2.1. Experimental

The neopentyl derivative of dehydroacetic acid 3-(3,3-dimethylbutanoyl)-4-hydroxy-6-neopentyl-2H-pyran-2-one (1) has been obtained by CF₃SO₃H/(CF₃CO)₂O activated acylation of carboxylic acids according to [19,20]. The white product has the crystalline powder form (melting point 77–78°C). Compound 1 can exist in two tautomeric enol forms, A and B (Figure 1).

IR spectra were recorded by accumulating 64 scans in the region of 4000–400 cm⁻¹ with a resolution of 4 cm⁻¹. A Bruker Vector 22 spectrometer was used [21]. The samples were compressed into KBr pellets.

Raman spectra of the pyrone were recorded in the 3500–50 cm⁻¹ region via the FTIR spectrometer VERTEX 70 and the Bruker FT-Raman RAM II module [21]. The 1064 nm excitation line provided by an Nd:YAG laser with a power of 50 mW was used.

2.2. Computational Details

The calculation of the vibrational spectra of compound 1 was performed using the B3LYP functional [22,23] and the basis set 6-311G**. The calculations were performed using the Gaussian09 program [24]. As a first approximation, the experimental coordinates of the atoms obtained through the X-ray diffraction method were used (Supplementary Information S1). Standard optimization methods were used to find minima on the potential surface. Full geometry optimization was performed without any restrictions. The Hessian analysis made it possible to determine the minima of potential energy.

Optimized geometrical parameters of the tautomers were used to calculate the harmonic vibration frequencies. Theoretical structural and spectral data were obtained for both tautomers at 298 K, 1 atm. The potential energy distribution was calculated to attribute the vibrations [25]. Calculated frequencies were scaled using a multiplier of 0.96. The theoretical spectral curves were constructed, taking the Lorentz band shape and a half-width of 10 cm⁻¹.

The calculation of natural bonding orbitals (NBO) has been performed to characterize the electronic properties of molecules [26]. The chemical potential, hardness, softness, and electrophilicity index are related to the first vertical ionization energy and electron affinity by the following formulas: μ ≈ −(IE + EA)/2, η ≈ (IE − EA), S = 1/η, and ω = μ²/2η [27]. The Fukui functions for nucleophilic [Math Processing Error] $f_k^{+}\left(r\right)=\left[q_k\left(N+1\right)-q_k\left(N\right)\right]$ and electrophilic [Math Processing Error] $f_k^{-}\left(r\right)=\left[q_k\left(N\right)-q_k\left(N-1\right)\right]$ attacks were calculated using the natural atomic charges on atoms q_k and the number of electrons N in a molecule. The local softness of atoms has also been calculated $s_k^{+}=S{f}_k^{+},s_k^{-}=S{f}_k^{-}$ [27].

Using the difference in free energies of the tautomers, their populations at 298.15 K can be calculated $p={\displaystyle \frac{\exp (-\Delta G_i/RT)}{{\displaystyle \sum _j\exp (-\Delta G_j/RT)}}}$ [28]. A polarizable continuum model was used to assess the influence of the polar environment on the tautomeric equilibrium [28].

3.1. Structural Analysis

As can be seen from the X-ray diffraction data in the crystalline state at room temperature, the A tautomer of compound 1 is realized (Supplementary Information S1). In the more stable tautomer A, an intramolecular hydrogen bond is realized. The measured distance between the O3 and O4 atoms is 2.437 Å. Supplementary Information S2 lists the measured bond lengths and angles of tautomer A.

The results of geometry optimization of tautomers A and B are shown in Figure 2 and in Supplementary Information S2. Gibbs’s free energy and Boltzmann weights of tautomers are shown in Table 1. It appears from our data that type A dominates. The content of tautomer B increases in the less polar chloroform but does not exceed 13%. Vibrational spectra were calculated for tautomers A and B.

As can be seen from the calculations and experimental X-ray data, the pyran ring of the molecule is flat. A satisfactory agreement is observed between the calculated geometrical parameters of tautomer A and the experimental X-ray data.

Bond lengths change during tautomeric transformation. In tautomeric form A, the calculated bond lengths are (Å) 1.313 (O(3)–C(7)), 1.250 (O(4)–C(27)), 1.413 (C(6)–C(7)), and 1.467 (C(6)–C(27)), and for the B tautomer, the length of these bonds changes to 1.259, 1.302, 1.458, and 1.411, respectively. Such changes in bond lengths are consistent with the change in their properties during the tautomeric transformation. The H-bond lengths in the A and B tautomers are also different. The calculated O(3)∙∙∙O(4) distances for tautomers A and B are 2.473 and 2.418 Å, respectively.

3.2. Frontier Orbitals and Descriptors

The HOMO and LUMO molecular orbitals for the A and B tautomers are located on the pyran ring (Figure 3). Conjugation leads to a flat structure for this ring. It is interesting to see how the charge distribution changes during tautomeric transformations. In the tautomeric transformation from form A to B, the negative charge on the O3 atom increases, and that on the O4 atom decreases (Supplementary Information S3). In the B form, the charges on the atoms C5, C6, and C7 increase, and on the C27, H44 atoms decrease. It follows from these data that the chemical properties change during the tautomeric transition.

The pyrone 1 molecule contains several functional groups. Their reactions can be described using descriptors. Form B was found to have higher ionization energy, electron affinity, chemical potential, electrophilic index, and energy band gap than Form A (Table 2). The dipole moment is higher for form A, and the softness of both molecules is the same.

The calculation of the local electrophilic indices makes it possible to estimate the reactivity of the atoms for two tautomeric forms (Supplementary Information S3). The electrophilic index of oxygen atoms is higher for the A form. For the carbon atoms C5, C6, C7, and C27, the electrophilicity index is higher for form A. It should be emphasized that the C6 atom is highly reactive. Detailed analysis of chemical descriptors allows finding new ways to obtain drugs with desired properties.

3.3. NBO Analysis

The molecular orbitals are similar for the two tautomeric forms, but there is an orbital σ(2)_C6–C7 = 0.8137(sp^1.00d^0.00)_C6 + 0.5812(sp^1.00d^0.00)_C7 in form A, which is not in form B. In form B there is an orbital σ(2)_O3–C7 = 0.8605(sp^1.00d^0.00)_O3 + 0.5095(sp^1.00d^0.00)_C7,which is not in form A. These extra orbitals are of π character and indicate an increase in bond order.

In form A, significant interactions of C6–C7, C8–C10 bond orbitals with antibonding orbitals of the O2–C5, O4–C27, C6–C7 σ₂(C6–C7)→σ*₂(O2–C5), σ₂(C6–C7)→σ*₂(O4–C27), σ₂(C8–C10)→σ*₂(C6–C7) with stabilization energies 34.18, 31.20, and 24.96 kcal/mol (Supplementary Information S4). Additionally, the molecule has lone electron pairs of oxygen atoms interactions with O2–C5, C5–C6, C6–C7, and O3–H44 bonds, n(LP₂O1)→σ₁*(O2–C5), n(LP₂O2)→σ₁*(O1–C5), n(LP₂O2)→σ₂*(C5–C6), and n(LP₂O4)→σ₁*(O3–H44) with energies 29.25, 40.10, 15.56, and 42.96 kcal/mol.

In the tautomeric form B, the delocalization of electrons is maximal for the C8–C10 bond and is distributed over the antibonding orbitals O3–C7 σ₂(C8–C10)→σ*₂(O3–C7) with the stabilization energies 27.83 kcal/mol. Additionally, the molecule has lone electron pairs of oxygen atom interactions n(LP₂O1)→σ₂*(O2–C5), n(LP₂O1)→σ₁*(C8–C10), n(LP₂O2)→σ₁*(O1–C5), n(LP₂O2)→σ₁*(C5–C6), and n(LP₂O3)→σ₁*(O4–H44) with energies 31.36, 34.08, 37.96, 15.85, and 63.18 kcal/mol.

3.4. Vibrational Analysis

The determination of the type of vibration in the experimental spectra was carried out by analyzing the potential energy, the atomic displacements, and the comparison with related compounds [29,30]. The experimental and calculated vibrational spectra for two tautomers A and B of compound 1 are shown in Figure 4 and Figure 5 and Table 3.

The sharp medium-intensity peak in the IR spectrum at 3107 cm⁻¹ and the frequency of 3108 cm⁻¹ in the Raman spectrum refer to CH stretching vibrations (C8–H9 bond). Experimental frequencies in the region 3100–2960 cm⁻¹ in vibrational spectra refer to ν_as(CH₂) and ν_as(CH₃) stretching vibrations. The symmetrical stretching vibrations of the methyl and methylene groups cause frequencies in the range of 2910–2860 cm⁻¹ in the experimental spectra.

Stretching of carbonyl groups without H-bonds (C5=O bond) causes a band at 1719 cm⁻¹ in the experimental IR and Raman spectra (Figure 4 and Figure 5). The stretching vibrations of the carbonyl group forming the H-bond (C3=O7 bond) are shifted to the low-frequency region of 1636 cm⁻¹.

The bands in the region 1460–1400 cm⁻¹ in the experimental spectra are due to the δ_as(CH₃) and δ_as(CH₂) bending vibrations. Symmetrical bending vibrations δ_s(CH₃) and δ_s(CH₂) cause bands in the region 1400–1340 cm⁻¹. The frequency at 1315 cm⁻¹ in the experimental IR spectrum and the band at 1318 cm⁻¹ in the experimental Raman spectrum are due to the wagging vibrations of the methylene groups.

Stretching vibrations of the CO and CC bonds of the pyran ring (C5–O1 and C5–C6 bonds) cause frequencies between 1290 and 1150 cm⁻¹ in the experimental spectra. The bands in the region of 1060 to 1000 cm⁻¹ in the experimental spectra were attributed to the deformation of the CCH angles and stretching of the CC bonds.

The rocking vibrations of the methyl groups ρ(CH₃)cause bands between 960 and 880 cm⁻¹ in the experimental IR and Raman spectra. Bands of average intensity in the region of 860–760 cm⁻¹ in the experimental spectra refer to CO and CC bonds (C5–O1 and C5–C6 bonds) stretching vibrations.

The band at 713 cm⁻¹ in the experimental spectra refers to the stretching vibrations of the CC bonds (C10–C11 bond). Bending vibrations of the pyran ring cause bands in the 620–470 cm⁻¹ region in the experimental spectra. Bending and torsional vibrations of the pyran ring cause bands in the 500–100 cm⁻¹ region of IR and Raman spectra.

It is important to understand the changes that occur in the vibrational spectra of compound 1 during the tautomeric transformation. The spectra of tautomeric forms A and B are similar (Figure 4 and Figure 5). For tautomers A and B, the frequencies of most bands remain unchanged, but their intensity changes. Bands 1726, 1599, 1576, 1533, 1422, 1315, and 1192 cm⁻¹ of the form A IR spectrum are shifted to frequencies 1721, 1617, 1580, 1536, 1400, 1341, and 1190 cm⁻¹ of the form B IR spectrum (Figure 4). Bands 1726, 1599, 1576, 1533, 1433, 1340, 1316, 1278, 1249, 1198, 837, 686, 607, 578, 487 cm⁻¹ in the Raman spectrum of form A are shifted to frequencies 1721, 1617, 1580, 1536, 1429, 1341, 1291, 1198, 853, 680, 579, 489 cm⁻¹ in the Raman spectrum of form B (Figure 5).

The theoretical spectra align with the experimental vibrational spectra of tautomer A across a wide frequency range (Figure 4 and Figure 5). Thus, the use of the DFT approximation for the considered molecular system is correct.

3.5. Hydrogen Bond

Compound 1 has a strong H-bond with a cyclic chelate structure. The enol form of β-diketones is a well-known case of a 6-membered ring (chelate) with a strong resonance-assisted H-bond [31,32,33,34]. The characteristic spectral features observed for such structures include strong absorption bands in the region of 1580–1630 cm⁻¹, instead of pronounced carbonyl stretching bands [16]. The stretching of the OH bond band shifts up to 2200 cm⁻¹ [16].

Additionally, due to the resonance of two enol tautomers (both are chelate enol forms), this structural fragment can be considered a quasisymmetric O∙∙∙H∙∙∙O hydrogen bond. This bond has a broad and shallow potential well with two minima, which leads to a series of diffuse absorption bands scattered over a wide wavenumber region.

The analysis of the observed IR spectrum 1 in the region of 2700–2000 cm⁻¹ shows that there are several weak bands, ν(OH) (Figure 6). The calculated ν(OH) frequencies after scaling are 2682 and 2240 cm⁻¹ for tautomers A and B, respectively, and they are in the range between 2700 and 2200 cm⁻¹. An empirical formula is proposed that establishes a correlation between the frequencies ν(OH) observed and those calculated in the harmonic approximation: ν_obs = −757 + 1.173 ν_harm [33]. The calculation by this formula yields ν(OH)frequencies of 2520 and 1980 cm⁻¹ for tautomers A and B, respectively. In the experimental IR spectrum of compound 1, the band 2524 cm⁻¹ is observed, which can be attributed to ν(OH) vibrations. The shift of this band to low frequencies depends on the strength of the intramolecular H-bond. We see that in the most energy-stable tautomer A, the H-bond is weaker.

This conclusion is consistent with the fact that the H-bond length for A and B tautomers is 2.473 and 2.418 Å, respectively. The strength of the H-bond can be described using Wiberg bond indices 0.158 (tautomer A) and 0.204 (tautomer B) [26]. These values of the Wiberg indices indicate that strong H-bonds are formed in compound 1 for both tautomers. It appears from our data that there is a correlation between the frequencies ν(OH)calculated in the harmonic approximation and the Wiberg indices. The stronger the H-bond, the lower the ν(OH) frequency and the higher the Wiberg index.

The strength of the intramolecular H-bond in compound 1 can be estimated as the interaction n(LP₂O4)→σ₁*(O3–H44) with the energy 42.96 kcal/mol of the tautomer A and n(LP₂O3)→σ₁*(O4–H44) with energy 63.18 kcal/mol of tautomer B. The energy of the donor-acceptor interaction of the H-bond is larger for the B tautomer; therefore, it is stronger. Interactions σ₁(O3–H44)→σ*₁(C7–C8), σ₂(C6–C7)→σ*₂(O4–C27), σ₂(C6–C7)→σ*₂(C8–C10), σ₂(C8–C10)→σ*₂(C6–C7) with energies 5.83, 31.20, 7.49, 24.96 kcal/mol (tautomer A), and σ₂(C8–C10)→σ*₂(O3–C7) with energy 27.83 kcal/mol (tautomer B) are realized due to the conjugation of bonds in a six-membered ring.