Solvent-assisted intramolecular proton transfer in thiopurinol: application of M06-2X functional Morteza Karimzadeh, Neda Manouchehri, Dariush Saberi & Khodabakhsh Niknam Structural Chemistry Computational and Experimental Studies of Chemical and Biological Systems ISSN 1040-0400 Struct Chem DOI 10.1007/s11224-017-1035-7
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Author's personal copy Struct Chem DOI 10.1007/s11224-017-1035-7
ORIGINAL RESEARCH
Solvent-assisted intramolecular proton transfer in thiopurinol: application of M06-2X functional Morteza Karimzadeh 1
&
Neda Manouchehri 1 & Dariush Saberi 2 & Khodabakhsh Niknam 1
Received: 9 August 2017 / Accepted: 12 September 2017 # Springer Science+Business Media, LLC 2017
Abstract All available conformers of tisopurine as an important pharmaceutical molecule are optimized and frequency calculations calculated at M06-2X/6-311++ G(2d,2p) level of theory. These conformers are classified in 22 different tautomers, tautomer Z showing the most stable tautomer in the gas phase. Effects of four different solvents on the most stable conformer of each tautomer is calculated. Solvents cause stabilization of all conformers and relative solvent stabilization is as follows: water > DMSO > acetone > toluene. Energy profile for such stabilization is illustrated and mechanism of proton transfer studied at the same level of theory. Solvent-assisted proton transfer performed when water and methanol used as solvents. Results indicate that explicit solvent effect has much more stabilization on tautomerization processes compared to implicit solvent effect.
Keywords Tisopurine . Intramolecular . Intermolecular . Double proton transfer . M06-2X
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-017-1035-7) contains supplementary material, which is available to authorized users. * Morteza Karimzadeh
[email protected] * Khodabakhsh Niknam
[email protected] 1
Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
2
Fisheries and Aquaculture Department, College of Agriculture and Natural Resources Persian Gulf University, Bushehr 75169, Iran
Introduction Tisopurine or thiopurinol (5H-Pyrazolo[3,4-d]pyrimidine thione-4), a titled thio-analogue of allopurinol, has a molecular formula of C5H4N4S and it is applicable for treatment of gout [1–3]. It is known as antiparasitic and antithrombotic agent having very similar pharmaceutical and biomedical behaviors to allopurinol counterparts. Tisopurine can be used as a drug and as an inhibitor of guanosine monophosphate reductase; thereby, it can influence generation of adenosine triphosphate from corresponding guanine. Tisopurine is also able to affect synthesis of protein by inhibiting effect on ribonucleic acid bioproduction. Potential inhibitor activity of tisopurine against xanthine oxidase was reported previously by Robin and his co-workers [4, 5]. So, it is conceivable to study about tautomerism of such important molecule because different tautomers may affect intermolecular interactions of tisopurine with other biological molecules. Till now, many articles have been published to investigate specially keto-enol, amid-imidic, and thione-thiol tautomersim [6–8]. Notwithstanding that importance of tautomerism, no theoretical calculations have been made in this regard. So, it is required to discuss about tautomerism properties of tisopurine. Solvents have also a significant role in this matter and its affectivity is clear in speeding-up tautomerization processes [9–11]. Their greater influence can easily be seen in switching of the bonds and changing electron affinity of studied molecule [12–15]. In this study, all tautomers of tisopurine will be conveyed on different polar and non-polar media followed by finding the most stable conformers of each tautomer. Then, intramolecular prototropic tautomersim assisted by water and methanol molecules will be studied to compare explicit effect of solvents with the ones does not have any solvent contribution in their intramolecular tautomerism [16, 17].
Author's personal copy Struct Chem Table 1
All available conformers for tisopurine which are calculated at M06-2X level of theory
A
B
C
D1
D2
E1
E2
F1
F2
G1
G2
H1
H2
I1
I2
J1
J2
N1
N2
N3
N4
K
L1
L2
M1
M2
O1
O2
P1
P2
Q1
Q2
Q3
Q4
R
S
T1
T2
U
Z
Author's personal copy Struct Chem Table 2 Relative Gibbs free energies (ΔG) for all 22 most stable tautomers (A-Z), calculated at M06-2X/6-311++G(2d,2p) level of theory both in the gas phase and in solvents Compound
ΔGgas
ΔGToluene
ΔGAcetone
ΔGDMSO
ΔGWater
A
32.47
26.81
19.95
19.24
19.01
B C
13.06 3.47
11.21 2.69
8.61 1.75
8.32 1.47
8.23 1.62
D1 E1
11.52 41.29
11.73 41.61
11.82 41.53
11.81 41.49
11.81 41.48
F2
3.89
5.69
7.78
7.99
8.06
G2 H1
22.51 30.42
21.03 27.10
12.23 22.71
19.84 22.23
19.79 22.07
Computational methods Optimization of geometries for all conformers performed based on framework of density functional theory and M06-2X functional. The 6-311++G(2d,2p) basis set selected to consider both diffuse and polarization functions on heavier sulfur atom involved in tisopurine [18, 19]. Symmetrical restrictions did not considered for optimized structures and C1 symmetry was chosen for all conformers. Afterwards, frequency calculations were done for optimized conformers to detect them as global or local minima. The Tomasi’s polarized continuum model (IEFPCM) utilized to explain effect of solvent [20–22]. The QST2 (Schlegel’s Synchronous Transit-Guided Quasi Newton) and QST3 optional were applied to locate each transition state (TS) between two minima by detecting only one imaginary frequency [23]. Drawing structures was done using Gauss View 5.0 graphical representation software for Gaussian programs [24]. Computations were done by applying GAUSSIAN 09 package program [25].
I1
39.46
38.60
37.33
37.18
37.14
J2 K
44.18 17.78
43.26 14.95
41.88 10.62
41.72 10.11
41.67 9.94
L2
58.03
59.10
59.84
59.89
59.91
M1 N1
28.29 50.84
29.64 50.81
31.02 50.39
31.15 50.32
31.67 50.30
O2 P1 Q2
49.07 56.70 60.07
49.42 56.25 61.27
49.71 55.32 62.13
49.72 55.19 62.15
49.72 55.16 62.17
R S
26.93 37.38
26.69 36.11
26.31 34.09
26.26 33.85
26.25 33.77
Results and discussion
T1 U Z
56.88 51.47 0
58.41 51.75 0
60.01 51.77 0
60.16 51.75 0
60.21 51.74 0
Structure and relative stability A closer look at structure of tisopurine, it is clear to find 40 conformers for tisopurine concerning all available
Scheme 1 Presentation for relative stability of tautomers A-Z by M06-2X/6-311++G(2d,2p) in different media
Author's personal copy Struct Chem
Scheme 2 Conversion of tautomer J1 to tautomer E2
conformers of tisopurine. All these conformers classified into 22 different tautomers as their structures were shown in Table 1. Numbering system can help us to establish discipline, so all tautomers were numbered through bolded alphabetical system from A-Z, but corresponding conformers of each tautomer was shown through bolded numerical numbering from 1 to 4. Based on our numbering system, F1 and F2 describes first and second conformers of tautomer F, respectively. In the case of structures having only one conformer, there is no more numerical numbering system and they are shown by a letter. By the way, all structures incorporated in Table 1 were optimized with M06-2X functional at 6-311++G(2d,2p) basis set. Frequency calculations were performed at the same level of theory to find that all structures in local or global minima. The most specific gas phase geometrical parameters involving bond distances, bond angles, and dihedral angles for all of the most stable conformers of each tautomer are shown in Table S1. From values of Table S1, it can be inferred that the most of stable tautomers are planar according to their dihedral angles involves C1-C6 central bond between two different pyarazole and pyrimidine heterocycles. Such planarity can be seen in A, B, C, D, F2, G2, H1, K, M1, R, S, T1, N1, and Z tautomers. Butterfly-like structures having hydrogen atom connected to one of the carbon atoms in C1-C6 central bond showed deviation from planarity in E1, I1, J2, L2, N1, O2, P1, and Q2. In the case of these tautomers, both of rings are planar, but the molecules are not planar. Tautomers are also showing normal bond angles based on their ability in having a bit more or less s-character.
Scheme 3 Conversion of tautomer C to tautomer D1
Despite formal independence of such parameters in a correctly selected coordinates, sometimes changing in bond angles, bond lengths, and dihedral angles leads to changing in other parameters. So, such geometrical parameters were also extracted when solvent used as a reaction medium. All extracted data associated with four different solvents from their polarity point of view were described in Table S2-S5. From obtained data, it is clear that the solvent effect on full geometrical parameters of all stable tautomers is negligible. These obtained data are the same as solvents. Computing energies (E), zero-point energies (ZPEs), sum of electronic and zero-point Energies (EZPE), sum of electronic and thermal Enthalpies (H), sum of electronic and thermal Free Energies (G), relative Gibbs free energies (ΔG), and polarity measurement for all 21 most stable tautomers (A-Z) were performed at M06-2X/6-311++G(2d,2p) level of theory. Looking at Table 2 shows relative stability of existent tautomers in the gas phase as follows: Z > C > F2 > D1 > B > K > G2 > R > M1 > H1 > A > S > I1 > E1 > J2 > O2 > N1 > U > P1 > T1 > L2 > Q2. As it is clear, C, F2, and Z tautomers are dominant tautomeric forms, and their differences in relative Gibbs energy are small. This will be more obvious when crystallographic X-ray structure of tisopurine [1] becomes similar with the most stable tautomer Z calculated at M06-2X/6311++G(2d,2p), and this indicates that suitable method of calculation is selected. Tautomer Z is more stable than tautomers C and F2 by 3.47 and 3.89 kcal/mol, respectively. Extra and longer resonance structure, annular tautomerism, and aromaticity of both rings may cause more stability of this tautomer relative to others.
Author's personal copy Struct Chem
Scheme 4 Conversion of tautomer Z to tautomer F2
Computational studies went through surveying solvent effect on all tautomers, because these tautomers may frequently exist in solution media in measurable proportions. Solvent may affect stability of tautomers and for this issue; nature of solvent becomes important. Thus, M06-2X/ 6-311++G(2d,2p) calculated tautomers in the gas phase were further studied in four different media. Toluene, acetone, dimethyl sulfoxide, and water were used, respectively, as non-polar, less-polar aprotic, more polar aprotic, and polar media. From values of Table 2, it can be understood that all tautomers become more stable going to more polar media and there is no exception for all of them. This is completely in agreement with obtained dipole moments for all tautomers. In other words, dipole moment of each tautomer becomes greater going to more polar media and this is due to strong interaction of tautomers with solvents make them to be more stable. However, relative stability of tautomers in each solvent did not make any changes and this is entirely compatible with calculated data obtained in the gas phase. Scheme 1 presents a full comparison for stability of tautomers in the gas phase and four different tested solvents (toluene, DMSO, acetone, and water). Tautomer Z being was considered as a reference zero being the most stable tautomer in the gas phase, and other relative quantities were calculated based on this tautomer. A closer look explains more stability of each tautomer in solvents compared to the gas phase. In addition, this scheme illustrates potency of each solvent in stabilizing each tautomer. Thereupon, solvent effects in stabilizing tautomers A-Z are as follows: water > DMSO > acetone > toluene.
Mechanism for intra- and interconversion of tautomers Intraconversion of some tautomers involving three most stable ones (tautomer C, F2, and Z) investigated through only removing a proton from an electronegative atom and sending it to another electronegative atom in one-step. Such one-step proton transfer rout surveyed for intraconversion of tautomer J1 to tautomer E2, tautomer C to tautomer D1, and tautomer Z to tautomer F2 (Schemes 2, 3, and 4). Scheme 2 illustrates conversion of tautomer J1 to tautomer E2 via a proton transfer route. Here, hydrogen atom H12 connected to nitrogen atom N5 of pyrimidinic ring in tautomer J1 transferred to nitrogen atom N7 of pyrazolic ring through transition state TS1 to form tautomer E2. Energy barrier for such transfer calculated to be 59.35 kcal/mol at M06-2X/6311++G(2d,2p) and the reverse reaction required 59.55 kcal/mol amounts of energy with the same method. Transition state TS1 demonstrates lengthen of N5H12 bond along with shortening of N7-H12 bond. Such higher amount of energy is due to formation of a rigid four-membered heterocyclic-like structure. These studies were performed with water when used as implicit media. Table 3 depicts a comparative study for conversion of tautomers C, D1, Z, F2, J1, and E2 computed at M062X/6-311++G(2d,2p) level of theory. Obtained rate constants and relative enthalpies indicates, respectively, the higher reaction rate and lower activation energy required for forward transformation of tautomer Z to tautomer F2 compared to others.
Table 3 Relative kinetic and thermodynamic data including zero-point corrected internal energies, relative enthalpies, and relative free Gibbs free energies along with equilibrium and rate constants of tautomerism calculated at M06-2X/6-311++G(2d,2p) in water as a solvent TS
Reactions
ΔEZPE
ΔH≠forward
ΔH
ΔG≠forward
ΔG
kforward
Keq
TS1 TS2 TS3
J1 → E2 C → D1 Z → F2
− 0.20 10.30 8.16
59.18 32.02 34.09
− 0.21 10.48 8.35
59.36 36.17 34.22
− 0.18 10.19 8.06
5.24E-45 1.04E-27 2.97E-26
1.36 2.50E-8 9.71E-7
Author's personal copy Struct Chem
Scheme 5 Conversion of tautomer J1′ to tautomer E2′
Scheme 6 Conversion of tautomer J1″ to tautomer E2″
Solvent-assisted proton transfer After studying proton transfer via a four-membered heterocyclic-like transition state in water as an implicit medium, it is decided to apply solvent explicit effect in such proton movement. Existence of protic solvents for many tautomerization processes is required, because such solvents create hydrogen bonding and lower energy barrier for tautomerism. Thus, water and methanol were selected to check solvent-explicit effect. Afterwards, all previously investigated tautomers J1, E2, C, D1, Z, and F2 involved in proton transfer processes were
Scheme 7 Conversion of tautomer C′ to tautomer D1′
then re-optimized when water and then methanol took place next to the same tautomers. Such new formed reagents were lettered by a prime such as J1′, E2′, C′, D1′, Z′, and F2′ when water used as an explicit-solvent medium and with a double prime such as J1″, E2″, C″, D1″, Z″, and F2″ when methanol used as an explicit solvent. Also, the corresponding transition states were numbered as TS1′, TS2′, and TS3′ in water. The same numbering system was used for transition states TS1″, TS2″, and TS3″ in methanol. As already described in Scheme 2, energy barrier for proton movement from nitrogen atom N5 to nitrogen atom N7 is equal to 59.36 kcal/mol.
Author's personal copy Struct Chem
Scheme 8 Conversion of tautomer C″ to tautomer D1″
Scheme 9 Conversion of tautomer Z′ to tautomer F2′
Such barrier becomes 15.71 and 13.27 kcal/mol, respectively, when water and methanol themselves contributed on proton transfer mechanism (Schemes 5 and 6). Such small energy barrier indicates stabilization of transition states TS1′ and TS2′ created by a newly formed six-membered heterocycliclike structure which has flexible structure than four-membered one. Looking at Schemes 7, 8, 9, and 10 indicates
Scheme 10 Conversion of tautomer Z″ to tautomer F2″
interconversion of other calculated tautomers beside water and methanol. A comparable explicit water and methanol effect on relative kinetic and thermodynamic data including internal energies, enthalpies, Gibbs free energies along with equilibrium, and rate constants has been brought in Table 4.
Author's personal copy Struct Chem Table 4 Relative kinetic and thermodynamic data including zero-point corrected internal energies, relative enthalpies, and relative free Gibbs free energies along with equilibrium and rate constants of tautomerism calculated at M06-2X/6-311++G(2d,2p) Reactions
ΔEZPE
ΔH≠forward
ΔH
ΔG≠forward
ΔG
kforward
Keq
TS1′ TS2′
J1′ → E2′ C′ → D1′
− 0.13 11.29
13.23 15.82
− 0.12 11.30
15.71 17.91
− 0.17 11.17
1.90E-12 4.36E-14
1.34 4.65E-9
TS3′
Z′ → F2′
9.45
14.32
9.48
16.42
9.35
5.64E-13
1.05E-7
TS Water
Methanol TS1″
J1″ → E2″
− 0.17
11.00
− 0.20
13.27
0.04
1.26E-10
0.93
TS2″
C″ → D1″
10.86
14.13
11.03
15.41
10.53
3.19E-12
1.39E-8
TS3″
Z″ → F2″
9.38
12.46
9.90
13.77
8.11
5.34E-11
8.91E-7
Conclusion Tautomerism processes of tisopurine were studied using Minnesota functional at M06-2X level of theory. Investigation of geometrical parameters of tisopurine showed mostly planar structure and some non-planar forms. Solvent effects showed polarity of solvent leads to stabilization of all available conformers. Among studied solvents, water and DMSO had higher effects on stabilization of studied conformers. Results showed that tautomer Z is the most stable tautomer both in solvents and in the gas phase. Mechanism of proton transfer was aided with and without of implicit and explicit solvent effect. Both of them had stabilization effect on proton transfer, but influence of explicit-aided solvent was much more. Methanol was selected as the best solvent for solvent-assisted proton movement.
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Acknowledgments We are grateful to Mr. Mehdi Rezapour and Mr. Mohammad Bashkar for their help. Funding information We are thankful from Persian Gulf University Research Council for partial support of this work.
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