Stereoselective Synthesis of Multisubstituted Cyclohexanes by Reaction of Conjugated Enynones with Malononitrile in the Presence of LDA

Reaction of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones, with malononitrile in the presence of lithium diisopropylamide LDA, as a base, in THF at room temperature for 3–7 h resulted in the formation of the product of dimerization, multisubstituted polyfunctional cyclohexanes, 4-aryl-2,6-bis(arylethynyl)-3-(aryloxomethyl)-4-hydroxycyclohexane-1,1-dicarbonitriles, in yields up to 60%. Varying the reaction conditions by decreasing time and temperature and changing the ratio of starting compounds (enynone and malononitrile) allowed isolating some intermediate compounds, which confirmed a plausible reaction mechanism. The relative stability of possible stereoisomers of such cyclohexanes was estimated by quantum chemical calculations (DFT method). The obtained cyclohexanes were found to possess photoluminescent properties.


Introduction
Conjugated enynones are an important class of organic compounds due to the presence of several functional groups in their structures: double and triple carbon-carbon bonds, along with the carbonyl group. These enynones are starting reagents in many important organic transformations [1,2].
In our previous work, we studied a multicomponent reaction of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones, with malononitrile and sodium alkoxides affording substituted pyridines [3]. In that study [3], we showed just one example of the synthesis of multisubstituted cyclohexane by the reaction of 1,5-diphenylpent-2-en-4-yn-1-ones with malononitrile using lithium diisopropylamide (LDA), as a base, instead of sodium alkoxides. We decided to investigate this intriguing reaction deeper. Thus, the main goal of the current work was to study the reactions of 1,5-diarylpent-2-en-4-yn-1-ones 1a-i ( Figure 1) with malononitrile in the presence of LDA. We also tried to isolate some intermediate structures to elucidate the reaction mechanism.
We note that in all described syntheses, the obtained cyclohexanes had identical stereochemistry of substituents in cyclohexane ring (Scheme 1) [18,21,22]. These cyclohexanes have four stereocenters, which means that theoretically, 16 stereoisomers can be obtained. However, only one pair of enantiomers of substituted cyclohexane was formed, and the reaction proceeds very diastereoselectively.
We note that in all described syntheses, the obtained cyclohexanes had identical stereochemistr substituents in cyclohexane ring (Scheme 1) [18,21,22]. These cyclohexanes have four stereocenter hich means that theoretically, 16 stereoisomers can be obtained. However, only one pair antiomers of substituted cyclohexane was formed, and the reaction proceeds ver astereoselectively.
We note that in all described syntheses, the obtained cyclohexanes had identical stereochemistry of substituents in cyclohexane ring (Scheme 1) [18,21,22]. These cyclohexanes have four stereocenters, which means that theoretically, 16 stereoisomers can be obtained. However, only one pair of enantiomers of substituted cyclohexane was formed, and the reaction proceeds very diastereoselectively.

Results and Discussion
The results of reactions of enynones 1a-i with malononitrile and LDA are presented in Table 1. Depending on reaction conditions, three types of products, target cyclohexanes 2 and intermediate compounds 3 and 4, were obtained. Th structures of the obtained compounds were determined by NMR and HRMS (see Experimental part and SI). Exact structures of compounds 2a, 2b, 2e and 3a were additionally confirmed by X-ray data (see Table 1, Experimental part and SI). Pairs of enantiomers (racemates) of cyclohexanes 2 were obtained. Other diastereomers were not formed since we collected all compounds after chromatographic separation. in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 °C led again to a mixt and 3a (entry 3). At lower temperature −70 °C for 0.5 h, a mixture of compound 3a and diaste of dimeric diketone 4a,b was obtained (entry 4). Prolongation of reaction till 3 h at −70 °C re the formation of all three reaction products 2a, 3a and 4a,b (entry 5). These data rev compounds 3 and 4 are intermediate compounds in the synthesis of 2.
Michael addition product 3a and diketone 4a,b have very close chromatographic r parameters. Thus, we were not able to individually isolate each of these substances by usual chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was su in getting these compounds. Diastereomers 4a,b may be discerned by NMR. purpose, an experiment using enynone 1a and malononitrile with an equivalent ratio 1:1 at room temperature for 1 h was done; under these conditions, compound 3a was obtained in a yield of 32% in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 °C led again to a mixture of 2a and 3a (entry 3). At lower temperature −70 °C for 0.5 h, a mixture of compound 3a and diastereomers of dimeric diketone 4a,b was obtained (entry 4). Prolongation of reaction till 3 h at −70 °C resulted in the formation of all three reaction products 2a, 3a and 4a,b (entry 5). These data reveal that compounds 3 and 4 are intermediate compounds in the synthesis of 2.
Michael addition product 3a and diketone 4a,b have very close chromatographic retention parameters. Thus, we were not able to individually isolate each of these substances by usual column chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was successful in getting these compounds. Diastereomers 4a,b may be discerned by NMR. purpose, an experiment using enynone 1a and malononitrile with an equivalent ratio 1:1 at room temperature for 1 h was done; under these conditions, compound 3a was obtained in a yield of 32% in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 °C led again to a mixture of 2a and 3a (entry 3). At lower temperature −70 °C for 0.5 h, a mixture of compound 3a and diastereomers of dimeric diketone 4a,b was obtained (entry 4). Prolongation of reaction till 3 h at −70 °C resulted in the formation of all three reaction products 2a, 3a and 4a,b (entry 5). These data reveal that compounds 3 and 4 are intermediate compounds in the synthesis of 2.
Michael addition product 3a and diketone 4a,b have very close chromatographic retention parameters. Thus, we were not able to individually isolate each of these substances by usual column chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was successful in getting these compounds. Diastereomers 4a,b may be discerned by NMR. purpose, an experiment using enynone 1a and malononitrile with an equivalent ratio 1:1 at room temperature for 1 h was done; under these conditions, compound 3a was obtained in a yield of 32% in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 °C led again to a mixture of 2a and 3a (entry 3). At lower temperature −70 °C for 0.5 h, a mixture of compound 3a and diastereomers of dimeric diketone 4a,b was obtained (entry 4). Prolongation of reaction till 3 h at −70 °C resulted in the formation of all three reaction products 2a, 3a and 4a,b (entry 5). These data reveal that compounds 3 and 4 are intermediate compounds in the synthesis of 2.
Michael addition product 3a and diketone 4a,b have very close chromatographic retention parameters. Thus, we were not able to individually isolate each of these substances by usual column chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was successful in getting these compounds. Diastereomers 4a,b may be discerned by NMR. purpose, an experiment using enynone 1a and malononitrile with an equivalent ratio 1:1 at room temperature for 1 h was done; under these conditions, compound 3a was obtained in a yield of 32% in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 °C led again to a mixture of 2a and 3a (entry 3). At lower temperature −70 °C for 0.5 h, a mixture of compound 3a and diastereomers of dimeric diketone 4a,b was obtained (entry 4). Prolongation of reaction till 3 h at −70 °C resulted in the formation of all three reaction products 2a, 3a and 4a,b (entry 5). These data reveal that compounds 3 and 4 are intermediate compounds in the synthesis of 2.
Michael addition product 3a and diketone 4a,b have very close chromatographic retention parameters. Thus, we were not able to individually isolate each of these substances by usual column chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was successful in getting these compounds. Diastereomers 4a,b may be discerned by NMR.  A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2.
14 Molecules 2020, 25 A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2. A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2.

15
Molecules 2020, 25 A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2.
According to NOESY correlations (see spectra in SI), the obtained cyclohexanes 2a-h have identical relative configurations: two acetylenic substituents are oriented to one side of the cyclohexane ring while hydroxy and carbonyl groups are directed to the other side ( Figure 2). In NOESY spectra, correlations between protons on one side of the cyclohexane ring are clearly observed. There are cross-peaks between H a and H b , H a and H d , H a and OH, H b and H d , H c and H e , H d and OH (Figure 2). NOESY correlations between protons on the opposite sides of the cyclohexane ring were not detected. This effect is caused by the fact that rotation around the cycle plane is limited. cyclohexane ring while hydroxy and carbonyl groups are directed to the other side ( Figure 2). In NOESY spectra, correlations between protons on one side of the cyclohexane ring are clearly observed. There are cross-peaks between H a and H b , H a and H d , H a and OH, H b and H d , H c and H e , H d and OH (Figure 2). NOESY correlations between protons on the opposite sides of the cyclohexane ring were not detected. This effect is caused by the fact that rotation around the cycle plane is limited.
There are some very specific signals of cyclohexane ring protons of 2 in 1 H NMR (Figure 2). Proton H a neighbor to CH2-group gives doublet of doublets in a range of 3.98-4.04 ppm in 1   The formation of cyclohexane 2 takes place at room temperature for 3 h at a ratio of starting enynone 1: malononitrile as 2:1 (Table 1, entries 1, 6-8, 10,11,13,14). The maximum yield of target cyclohexane 2a was reached in the reaction of diphenyl enynone 1a (entry 1). Enynones bearing one substituent in the aromatic ring at carbonyl group (1b, c) or in the aromatic ring at triple bond (1d, e, f) gave target cyclohexanes 2 in lower yields (entries 6-8, 10, 11). An even more dramatic decrease of reaction product yield was observed when there were two substituents in aromatic rings of enynones 1 g, h (entries 13,14). In the series of substituted enynones, yields of 2 were higher in cases of electrondonating substituents in aromatic rings of enynones 1b, d, f (entries 6,8,11). On the other hand, enynone 1i bearing a very strong acceptor nitro group gave rise to a complex mixture of reaction products (entry 15). An increase in reaction time until 7 h led to a substantial decreasing in yields of cyclohexanes 2 (compare pairs of entries 8 and 9, 11 and 12). This may be caused by the destruction of compounds 2 under the basic reaction conditions.
In some cases, acyclic compounds 3, as products of Michael addition of malononitrile to the double bond C=C of starting enynones 1, were detected in reaction products along with cyclohexanes 2 (entries 8, 10,11,14). Compounds 3 are intermediate structures laying on a way of formation of 2 from 1. We decided to find conditions for the preparation of compounds 3 in higher yields. For this The formation of cyclohexane 2 takes place at room temperature for 3 h at a ratio of starting enynone 1: malononitrile as 2:1 (Table 1, entries 1, 6-8, 10,11,13,14). The maximum yield of target cyclohexane 2a was reached in the reaction of diphenyl enynone 1a (entry 1). Enynones bearing one substituent in the aromatic ring at carbonyl group (1b, c) or in the aromatic ring at triple bond (1d, e, f) gave target cyclohexanes 2 in lower yields (entries 6-8, 10, 11). An even more dramatic decrease of reaction product yield was observed when there were two substituents in aromatic rings of enynones 1 g, h (entries 13,14). In the series of substituted enynones, yields of 2 were higher in cases of electron-donating substituents in aromatic rings of enynones 1b, d, f (entries 6,8,11). On the other hand, enynone 1i bearing a very strong acceptor nitro group gave rise to a complex mixture of reaction products (entry 15). An increase in reaction time until 7 h led to a substantial decreasing in yields of cyclohexanes 2 (compare pairs of entries 8 and 9, 11 and 12). This may be caused by the destruction of compounds 2 under the basic reaction conditions.
In some cases, acyclic compounds 3, as products of Michael addition of malononitrile to the double bond C=C of starting enynones 1, were detected in reaction products along with cyclohexanes 2 (entries 8, 10,11,14). Compounds 3 are intermediate structures laying on a way of formation of 2 from 1. We decided to find conditions for the preparation of compounds 3 in higher yields. For this purpose, an experiment using enynone 1a and malononitrile with an equivalent ratio 1:1 at room temperature for 1 h was done; under these conditions, compound 3a was obtained in a yield of 32% in a mixture with 2a (entry 2). Decrease of reaction temperature to −40 • C led again to a mixture of 2a and Michael addition product 3a and diketone 4a,b have very close chromatographic retention parameters. Thus, we were not able to individually isolate each of these substances by usual column chromatography on silica gel. However, preparative HPLC separation of 3a and 4a,b was successful in getting these compounds. Diastereomers 4a,b may be discerned by NMR.
A plausible reaction mechanism is presented in Scheme 2. The Michael addition of malononitrile anion to the carbon-carbon double bond of enynone 1 gives rise to anion A, which is isomerized into anion B. Aqueous work up at this reaction step affords compound 3. Anion B may react with one more molecule of 1 affording anion C, and this stage goes stereoselectively. Work up to at this stage provides compound 4. Cyclization of anion C into species D forms cyclohexane ring. This stage proceeds very stereoselectively, furnishing only one stereoisomer of 2. Finally, aqueous workup of anion D results in the formation of compound 2.  DFT calculations of relative energies of 8 enantiomeric pairs of compound 2a showed that the obtained isomer 2a had minimal energy. The difference in relative energies of diastereomers reaches up to 49 kJ/mol (see Supporting Information). In the most stable isomer, all the bulky substituents, except the OH group, take equatorial positions. There is an additional stabilization of the structure by hydrogen bonding between the carbonyl oxygen and a hydroxyl group (Figure 3). Additionally, photoluminescent properties of the obtained cyclohexanes 2 were investigated. It was found that upon excitation at 436-465 nm, maximums of emission were observed at 370-550 nm. Compound 2a having four phenyl rings, showed the maximum of emission at 365 nm upon the excitation at 446 nm, while compounds 2b, 2c, 2e, having substituted aromatic rings, revealed the maximums of emission at 520-550 nm upon the excitation at 436-465 nm (see details in SI). Quantum yields of photoluminescence for 2a, 2b and 2c were 1.36%, 4.95% and 2.81%, respectively. We suggested that quantum yields were low because of the flexibility of the saturated cyclohexane cycle. Cyclohexanes 2 have many degrees of freedom, and a significant part of the absorbed energy is spent on vibrations. This problem theoretically may be solved by coordination with a metal ion. Compounds 2 have several groups, CN, CO, OH, that are typical for aggregation-induced emissionbased sensors for low concentration toxic ion detection [30]. It may be a perspective direction for further research.

Conclusions
We developed a synthesis of multisubstituted polyfunctional cyclohexanes, bearing two cyano groups and two arylethynyl substituents, by the reaction of conjugated 1,5-diarylpent-1-en-4-yn-1ones with malononitrile in the presence of a strong base as LDA. This is a stereoselective dimerization leading to the formation of only one diastereomer of such cyclohexanes. Varying reaction conditions (ratio of starting compounds, reaction temperature and time), we were able to isolate some intermediate compounds laying on the reaction pathway to target cyclohexanes. That shed light on the proposed reaction mechanism. The obtained cyclohexanes were found to show photoluminescent properties.

Experimental Section
The NMR spectra of solutions of compounds in CDCl3 were recorded on Bruker AVANCE III 400 spectrometer [at 400, 100 and 61 MHz for 1 H, 13 C NMR spectra, respectively] at 25 °C. The solvent residual signals CDCl3 (δ 7.26 ppm) for 1 H NMR spectra, the carbon signal of CDCl3 (δ 77.0 ppm) for 13 C NMR spectra. IR spectra of compounds were taken with a Bruker spectrometer. HRMS was carried out on a Bruker maXis HRMS-ESI-QTOF instrument. Photoluminescence properties were measured on Fluorolog-3 (Horiba) spectrofluorimeter at room temperature. Steady-state measurements were performed using Xe-arc lamp (450 W) as an excitation source with slits spectral width of 3 nm. LED (370 nm, pulse duration of 1.2 ns) was used to carry out lifetime measurements. Quantum yield was obtained through the absolute technique using an integrating sphere (Quantaphi, 6 inches). The preparative reactions were monitored by thin-layer chromatography carried out on silica gel plates (Alugram SIL G/UV-254), using a UV light for detection. Preparative TLC was performed on silica gel Chemapol L 5/40, respectively. HPLC was done on a Waters machine using Additionally, photoluminescent properties of the obtained cyclohexanes 2 were investigated. It was found that upon excitation at 436-465 nm, maximums of emission were observed at 370-550 nm. Compound 2a having four phenyl rings, showed the maximum of emission at 365 nm upon the excitation at 446 nm, while compounds 2b, 2c, 2e, having substituted aromatic rings, revealed the maximums of emission at 520-550 nm upon the excitation at 436-465 nm (see details in SI). Quantum yields of photoluminescence for 2a, 2b and 2c were 1.36%, 4.95% and 2.81%, respectively. We suggested that quantum yields were low because of the flexibility of the saturated cyclohexane cycle. Cyclohexanes 2 have many degrees of freedom, and a significant part of the absorbed energy is spent on vibrations. This problem theoretically may be solved by coordination with a metal ion. Compounds 2 have several groups, CN, CO, OH, that are typical for aggregation-induced emission-based sensors for low concentration toxic ion detection [30]. It may be a perspective direction for further research.

Conclusions
We developed a synthesis of multisubstituted polyfunctional cyclohexanes, bearing two cyano groups and two arylethynyl substituents, by the reaction of conjugated 1,5-diarylpent-1-en-4-yn-1-ones with malononitrile in the presence of a strong base as LDA. This is a stereoselective dimerization leading to the formation of only one diastereomer of such cyclohexanes. Varying reaction conditions (ratio of starting compounds, reaction temperature and time), we were able to isolate some intermediate compounds laying on the reaction pathway to target cyclohexanes. That shed light on the proposed reaction mechanism. The obtained cyclohexanes were found to show photoluminescent properties.

Experimental Section
The NMR spectra of solutions of compounds in CDCl 3 were recorded on Bruker AVANCE III 400 spectrometer [at 400, 100 and 61 MHz for 1 H, 13 C NMR spectra, respectively] at 25 • C. The solvent residual signals CDCl 3 (δ 7.26 ppm) for 1 H NMR spectra, the carbon signal of CDCl 3 (δ 77.0 ppm) for 13 C NMR spectra. IR spectra of compounds were taken with a Bruker spectrometer. HRMS was carried out on a Bruker maXis HRMS-ESI-QTOF instrument. Photoluminescence properties were measured on Fluorolog-3 (Horiba) spectrofluorimeter at room temperature. Steady-state measurements were performed using Xe-arc lamp (450 W) as an excitation source with slits spectral width of 3 nm. LED (370 nm, pulse duration of 1.2 ns) was used to carry out lifetime measurements. Quantum yield was obtained through the absolute technique using an integrating sphere (Quanta-phi, 6 inches). The preparative reactions were monitored by thin-layer chromatography carried out on silica gel plates (Alugram SIL G/UV-254), using a UV light for detection. Preparative TLC was performed on silica gel Chemapol L 5/40, respectively. HPLC was done on a Waters machine using gradient elution with acetonitrile-water mixtures.

DFT Calculations
All computations were carried out at the DFT/HF hybrid level of theory using hybrid exchange functional M06 by using GAUSSIAN 2009 program packages [33]. The geometries optimization was performed using the M06/6-311+G(2d,2p) basis set (standard 6-311 basis set added with polarization (d, p) and diffuse functions) using water as a solvent. Optimizations were performed on all degrees of freedom, and solvent-phase optimized structures were verified as true minima with no imaginary frequencies. The Hessian matrix was calculated analytically for the optimized structures in order to prove the location of the correct minima and to estimate the thermodynamic parameters. Solvent-phase calculations used the polarizable continuum model (PCM).