Computational Study of the Keto-Enol Tautomerism of 3-Phenyl-2,4-Pentanedione in the Gaseous Phase and Solvents Using DFT Methods

The study of tautomerics equilibria is of vital importance as tautomeric compounds reactivity highly depends on the proportion of each tautomer. Herein, the tautomeric equilibrium of the 3-phenyl-2,4-pentanedione was studied theoretically by the b3lyp/6-31+g(d)methods. The effect of four solvents was considered (water, methanol, carbon tetrachloride and Cyclohexane). The tautomeric equilibrium takes place through four-membered ring transition state. The barrier heights energies of the tautomerics equilibria reaction of the transition state with reference to Keto were found to be 31.26, 31.23, 30.84, 30.82 and 30.61 kcal mol -1 in water, methanol, carbon tetrachloride, Cyclohexane and the gas-phase, respectively. Furthermore, the electronics energies differences between the Keto-form and Enol-form were found to be -16.50, -16.55, -17.27, -17.34 and -17.89 kcal mol -1 in the same previous solvents respectively. The DFT calculations revealed that the Keto-form is more stable one in all investigations.

Tautomer ism in organic chemistr y has been extensively studied by chemists experimentally and theoretically due to its vast usage as organic reagents in medicinal and organic chemistry. The organic compounds that have carbonyl functional groups with alpha hydrogen atoms can be found at equilibrium as ketone or enol tautomeric continual isomers. These tautomers are crucial due to their unique properties such as the presence of different hetero-heavy donor atoms and functional groups as well as their solubility in polar and nonpolar solvents. Thus, they facilitate their applications in chemistry to be intermediates in organic synthesis and chelating ligands of heavy metals. Furthermore, they have a key role in biology as an antitumor, antibacterial, anticonvulsant, antidepressant, and the dynamics of biological systems happened by the interactions of specific site like bond of hydrogen. Therefore, a profound understanding of the Keto-Enol tautomeric mechanism is vitally significant to be understood.
The stability of these two tautomeric forms of carbonyl compounds in different solvents has been detected in the condensed and gas phases by spectroscopic approaches such as nuclear magnetic resonance (NMR) and infrared techniques (IR). Therefore, the effect of solvents on the stability of keto and enol tautomeric forms for different dicarbonyl compounds such as b-diketones, b-Dicarbonyls 19 , 3-phenylazo-2,4-pentanedione 20 , pentan-2,4dione, b-ketoester, b-diketones 21 , b-ketonitrile, alpha-ketophosphonates, and acetylacetone have reported in the literature. Their results summary revealed that polar solvents stabilize the keto tautomer over the corresponding enol tautomer and this was attributed to the high polarity of the Keto-form compared to the Enolform. Furthermore, when there is no interaction between the solvent and the keto and enol forms then the keto tautomer is more stable in solvents with high dielectric constants than the enol form. This was assigned to the formation of bonds of hydrogen between the keto isomer and solvent which is unfavorable in the case of the enol form. Therefore, the stability of tautomeric isomers in the solvent depends on the interaction between the solvent and the tautomer.
This approach can be used to investigate the Keto-Enol tautomerization mechanism, using density functional theory (DFT) calculations. In this method, the thermodynamic functions of tautomerization can be calculated by computer simulation in different solvents and gas phases to explore the effect of solvents on the stability of Keto-Enol tautomeric forms. For example, Linear and Cyclic-Diketones 22 , b-Diketones 23 , a-and β b-Cyclodiones 24 , Cyclohexanone 25 , Acetylacetone 26 , and 4(substitutedphenylazo)-3;5-diacetamido-1-H-pyrazoles 27 , are reported in the literature. The common results of these studies are that the solvents that can destroy hydrogen bonds the enol form is unstable due to an unfavorable entropy of enolization but the keto form is stable due to the electrostatic interactions. This can lead to a reduction of enol forms in these solvents but a greater extent than expected because of the unfavorable entropy change. However, the keto form is more enthalpically stable in the solvents that can be acted as hydrogen bond protons acceptors and donors but is not stabilized as much as the eno1 tautomer. The entropy of enolization is unfavorable in these solvents, but due to the enthalpy stabilization of the enol tautomer the percentage of enol is greater than would be expected on the basis of dielectric constant. This article will investigate keto-enol tautomerism of 3-phenyl-2,4-pentanedione in the gaseous phase and in solvents to see the effect of these solvents on the stability of ketol-Enol Tautomerism.

Computational Methods
Calculations of the title compound were carried out with Gaussian 09 28 using the Density Functional Theory calculations (DFT) B3LYP methods, to predict the molecular structure. Molecular geometries of tautomeric forms of 3-phenyl-2,4-pentanedione in the gaseous phase and in solvents were fully optimized using Density Functional Study (DFT) calculations and high level basis set 6-31+g(d). Also, the geometries of the Ketoform, transition state and Enol-form involved in the reactions were all fully optimized by using B3LYP/6-31+g(d). The vibrational analysis calculations were doing to molecular structures obtained, to characterize them as local minima or transition states. For the later structures, Intrinsic Reaction Coordinate IRC calculations 29 were doing along the vector of transition which explained by the mode of vibration of this imaginary frequency to check that the structure of the saddle point connected downhill the corresponding forward and backward minima. The investigation of the molecular structures of transition state through the reaction pathway can be allowed by the above mentioned methodology. In the Gaussian calculations the standard condition is 298 K temperature and 1 atm pressure.
The solvents effect on the tautomerics molecular structure parameters were studied by the self consistent reaction-field (SCRF) method of calculations depend on PCM solvation model developed by Tomasi and co-workers 28 , as implemented in G09 28 . The solvents chosen for this work are polar solvent , water (the dielectric constant of liquid water, e equal 78.40) and methanol (the dielectric constant of liquid methanol, e equal 32.60), and nonpolar solvents like cyclohexane (e equal 15.60) and carbon tetrachloride (e equal 2.20).

Tautomeric Isomers of the 3-Phenyl-2,4-Pentanedione
As Scheme1 shows the 3-Phenyl-2,4-Pentanedione remains in dynamic equilibrium between two tautomeric forms which are known as Keto and Enol isomers. The enolform can be generated as a consequence of shifting a-carbon atom hydrogen in any carbonyl group in the keto form of the molecule. As it is reported in the literature articles, the Enol-form is less stable than the Ketoform due to the high stability of C=O bonds compared to C=C bonds, but this is still a matter of debate due to the stability still depends on different factors such as the solvent.Therefore, this study is going to discuss the stability of Keto-Enol isomers of the 3-Phenyl-2,4-Pentanedione in different solvents.

Geometries Analysis of Keto, Enol, and transition state
T h e b 3 l y p / 6 -3 1 + g ( d ) o p t i m i z e d geometries of The gas phase of the Enol, Keto, and transition state of the 3-Phenyl-2,4-Pentanedione and their corresponding chosen molecular structural simulated parameters are displayed in Fig. 1 and Table 1, respectively. The reaction of internal proton transfer (IPT) of Enol transition state Keto was regarded, since an internal proton transfer (H 17 ) on (C 12 ) in the keto form to the carbonyl oxygen atom (O 15 ). This shift is attended by a rearrangement of the four-membered ring, not six-membered due to the 3-phenyl-2,4-pentanedione carbonyl groups are not planar. Therefore, the calculated geometric parameters in Table 1   For numbering of atoms, see Fig. 1, Bond angles in degrees, bond distances in Angstrom.

Energies of Keto, Enol, and transition state
The relative energies of the 3-phenyl-2,4-pentanedione as depicted in Fig. 2 were calculated from the total energy difference between transition states and the Keto-forms, and the data were summarized in Table 2 for all given phases. The results revealed that relative energies of the transition state for Keto were found to be 30.61, 30.82, 30.84, 31.23, and 31.26 kcal mol -1 in the gaseous phase, cyclohexane, carbon tetrachloride, methanol, and water, respectively. Similarly, the total electronics energy differences between the two tautomers were -17.89, -17.34, -17.27, -16.55, and -16.50 kcal mol -1 in the gaseous phase, cyclohexane, carbon tetrachloride, methanol, and water, respectively. From these results, we obtained that in the gas and solution phases, the Keto-form is more stable than Enol-form, since IPT reaction between the two tautomers has a similar attitude. Furthermore, Fig. 2b shows increases of the barrier height on going from the gas phase to cyclohexane to carbon tetrachloride to methanol to water phase. These trends can be explained by the internal proton transfer reaction barriers being decreased as accordance with a decrease in the dipole moment of the solvents used. Therefore, in a polar protic solvent like water and alcohol, the lone pairs are involved in hydrogen bonding with the solvent which makes them less available to hydrogen bond in the Enol form. This is also in good agreement with reported literature on the effect of the solvent polarity on the keto form stability in the polar fluids where the Keto-form has larger dipole-moment was more favorable one 31 . The relative stability of keto form relative to enol one was found to be exist regardless of the solvent used 32 . On the other hand, the size of the substituent group in beta diketone increases 33 , and the equilibrium shifts to favor of the keto tautomer due to steric hindrance of the phenyl-group attached on third-carbon of 2,4-pentanedione. Steric hindrance of bulky groups was reported to be the force of driving able to shift from the more common Keto-Enol tautomers to the βbeta-diketo 34 . According to the valence bond theory(VBT), the interaction between the lone pair of electrons of carbonyl oxygen as an acceptor-atom and the C-H orbital is responsible for proton transfer(PT). Therefore, the angle carbon hydrogen oxygen (C-H…O) and, the distance oxygen hydrogen( O…H) may be play an important role in the proton-transfer reactions.   To further explain the stability of the keto tautomer in different solvents the bond angles were used. The results revealed that angles (12,17,15)  respectively. We conclude that the hydrogen bond is most alike in all phases and therefore it is suitable to see almost the same energy barrier internal proton transfer reaction process in all phases. This can be interpreted as was reported in the literature that an intramolecularly H-bonded keto structure highly predominates among pyruvic acid isomers. Moreover, in a similar study, it was found that the transition states of the tautomerism between the keto-enol form were 4-membered ring conformations and the keto form was more stable 30 . The finding in this study agrees with what has been mentioned before for neutral system, the Enol-form is less stable than the Keto-form 35,36 .

CONCLUSION
We h a ve s t u d i e d t h e k e t o -e n o l tautomer isation reaction of 3-phenyl-2,4pentanedione by the density functional theory method in gas phase as well as in different solvents. We found that the total electronics energies differences between the keto and enol are -17.89, -17.34, -17.27, -16.55, and -16.50 kcal mol -1 in the gase phase, cyclohexane, carbon tetrachloride, methanol, and water, respectively. Therefore, the Keto-form is more stable than the enol form in the gase phase and solution using b3lyp/6-31+d(d) levels of theory. The internal proton transfer reaction process between Enol-tautomers and Ketotautomers follows almost similar way in gase phase and solutions. As a result of that, the internal proton transfer reaction barrier process is decreases with the decrease in the dipole moment of the solvent used. Furthermore, the size of substituent group in beta diketone increases, and the equilibrium shifts would favor the keto tautomer because of the steric hindrance of the phenyl group attached to the third carbon in 2,4-pentanedione.