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Original article
9 (
1_suppl
); S776-S780
doi:
10.1016/j.arabjc.2011.08.014

A DFT study of solvation effects and NBO analysis on the tautomerism of 1-substituted hydantoin

, , ,
a Young Researchers Club, Arak Branch, Islamic Azad University, Arak, Iran
b Department of Chemistry, Dezful Branch, Islamic Azad University, Dezful, Iran
c Department of Chemistry, Varamin Pishva Branch, Islamic Azad University, Varamin Pishva, Iran

⁎Corresponding author. Tel.: +98 9173235388; fax: +98 21 88257969. m-shabanian@phd.araku.ac.ir (Meisam Shabanian)

Received: , Accepted: ,
© The Author(s) 2011
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

1-Substituted hydantoins (1-SH) have been known as a benefit intermediate for producing agricultural and pharmaceuticals. The effect of solvent polarity on the tautomeric equilibria of 1-substituted hydantoin ring is studied by the density functional theory calculation (B3LYP/6–31++G(d,p)) level for predominant tautomeric forms of hydantoin derivatives (1-NO2, 1-CF3, 1-Br, 1-H, 1-CH⚌CH2, 1-OH, 1-CH3) in the gas phase and selected solvents (benzene (non-polar solvent), tetrahydrofuran (THF) (polar aprotic solvent) and water (protic solvent)). For electron withdrawing and releasing derivatives in the gas phase and solution Hy1 forms is more stable and dominant form. In addition variation of dipole moments and charges on atoms in the solvents are studied.

Keywords

1-Substituted hydantoins
DFT study
Tautomerism
Dipole moments
1

1 Introduction

Hydantoins, glycolylurea, consist a group of compounds that has been of considerable interest. Many of the compounds possess clinically useful activity, especially as anticonvulsants (e.g., norantoin, mepheenytoin, nirvanol, and methetoin). Many biological activities of hydantoin derivatives are known, as in their uses as herbicides and fungicides and some N-substituted derivatives of hydantoin are used as chlorinating or brominating agents in disinfectant/sanitizer or biocide products. Both the electron distribution and the stereochemistry of the hydantoins are important for their biological activity. For this reason and along with a research program to study the structure–activity relationships for this class of compounds, this paper reviews the relevant literature on the structure of hydantoin derivatives both in solution and in the solid state (Ware, 1950; Kleinpeter, 1997).

Tautomerism interconversions (Grochowski et al., 2004; Belova et al., 2008) have been investigated by chemists during last decades. Recently, study of tautomerism received renewed attention due to its importance on the determination of compounds’ properties and their area of applications. The importance of tautomerism is revealed more since in recent years the investigation about tautomerism has been the major topic in theoretical chemistry. For example, tautomerisms in keto-enol (Misra and Dalai, 2007; Zborowski and Korenova, 2004), imine–enamine (Oziminski et al., 2004; Dines and Onoh, 2006), purine (Shukla and Mishra, 2000), pirimidine (Bonacin et al., 2007) and many other systems (Ralhan and Ray, 2003) have been studied during the past decades. Thereupon, compounds containing different tautomers can be the subject of interest by theoretical chemists (Tavakol, 2010).

In this article we studied the tautomerism of seven 1-substituted hydantoins in the gas phase and solution using polarisable continuum method (PCM) at the B3LYP/6–31++G(d,p) level of theory.

2

2 Computational methods

All these calculations were carried out on a Pentium V personal computer by means of GAUSSIAN03 program package (Frisch et al., 2004) and for our computations. First, all the compound’s structures were drawn using Gauss View 03 (Dennington et al., 2003) and optimized in semi. To characterize all the optimized geometries the vibrational frequencies for all the conformers have been done at B3LYP levels. The stationary structures are confirmed by ascertaining that all ground states have only real frequencies. The tautomers were also optimized in solvents according to the polarisable continuum method of Tomasi and co-workers, which exploits the generating polyhedra procedure (Miertus et al., 1981; Cances et al., 1997; Cossi et al., 1998; Barone and Cossi, 1998; Barone et al., 1998) to build the cavity in the polarisable continuum medium, where the solute is accommodated. Atomic charges in all the structures were obtained using the Natural Population Analysis (NPA) method within the Natural Bond Orbital (NBO) approach (Reed et al., 1988; Najafi Chermahini et al., 2007).

3

3 Results and discussion

3.1

3.1 Gas phase

Structures of hydantoin derivatives are depicted in Fig. 1 and the results of energy comparisons of five tautomers in the gas phase and different solvents are given in Table 1. In agreement with previous results, in the gas phase all Hy1 forms are more stable than the other forms. The major difference between Hy1 and the other forms in the gas phase was found for 1-methyle hydantoin with 24.07 kcal mol−1. The order of stability of Hy1 tautomer over the other tautomers in the gas phase is CH3 > H > CH⚌CH2 > OH > Br > NO2 > CF3.

Tautomeric forms of hydantoin derivatives and numbering of hydantoin ring.
Figure 1
Tautomeric forms of hydantoin derivatives and numbering of hydantoin ring.
Table 1 Total energiesa at B3LYP/6–31++G∗∗ in the gas phase and solvents.
R Tautomer Gas (1.0) Benzene (2.2) THF (7.6) Water (78.4)
NO2 Hy1 −581.2074691 −581.2221109 −581.2320934 −581.2367362
Hy2 −581.1814368 −581.1932298 −581.2015427 −581.2060233
Hy3 −581.1834681 −581.2002005 −581.2120739 −581.217642
Hy4 −581.1711189 −581.1904285 −581.2039496 −581.2107403
Hy5 −581.1591994 −581.1753041 −581.186004 −581.190941
CF3 Hy1 −713.7845745 −713.7963805 −713.8042665 −713.8078671
Hy2 −713.7488251 −713.7589838 −713.7683018 −713.7743826
Hy3 −713.7610168 −713.7750443 −713.7850663 −713.7897254
Hy4 −713.7479111 −713.7641756 −713.7753535 −713.7810888
Hy5 −713.7376467 −713.7510511 −713.7597643 −713.7637658
Br Hy1 −2947.821781 −2947.8339021 −2947.8420475 −2947.8455984
Hy2 −2947.7831188 −2947.7974126 −2947.8156584 −2947.8145562
Hy3 −2947.7956906 −2947.8101048 −2947.8203488 −2947.8249864
Hy4 −2947.7824059 −2947.7991082 −2947.8105747 −2947.8161127
Hy5 −2947.7746538 −2947.7883321 −2947.7971482 −2947.800963
H Hy1 −376.7405171 −376.7556339 −376.7659129 −376.7703092
Hy2 −376.6983782 −376.7196312 −376.7361504 −376.7441062
Hy3 −376.7021526 −376.7221592 −376.7370945 −376.7443175
Hy4 −376.7013924 −376.7208266 −376.7341045 −376.7402239
Hy5 −376.6932919 −376.7100632 −376.7209578 −376.7255222
CH3 Hy1 −416.0542389 −416.066013 −416.0739606 −416.0774713
Hy2 −416.0082409 −416.0245805 −416.0369986 −416.0439921
Hy3 −416.0158605 −416.0327035 −416.0454155 −416.0517596
Hy4 −416.0156317 −416.0313783 −416.0421626 −416.0474911
Hy5 −416.0059184 −416.0194233 −416.0281578 −416.0320566
CH⚌CH2 Hy1 −454.1438696 −454.155888 −454.1638078 −454.1672786
Hy2 −454.098425 −454.1151325 −454.1276585 −454.1351203
Hy3 −454.1170664 −454.1311998 −454.1411281 −454.1456436
Hy4 −454.1021849 −454.1183108 −454.1295859 −454.134804
Hy5 −454.0907753 −454.1046771 −454.113678 −454.1175365
OH Hy1 −451.9012817 −451.9178215 −451.9290471 −451.9339936
Hy2 −451.86771 −451.890121 −451.9033081 −451.9092211
Hy3 −451.8748703 −451.8769226 −451.906554 −451.912549
Hy4 −451.860528 −451.8769226 −451.8959356 −451.9012212
Hy5 −451.8507417 −451.8698025 −451.8823162 −451.8878452
a Hartree.

This indicates that the stability of Hy1 form decreases with the increase withdrawing effect of substituents. The calculated dipole moments for the hydantoins are presented in Table 2. In the Hy2 tautomers, the electron withdrawing derivatives have smaller dipole moments than the electron releasing ones; but in Hy4 forms electron donating derivatives have lower dipole moments values than electron withdrawing substituents. This maybe explained by the consideration of charge values on the atoms of hydantoin ring. It is well known that in haydantoin N1 and N3 atoms carry the most negative charge. The Hy2 isomer of 1-NO2 derivative has the least charge density on N1 and N3. It is noticeable that the differences between the dipole moments of 1-H and 2-H forms are related to nature substituents.

Table 2 Calculated dipole moments of optimized tautomers of 1-substituted hydantoin (Debye).
R Tautomer Gas (1.0) Benzene (2.2) THF (7.6) Water (78.4)
NO2 Hy1 2.6038 3.2247 3.7160 3.9700
Hy2 3.0670 3.8083 4.4560 4.8578
Hy3 6.2865 7.8248 9.0553 9.6786
Hy4 6.9441 8.5545 9.8821 10.5669
Hy5 3.6635 4.6294 5.4782 5.9043
CF3 Hy1 1.3475 1.5638 1.7249 1.7905
Hy2 5.0520 6.3704 7.2312 8.0778
Hy3 5.5358 6.8991 8.0413 8.6616
Hy4 5.9082 7.1693 8.1428 8.6173
Hy5 1.7713 2.1689 2.4807 2.5991
Br Hy1 1.9298 2.2431 2.4729 2.5882
Hy2 7.0953 8.8554 6.7323 11.0407
Hy3 5.0617 6.3101 7.3319 7.8312
Hy4 5.1598 6.3006 7.2013 7.6384
Hy5 1.3389 1.5940 1.7887 1.8825
H Hy1 2.7821 3.2723 3.6437 3.8137
Hy2 7.6712 9.8882 11.8194 12.5808
Hy3 7.8371 9.6297 11.0666 11.7583
Hy4 5.2094 6.3199 7.1838 7.5898
Hy5 1.8784 2.2479 2.5263 2.6560
CH3 Hy1 3.0149 3.4165 3.7002 3.8320
Hy2 8.8193 10.6037 12.0025 12.7320
Hy3 7.7192 9.4854 10.9136 11.6196
Hy4 4.9890 6.0886 6.9381 7.3840
Hy5 2.3506 2.5999 2.7825 2.8707
CH⚌CH2 Hy1 1.8262 2.0860 2.2985 2.3802
Hy2 7.4423 9.2216 10.6757 11.4296
Hy3 4.6670 5.8457 6.8213 7.3045
Hy4 3.7335 4.5451 5.2161 5.5522
Hy5 1.4103 1.5789 1.7212 1.7831
OH Hy1 2.0019 2.5576 3.0234 3.2656
Hy2 7.2315 6.0234 7.0601 7.5663
Hy3 4.5590 5.9384 7.1507 7.8244
Hy4 4.4355 5.5754 6.9989 5.4223
Hy5 2.0633 2.3916 2.6936 2.8601

The calculated values of NBO charges using the Natural Population Analysis (NPA) of optimized structures of hydantoin derivatives are listed in Table 3. As it was noticed previously, the hydantoin’s nitrogen atoms at position 1 or 3 carry the largest negative charge and these positions will most effectively interact with electrophiles. There is no uniform trend for the variation of charges to relate to the different substituents of hydantoins in the gas phase, Table 3.

Table 3 Calculated NBO charges on ring atoms of 1-substituted hydantoin.
R ∊= 1.0 2.2 7.6 78.4 1.0 2.2 7.6 78.4 1.0 2.2 7.6 78.4 1.0 2.2 7.6 78.4 1.0 2.2 7.6 78.4
Atom Hyl Hy2 Hy3 Hy4 Hy5
NO2 Nl −0.035 −0.332 −0.318 3.347 −0.319 −0.304 −0.294 3.358 −0.357 −0.336 −0.323 −0.315 −0.310 −0.293 −0.280 3.366 −0.285 −0.275 −0.267 3.372
C2 0.821 0.834 0.842 3.420 0.769 0.788 0.802 3.401 0.799 0.811 0.817 0.819 0.798 0.806 0.811 3.404 0.719 0.731 0.740 3.371
N3 −0.680 −0.674 −0.670 3.166 −0.545 −0.573 −0.595 3.198 −0.562 −0.583 −0.598 −0.604 −0.657 −0.654 −0.652 3.175 −0.598 −0.606 −0.609 3.197
C4 0.685 0.697 0.705 3.352 0.656 0.668 0.674 3.335 0.617 0.638 0.654 0.662 0.479 0.490 0.500 3.253 0.457 0.461 0.465 3.233
C5 −0.334 −0.336 −0.339 2.830 −0.345 −0.345 −0.345 2.827 −0.320 −0.323 −0.326 −0.327 −0.215 −0.220 −0.223 2.888 −0.196 −0.205 −0.212 2.892
CF3 Nl −0.593 −0.587 −0.583 −0.581 −0.589 −0.577 −0.569 −0.563 −0.604 −0.598 −0.593 −0.590 −0.555 −0.552 −0.549 −0.547 −0.509 −0.510 −0.512 3.244
C2 0.853 0.845 0.852 0.855 0.780 0.801 0.810 0.820 0.812 0.820 0.825 0.827 0.805 0.807 0.808 0.807 0.722 0.729 0.733 3.367
N3 −0.681 −0.676 −0.673 −0.671 −0.557 −0.599 −0.614 −0.636 −0.562 −0.585 −0.603 −0.612 −0.653 −0.651 −0.649 −0.648 −0.606 −0.618 −0.625 3.187
C4 0.685 0.696 0.703 0.707 0.657 0.665 0.672 0.670 0.612 0.632 0.647 0.654 0.462 0.467 0.471 0.473 0.442 0.440 0.439 3.219
C5 −0.324 −0.328 −0.330 −0.331 −0.338 −0.330 −0.341 −0.332 −0.307 −0.311 −0.313 −0.312 −0.201 0.205 −0.207 −0.207 −0.186 −0.194 −0.200 2.899
Br Nl −0.602 −0.595 −0.589 3.207 −0.586 −0.575 −0.558 −0.561 −0.612 −0.603 −0.595 −0.591 −0.559 −0.553 −0.549 −0.547 −0.507 −0.509 −0.510 3.244
C2 0.812 0.819 0.823 3.410 0.767 0.781 0.790 0.797 0.790 0.795 0.707 0.707 0.777 0.777 0.774 0.772 0.690 0.695 0.698 3.349
N3 −0.682 −0.678 −0.676 3.163 −0.583 −0.621 −0.670 −0.664 −0.557 −0.584 −0.603 −0.613 −0.653 −0.652 −0.651 −0.651 −0.613 −0.629 −0.639 3.180
C4 0.686 0.696 0.702 3.350 0.657 0.662 0.665 0.663 0.605 0.624 0.638 0.645 0.456 0.460 0.463 0.465 0.440 0.436 0.434 3.215
C5 −0.317 −0.321 −0.324 2.838 −0.330 −0.332 −0.332 −0.334 −0.305 −0.310 −0.313 −0.315 −0.204 −0.208 −0.210 −0.210 −0.194 −0.202 −0.209 2.894
H Nl −0.694 −0.687 −0.681 −0.678 −0.696 −0.681 −0.660 −0.653 −0.707 −0.697 −0.687 −0.683 −0.644 −0.641 −0.638 −0.637 −0.597 −0.600 −0.603 −0.604
C2 01.810 0.814 0.817 0.818 0.754 0.773 0.784 0.789 0.786 0.789 0.788 0.788 0.773 −0.769 0.764 0.761 0.683 0.685 0.686 0.687
N3 −0.689 −0.686 −0.684 −0.683 −0.583 −0.635 −0.678 −0.693 −0.526 −0.569 −0.604 −0.622 −0.660 −0.661 −0.661 −0.661 −0.629 −0.651 −0.666 −0.673
C4 0.682 0.691 0.696 0.698 0.653 0.658 0.658 0.658 0.586 0.606 0.622 0.630 0.447 0.446 0.446 0.447 0.431 0.424 0.418 0.415
C5 −0.330 −0.333 −0.335 −0.335 −0.351 −0.348 −0.345 −0.345 −0.331 −0.333 −0.334 −0.335 −0.215 −0.217 −0.217 −0.216 −0.208 −0.215 −0.220 −0.222
CH3 Nl −0.519 −0.509 −0.501 −0.497 −0.514 −0.476 −0.215 −0.469 −0.533 −0.519 −0.507 3.251 −0.474 −0.467 −0.461 3.272 −0.428 −0.426 −0.425 −0.425
C2 0.821 0.826 0.830 0.831 0.774 0.798 0.626 0.803 0.798 0.801 0.802 3.398 0.785 0.783 0.780 3.386 0.693 0.698 0.701 0.702
N3 −0.685 −0.681 −0.697 −0.678 −0.602 −0.671 −0.553 −0.685 −0.523 −0.565 −0.599 3.193 −0.656 −0.658 −0.658 3.171 −0.631 −0.651 −0.664 −0.670
C4 0.684 0.693 0.699 0.701 0.653 0.658 −0.407 0.658 0.588 0.608 0.624 3.314 0.458 0.455 0.456 3.226 0.434 0.428 0.423 0.421
C5 −0.315 −0.319 −0.322 −0.323 −0.330 −0.332 −0.236 −0.333 −0.315 −0.318 −0.321 2.839 −0.206 −0.209 −0.210 2.895 −0.196 −0.203 −0.208 −0.210
CH⚌CH2 Nl −0.502 −0.496 −0.491 −0.489 −0.490 −0.478 −0.469 −0.464 −0.512 −0.505 −0.499 −0.496 −0.467 −0.463 −0.460 −0.459 −0.431 −0.432 −0.433 3.287
C2 0.825 0.833 0.837 0.839 0.772 0.789 0.800 0.807 0.803 0.808 0.810 0.811 0.795 0.795 0.793 0.793 0.707 0.711 0.714 3.356
N3 −0.681 −0.678 −0.675 −0.673 −0.580 −0.620 −0.650 −0.665 −0.563 −0.590 −0.610 −0.619 −0.668 −0.666 −0.662 −0.661 0.619 −0.636 −0.647 3.175
C4 0.686 0.696 0.702 0.705 0.655 0.661 0.664 0.664 0.607 0.625 0.639 0.646 0.435 0.447 0.458 0.464 0.440 0.435 0.431 3.214
C5 −0.323 −0.327 −0.330 −0.331 −0.335 −0.337 −0.339 −0.339 −0.308 −0.313 −0.316 −0.318 −0.140 −0.158 −0.176 −0.187 −0.190 −0.198 −0.203 2.897
OH Nl −0.243 −0.237 −0.228 3.390 −0.244 −0.214 −0.203 −0.196 −0.259 −0.249 −0.238 −0.231 −0.206 −0.196 −0.177 −0.165 0.136 −0.131 −0.127 −0.125
C2 0.807 0.814 0.817 3.406 0.755 0.770 0.781 0.789 0.785 0.790 0.791 0.791 0.782 0.779 0.771 0.764 0.678 0.682 0.684 0.685
N3 −0.684 −0.680 −0.677 3.162 −0.566 −0.643 −0.664 −0.674 −0.569 −0.594 −0.614 −0.626 −0.661 −0.659 −0.659 −0.663 −0.626 −0.646 −0.659 −0.664
C4 0.683 0.694 0.699 3.349 0.656 0.663 0.666 0.666 0.608 0.626 0.639 0.646 0.456 0.459 0.460 0.446 0.437 0.432 0.428 0.426
C5 −0.334 −0.336 −0.338 2.830 −0.351 −0.348 −0.348 −0.348 −0.319 −0.323 −0.326 −0.327 −0.212 −0.218 −0.224 −0.189 −0.207 −0.217 −0.223 −0.225

3.2

3.2 Solvent effects

Solvent effects are relevant in the tautomers stability phenomena, since polarity differences among the tautomers can induce significant changes in their relative energies in solution. PCM/B3LYP calculations were used to analyze the solvent effects on tautomerism of hydantoin derivatives. It is important to stress that the PCM model does not consider the presence of explicit solvent molecules; hence specific solute–solvent interactions are not described and the calculated solvation effects arise only from mutual solute–solvent electrostatic polarization. The data presented in Table 1 show that the polar solvents increase the stability of all hydantoins in comparison to gas phase. The difference between the total energies of Hy1 and the other forms do not show a regular trend when changing from gas phase to most polar solvents (water).

The solvent interactions have not pronounced an effect on the order of stability of the tautomers in the gas phase. The solvent represented by a polarizable continuum is found to show significant effect on the dipole moments of the individual solute conformers. The dipole moments (l) increase by changing the gas phase to the solution as well as by increasing the solvent polarity. The most significant variations being obtained in hydantoin in Hy2 form with 4.9096 D, Table 2. We have examined the charge distribution of tautomers in the solvent as well as gas phase by using calculated NBO charges. The charge distribution in solvents with the increase of polarity differently varies for any atoms.

4

4 Conclusion

  1. In the gas phase and solution all Hy1 forms were more stable than the other tautomers. On the other hand, interestingly enough, the highly elaborate B3LYP/6–31++G(d,p) type DFT calculations yield results in estimating the stability order of these tautomers as Hy1 > Hy2 > Hy2 > Hy4 > Hy5 (Table 1). In the solution and with increase of polarity; Hy1 isomers were more stable. With increase of polarity, total energies of all compounds were more negative.

  2. The dipole moments of all compounds are affected by solvent. With increase of the polarity of solvents the dipole moments of the tautomers were increased.

  3. The charges on all five positions were affected by substituents and solvents.

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