A DFT approach for simple and solvent assisted-proton movement: Biurea as a case of study

Accepted Manuscript A DFT approach for simple and solvent assisted-proton movement: Biurea as a case of study Abdol Reza Hajipour, Sirous Ghorbani, Morteza Karimzadeh, Saeideh Jajarmi, Alireza Najafi Chermahini PII: DOI: Reference:

S2210-271X(16)30067-6 http://dx.doi.org/10.1016/j.comptc.2016.03.009 COMPTC 2079

To appear in:

Computational & Theoretical Chemistry

Received Date: Revised Date: Accepted Date:

5 March 2016 7 March 2016 8 March 2016

Please cite this article as: A.R. Hajipour, S. Ghorbani, M. Karimzadeh, S. Jajarmi, A.N. Chermahini, A DFT approach for simple and solvent assisted-proton movement: Biurea as a case of study, Computational & Theoretical Chemistry (2016), doi: http://dx.doi.org/10.1016/j.comptc.2016.03.009

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A DFT approach for simple and solvent assisted-proton movement: Biurea as a case of study Abdol Reza Hajipour,*a,b Sirous Ghorbani,a Morteza Karimzadeh,a Saeideh Jajarmi,a Alireza Najafi Chermahini*a a

Department of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran. Tel.: +98

311 391 3262; fax: +98 311 391 2350. b

Department of Neuroscience, University of Wisconsin, Medical School, 1300 University

Avenue, Madison, WI 53706-1532, USA. E-mail addresses of corresponding author: Alireza Najafi Chermahini [email protected]; Abdol Reza Hajipour: [email protected]

1

Abstract: 306 conformers of Biurea as a biologically important molecule were optimized and frequency calculation was performed for each conformer. Then, these conformers were classified in seven tautomeric categories. Five most stable tautomers were selected and their stabilities were investigated carefully. Results showed that none of the tautomers are planar and tautomer 2 having two carbonyl function trans to each other is the most stable one. A full scheme transformation of these tautomers to each other was also conveyed through proton exchange routs. Solvent effects were studied for all tautomers and the results were compared with the gas phase. The obtained data showed that all the solvents stabilize all the available tautomers and order of solvent effect is as follow as: water > DMSO > acetone > toluene. But solvents did not have significant effect on the relative Gibbs free energy values. Then, prototropic tautomerism was performed using one-water molecule both in the gas and water phases. Explicit water indicated very important role in proton jumping. Explicit water molecule can lower energy barrier of tautomerism around 20-26 kcal/mol, whereas implicit water lowers such an energy by an amount of 1-2 kcal/mol. Keywords Biurea; Prototropic; Solvent effect; B3LYP; Tautomerism; Proton transfer

2

1. Introduction Biurea or Hydrazine-1,2-dicarboxamide with a molecular formula of C2H6N4O2 is a white solid which is mainly produced by reaction of hydrazine or its salts with urea in industrial scale [1-2]. A large amount of this compound is present in bread flour, aquaculture products and food industrials containing azodicarbonamide (ADC) [3]. ADC itself is usually made by oxidation of Biurea. Upon inhalation of ADC dusts, it is converted to metabolically inert and low toxic Biurea which is rapidly eliminates from all tissues via urine [4-5]. Biurea can also be applicable in the preparation of expanded polypropylene for conductor insulating [6]. According to reported X-ray structure, the Biurea skeleton created by N1sp3-C2sp2(O7)-N3sp3-N4sp3-C5sp2(O8)-N6sp3 atoms is nonplanar and deviation from planarity is due to two facts (Fig. 1): the first one is because of rotation around the central N3-N4 bond which makes C2-N3-N4 and N3-N4-C5 planes to be inclined at 68.7◦, and the second one is due to the rotation around C2-N3 and N4-C5 bonds which makes N1-C2(O7)-N3 and N4-C5(O8)-N6 planes to be inclined at 83.6◦ [7]. Previously reported ab initio calulations confirmed that urea structure is planar in the crystal, but nonplanar in the gas phase [8].

Fig. 1 Structure of biurea and its numbering system

However, to the best of our knowledge, there is only one theoretical report which demonstrates assigning vibrational bands of this molecule using DFT calculations at B3LYP/3-21G and 3

B3LYP/6-31G(d,p) levels of theory and there is no computational study about tautomeric preferences and conformational analysis of such important biological molecule in the gas and solution phases [9]. Therefore, knowing about complete and step by step scheme of tautomerism of Biurea including both internal rotations routs and intramolecular proton transfer is needed, because application of such tautomers in chelating with metal ions or changing in the polarity of the medium may affect their chemical and biological properties [10-15]. Therefore, the current paper is to throw light upon mechanism of tautomeric equilibrium both in the gas phase and in the solution with and without micro-hydrated medium. 2. Computational Details Initially geometries of all tautomers were optimized within density functional theory (DFT) framework involving B3LYP functional and 6-311++G(d,p) basis set [16-18]. No symmetry restrictions were concerned and C1 symmetry considered for all of the studied tautomers. Then, frequency calculations were performed for each case using the same methods to establish structures as local or global minima. Zero-Point Vibrational Energy (ZPVE) corrected with appropriate scaling factor [19]. The Tomasi’s Polarized Continuum Model (PCM) using the Integral Equation Formalism variant (IEFPCM) was also used to concern the effects of different solvents [20-22]. The QST2 (Synchronous Transit-Guided Quasi-Newton) calculations and in some cases QST3 methods were employed to locate each transition state between two minima [23-24]. All transition states showed only one imaginary frequency. All calculations were performed by GAUSSIAN 09 package program [25]. 3. Structure and Relative Stability

4

306 conformers of Biurea involving seven tautomeric forms were optimized at B3LYP/6311++G(d,p) level of theory. Structures of these forms were shown in supplementary information section (Fig. S1). The structures of all considered isomers verified to be at the minimum energy through vibrational analysis and did not show imaginary frequency. Among them, seven most stable tautomeric forms were selected based on their higher population in comparison with their conformers and are numbered as 1-7 (Scheme 1).

B H 8 N O 4 C5 H N H 6

1 NH2 H 8 2 C N O N 4 C O 5 7 3H NH2 6 2

1 NH2 6 C N 5 NH2 O 2 N 4 CH 3 7 O H 8 7

A

C

1 H N H 8 H 2C N O O 3N 4 C5 H 7 nd H N 1a 2 H 6 D D 4 1 H 1 NH2 N H 2 C N O8 H 2C O 3N O 3N 4 C 5 7 H 7 H NH2 6 7 H 5 3 O 6 H C N 5 NH2 N 2 N 4 CH 1 3 O 8 H 6

1 NH2 H 2C N O8 O 3 N 4 C5 7 H NH2 6 1

Scheme 1 Seven most stable tautomers of Biurea

By employing B3LYP/6-311++G(d,p) model, the geometrical parameters involving bond lengths, angles and dihedrals were obtained for the former tautomersin the gas phase (Table 1). Crystallographic data were not available for all of the tautomers except tautomer 2. Comparing the obtained geometrical parameters for the tautomer 2 with the previously reported experimental values showed excellent correlation. A closer look at the values shows that none of tautomers are planar and deviation from planarity was calculated to be more than 30 degree for each tautomer and the reason for this is maybe due to the lack of extra resonance structure in these series.

5

Another reason for being out of planarity is presence of weak double bond involving two central nitrogen N3 and N4 atoms near each other. Table 1 Obtained geometrical parameters for seven most stable tautomers of Biurea 1-7 calculated at B3LYP/6311++G(d,p) level of theory in comparison with experimental data 1

2

3

4

5

6

7

Experimental

N1-C2

1.37

1.36

1.36

1.26

1.27

1.26

1.35

1.32

C2-N3

1.40

1.41

1.40

1.39

1.39

1.45

1.48

1.36

N3-N4

1.43

1.39

1.38

1.38

1.42

1.24

1.23

1.39

N4-C5

1.29

1.41

1.40

1.39

1.29

1.49

1.49

1.36

C5-N6

1.36

1.36

1.26

1.26

1.36

1.43

1.42

1.32

C2-O7

1.22

1.22

1.22

1.35

1.36

1.34

1.21

1.36

C5-O8

1.35

1.22

1.35

1.35

1.35

1.40

1.42

1.25

N1-C2-N3

114.55

114.94

115.14

129.59

129.38

116.55

114.99

118.1

C2-N3-N4

117.72

120.79

121.60

118.30

114.68

112.60

113.64

120.6

N3-N4-C5

112.04

120.78

117.78

118.31

111.95

113.48

112.39

120.6

N4-C5-N6

127.80

114.97

129.51

129.59

128.20

107.89

106.63

118.1

N1-C2-O7

124.66

125.09

124.84

121.91

153.94

126.98

126.93

123.2

N3-C2-O7

120.67

119.94

120.02

108.48

109.14

116.47

118.01

118.7

N4-C5-O8

118.78

119.91

108.52

108.48

118.45

112.71

106.87

118.7

N6-C5-O8

113.38

125.10

121.94

121.91

113.31

113.25

112.02

123.2

N1-C2-N3-N4

-23.89

-17.48

-13.03

-14.42

-20.08

-179.15

23.90

--

C2-N3-N4-C5

141.67

127.33

126.14

124.92

135.48

178.60

176.82

--

N3-N4-C5-N6

1.31

-16.79

-15.45

-14.40

1.68

140.23

137.74

--

O7-C2-N3-N4

159.97

164.70

167.12

166.96

162.52

0.91

-149.82

--

N3-N4-C5-O8

178.87

164.99

166.39

199.99

179.34

14.41

-102.31

--

Bond Lengtha

Bond angleb

Tetrahedral angleb

a

Bond lengths are in angstrom

b

Angles are in degree

6

Values of internal energies (E), zero-point energies (ZPEs), corrected zero-point energies (EZPE), enthalpies (H), Gibbs free energies (G), relative Gibbs free energies (ΔG) and dipole moments for all selected seven most stable tautomers (1-7), intermediate (IM) and transition states (TSs) was calculated at B3LYP/6-311++G(d,p) level of theory and demonstrated in Table 2. A look at the obtained free energy values shows that tautomer 2 is the most stable tautomer. The order of stabilities for selected tautomers is as follows: 2>1>3>5>4>7>6. The same trend will be seen if one considers obtained values for E, EZPE and H. Donation of electrons from two terminal nitrogen N1 and N6 atoms and also from two central nitrogen N3 and N4 atoms to the corresponding π* of carbonyl groups (C2=O7 and C5=O8 double bonds) can be a reason for more stability of tautomer 2 compared to others. Also, generated stronger bonds between carbon and oxygen atoms in comparison with carbon and nitrogen atoms can be another reason for such stability. Tautomers 6 and 7 with having weaker nitrogen-nitrogen double bond (N3=N4) are the most unstable ones. A deeper look shows that tautomers 1 and 3 with having one carbonyl functional group are more stable than tautomers 4 and 5 which they do not have even one C=O group. Detailed study for comparison of stabilities for tautomers has been brought in the NBO analysis section. Table 2 Calculated energies, zero-point energies, corrected zero-point energies, enthalpies, Gibbs free energies for all selected tautomers, intermediates and transition states of Biurea in the gas phase Compound

Ea

ZPE

EaZPE

Ha298.15

Ga298.15

Relative Gb298.15

NIFc

DMd

1 2 3 4 5 IMD TSA TSB TSC TS1D TS2D

-449.433801 -449.455158 -449.427515 -449.399962 -449.406237 -449.427515 -444.789483 -444.739119 -444.743814 -444.743814 -444.793411

0.107340 0.106696 0.107355 0.107445 0.107315 0.107301 0.101441 0.101830 0.101490 0.101497 0.101839

-449.326461 -449.348462 -449.320160 -449.292517 -449.298922 -449.320155 -449.282876 -449.273255 -449.245869 -449.245866 -449.255547

-449.317166 -449.338447 -449.310808 -449.283396 -449.289742 -449.310805 -444.137440 -444.107418 -444.170301 -444.170300 -444.140100

-449.359780 -449.383033 -449.353543 -449.325755 -449.332257 -449.353536 -444.710707 -444.700313 -444.134191 -444.134140 -444.184100

14.59 0.00 18.50 35.94 31.86 18.51 41.87 43.88 09.11 09.11 98.40

0 0 0 0 0 0 1 1 1 1 1

4.34 1.05 3.13 2.49 3.01 3.13 1.44 1.14 1.47 1.47 7.13

7

a

Energies, corrected zero-point energies, enthalpies and Gibbs free energies are in Hartree.

b

Relative Gibbs free energies are in kcal/mol.

c

Number of imaginary frequencies

d

Dipole moments are in Debye.

4. Interconversion of Tautomers Interconversion of five most stable tautomers 1-5 to each other was investigated through jumping proton from one atom to another one. Regardless of tautomer 6 and 7 was due to the significant differences in the obtained free energy Gibbs values of these structures compared to the most stable tautomer 2. The question arises from the probability of making one tautomer from another one through one step process? Such transforms proceed through proton transfer or internal rotations? The next question is finding rate determining step of a reaction? These questions will be answered one by one through different paths A-D in the following. Relative thermodynamic and kinetic data, equilibrium constant and rate constant for all paths A-D calculated in the gas phase and were shown in Table 3. These data will be later discussed in details. Table 3 Relative thermodynamic and kinetic data, equilibrium constant and rate constant for all of the paths A-D in the gas phase calculated at B3LYP/6-311++G(d,p) level of theory

a

TS

Reactions

ΔEZPEa

ΔH≠a

ΔHa

ΔG≠aforward

ΔGa

kforward

Keq

TSA

1→2

-13.81

27.41

-13.35

27.24

-14.59

6.67E-08

5.02E+10

TSB

2→3

17.76

46.76

17.34

47.88

18.50

4.93E-23

2.69E-14

TSC

3→4

17.35

46.46

17.20

46.61

17.44

4.21E-22

1.62E-13

TS1D

4→IMD

-17.34

29.26

-17.19

29.18

-17.43

2.52E-09

6.08E+12

TS2D

IMD→5

13.32

40.50

13.22

40.39

13.35

1.53E-17

1.61E-10

ΔEZPE, ΔH≠, ΔH, ΔG≠forwardand ΔG are in kcal/mol

Path A: This path simply demonstrates conversion of tautomer 1 to tautomer 2 through only onestep proton transfer rout as shown in Fig. 2. Formation of transition state TSA needs 22.48 8

kcal/mol energies. Here, the bond length between H12 and O8 atoms is increased around 0.35 A going from tautomer 1 to TSA. In addition, the bond distance between N4 and H12 atoms is decreased to reach 1.34 A in TSA. Differences in Gibbs energy values for both the forward and reverse reaction shows that, overall, the reaction is exothermic and by this way, the most stable tautomer 2 is produced. More electronegativity of oxygen O8 atom compared to nitrogen N4 atom makes easier breaking of O8-H12 bond. Energy barrier for such proton transfer reaction shows comparable values with our obtained data for other linear and heterocyclic molecules [2633].

Fig. 2 Reaction path A: conversion of tautomer 1 to tautomer 2

Path B: Current path shows interconversion of tautomer 2 to tautomer 3 through one-step proton exchange between different nitrogen N6 and oxygen O8 atoms as demonstrated in Fig. 3. Jumping proton from nitrogen N6 atom to oxygen O8 atom needs 47.88 kcal/mol energies to occur and form TSB. The tautomerism process, overall, is endothermic and detaching proton takes place from the less electronegative N6 atom. Breaking N6-H14 single bond along with formation of a four-membered heterocyclic like transition state TSB confirms obtained higher energy barrier for such a transformation.

9

Fig. 3 Reaction path B: conversion of tautomer 2 to tautomer 3

Path C: This path also shows one-step proton exchange between tautomer 3 and tautomer 4 which proceed in one-step like the previously discussed paths (Fig. 3). Here, the required energy barrier was calculated to be 46.62 kcal/mol which is similar to path B. Shortening of the O7-H9 bond along with lengthening of N1-H9 bond can easily be seen going from tautomer 1 to transition state TSC and then to tautomer 4. It is seen that bond distance between hydrogen H9 atom with oxygen O7 atom is approximately identical with the created bond length between hydrogen H9 atom with nitrogen N1 atom in TSC which it confirms breaking of a bond and formation of another bond.

Fig. 4 Reaction path C: conversion of tautomer 3 to tautomer 4

Path D: In contrast to previously reported paths, this paths goes from two-steps which both of them involves H-jumping from oxygen and nitrogen atoms (Fig. 5). In the first step, O8-H14 bond length is increased from 0.97 A in tautomer 4 into 1.31 A in TS1D and then into 1.22 A in IMD. Also, N6-H14 bond distance is decreased going from, respectively, tautomer 4 to TS1D and then to IMD. Such prototropic tautomerism needs 29.18 kcal/mol energies to occur. In the second 10

step, weakening of N4-H12 and C5-O8 bonds and also strengthen of O8-H12 and C5-N4 bonds are observed. Proton exchange in this step needs more energy barrier than the first step and can be identified as a rate-determining step of the reaction. If one considers the reverse reaction, the first step will be rate-determining step in contrast to forward reaction. Slightly lower energy barrier value obtained for Biurea is due to more flexibility of this molecule.

Fig. 5 Reaction path D: conversion of tautomer 4 to tautomer 5

4. Solvent Effects Solvents play important roles in the stability of tautomers because solvents are able to change the polarity of medium. Considering the fact that dipole moments of different tautomers will depend on polarity of medium, it can be infer that stability of tautomers may affect according to such changes. Therefore, it is decided to investigate solvent effects on Biurea tautomers. Energies, zero-point energies, corrected zero-point energies, enthalpies, Gibbs free energies for all tautomers of Biurea was calculated at B3LYP/6-311++G(d,p) level of theory for four different polar and non-polar solvents involving acetone, DMSO, Toluene and water (Tables 2S-5S).

11

A first look at Tables 2S-5S shows that higher dipole moments can be obtained for tautomers 15 in all used solvents in comparison with the gas phase. From the values of Tables 3-6 with only one exception, one can easily say that the more polar the solvent, the more obtained dipole moment. Such trends are observed for tautomers 1, 3, 4 and 5 but not for tautomer 2. In contrast to tautomers 1, 3, 4 and 5, the observed dipole moment for tautomer 2 is higher when poalrity of solvent decreased. Gibbs energy values show that the order of stabilities of tautomers does not change and this order remains as: tautomer 2> tautomer 1> tautomer 3> tautomer 5>tautomer 4> tautomer 7> tautomer 6. But it should be regarded that all these tautomers stabilize in all used solvents and such stabilization is much more when the polarity of the solvent increased. Solvent stabilization energy lies in the range of 4-14 kcal/mol. Relative thermodynamic and kinetic data, equilibrium constants and rate constants for all paths A-D in the solvent were shown in Table 4. It is clear that there is only slightly differences in these values compared to each other and also gas phase one and such differences are negligible. Table 4 Relative thermodynamic and kinetic data, equilibrium constants and rate constants for all of the paths A-D in the solvent calculated at B3LYP/6-311++G(d,p) level of theory TS

Reactions

ΔE

a ZPE

ΔH≠

a

ΔH

a

ΔG≠

a forward

ΔG

a

kforward

Keq

Acetone TSA

1→2

-15.73

27.32

-15.37

27.24

-16.35

6.67E-08

9.81E+11

TSB

2→3

19.07

18.75

17.34

49.27

19.57

4.72E-24

4.43E-15

TSC

3→4

19.13

18.94

17.20

48.87

19.37

9.27E-24

6.21E-15

TS1D

4→IM D

-19.10

-18.92

-17.19

29.51

-19.27

1.45E-09

2.73E+15

TS2D

IMD→5

15.38

42.52

15.26

42.58

15.45

3.79E-19

4.64E-12

DMSO TSA

1→2

-15.84

27.30

-15.47

27.20

-16.51

7.13E-08

1.29E+12

TSB

2→3

19.13

48.50

18.81

49.34

19.64

4.19E-24

3.93E-15

TSC

3→4

19.23

48.39

19.02

49.02

19.50

7.20E-24

4.99E-15

12

TS1D

4→IM D

-19.24

29.37

-19.03

29.51

-19.53

1.44E-09

2.11E+14

TS2D

IMD→5

15.53

42.64

15.38

42.88

15.73

2.28E-19

2.90E-12

Toluene TSA

1→2

-14.74

27.34

-14.35

27.25

-15.36

6.56E-08

1.84E+11

TSB

2→3

18.74

47.63

18.35

48.62

19.37

1.41E-23

6.21E-15

TSC

3→4

17.90

47.14

17.78

47.36

17.96

1.19E-22

6.72E-14

TS1D

4→IM D

-18.15

29.36

-18.02

29.41

-18.21

1.71E-09

2.27E+13

TS2D

IMD→5

14.26

41.45

14.18

41.32

14.24

3.18E-18

3.78E-11

Water TSA

1→2

-15.86

27.31

-15.50

27.19

-16.49

7.25E-08

1.24E+12

TSB

2→3

19.14

48.52

18.83

49.26

19.64

4.80E-24

3.94E-15

TSC

3→4

19.25

48.41

19.05

49.01

19.50

7.32E-24

4.99E-15

TS1D

4→IM D

-19.26

29.36

-19.05

29.51

-19.54

1.45E-09

2.15E+14

TS2D

IMD→5

15.56

42.67

15.41

42.89

15.75

2.24E-19

2.81E-12

a

ΔEZPE, ΔH≠, ΔH, ΔG≠forwardand ΔGare in kcal/mol

5. Water-catalyzed proton exchange: Considering the fact that water can catalyze movement of protons from one atom to another one, we studied such movement in the presence of water molecule through explicit solvent method. Presence of water molecule is needed in some of tautomerism processes, because water molecule causes formation of hydrogen bonding and makes lowering of energy barrier. Therefore, we placed one water molecule near Biurea where the bond breaking and formation was occurred. New reactants, transition states and intermediates were optimized at B3LYP/6-311++G(d,p) level of theory and frequency calculations were performed at the same level. We used prime (´) and double prime (´´) to make differences in H-jumping with and without water molecule. Therefore, all the new formed structure will be shown using prime and double prime symbols, respectively, for the gas and solution phases. Relative kinetic and thermodynamic data

13

simultaneous with rate constants and equilibrium constants of water-assisted tautomersim were brought for paths A´-E´ and A´´-E´´ in Table 5. Table 5 Relative thermodynamic and kinetic data for the isomers of Biurea assisted by one water molecule TS

Reactions

ΔEZPEa

ΔH≠a

ΔHa

ΔG≠aforward

ΔGa

kforward

Keq

Gas phase TS′A

1′→2′

-12.10

5.45

-11.65

6.91

-12.86

5.34E+07

2.70E+09

TS′B

2′→3′

14.64

18.87

14.14

21.74

15.41

7.18E-04

4.98E-12

TS′C

3′→4′

14.58

18.85

14.18

21.38

15.14

1.32E-03

7.86E-12

TS′1D

4′→IM′D

-14.57

4.68

-14.17

6.24

-15.13

1.65E+08

1.25E+11

TS′2D

IM′D→5′

11.17

16.48

10.83

19.02

11.73

7.08E-02

4.01E+08

Water

a

TS′′A

1′′→2′′

-13.66

4.71

-13.00

5.94

-15.13

2.74E+08

1.25E+11

TS′′B

2′′→3′′

16.36

19.75

15.81

22.83

17.30

1.14E-04

2.05E-13

TS′′C

3′′→4′′

16.44

19.79

15.87

22.94

17.47

9.47E-05

1.54E-13

TS′′1D

4′′→IM′′D

-16.44

3.92

-15.87

5.47

-17.47

6.07E+08

4.88E+12

TS′′2D

IM′′D→5′′

13.28

17.50

12.82

20.41

14.23

6.77E-03

3.66E-11

ΔEZPE, ΔH≠, ΔH, ΔG≠forward and ΔG are in kcal/mol

As already mentioned, energy barriers for proton movement involving tautomerism of 1→2, 2→3, 3→4, 4→IMD, IMD→5 were, respectively, 27.24, 47.88, 46.62, 29.18 and 40.39 kcal/mol. These values were lowered to 6.91, 21.74, 21.38, 6.24 and 19.02 kcal/mol, respectively, when prototropic tautomerism were assisted by one-water molecule and performed in the gas phase (Fig. 6-10). As it is clear, energy barrier decreased around 20-26 kcal/mol for each path. The reason for this is because of formation of six-membered heterocyclic like structures in transition states TSA´, TSB´, TSC´, TSD1´, TSD2´. There are not many differences between the obtained energy barrier values of tautomerism assisted by one-water molecule for the gas and water 14

media. Such data are reduced to 5.94, 22.83, 22.94, 5.47 and 20.41 kcal/mol when H-jumping can be done through helping one-water molecule.

Fig. 6 path A´: proton transfer between 1´ and 2´

Fig. 7 path B´: proton transfer between 2´ and 3´

Fig. 8 path C´: proton transfer between 3´ and 4´

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Fig. 9 path D1´: proton transfer between 4´ and IM´

Fig. 10 path D2´: proton transfer between IM´ and 5´

Conclusion Investigation on geometrical parameters showed that all selected tautomers 1-7 are not planar and deviation from planarity is more than 30 degree for each tautomer. Comparing stabilization energy of conformers indicated that tautomer 2 with having two C=O double bond in a trans conformation is the most stable tautomer. Solvent effects for comparative stabilization energy of tautomers showed that tautomer 2 is the most stable one in all polar and non-polar solvents. Conversion of tautomers to each other was also surveyed through different paths A-D. The results showed that the needed energy for such transformation is really high and implicit water cannot play an important role to lower the energy barrier. For this reason, explicit-water effect was also investigated both in the gas and water media. The obtained data indicated that when prototropic tautomerism assisted by one-water molecule, energy barrier reduced by an amount of 20-26 kcal/mol. Acknowledgements

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Graphical Abstract

A DFT approach for simple and solvent assisted-proton movement: Biurea as a case of study Abdol Reza Hajipour, Sirous Ghorbani, Morteza Karimzadeh, Saeideh Jajarmi, Alireza Najafi Chermahini

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Highlights 

Tautomerism of Biurea was investigated both in the gas phase and in the solution using B3LYP/6-311++G(d,p) functional.



Interconversion of the most stable tautomers to each other was also studied through proton transfer route both in the gas phase and in the solution.



Simple and water-assisted tautomerism were compared.

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