389 1448 1476

1178 1195 1228 1318 1368 1339 1381 1453 1483 1573 1618

1166 1218 1195 #

*

*

Page 16 of 41

#

1017

553

DMMP in MeCN

Raman Intensity

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

890


2000

-1

Wavenumber/cm

Figure 3. 273.9 nm resonance Raman spectra of DMMP in CH3CN, CH3OH, and H2O. Asterisk (*) marks the solvent subtraction. Pound (#) marks the residual uncertain laser lines.

To further interpret these variations in the vibrational spectra, which appear to be related to the excited-state structure, the solvent effect, and the presence of different tautomeric forms of DMMP, implicit and explicit solvation models were examined at the B3LYP/6-311++G(3df,p) level of theory. Figures S2 and S3 show the geometries of eight DMMP(H2O)n and six DMMP(CH3OH)n clusters (n = 1–4). The obtained results indicate that DMMP could bind to a maximum of four water and three methanol molecules, with similar binding energies of ~12 kcal/mol (Figure S2, S3 and Table S1). Figure S2 shows that the NH···O and OH···O 16 ACS Paragon Plus Environment

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hydrogen bonds (H-bonds), which measure 1.8–1.9 Å, elongate the N-H bond in the heterocyclic ring to 1.035 and 1.037 Å relative to that of DMMP (1.013 Å) in the water and methanol models, respectively. In the case of DMMP(H2O)n, the NH···O H-bond distance decreased from 1.912 Å in DMMP(H2O) to 1.827 Å in DMMP(H2O)4 via the longer H-bonds in DMMP(H2O)2 (1.851 Å) and DMMP(H2O)3 (1.836 Å), as shown in Figure 4. In this system, H-bonding interactions formed between adjacent molecules to create a H-bonding network. Long OH···Nring H-bond distances of 1.990 and 1.920 Å were determined in the DMMP(H2O)4 and DMMP(CH3OH)3 clusters, respectively. Interestingly, the strong OH···S H-bonds present in the DMMP(H2O)4 cluster measured 2.328 and 2.349 Å, as previously reported in 2-pyridone.58 Moreover, for the DMMP(CH3OH)n cluster, the NH···O hydrogen bond distances varied between 1.877 and 1.811 Å. Strong OH···O hydrogen bonds were also formed between the three methanol molecules in the DMMP(CH3OH)3 cluster.

Figure 4. Geometry of DMMP(solvent)n clusters at B3LYP/6-311++G(3df, p) level of theory using the PCM solvent model. (Unit: bond length in Å)



Page 18 of 41

To confirm the vibrational spectra obtained in solution, resonance Raman experiments were also carried out in different solvents. However, the resonance Raman spectra of DMMP could not be obtained in cyclohexane due to its poor solubility at low concentration. Figure S4 shows the resonance Raman spectra of DMMP in acetonitrile, methanol, and water at excitation wavelengths of 245.9, 252.7, 266, 273.9, and 282.4 nm. As shown, similar wavenumbers were observed in the same solvent at different excitation wavelengths, indicating that these excitation wavelengths are existent within the absorption band of S4(ππ*) character. Through direct comparison between the DFT and FT-Raman results, twelve fundamentals of the thione form of DMMP could be assigned to the 273.9 nm resonance Raman spectrum in acetonitrile, as shown in Table S4. In addition, Figure S5 shows the 282.4 nm resonance Raman spectrum of the frequencies of fundamentals, combinations, and overtones of the DMMP(H2O)4 cluster in water.

Given that addition of the third and fourth water molecules resulted in slight changes in the geometry and vibrational modes of DMMP, we also calculated the structure and vibrational frequencies of the DMMP(H2O)2 cluster in isolation. Table 3 lists a number of the experimental and calculated vibrational frequencies of the DMMP(H2O)2 cluster along with their tentative assignments. The full assignment can be found in Table S4. As shown in Table 3, the calculated results correspond reasonably well with the experimentally observed DMMP vibrational modes. The calculated results also show that the vibrational wavenumber for ν9 and ν12 was shifted significantly due to NH···O hydrogen bonding, which is consistent with the experimental results.

To further investigate the strength and visualize the hydrogen bonding (noncovalent interaction, NCI), the reduced density gradient (RDG) approach

59

was applied. Plots revealing 18


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the hydrogen bonding interactions are shown in Figure S6. In DMMP (Figure S6, top) there is an area of non-bonded overlap at the center of the pyrimidine ring. In DMMP(H2O), DMMP(H2O)2, and DMMP(H2O)4, the noncovalent surfaces show that there are two, three, and six noncovalent interactions, respectively, between the donor and acceptor moieties among the hydrogen, oxygen, nitrogen, and sulfur atoms, which is characteristic of hydrogen bonding.


The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

Page 20 of 41

Table 3. Observed in different solvents and calculated normal Raman frequencies (cm-1) of DMMP-(Solvent)n (Solvent=H2O and CH3CN; n=0~4) clusters at the B3LYP/6-311++G(3df, p) level of theory using the PCM solvent model.

Observed.

Mode

ν9

ν11

ν12

ν18

ν21

ν22

ν23

in MeCN

in MeOH

1611

1618

1560

1476

1366

1218

1195

1166

1573

1483

1368

1228

1195

1178

a

Cluster b in H2O

1622

1571

1486

1371

1231

1191

1184

Descriptions (PED%) c

nd MeCN

1644(436/43)

1574(1117/175)

1472(365/70)

1410(40/113)

1248(413/83)

1183(113/27)

1181(198/25)

0

1

2

3

4

1644(444/44)

1654(410/38)

1660(456/29)

1657(585/28)

1659(486/28)

C5C6 stretch(24)+H17N1C2 (18)+H19O18H17N1 torsion (16)

1644(437/42)

1656(428/39)

1656(500/31)

1656(531/33)

1573(1127/190)

1592(964/154)

1594(958/173)

1592(864/190)

1592(864/197)

C5C6 stretch (10)+N3C4 stretch (21)+N1C6 stretch (12)+ H17N1C2 in plane bend (22)

1574(1110/174)

1603(945/126)

1596(863/161)

1597(819/162)

1472(372/71)

1507(138/109)

1511(88/107)

1521(90/93)

1523(87/90)

C5C6N1 in plane bend (11)+H17N1C2 in plane bend (16)+C4N3C2 in plane bend (10)

1473(366/72)

1513(121/128)

1514(66/108)

1522(89/108)

1409(41/115)

1410(2/92)

1409(10/101)

1409(8/91)

1408(9/88)

C12C6 stretch (14)+C4N3C2 in plane bend (18)

1410(45/108)

1410(44/105)

1410(39/60)

1409(6/96)

1247(421/81)

1253(549/64)

1257(672/63)

1257(644/69)

1260(670/73)

N3C2 stretch (44)

1249(414/82)

1253(561/67)

1257(649/65)

1257(672/71)

1183(136/29)

1201(233/62)

1206(222/64)

1208(235/45)

1208(185/44)

N1C6 stretch (22)+N1C2 stretch (25)+H7C5C4 in plane bend (14)

1182(32/17)

1205(235/59)

1205(224/60)

1208(215/44)

1181(202/27)

1188(53/15)

1190(40/11)

1194(47/7)

1181(296/33)

1187(42/13)

1188(38/11)

1191(44/8)

in

plane

bend

N3C2 stretch (12)+H7C5C4 in plane bend (31) 1196(53/7)

20


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ν26


1017

ν31

890

ν34

553

1016

892

555

1019

893

556

1044(1/30)

909(56/7)

563(1/50)

1044(1/32)

1042(1/30)

1042(2/29)

1042(4/33)

1044(1/31)

1043(3/28)

1042(30/15)

1041(21/18)

909(60/7)

902(67/10)

902(80/12)

904(86/14)

909(57/7)

903(65/10)

902(76/13)

905(77/15)

563(1/48)

565(3/34)

568(3/32)

561(2/50)

563(1/47)

565(2/34)

568(2/31)

564(1/20)

1039(1/30)

C5C6stretch(10)+H13C12H15 in plane bend (12)+H15C12C6N1 torsion (23)+H13C12C6N1 torsion (20)

902(93/17)

S16C2 stretch (25)+C6N1C2 in plane bend (12)

562(3/39)

C8C4 stretch (12)+N1C2N3 in plane bend (10)+C8C5N3C4 out of plane bend (10)+C12N1C5C6 out of plane bend (16)

a

Resonance Raman shifts observed at 273.9 nm excitation wavelength.

b

Calculated vibration frequencies of DMMP-(Solvent)n (Solvent=H2O and CH3CN; n=0~4) clusters with PCM model. relative intensity of Raman. Both sides of slash

represent IR intensities and Raman activities in parentheses, respectively. c

PED: potential energy distribution at the B3LYP/6-311++G(3df, p) level of theory, only contributions larger than 10% were given. Unit in a.u.: cm−1.

d

n represents the number of solvent molecules; For Solvent=H2O on the first line and CH3OH on the second line.

21



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3.3 Excited-state photoinduced tautomerism of DMMP

The strong absorption bands decreased in intensity upon 266 nm pulsed laser irradiation of solutions of DMMP in cyclohexane, acetonitrile and water, with many bands disappearing as the laser photolysis time was increased. This attenuation was accompanied by the appearance of new absorption signals, as shown in Figures 5 and S7-S13. For example, in Figure 5(A), the appearance of two new bands at 244 and 308 nm in acetonitrile coincided with decreases in intensity of the characteristic absorption bands at 356, 288 and 220 nm, and this transformation was complete within 20 min. In contrast, this transformation was significantly slower in water, as shown in Figure 5(B), where approximately one third of the thione DMMP tautomer remained intact after 40 min of photolysis. The results indicate that the intermolecular H-bonding interactions greatly contribute the excited-state proton transfer process, similar to a previously reported solvent-assistant ESPT reaction.60-63 More interestingly, three new bands appeared at 304, 256, and 220 nm in cyclohexane along with the characteristic thiol bands at 271 and 236 nm after 5 min of photolysis. Upon continued exposure of this sample to photolysis, an additional three new absorption bands were observed at ~320, 250, and 202 nm, with the band at ~320 nm being the most intense after 20 min. Similar experimental results were obtained upon photolysis at 355 and 223.1 nm, demonstrating that the reaction rate decreases in the order 355 > 266 > 223.1 nm for the photolysis wavelengths and in the order cyclohexane ≈ acetonitrile > water for the type of solvent. Thus, it appears that the tautomeric hydrogen transfer process in DMMP occurs at lower excited states (i.e., S2, S1, and/or Tn excited states), in agreement with previously reported ESIPT reaction systems due to the hydrogen-bonding chain between solute and solvents. 64-68


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1.0

A

origin 0.5 min 0.8 min 1min 2min 3min 4min 5min 6min 7min 19min

0.6

0.4

B

0.6

0.4

0.2

0.2

0.0

200

origin 3min 9min 15min 30min 40min

0.8

Abs

0.8

Abs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.0

250

300

350

4 00

200

250

Wavenumber/nm

300

350

400

Wavenumber/nm

Figure 5. UV spectra of 3.9×10-5 mol/L DMMP in CH3CN (A) and H2O (B) at different photolysis minutes upon 266 nm pulsed laser.

DFT calculations at the B3LYP/6-311++G(3df,p) level of theory using the PCM solvation method with water indicate that the ground state DMMP-thiol tautomer is 5.5 kcal/mol higher in energy than the DMMP-thione tautomer, which are connected via a transition state lying at 33.6 kcal/mol based on DMMP-thione (S0). Therefore, the ground-state proton transfer reaction between DMMP-thione and DMMP-thiol is inhibited as a result of this high energy barrier, which is a similar result to those previously reported for 2HP and 2PY.27 Figure 6 shows that the energies of the S4 (ππ*) state of DMMP-thione (103.8 kcal/mol) and the S1, min (nπ*) state of DMMP-thiol (101.1 kcal/mol) are essentially equivalent. Furthermore, as the transition state (T1, 104.7 kcal/mol) has an energy comparable to the S4 state of thione DMMP (103.8 kcal/mol). It is concluded that, after absorption of ultraviolet radiation (223~355 nm) one main relaxation



Page 24 of 41

mechanism may occur, via which the lowest 1(nπ*) state can be populated, with subsequent evolution to the lowest 3(ππ*) state.

In addition to calculating the energies of these various species, spin-orbit coupling (SOC) constants were also computed between the ground and triplet states and between the singlet and triplet states using the single-particle BP operator with an effective charge approximation in PySOC69. The calculations suggest an initial population of the higher excited state, with subsequent evolution to the lower excited state via internal conversion. Then, transition occurs via the conical intersection involving the highest 1(ππ*) and lowest 1(nπ*) states, (1ππ*/1nπ*)CI, which is associated with a low-energy singlet-triplet crossing, S1/T1(1nπ*/3ππ*)STC, with a maximum computed SOC of 140 cm-1. However, transitions via S2(1ππ*)/T2(3nπ*) and S3(1nπ*)/T3(3ππ*) with computed SOC values of 122 and 130 cm-1, respectively, are also possible, indicating that transition from the 1(nπ*) state to the lowest 3(ππ*) triplet state is accessible. Further radiationless decay to the ground state is impossible through (gs/3ππ*)STC, with a SOC of near zero. Thus, it is postulated that the most possible mechanisms related to the triplet and singlet manifolds in the Franck–Condon region along the minimum energy path of the 1

(ππ*) state leads DMMP to the lowest triplet state, T1 3(ππ*), with a subsequent ESPT reaction

process.


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Figure 6. Potential energy surface diagrams for ESIPT tautomerization reactions for DMMP in H2O using the PCM solvent model (left) and water-assisted (right). Values are in kcal/mol. As DMMP can form clusters with water molecules, we calculated the proton transfer process using only a single water molecule due to the difficulty and large workload involved in such calculations (see Figure 6 (right)). One key difference lies in that the electronic transition of DMMP-thiol(H2O) changes from (n,π*) to (π,π*) in the S1 state due to solvent hydrogenbonding, which may account for the water molecule stabilizing the ππ* transition60, 61, 70. This scenario leads to the S4 state of DMMP-thione(H2O) and the S1 state of DMMP-thiol(H2O) having correlated singlet excited states. However, clear differences do exist between DMMP and the DMMP(H2O) cluster, as the transition energy of the DMMP(H2O) cluster was reduced to 93.9 kcal/mol, which is lower than the energy of the S4 state of DMMP (104.7 kcal/mol).

Although revealing, the aforementioned results represent only preliminary results in the context of the excited-state hydrogen transfer tautomerization process of DMMP, and so further theoretical and experimental investigations are required to determine the predominant mechanism. For instance, time-resolved transient spectroscopy could be employed to trap possible reaction intermediates. In addition, the ICs, ISCs, and conical intersections between the 25 ACS Paragon Plus Environment


Page 26 of 41

S2, S1, T1, and S0 states must be fully characterized, as these are of particular importance to elucidate the ESIPT reaction mechanism. More importantly, if ultrafast time-resolved spectroscopic experiments can detect T1 (DMMP-thione) and/or T1 (DMMP-thiol), the reaction mechanism could potentially be explained as follows:

4. Conclusion

In summary, resonance Raman spectroscopy was employed to assign the vibrational spectra of 4,6-dimethyl-2-mercaptopyrimidine (DMMP) in acetonitrile, methanol, and water through a combination of Fourier-transform (FT) infrared spectroscopy, FT-Raman UV-Vis spectroscopy, and density functional theoretical (DFT) calculations. The FT-Raman spectra confirmed that DMMP forms a dimer in its neat solid form through intermolecular hydrogen bonds. In methanol and water, the majority of the Raman spectra were assigned to the vibrational modes of DMMP(solvent)n clusters (n = 1–4), which formed through NH···O hydrogen bonding interactions. The presence of these intermolecular NH···O hydrogen bonding interactions, which are key constituents of the stable DMMP thione tautomer, revealed significant structural differences in the predominant DMMP species in the solvents examined herein. Conversion between the thione and thiol tautomeric forms of DMMP was established by UV spectroscopy in water and acetonitrile under 266 nm laser photoirradiation, which induced the hydrogen transfer reaction. The obtained results suggest that tautomerization should occur easily in lower excited 26 ACS Paragon Plus Environment

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states in these two solvents. Furthermore, intermolecular hydrogen bonding interactions between DMMP and polar protonic solvents may reveal important insights regarding the excited-state proton transfer (ESPT) reaction mechanism. Therefore, DMMP could be used to provide insight into the photoinduced hydrogen-atom detachment–attachment mechanism for sulfur-substituted nucleic acid bases. According to the experimental results obtained herein, the excited state thione → thiol tautomerization could be successfully explored by combining spectroscopic techniques with DFT, which may well provide an improved understanding of the tautomeric equilibria of sulfur-substituted pyrimidine and its derivatives for application in biological and medicinal chemistry.

In addition, the present spin-orbit coupling calculations reveal that the excited-state triplet hydrogen transfer process, regardless of the presence of a conical intersection, can efficiently stabilize the triplet transition state of DMMP. DMMP-thiol formation may originate from the S4 state of DMMP-thione by its internal conversion to the S2 state, via a S2/S1 conical intersection, with subsequent evolution to the T1 state via intersystem crossing (ISC), on which the ESPT process occurs to form the DMMP-thiol upon less than 266 nm radiation. A second possible reaction mechanism involves the lower-energy singlet excited state S1, from which direct ISC to the T1 state of DMMP-thione close to the Franck–Condon region passes the triplet transition state to DMMP-thiol upon 355 nm photolysis. Only the triplet state can greatly decrease the barrier of ESPT. Our calculations of the singlet states, including the first excited-state singlet state, demonstrate that the transition barrier is much higher than the triplet state process. Broadly, these predictions may serve as a guide for understanding a wide variety of photochemical



Page 28 of 41

reaction mechanisms that merit further study by specialized spectroscopic techniques, including further developments in studies of sulfur-substituted nuclei acids.

ASSOCIATED CONTENT Supporting Information.

This material is available free of charge via the Internet at http://pubs.acs.org. UV spectra in different solvents(Figure S1); Optimized geometries of gaseous DMMP and DMMP with PCM and DMMP(solvent)n (solvent=H2O and CH3OH; n=1~4) (c-j) with H2O and CH3OH solvation models at the B3LYP/6-311++G(3df,p) level of theory (Figures S2 and S3); Resonance Raman spectra of DMMP at selected excitation wavelengths in CH3CN, CH3OH, and H2O (Figure S4); 282.4 nm resonance Raman assignments for DMMP in H2O (Figure S5); Plots of reduced density gradient versus the electron density (Figure S6); UV spectra of DMMP in different solvents for different photolysis durations upon 266 and 355 nm pulsed laser exposure (Figures S7–S13); Energies (∆E) and enthalpies (∆H) of thiol and thione DMMP relative to the thiol monomer in the gas phase calculated using B3LYP/6-311++G(3df,p) with the PCM solvation model (Table S1); Wavenumber difference (∆ν) between contiguous vibrational modes from FT-Raman experiments and computed frequencies at the B3LYP/6-311++G(3df,p) level of theory for the DMMP monomer and dimer (Table S2); Zero-point corrected binding energies (in kcal/mol) of DMMP(solvent)n (solvent=H2O, CH3OH; n=1~4) using B3LYP/6-311++G(3df,p) with the PCM solvation model (Table S3); Experimentally observed Raman wavenumbers of crystalline and aqueous DMMP, all Raman frequencies of the DMMP-(H2O)2 cluster in water were calculated at B3LYP/6-311++G(3df,p) with the PCM solvation model (Table S4); Molecular orbitals associated with electronic transitions of DMMP-H2O cluster (Table S5); Cartesian coordinates of DMMP and DMMP(Solvent)n (Solvent=CH3OH, H2O; n=1~4) with the PCM model (Table S6). (PDF).

AUTHOR INFORMATION 28 ACS Paragon Plus Environment

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Corresponding Author Yanying Zhao

E-mail: [email protected] Phone number: +86-571-868-436-27 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant Nos. 21473162 and 21273202). Y. Zhao is grateful for the Project Grants 521 Talents Cultivation of Zhejiang Sci-Tech University. We are also grateful for support from the Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology of Zhejiang Sci-Tech University.



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