untitled European Journal of Chemistry 3 (3) (2012) 348‐355 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2012 EURJCHEM DOI:10.5155/eurjchem.3.3.348‐355.638 European Journal of Chemistry Journal homepage: www.eurjchem.com Theoretical density functional study of gas‐phase tautomerization and acidity of 5‐methylhydantoin and its thio derivatives Zaki Sulieman Safi Department of Chemistry, Faculty of Science, Al Azhar University‐Gaza, 1277, Gaza, Palestine *Corresponding author at: Department of Chemistry, Faculty of Science, Al Azhar University‐Gaza, 1277, Gaza, Palestine. Tel.: +970.8.2824010; fax: +970.8.2823180. E‐mail address: z.safi@alazhar‐gaza.edu (Z.S. Safi). ARTICLE INFORMATION ABSTRACT Received: 22 May 2012 Received in revised form: 19 July 2012 Accepted: 21 July 2012 Online: 30 September 2012 KEYWORDS Tautomerization and acidities of various 5‐methylhydantoins and their thio derivatives were predicted using Density Functional Theory (DFT). The functional used was B3LYP and the basis set for all atoms was 6‐311+(d,p). Single point energy computations were performed at the 6‐311+G(2df,2p) basis set. The relative stabilities of the different tautomers of the 2,4‐ dioxo, 2‐thio‐4‐oxo, 4‐thio‐2‐oxo and 2,4‐dithio derivatives of the deprotonated 5‐ methylhydantoin have been studied. In all cases, the most stable deprotonated conformers are the oxo‐thione, the dioxo or the dithio. As for the neutral and the protonated 5‐ methylhydantoin‐thio derivatives, the tautomerization activation barriers are high enough as to conclude that the oxo‐thione structures should be found in the gas phase. It was revealed that the ring‐nitrogen atom at position 3 (N3) is more acidic than that at position 1 (N1), hence 5‐methylhydantoin thio derivatives in the gas phase are an N3‐acid. It has been found that the 2,4‐dithio species is the most acidic compound among all the investigated compounds. The acidity values were found to be 343 (2O4O), 337 (2S4O), 336 (2O4S) and 332 kcal/mol (2S4S). DFT B3LYP Acidity Deprotonation Tautomerization 5‐Methylhydantoin 1. Introduction Acidity and basicity of polyfunctional heterocyclic organic compounds are fundamental aspects in chemistry and central to the understanding of chemical reactivity [1‐3]. Studies of acidities and basicities have received great attention from both experimental [4] and theoretical investigations [5‐10]. Most of these studies have been carried out to predict the correct protonation and deprotonation sites and the possible role played by the protonation and deprotonation processes in decreasing the activation barrier for the 1,3‐hydrogen transfer process. Of particular interest, the structural and reactivity changes caused by substitution of an oxygen atom by the bulkier and more polarizable sulfur atom is vital to the understanding of reasons of their different roles in biological activity. Hydantoin and its thio derivatives are of significant medicinal and pharmaceutical interest, especially as anticonvulsants (e.g., norantoin, mephenytoin, nirvanol, and methetoin) [11‐16]. Chemically, these compounds are polyfunctional heterocyclic organic compounds with the structure similar to imidazole with additional hydrogen atom at N3 and two oxygen/sulfur atoms at C2 and C4 positions, respectively. Recently, the gas phase tautomerization and protonation of four combinations of these species were reported [17,18]. These studies were performed by using DFT employing the B3LYP and BP86 levels of theory with the 6‐ 311+(2df,2p)//6‐311+(d,p) basis functions. In continuation with our previous work on tautomeization [17] and protonation [18] of 5‐methylhydantoin and its thio derivatives, the present paper is reporting a systematic theoretical study with the following two objectives. The first one is to study the gas‐phase relative stabilities of tautomers and rotaomers, the energy barriers of 1,3‐H migration from the most sable oxo‐thione, dioxo and dithio forms to the most stable enolic structures, to investigate the enolioztion mechanism when the oxygen atom is substituted by a bulkier atom such as sulfur and to investigate the possible catalytic role of the deprotonation process of the different imidic groups on the tautomerization process. The second one is to determine the gas‐phase acidity of the acidic centers of the neutral species and compare them with that of the radical ones at different basis sets. The molecules considered in this theoretical survey are 5‐methyl‐2,4‐dioxo imidazolidine (2O4O), 5‐methyl‐2‐oxo‐ 4‐thio imidazolidine (2O4S), 5‐methyl‐2‐thio‐4‐oxo imidazole‐ idine (2S4O), and 5‐methyl‐2,4‐dithio imidazolidine (2S4S) (Scheme 1). 2. Computational details The geometries of the species under considerations were fully optimized with the aid of the Gaussian 09 set of programs [19], using the hybrid density functional theory (DFT) [20,21] at the B3LYP level [22‐24] combined with the polarized triple split valence 6‐311+G(d,p) basis functions. The relative B3LYP energies are often in excellent agreement with high‐level ab initio results [18,25,26]. Harmonic vibrational frequencies were calculated at the same level of theory to identify the local minima and transition states (TS) and to estimate the corresponding ZPE. Final energies were obtained in single‐ point calculations carried out at the B3LYP/6‐311+G(2df,2p) level. The corresponding relative energies were evaluated with inclusion of the corresponding ZPE corrections scaled by a factor of 0.9806 [27] and the thermal correction of energies. Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 349 Figure 1. Relative stability of the most stable deprotonated forms of 5‐methylhydantoin and its thio derivatives. All values are in kcal/mol. Enthalpies were evaluated by considering the thermal corrections at 298.15 K. The gas phase‐acidity was defined as the enthalpy of deprotonation (H298) for reaction (A) [7]. AH (g)  A‐ (g) +H+ (g) (A) The enthalpy of deprotonation, H298, was computed using equations 1 and 2, H298 = E298 + (pV) (1) E298 = [E298(A‐)+3/2RT] – E298(AH) (2) where E298 stands for the total energies of the stable conformations of acids and their anions (including the thermal energy correction at T = 298.15 K). In equation 1, we substituted (pV) = RT [one mole of gas is obtained in the reaction (A)]. Notice that there is an inverse relationship between the magnitude of the H298 and the strength of the acid. The larger the value of the H298, the weaker is the acid [7]. 3. Results and discussion The structures of all different species that can be envisaged from deprotonation and tautomerization of the compounds under investigation are presented in Scheme 1. Thus, the first two structures in Scheme 1, HN1 and HN3, correspond to the anions derived from the elimination of the imide protons N1‐H and N3‐H, respectively, while the remaining species are tautomers that produced by a 1,3‐proton migration. All structures that are listed are minima on potential energy surface, PES. The full set of data (total energies, ZPE corrections, thermal corrections to energies (TCE) and thermal corrections to enthalpies (TCH)) for all tautomers in Scheme 1 are given in Table 1‐4 of the Supporting Information. The relative energies of the two anions, HN1 and HN3, which are derived from the deprotonation of 5‐methylhydantoin and its thio derivatives and the first most stable enolic structures are shown in Figure 1. The relative energies and enthalpies of these and the remaining tautomers in Scheme 1 are reported in Table 5, together with information on the transition states connecting the most stable conformers in each case. NHN Y X H3C H NHN Y X H3C H NN Y X H3C H H NN Y X H3C H H NHN Y X H3C H NHN Y X H3C H NN Y X H3C H H NN Y X H3C H H NHN Y X H3C H NHN Y X H3C H HN1 HN3 X=O, Y=O, 2O4O X=S, Y=O, 2O4S X=O, Y=S, 2S4O X=S, Y=S, 2S4S NN Y X H3C H 1a-HN1 1b-HN1 H NN Y X H3C H H 2b-HN12a-HN1 3b-HN13a-HN1 4a-HN3 4b-HN3 5a-HN3 5b-HN3 neutral NHHN Y X H3C H 1 2 3 45 Scheme 1 350 Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 Table 1. The total energies in atomic units at B3LYP/6‐311+G(d,p) (E1) B3LYP/6‐311+G(2df,2p)//6‐311+G(d,p) (E2), zero‐point energy (ZPE), thermal correction to energy (TCE), thermal correction to enthalpy (TCH) of the 2O4O molecule. All values are in Hartree. Species E1 E2 ZPE TCE TCH Neutral ‐416.161560 ‐416.1855910 0.108153 0.115528 0.116472 HN1 ‐415.596786 ‐415.6197440 0.094269 0.101247 0.102191 HN3 ‐415.604876 ‐415.6279560 0.094840 0.101672 0.102616 1a‐HN1 ‐415.579553 ‐415.6026830 0.094751 0.101640 0.102584 1b‐HN1 ‐415.578788 ‐415.6019300 0.094791 0.101639 0.102583 2a‐HN1 ‐415.556466 ‐415.5794640 0.093859 0.100855 0.101799 2b‐HN1 ‐415.548904 ‐415.5725680 0.093335 0.100451 0.101395 3a‐HN1 ‐415.548605 ‐415.5722840 0.092950 0.100492 0.101436 3b‐HN1 ‐415.548605 ‐415.5722840 0.092952 0.100494 0.101438 4a‐HN3 ‐415.579553 ‐415.6026840 0.094751 0.101639 0.102583 4b‐HN3 ‐415.578788 ‐415.6019290 0.094790 0.101637 0.102581 5a‐HN3 ‐415.561657 ‐415.5853950 0.093493 0.100979 0.101923 5b‐HN3 ‐415.552378 ‐415.5767140 0.093145 0.100724 0.101668 TS3(HN1‐3a‐HN1) ‐415.4833816 ‐415.5066209 0.088102 0.095452 0.096396 TS2(HN3‐5a‐HN3) ‐415.4911592 ‐415.5145564 0.088568 0.095305 0.096249 TS3(HN3‐HN1) ‐415.4761668 ‐415.4986933 0.088738 0.095473 0.096417 TS1(HN1‐1a‐HN1) ‐415.5286788 ‐415.5519821 0.089368 0.096093 0.097037 TS2(HN1‐2a‐HN1) ‐415.5021294 ‐415.5256775 0.088621 0.095487 0.096431 TS1(HN3‐4a‐HN3) ‐415.5259848 ‐415.5494008 0.089119 0.095905 0.096849 Table 2. The total energies in atomic units at B3LYP/6‐311+G(d,p) (E1) B3LYP/6‐311+G(2df,2p)//6‐311+G(d,p) (E2), zero‐point energy (ZPE), thermal correction to energy (TCE), thermal correction to enthalpy (TCH) of the 2S40 molecule. All values are in Hartree. Species E1 E2 ZPE TCE TCH Neutral ‐739.115711 ‐739.1405330 0.105919 0.113616 0.114560 HN1 ‐738.567280 ‐738.5906630 0.092559 0.099902 0.100847 HN3 ‐738.568630 ‐738.5921120 0.092571 0.099870 0.100814 1a‐HN1 ‐738.540920 ‐738.5650810 0.088736 0.096417 0.097362 1b‐HN1 ‐738.540844 ‐738.5650570 0.088830 0.096437 0.097381 2a‐HN1 ‐738.524820 ‐738.5480440 0.092085 0.099443 0.100387 2b‐HN1 ‐738.516135 ‐738.5400770 0.091522 0.099020 0.099964 3a‐HN1 ‐738.527882 ‐738.5523850 0.091282 0.099415 0.100359 3b‐HN1 ‐738.527882 ‐738.5523850 0.091282 0.099415 0.100360 4a‐HN3 ‐738.540920 ‐738.5650800 0.088733 0.096416 0.097361 4b‐HN3 ‐738.540844 ‐738.5650570 0.088828 0.096436 0.097380 5a‐HN3 ‐738.540340 ‐738.5647640 0.091755 0.099831 0.100776 5b‐HN3 ‐738.530258 ‐738.5554920 0.090885 0.099413 0.100357 TS1(HN3‐4a‐HN3) ‐738.503264 ‐738.5271504 0.085796 0.093020 0.093964 TS2(HN3‐5a‐HN3) ‐738.455048 ‐738.4790078 0.086372 0.093603 0.094547 TS3(HN3‐HN1) ‐738.429890 ‐738.4528700 0.085855 0.093033 0.093977 TS4(HN1‐1a‐HN1) ‐738.508102 ‐738.5318740 0.086092 0.093253 0.094197 TS5(HN1‐2a‐HN1) ‐738.468998 ‐738.4928810 0.086879 0.094083 0.095027 TS6(HN1‐3a‐HN1) ‐738.497638 ‐738.5211670 0.086966 0.094222 0.095167 Table 3. The total energies in atomic units at B3LYP/6‐311+G(d,p) (E1) B3LYP/6‐311+G(2df,2p)//6‐311+G(d,p) (E2), zero‐point energy (ZPE), thermal correction to energy (TCE), thermal correction to enthalpy (TCH) of the 2O4S molecule. All values are in Hartree. Species E1 E2 ZPE TCE TCH Neutral ‐739.116632 ‐739.14118 0.105908 0.113659 0.114603 HN1 ‐738.563080 ‐738.58637 0.092365 0.099641 0.100585 HN3 ‐738.571030 ‐738.59434 0.092729 0.099982 0.100927 1a‐HN1 ‐738.547970 ‐738.57128 0.092828 0.100061 0.101006 1b‐HN1 ‐738.546550 ‐738.56984 0.092827 0.100042 0.100986 2a‐HN1 ‐738.520230 ‐738.54435 0.087893 0.095661 0.096605 2b‐HN1 ‐738.519030 ‐738.54371 0.087785 0.095610 0.096555 3a‐HN1 ‐738.536200 ‐738.56278 0.088196 0.096198 0.097142 3b‐HN1 ‐738.536200 ‐738.56278 0.088198 0.096198 0.097142 4a‐HN3 ‐738.547970 ‐738.57128 0.092827 0.100060 0.101004 4b‐HN3 ‐738.546550 ‐738.56984 0.092833 0.100047 0.100991 5a‐HN3 ‐738.531590 ‐738.55775 0.087723 0.096006 0.096950 5b‐HN3 ‐738.531590 ‐738.55775 0.087722 0.096006 0.096950 TS1(HN3‐4a‐HN3) ‐738.489180 ‐738.51285 0.087067 0.094276 0.095220 TS2(HN3‐5a‐HN3) ‐738.475280 ‐738.49936 0.085157 0.092605 0.093550 TS3(HN3‐HN1) ‐738.440200 ‐738.46296 0.086364 0.093462 0.094406 TS4(HN1‐1a‐HN1) ‐738.494780 ‐738.51836 0.087459 0.094493 0.095437 TS5(HN1‐2a‐HN1) ‐738.483310 ‐738.50714 0.085454 0.092705 0.093650 TS6(HN1‐3a‐HN1) ‐738.513760 ‐738.53725 0.087958 0.095125 0.096070 3.1. Relative stabilities and catalytic effects of deprotonation process As mentioned above, oxo‐ and thiohydantoin derivatives present different tautomers that can be generated through appropriate hydrogen shifts. Therefore, in order to rationalize their intrinsic reactivity, we must establish which tautomer is predominant in the gas phase. Recently, we have shown, in neutral [17] and protonated [18] molecules, that the dioxo tautomers in the case of 2,4‐dioxohydantoin and the oxothione or the dithione tautomer in the case of thiohydantoin are the most stable. It was also found that the energy barriers connecting different neutral tautomers are very high. Therefore, the aforementioned tautomers, if the molecule is not excited, will be the only ones present in the gas phase. Our first result, to be noted, deduced from the relative energy calculations listed in Table 5 and shown in Figure 1, is that in general, in all cases, the most stable deprotonated structure corresponds to the anion HN3, which produced by the direct elimination of the imide proton N3‐H. Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 351 Table 4. The total energies in atomic units at B3LYP/6‐311+G(d,p) (E1) B3LYP/6‐311+G(2df,2p)//6‐311+G(d,p) (E2), zero‐point energy (ZPE), thermal correction to energy (TCE), thermal correction to enthalpy (TCH) of the 2S4S molecule. All values are in Hartree. Species E1 E2 ZPE TCE TCH Neutral ‐1062.071259 ‐1062.096568 0.103742 0.111765 0.112709 HN1 ‐1061.531903 ‐1061.555677 0.090629 0.098273 0.099217 HN3 ‐1061.532566 ‐1061.556352 0.090253 0.098049 0.098993 1a‐HN1 ‐1061.509142 ‐1061.533454 0.086779 0.094816 0.095760 1b‐HN1 ‐1061.508605 ‐1061.532977 0.086891 0.094854 0.095798 2a‐HN1 ‐1061.487869 ‐1061.512225 0.086167 0.094254 0.095198 2b‐HN1 ‐1061.486115 ‐1061.511082 0.085957 0.094164 0.095108 3a‐HN1 ‐1061.512344 ‐1061.539316 0.086580 0.095051 0.095996 3b‐HN1 ‐1061.512344 ‐1061.539315 0.086580 0.095052 0.095996 4a‐HN3 ‐1061.509142 ‐1061.533455 0.086779 0.094817 0.095761 4b‐HN3 ‐1061.508605 ‐1061.532976 0.086891 0.094854 0.095798 5a‐HN3 ‐1061.509724 ‐1061.536140 0.086579 0.095083 0.096027 5b‐HN3 ‐1061.509724 ‐1061.536139 0.086582 0.095083 0.096027 TS1(HN3‐4a‐HN3) ‐1061.466864 ‐1061.490962 0.083851 0.091416 0.092360 TS2(HN3‐5a‐HN3) ‐1061.441384 ‐1061.465937 0.083376 0.091127 0.092071 TS3(HN3‐HN1) ‐1061.393450 ‐1061.416640 0.083356 0.090950 0.091894 TS4(HN1‐1a‐HN1) ‐1061.474460 ‐1061.498560 0.084123 0.091620 0.092564 TS5(HN1‐2a‐HN1) ‐1061.452251 ‐1061.477171 0.084003 0.092031 0.092975 TS6(HN1‐3a‐HN1) ‐1061.452251 ‐1061.477171 0.084003 0.092031 0.092975 Table 5. Relative energies and enthalpies of the deprotonated tautomers and rotaomers of 5‐methyldynatoin and its thio derivatives in gas phase. All values are given in kcal/mol. Species 2O4O 2S4O 2O4S 2S4S E H E H E H E H HN1 4.5 4.9 0.9 0.9 4.6 4.8 0.8 0.6 HN3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1a‐HN1 15.8 15.8 12.5 14.8 14.6 14.5 10.2 12.4 1b‐HN1 16.3 16.3 12.6 14.9 15.5 15.4 10.6 12.7 2a‐HN1 29.3 29.9 27.1 27.4 25.7 28.7 22.8 25.4 2b‐HN1 33.1 34.0 31.5 32.1 26.0 29.1 23.4 26.0 3a‐HN1 33.1 34.2 23.9 24.7 14.7 17.5 6.6 8.9 3b‐HN1 33.1 34.2 23.9 24.7 14.7 17.5 6.6 8.9 4a‐HN3 15.8 15.8 12.5 14.8 14.6 14.5 10.2 12.4 4b‐HN3 16.3 16.3 12.6 14.9 15.5 15.4 10.6 12.7 5a‐HN3 25.5 26.3 16.6 17.2 17.4 20.5 8.6 10.9 5b‐HN3 30.5 31.6 21.7 22.7 17.4 20.5 8.6 10.9 TS1(HN3‐4a‐HN3) 42.2 45.8 32.4 36.5 44.1 45.5 33.0 36.9 TS1(HN3‐5a‐HN3) 63.4 67.3 63.3 67.1 50.4 55.1 48.2 52.5 TS3(HN3‐HN1) 73.5 77.3 79.0 83.2 74.5 78.4 79.1 83.3 TS4(HN1‐1a‐HN1) 40.9 44.3 29.7 33.7 41.1 44.3 28.3 36.7 TS5(HN1‐2a‐HN1) 56.6 60.4 55.2 58.7 45.8 50.2 41.1 46.0 TS6(HN1‐3a‐HN1) 68.2 72.4 37.6 41.0 29.9 32.8 28.1 35.2 In fact, isomer HN3 was found largely more stable in the cases 2O4O and 2O4S than isomer HN1 by about 4.5 and 4.6 kcal/mol,respectively. While this energy gap drops to 0.9 and 0.8kcal/mol,respectively, in the cases of 2S4O and 2S4S. For 2O4O compound, it was found that the relative stability trend of the most stable tautomers is as follow: HN3 > HN1 > 1a‐HN1  4a‐HN3 > 5a‐HN3 > 2a‐HN1 > 3a‐HN1. It was also found that the first less stable enolic structures 1a‐HN1 and 4a‐HN3 are almost degenerate, which is similar to the results obtained in the case of the neutral [17] and the protonated species [18]. Therefore, our tabulated results show that forms 1a‐HN1 and 4a‐HN3 are estimated to be 15.8 kcal/mol less stable than the global minimum isomer HN3 (Table 5). For 2S4O, 2O4S and 2S4S species, our results suggest that the most stable deprotonated species corresponds to the HN3 isomer (Table 5 and Figure 1). The relative stability trends of the most stable species are as follow: 2S4O: HN3 > HN1 > 1a‐HN1  4a‐HN3 > 5a‐HN3 > 3a‐HN1 > 2a‐HN1, 2O4S: HN3 > HN1 > 1a‐HN1  4a‐HN3 > 3a‐HN1 > 5a‐HN3 > 2a‐HN1, and 2S4S: HN3 > HN1 > 3a‐HN1 > 5a‐HN3 > 1a‐HN1  4a‐HN3 > 2a‐HN1, For 2S4O and 2O4S compounds, the most stable enolic structures correspond to the 1a‐HN1 and 4a‐HN3 tautomers and they were found to be largely less stable by about 14.6 and 12.5 kcal/mol, respectively, than the global minimum, HN3 isomer. The situation is completely different as far as the 2S4S species is concerned. The first stable enolic structure corresponds to form 3a‐HN1, which can be produced starting from HN1 isomer by a 1,‐3 H migration from the C5H group to the adjacent C4=S group. Our calculated results indicate that the enolic structure 3a‐HN1 was found to be largely stable by bout 2.0 and 3.6 kcal/mol, respectively, more stable than 5a‐ HN3 and 4a‐HN3 forms, which can be produced by a suitable 1,3‐H transfer starting from the global minimum, HN3 isomer. In summary, the results reported for the 2O4O, 2S4O and 2O4S species suggest that the 1,3‐H migration can take place at the heteroatom attached to C2 of the HN3 and HN1 isomer, regardless of the heteroatom type and the deprotonation site. Whereas, in the case of 2S4S, the 1,3‐H migration is favored at the sulfur atom attached to C4 of the HN1 isomer. To study, which of the enolic structures can be observed in the gas phase, the transition states for 1,3‐H migration have been calculated. Figure 2a‐d shows schematic representation of the corresponding potential energy surface (PESs) of the tautomerization process of the species under investigation. The relative energies corresponding to the transition states, which connect the most stable deprotnated dioxo, dithio, and oxo/thio tautomers, HN3, with other species are listed in Table 5. As indicated above, tautomer HN3 is the global minimum in all cases, but there are significant similarities regarding the relative stability of the remaining tautomers. On going from the global minimum, HN3 isomer, to the enolic forms, 4a‐HN3 and 5a‐HN3, two possible enolization mechanisms, TS1 and TS2, are proposed. The first mechanism (TS1) corresponds to the enolization of the oxo (or thione) groups attached to C2 by a 1,3‐H shift from the adjacent N‐H 352 Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 Figure 2. Energy profile of the unimolecular tautomerization processes of the deprotonated species (a) 2O4O, (b) 2S4O, (c) 2O4S and (d) 2S4S. All values are in kcal/mol Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 353 Table 6. Calculated 298 K deprotonation energies, H298, of the 5‐methylhydantoin and its thio derivatives at B3LYP with 6‐311G(d,p) and 6‐311+G(2df,2p)//‐ 311+G(d,p) c. All values are in kcal/mol. Species Method Neutral Radical N1 N3 N1 N3 2O4O B3LYPa 356 351 201 196 B3LYPb 348 343 199 193 2S4O B3LYPa 341 341 216 214 B3LYPb 338 337 221 219 2O4S B3LYPa 346 335 220 214 B3LYPb 341 336 220 217 2S4S B3LYPa 334 334 218 217 B3LYPb 333 332 226 222 a B3LYP/6‐311G(d,p). b B3LYP/6‐311+G(2df,2p)//6‐311G(d,p). c H298 = Etot+ZPVE+(H298‐H0) + 6.2 kJ; scaled ZPVE by 0.9806 empirical factor. group to yield form 4a‐HN3, while the second mechanism (TS2) is accomplished by the enolization of the oxo (or thione) groups by a 1,3‐H transfer from the adjacent CH group to yield species 5a‐HN3. Our results indicate that for all compounds the first mechanism (TS1) is thermodynamically favored than the second one (TS2). Also importantly, the first enolization process (TS1) is more favorable when the heteroatom attached to C2 group is sulfur than that of the oxygen atom. For example, for compounds 2S4O and 2S4S transition barrier is estimated to be 32.4 and 33.0 kcal/mol above the minimum. Similarly, for compounds, 2O4S and 2O4O tautomerization barriers (TS1) are found to be 44.1 and 42.2 kcal/mol, respectively, above the minimum. For compounds 2O4S and 2S4S, the tautomerization barriers (TS2) are estimated to be 50.4 and 48.2 kcal/mol, respectively, above the global minimum. Similarly, for compounds 2S4O and 2O4O transition barriers (TS2) lies 63.8 and 63.4 kcal/mol, respectively, above the global minimum. These results seem to be consistent with our previous studies [17,18], in the sense that the oxo (or thione) group attached to C2 should be more basic than that attached to C4. Additionally, sulfur seems to be more basic than oxygen. Also, the enoliztion process of sulfur atom is thermodynamically favored than the oxygen one. The same conclusion can also be reached if we follow the formation of the enolic structures starting from the second most stable isomer, HN1. For example, for all compounds the formation of 1a‐HN1 is thermodynamically more favored than 2a‐HN1. It is also worth mention that the formation of 1a‐HN1 and 2a‐HN3 can be produced by enoliztion of the oxo (or thione) groups attached to C2 and C4 by a 1,3‐H shift from the N3‐H. The enolization mechanism of the oxo (or thione) groups attached to C2 can be proceed either by a 1,3‐H shift from the N3–H group to yield species 1a‐HN1 or by a 1,3‐H shift from the N1‐H group to yield structure 4a‐HN3. Although, our results indicate that the two tautomers are degenerate, the first mechanism is thermodynamically favored than the second one. Also importantly, these mechanisms are thermodynamically favored when the heteroatom attached to C2 is sulfur in all cases. These findings can be well explained as follow:,in compounds 2S4O and 2S4S, on going from HN3 or HN1 to either 4a‐HN3 or 1a‐HN1 a C=S and a N‐H bonds are replaced by a C=N and a S‐H bonds, respectively, while for compounds 2O4S and 2O4O one replaces a C=O and a N‐H bonds by a C=N and a O‐H bonds. However an S‐H bond is weaker than a N‐H linkage, a C=N bond is significantly stronger than a C=S one, so that the overall enolization process is more favorable for 2S4O and 2S4S than for compounds 2O4S and 2O4O. On the other hand, when these results are compared with those obtained for the neutral [17] and the protonated [18] species, in compound 2O4O the activation barriers of the enolization process was found to be 12.7 and 7.9 kcal/mol lower than those obtained for the neutral[17] and protonated [18] species, respectively. In summary, in what concerns the tautomer stability, the most important conclusion is that for 2S4O and 2O4S the most stable tautomer is the oxo‐thione form. Similarly, for 2S2S and 2O4O compounds the dithione and the dioxo forms, respectively, are the most stable ones. On the other hand, as shown in Figure 2, the energy barriers connecting the different tautomers are very high, and therefore we can safely conclude that only the aforementioned tautomers will exist in the gas phase. 3.2. Gas‐phase acidity In Table 6 we have summarized the calculated acidities for the neutral 5‐methylhydantoin and its thio derivatives. These values were obtained from DFT calculations using the B3LYP functional at 6‐311G(d,p) and 6‐311+G(2df,2p)//6‐311+G(d,p) basis functions. For sake of comparison we included the acidity of the radical molecule at the same basis functions. The full set of data (total energies, ZPE corrections, TCE and TCH) for all species under investigation are given in Tables 7 and 8 of the Supporting Information. The analysis of the data listed in Table 6 indicates that the values obtained from the 6‐311G(d,p) basis function are more than 8 kcal/mol higher than those obtained using 6‐311+G(2fd,2p)//6‐311+G(d,p) one. This suggests that diffuse functions are required to lower the computed deprotonation energies of anions [5,6,28]. As it is found in literature [29,30], data reported in Table 6 indicates that the most acidic site of 5‐methylhydantoin and its thio derivatives is the N3‐H group. It is noticed that, there is an inverse relationship between the magnitude of the H298 and the strength of the acid. The larger the value of the H298, the weaker is the acid. For 2O4O and 2O4S, it is found that the acidity difference between N3 and N1 atoms is quite substantial and amounts to about 5.0 kcal/mol in favor of the former. Whereas, for 2S4O and 2S4S species, this acidity difference decreases to about 1.0 kcal/mol. The reason for this behavior is probably due to the high polarizability and size of the sulfur atom attached to C2 over the oxygen, which allows a delocalization of the negative charge at both atoms. Our results suggest that the gas phase acidity trend of the molecules under investigation is as follow: 2S4S > 2S4O > 2O4O > 2O4O, which agrees with those reported experimentally [29]. Experimental data [30] showed that 2‐thiohydantoin (pka=8.5) is slightly stronger acid than hydantoin (pka = 9.0). From the results, we can deduce that both NH bonds are characterized by a weak acidity, which is sensibly lower than that of uracil and its thio derivatives (320‐333 kcal/mol) [5,6] and higher than that of formamide (359 kcal/mol), N‐methylformamide (~361 kcal/mol) or N‐methylacetamide (362 kcal/mol) [31]. From the results obtained in this study, we can deduce that both NH bonds are characterized by a weak acidity, which is sensibly lower than that of uracil and its thio derivatives (320‐333 kcal/mol) [5,6] and higher than that of formamide (359 kcal/mol), N‐methylformamide (~361 kcal/mol) or N‐ methylacetamide (362 kcal/mol)[31]. In order to confirm our results concerning the acidity trend of the compounds under probe, an appropriate isodesmic reaction has been considered. Reactions 1 and 2 (Table 9) permit us to compare the relative stability of both HN1 and HN3 anions for the all the compounds. 354 Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 Table 7. B3LYP/6‐311G(d,p) Optimized energies, E, zero‐point energy, ZPE, thermal correction to energy, TCE, thermal correction to enthalpy, TCH, of the neutral and cationic Radicals of 2O4O, 2S4O, 2O4S and 2S4S molecules. All values are in hartree. Species E ZPE TCE TCH 2O4O‐neutral Neutral ‐416.1503667 0.108394 0.115724 0.116669 N1 ‐415.5715871 0.094329 0.101299 0.102243 N3 ‐415.5799112 0.094942 0.101742 0.102686 2O4O‐Radical Neutral ‐415.8013220 0.105860 0.113224 0.114169 N1 ‐415.4713249 0.094462 0.1016 0.102544 N3 ‐415.4713250 0.093280 0.100747 0.101691 2S4O‐neutral Neutral ‐739.1077140 0.106177 0.113817 0.114761 N1 ‐738.5522520 0.092733 0.100062 0.101007 N3 ‐738.5524940 0.092668 0.099956 0.100900 2S4O‐Radical Neutral ‐738.7950590 0.105653 0.113406 0.114350 N1 ‐738.4399897 0.092255 0.099751 0.100695 N3 ‐738.4287180 0.092291 0.099961 0.100905 2O4S‐neutral Neutral ‐739.108544 0.106138 0.113845 0.114789 N1 ‐738.545945 0.092402 0.099697 0.100642 N3 ‐738.555045 0.092996 0.100209 0.101154 2O4S‐radical Neutral ‐738.7916610 0.105486 0.113239 0.114183 N1 ‐738.4306228 0.092319 0.099757 0.100702 N3 ‐738.4327490 0.092511 0.10008 0.101024 2S4S‐neutral Neutral ‐1062.065926 0.103997 0.111957 0.112901 N1 ‐1061.522989 0.090781 0.098411 0.099356 N3 ‐1061.522866 0.090482 0.098242 0.099186 2S4S‐radical Neutral ‐1061.758258 0.103163 0.111128 0.112072 N1 ‐1061.399692 0.090127 0.097925 0.098869 N3 ‐1061.392742 0.089747 0.097600 0.098544 Table 8. B3LYP/6‐311+G(d,p) Optimized energies, E1, B3LYP/6‐311+G(2df,2p)/6‐311+G(d,p), single point energy, E2, zero‐point energy, ZPE, thermal correction to energy, TCE, thermal correction to enthalpy, TCH, of the neutral and cationic radicals of 2O4O, 2S4O, 2O4S and 2S4S molecules. All values are in hartree. Species E1 E2 ZPE TCE TCH 2O4O‐radical Neutral ‐415.8066260 ‐415.8315030 0.105699 0.113085 0.114029 N1 ‐415.4821725 ‐415.5058033 0.094266 0.101435 0.102379 N3 ‐415.4610542 ‐415.4848640 0.093121 0.100618 0.101562 2S4O‐radical Neutral ‐738.8012690 ‐738.8278380 0.105454 0.113250 0.114195 N1 ‐738.4494504 ‐738.4614016 0.092133 0.099645 0.100589 N3 ‐738.4391405 ‐738.4639790 0.092315 0.099969 0.100913 2O4S‐radical Neutral ‐738.7975870 ‐738.8240070 0.105340 0.113118 0.114062 N1 ‐738.4386779 ‐738.4628818 0.092125 0.099597 0.100541 N3 ‐738.4430888 ‐738.4676920 0.092466 0.100049 0.100993 2S4S‐radical Neutral ‐1061.763577 ‐1061.790435 0.102948 0.110960 0.111904 N1 ‐1061.406195 ‐1061.419329 0.089998 0.097814 0.098758 N3 ‐1061.400349 ‐1061.425133 0.089574 0.097463 0.098407 Table 9. Relative stability of both HN1 and HN3 anions by using an appropriate Isodesmic reaction Species Reaction E, kcal/mol 2O4O 2S4O 2O4S 2S4S (1) HN1 ‐isomer ‐67.6 ‐77.0 ‐74.2 ‐82.3 (2) HN3‐ isomer ‐72.2 ‐77.9 ‐78.7 ‐83.1 The first conspicuous fact is that both reactions 1 and 2 are endothermic, which indicates that both HN1 and HN3 isomers are stabilized upon deprotonation. It was found that the stabilization energy is greater for the HN3 isomer than the HN1 isomer, indicating that the N3‐H group is more acidic than the N1‐H (Table 9). The results presented in chart 1 show that the deprotonated anions in the case of the 2S4S compound are the most stable anions among all the species under probe. Therefore, the relative stability trend might be arranged as Safi / European Journal of Chemistry 3 (3) (2012) 348‐355 355 follow: 2S4S > 2O4S > 224O > 2O4O, in agreement with our previous arrangement based on the deprotonation energies. As it has been shown above, the most acidic site of the neutral 5‐methylhydantoin and it thio derivatives is the N3‐H group. Our results for the neutral radicals indicate that this is also the case in all cases. It is worth to mention that the radical cations have been obtained by ionization of the neutral molecules and then by deprotonation of the acidic sites in the ionized structures (Scheme 2). Our results show some significant changes, however, as far as the acidity of their radical cations is concerned. As should be expected, the 5‐ methylhydantoin and thiohydantoin radical cations are more acidic than the corresponding neutrals, but still in all of them the N3‐H group remains as the most acidic site, although the gap with respect to the N1‐H acidity is rather small for the particular case of 2S4S and 2S4O. It is found that the acidity values of the radical molecules are higher than those of the corresponding neutrals. Our tabulated results (Table 6) indicate that the acidity difference is ranging from 107 to 150 kcal/mol in favor of the radical cations. HN NH X YH3C HN NH X YH3C + - H+- e + + HN3 N NH X YH3C HN N X YH3C HN1 Scheme 2 4. Conclusions Similar to what was found previouly in protonation processes, the diketo, dithio, keto/thio and thio/keto isomers of the 5‐methylhydantoin thio derivatives remain the most stable structures. It has been shown that, in all cases, HN3 isomers were found to be more stable than the HN1 ones. For 2O4O, 2S4O and 2O4S compounds, the 1,3‐H transfer is favored at the heteroatom attached to C2, regardless of its type. Whereas, for 2S4S compound the 1,3‐H transfer is favored at the sulfur atom attached to C4. The barriers for proton migration between different tautomers are rather large. Our results showed that the ring‐nitrogen atom at position 3 (N3) is more acidic than that at position 1 (N1), hence the 5‐ methylhydantoin and its thio derivatives are an N3‐acid. 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