Unscrambling COOH and NH groups microsolvation in neat Dimethyl-Sulfoxide: Insights from 1. H-NMR Spectroscopy and Computational Studies

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1 Electronic Supplementary Material (ESI) for Physical Chemistry Chemical Physics. This journal is the Owner Societies 2017 ELECTRONIC SUPPLEMENTARY INFORMATION Unscrambling COOH and NH groups microsolvation in neat Dimethyl-Sulfoxide: Insights from 1 H-NMR Spectroscopy and Computational Studies Panteleimon G. Takis, a, Konstantinos D. Papavasileiou, b Loukas D. Peristeras,* b Georgios C. Boulougouris, c Vasilios S. Melissas d and Anastassios N. Troganis* a * Corresponding authors: l.peristeras@inn.demokritos.gr, Tel: , Fax: atrogani@uoi.gr, Tel.: , Fax: a Department of Biological Applications and Technology, University of Ioannina, Ioannina, Greece b National Center for Scientific Research Demokritos, Institute of Nanoscience and Nanotechnology, Molecular Thermodynamics and Modelling of Materials Laboratory, GR Aghia Paraskevi Attikis, Greece c Department of Molecular Biology and Genetics, Democritius University, Alexandroupolis, 68100, Greece d Department of Chemistry, University of Ioannina, Ioannina, Greece Present address: GIOTTO Biotech S.r.l., Via Madonna del Piano 6, I 50019, Sesto Fiorentino, Firenze, Italy

2 Index Pages Index... SI-1 1 H-NMR δ shifting examples of acids DMSO interaction... SI-2 13 C-NMR results for benzoic acid... SI-4 13 C-NMR δ shifting example of benzoic acid DMSO interaction... SI-5 1 H-NMR δ shifting examples of ethyl acetamidocyanoacetate DMSO interaction... SI-6 The acetic acid dimer without DMSO molecule (X3LYP/cc-pVTZ)... SI-7 Acetic acid Dimer (Fig. S5)... SI-7 The less probable [(2 x Acetic acid) DMSO] complexes (MP2/cc-pVTZ)... SI-8 [(2 x Acetic acid) DMSO] (Fig. S6 A)... SI-8 [(2 x Acetic acid) DMSO] (Fig. S6 B)... SI-9 Depiction, geometrical details and energetics of the fully optimized molecules and complexes... SI-10 B3LYP/cc-pVTZ... SI-10 DMSO (Fig. S7)... SI-10 Acetic acid (Fig. S8)... SI-11 Acetic acid DMSO complex (Fig. S9)... SI-12 Acetic acid dimer DMSO complex (Fig. S10)... SI-13 Ethyl acetamidocyanoacetate (Fig. S11)... SI-14 Ethyl acetamidocyanoacetate DMSO complex (Fig. S12)... SI-15 X3LYP/cc-pVTZ... SI-16 DMSO (Fig. S13)... SI-16 Acetic acid (Fig. S14)... SI-17 Acetic acid DMSO complex (Fig. S15)... SI-18 Acetic acid dimer DMSO complex (Fig. S16)... SI-19 Ethyl acetamidocyanoacetate (Fig. S17)... SI-20 Ethyl acetamidocyanoacetate DMSO complex (Fig. S18)... SI-21 MP2/cc-pVTZ... SI-22 DMSO (Fig. S19)... SI-22 Acetic acid (Fig. S20)... SI-23 Acetic acid DMSO complex (Fig. S21)... SI-24 Acetic acid dimer DMSO complex (Fig. S22)... SI-25 Ethyl acetamidocyanoacetate (Fig. S23)... SI-26 Ethyl acetamidocyanoacetate DMSO complex (Fig. S24)... SI-27 Particle based molecule species traced during the MD simulation of the 1M acetic acid in DMSO solution.... SI-28 SI-1

3 1 H-NMR δ shifting examples of acids DMSO interaction Figure S1. A) The 1 H-NMR chemical shifts of CH 3 group of acetic acid in its various concentrations. B) The 1 H-NMR chemical shifts of DMSO protons in the various concentrations (the same as in the Figure S1A) of acetic acid. All spectra are scaled to the same intensity. Figure S2. A) The 1 H-NMR chemical shifts of the aromatic protons of benzoic acid in its various concentrations. B) The 1 H-NMR chemical shifts of DMSO protons in the various concentrations (the same as in the Figure S2A) of benzoic acid. All spectra are scaled to the same intensity. SI-2

4 Table S1. The 1 H-NMR chemical shifts differences Δδ of DMSO protons from the acetic and benzoic acid titration in neat DMSO for various temperatures. T (K) Δδ (in ppm) of 1 H-NMR DMSO from 50 μμ to 1 M acid concentration Acetic acid Benzoic acid SI-3

5 13 C-NMR results for benzoic acid The following equations were employed in order to calculate the K 1 and K 2 association constants of benzoic acid DMSO complex and benzoic acid benzoic acid complex, respectively: C + K C 2 m 2 m 0,s = c + ( m - c), (S1) C0 d d d d Equation (S1) could be simplified into: ( ) d d d d m c + m - c, (S2) C0 C because the expected K 2 as well as the calculated C m values are much less than unity. Table S2. Calculated association constants (K 1, K 2 ) of benzoic acid interactions in DMSO by 13 C NMR data (± SE, standard error). T (K) K 1 K 2 Benzoic acid DMSO Benzoic acid dimer ± ± ± ± ± ± ± ± ± ± SI-4

6 13 C-NMR δ shifting example of benzoic acid DMSO interaction Figure S3. The 13 C-NMR chemical shifts evolution of benzoic acid in its various concentrations at 298 K. SI-5

7 1 H-NMR δ shifting examples of ethyl acetamidocyanoacetate DMSO interaction Figure S4. A) The 1 H-NMR chemical shifts of NH proton of the ethyl acetamidocyanoacetate in its various concentrations. B) The 1 H-NMR chemical shifts of DMSO protons in the various concentrations of ethyl acetamidocyanoacetate. All spectra are scaled to the same intensity. Table S3. The 1 H-NMR chemical shifts differences Δδ of DMSO and NH protons from the ethyl acetamidocyanoacetate titration in neat DMSO for various temperatures. T (K) Δδ (in ppm) of 1 H-NMR DMSO from 50 μμ to 1 M model peptide concentration Δδ (in ppm) of 1 H-NMR NH group from 50 μμ to 1 M model peptide concentration SI-6

In this section, the fully optimized structure coordinates of all systems studied along with their electronic (E elec ), zero-point (ZPE) and Gibbs free energies at 298.

8 In this section, the fully optimized structure coordinates of all systems studied along with their electronic (E elec ), zero-point (ZPE) and Gibbs free energies at K and 1 atm (G 298 ) are provided. The acetic acid dimer without DMSO molecule (X3LYP/cc-pVTZ) Figure S5.. Fully optimized structure of the acetic acid dimer at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent, without any DMSO molecule. Acetic acid Dimer (Fig. S5) 16 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees C H H H C O H O C O O H C H H H SI-7

9 The less probable [(2 x Acetic acid) DMSO] complexes (MP2/cc-pVTZ) A B Figure S6. Two fully optimized structures of two acetic acid molecules interaction with one DMSO molecule, optimized at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. Both structures are less abundant in the solution compared to the one reported in the main article (Fig. 5C), according to our extensive MD results analysis. [(2 x Acetic acid) DMSO] (Fig. S6 A) 26 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees S O C H H H C H H H H O H O C C C H H H C H H H O O SI-8

10 26 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees [(2 x Acetic acid) DMSO] (Fig. S6 B) C C O H O H H H C C O H O H H H C S C O H H H H H H SI-9

11 Depiction, geometrical details and energetics of the fully optimized molecules and complexes B3LYP/cc-pVTZ Figure S7. Fully optimized structure of DMSO at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 10 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees DMSO (Fig. S7) S O C H H H C H H H SI-10

12 Figure S8. Fully optimized structure of acetic acid at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 8 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid (Fig. S8) C H H H C O H O SI-11

Figure S9. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 18 Atoms E elec = -782.

13 Figure S9. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 18 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid DMSO complex (Fig. S9) S O C H H H C H H H H O C C H H H O SI-12

Figure S10. Fully optimized structure of the acetic acid dimer plus one DMSO molecule complex at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent.

14 Figure S10. Fully optimized structure of the acetic acid dimer plus one DMSO molecule complex at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 26 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid dimer DMSO complex (Fig. S10) C H H H C O H O C O O H C H H H S O C H H H C H H H SI-13

15 Figure S11. Fully optimized structure of the ethyl acetamidocyanoacetate molecule at the B3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 19 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Ethyl acetamidocyanoacetate (Fig. S11) N C H H C C H H H O C N C O O C H H H SI-14

16 Figure S12. Fully optimized structure of the ethyl acetamidocyanoacetate plus one DMSO molecule complex at the B3LYP/cc-pVTZ level of theory, applying the IEF- PCM model for bulk DMSO solvent. Ethyl acetamidocyanoacetate DMSO complex (Fig. S12) 29 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees N C H H C C H H H O C N C O O C H H H S O C H H H C H H H SI-15

17 X3LYP/cc-pVTZ Figure S13. Fully optimized structure of DMSO at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 10 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees DMSO (Fig. S13) S O C H H H C H H H SI-16

18 Figure S14. Fully optimized structure of acetic acid at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 8 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid (Fig. S14) C H H H C O H O SI-17

Figure S15. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 18 Atoms E elec = -782.

19 Figure S15. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 18 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid DMSO complex (Fig. S15) S O C H H H C H H H H O C C H H H O SI-18

20 Figure S16. Fully optimized structure of the acetic acid dimer plus one DMSO molecule complex at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 26 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid dimer DMSO complex (Fig. S16) C H H H C O H O C O O H C H H H S O C H H H C H H H SI-19

21 Figure S17. Fully optimized structure of the ethyl acetamidocyanoacetate molecule at the X3LYP/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 19 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Ethyl acetamidocyanoacetate (Fig. S17) N C H H C C H H H O C N C O O C H H H SI-20

Figure S18. Fully optimized structure of the ethyl acetamidocyanoacetate plus one DMSO molecule complex at the X3LYP/cc-pVTZ level of theory, applying the IEF- PCM model for bulk DMSO solvent.

22 Figure S18. Fully optimized structure of the ethyl acetamidocyanoacetate plus one DMSO molecule complex at the X3LYP/cc-pVTZ level of theory, applying the IEF- PCM model for bulk DMSO solvent. Ethyl acetamidocyanoacetate DMSO complex (Fig. S18) 29 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees N C H H C C H H H O C N C O O C H H H S O C H H H C H H H SI-21

23 MP2/cc-pVTZ Figure S19. Fully optimized structure of DMSO at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 10 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees DMSO (Fig. S19) S O C H H H C H H H SI-22

Figure S20. Fully optimized structure of acetic acid at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 8 Atoms E elec = -228.77002240 Hartrees ZPE = 0.

24 Figure S20. Fully optimized structure of acetic acid at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 8 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid (Fig. S20) C H H H C O H O SI-23

Figure S21. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent.

25 Figure S21. Fully optimized structure of the acetic acid plus one DMSO molecule complex at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. (For the H-bonds distances see Fig. 5B) 18 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid DMSO complex (Fig. S21) S O C H H H C H H H H O C C H H H O SI-24

26 Figure S22. Fully optimized structure of the acetic acid dimer plus one DMSO molecule complex at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent (For the H-bonds distances see Fig. 5C). 26 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Acetic acid dimer DMSO complex (Fig. S22) C H H H C O H O C O O H C H H H S O C H H H C H H H SI-25

27 Figure S23. Fully optimized structure of the ethyl acetamidocyanoacetate molecule at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. 19 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees Ethyl acetamidocyanoacetate (Fig. S23) N C H H C C H H H O C N C O O C H H H SI-26

28 Figure S24. Fully optimized structure of the ethyl acetamidocyanoacetate plus one DMSO molecule complex at the MP2/cc-pVTZ level of theory, applying the IEF-PCM model for bulk DMSO solvent. (For the H-bonds distances see Fig. 6B) Ethyl acetamidocyanoacetate DMSO complex (Fig. S24) 29 Atoms E elec = Hartrees ZPE = Hartrees G 298 = Hartrees N C H H C C H H H O C N C O O C H H H S O C H H H C H H H SI-27

29 Particle based molecule species traced during the MD simulation of the 1M acetic acid in DMSO solution. Table S4. Molecular species traced during the MD simulation of the 1M acetic acid in DMSO solution. Molecule species spc1 corresponds to DMSO (S), while molecule species 3 corresponds to acetic acid (E). Up to molecule species scp6 a significant number of reversible was observed. Molecules species scp7 and scp8 appeared rarely during the 2ns of the NVE MD simulation. Molecules species scp9 to spc11 not only were traced more rarely but also participate in reactions with low number of occurrences of even observed as non-reversible (Table S4). To this end, the quality of analysis that can be improved further, if needed, either by increasing the observation frequency (i.e. number of configuration dumped during the simulation) and the observation time (i.e. simulation time) or by refining further the criteria adopted for the calculation of H-bonds defining the particle based molecular species. ID Molecular species (particle based) Syntactic type <n> [molecules] <C> [mol/lt] spc1 S S ± spc2 ES E-S ± spc3 E E ± spc4 E 2 S E-E-S ± spc5 E 2 S E-S-E ± spc6 E 2 (open) E-E ± spc7 E 3 S E-E-E-S ± spc8 E 2 (closed) E=E ± spc9 E 3 S S-E E E ± spc10 E 3 S E-E-S-E ± spc11 E 3 E-E-E ± SI-28

30 Table S5. Reactions traced during the MD simulations of the 1M acetic acid in DMSO solution. ID Reaction Forward Reverse K Higher occurrence (significant) 1 S [spc1] + E [spc3] D ES [spc2] E [spc3] + ES [spc2] D E 2 S [spc4] E 2 [spc6] + S [spc1] D E 2 S [spc4] E [spc3] + ES [spc2] D E 2 S [spc5] E [spc3] + ES [spc2] D E 2 [spc6] + S [spc1] S [spc1] + 2 E [spc3] D E 2 S [spc4] E [spc3] D E 2 [spc6] Low occurrence (insignificant) 8 E [spc3] + E 2 S [spc4] D E 3 S [spc7] E 2 [spc6] D E 2 [spc8] ES [spc2] D S [spc1] + E 2 S [spc4] E [spc3] + E 2 S [spc4] D E 3 S [spc9] S [spc1] + 2 E [spc3] D E 2 S [spc5] S [spc1] + E 3 [spc10] D E 3 S [spc7] E 2 [spc6] + ES [spc2] D E 3 S [spc7] E [spc3] D E 2 [spc8] E [spc3] + E 2 S [spc4] D E 3 S [spc11] S [spc1] + E 3 [spc10] D E 3 S [spc9] E [spc3] + E 2 S [spc4] D E 3 S [spc11] S [spc1] + E 3 [spc10] D E 3 S [spc9] E [spc3] + ES [spc2] D E 3 S [spc7] E 3 S [spc7] D 2 E [spc3] + ES [spc2] Non reversible (analysis false) 22 E [spc3] + ES [spc2] " E [spc3] + ES [spc2] S [spc1] + ES [spc2] " S [spc1] + ES [spc2] S [spc1] + E 2 S [spc4] " S [spc1] + E 2 S [spc4] 3 25 E 2 S [spc5] " E 2 S [spc4] 5 26 E [spc3] + E 2 S [spc5] " E 3 S [spc11] 1 27 E [spc3] + E 2 S [spc5] " E 3 S [spc9] 1 28 E 3 S [spc11] " 2 E [spc3] + ES [spc2] 1 29 E 3 S [spc9] " E 3 S [spc11] 1 30 S [spc1] + E 2 S [spc4] " E [spc3] + S [spc1] + ES [spc2] 1 31 E 2 S [spc4] + ES [spc2] " S [spc1] + E 3 S [spc9] 1 32 E 2 [spc6] + ES [spc2] " S [spc1] + E 3 [spc10] 1 33 E 3 [spc10] " E 2 [spc6] + E [spc3] 1 34 S [spc1] + E 2 S [spc5] " 2 ES [spc2] 1 SI-29

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