Computational Study on the Acid Catalyzed Reactions of Fluorine-containing 2,4-dialkoxy-3,4-dihydro-2h-pyrans with Aromatic Compounds

The reaction of

As we proposed in our previous report [16], the selective formation of dihydropyrans (2) from 1 and of butadiene derivatives (6) from 5 could be explained by the kinetically controlled reactions of pyrylium (7a) at C-4 and the thermodynamically controlled reaction of 7b at C-6, respectively (Figure 1).Such pyryliums (7a,b) are assumed to form easily from 1 and 5 in the strong acid, trifluoroacetic acid.Moreover, the unexpected formation of 7a in the course of the reaction of dihydropyran (1) giving 4H-pyrans (3) and butadiene derivatives (4) is also figured out under weaker acidic conditions such as the presence of catalytic p-toluenesulfonic acid in refluxing acetonitrile.In this case, it is probable that 3 and 4 are directly derived from 4-cation (8a) and 6-cation (9a), respectively, which are the precursors of pyrylium (7a).Here we wish to report our DFT calculation study for these acid catalyzed reactions of dihydropyrans, 1 and 5, with aromatic compounds.The mechanisms giving 4H-pyrans (3) and 1,3-butadienes (4) from 1 in the presence of p-toluenesulfonic acid catalyst were elucidated by making use of benzene as a model of aromatic compounds.Additionally, the pathways via cations, 8a and 9b, for the reactions of 1 and 5 in trifluoroacetic acid giving dihydropyrans (2) and 1,3-butadienes (6), respectively, were also examined to support the proposed mechanisms via pyryliums [16] further.

Computational Method
All calculations employed in this paper were accomplished by making use of the computer programs packages PC SPARTAN 02 and PC SPARTAN 04 [17].All calculations for geometrical optimizations were performed with the 6-31G* basis set at B3LYP level [18].The starting geometries employed for all optimizations were resulted from molecular mechanics using SYBYL [19] force field and subsequent semi-empirical PM3 [20] optimizations.The calculations for transition state geometries and their energies were also taken with the 6-31G* basis set at B3LYP level.

Results and Discussion
In trifluoroacetic acid, pyryliums (7a,b) are assumed to form from 1 and 5 via 4-cations (8a,b) or 6-cations (9a,b) as illustrated in Scheme 2. As we proposed in previous report [16], the selective formation of dihydropyrans ( 2) from 1 and of butadiene derivatives (6) from 5 could be reasonably explained by the kinetically controlled reaction of pyrylium (7a) with aromatic compounds giving the precursor, 4H-pyrans (3) and the thermodynamically controlled reaction of 7b with aromatic compounds affording the intermediate, 2H-pyrans (10) Meanwhile, the formation of pyrylium (7a) was hardly considered to occur in the reaction of dihydropyran (1) with aromatic compounds giving 4H-pyrans (3) and butadiene derivatives (4) under weaker acidic conditions such as the presence of catalytic p-toluenesulfonic acid in acetonitrile.In this case, the alternative pathways in which 3 and 4 are directly derived from 4-cation (8a) and 6-cation (9a), respectively, are possible.We figured out the optimized structures of 8a and 9a using RB3LYP/6-31G* as depicted in Figure 2 together with the result for dihydropyran (2) to confirm these reaction pathways.
The results exhibit that 4-cation (8a) is ca.21 kcal/mol more stable than 6-cation (9a).This value accounts for the exclusive formation of 8a in the presence of acid catalyst, which suggest that 1,3-butadienes (4) are not derived from 9a.On the other hand, the reaction of 8a with aromatic compounds giving 2 followed by the elimination of ethanol from 2 can afford 4H-pyrans (3).According to the energy value for 2 (Ar = Ph) and our previous calculation results for 3 (Ar = Ph) [16,21], the latter elimination process from 2 to 3 is estimated to be an endothermic step with ca.27 kcal/mol, which would negatively affect the conversion of 2 to 3 even if the reaction is carried out in refluxing acetonitrile.Though the de-ethanolization on 4-cation (8a) giving pyrylium (7a) [22] is also computed to be an endothermic process, the required external energy is no more than 11.3 kcal/mol.It means this elimination reaction is presumed to proceed readily in refluxing acetonitrile.Therefore, the above results strongly suggest the formation of 1,3-butadienes (4) and 4H-pyrans (3) via pyrylium (7a).The conversion from 1 to pyrylium (7a) is noteworthy in spite of the conditions using only a catalytic amount of p-toluenesulfonic acid.As is described in previous report [16], the kinetically controlled reaction of 7a with aromatic compounds is predicted to proceed selectively at C-4 to give 4H-pyrans (3) because the frontier electron density (LUMO of 7a) at C-4 is considerably larger than that at C-6 [23].In contrast, the energy of 4H-pyrans (3) is very close to 2H-pyrans (11) [24] which are the precursors of 1,3butadienes (4) shown in Figure 2 to attribute the preparation of both 3 and 11 to the thermodynamically controlled reaction of 7a with aromatic compounds.Relatively high temperature (the temperature of refluxing acetonitrile) required for the reaction of 1 giving 3 and 4 is consistent with the thermodynamically controlled reaction of pyrylium (7a) with aromatic compounds.
Next, we estimated the activation energy for the ring-opening process from 2H-pyrans (11) resulted by the reaction of pyrylium (7a) with aromatic compounds at 6-position (Figure 3).The optimized transition state structure (TS11; Ar = Ph) [25] and the most stable structure of 4 (Ar = Ph) are illustrated together with their energies.The energy difference between 11 (Ar = Ph) [16] and TS11 (Ar = Ph) is estimated to be ca.15 kcal/mol, which corresponds to the activation energy of this process.The (E,Z)-dienes (4') given by ring-opening of 11 readily isomerize to thermodynamically more stable (E,E)-dienes (4) via protonation and deprotonation processes (Figure 3).The dienes 4' (Ar = Ph) and 4 (Ar = Ph) are calculated to be ca.8 kcal/mol and ca. 9 kcal/mol more stable than 11 (Ar = Ph), respectively.The above results suggest that the irreversible ring-opening of the intermediates (11) will easily occur at acetonitrile reflux temperature to afford 4. Figure 3. Ring-opening process from 2H-pyrans (11) to (E,E)-dienes (4).In addition, we examined the process from 4-cation (8a) to pyrylium (7a) to support the mechanism presented in our previous report [16] for the reaction of dihydropyran (1) with aromatic compounds in trifluoroacetic acid at ambient temperature giving dihydro-4H-pyrans (2) solely (Scheme 1).As is mentioned before, this elimination is an endothermic reaction requiring the external energy of 11.3 kcal/mol [22].Therefore, this result predicts that the reaction of the first intermediate, 4-cation (8a), with aromatic compounds directly affording dihydro-4H-pyrans (2) have precedence over the course via 4H-pyrans (3) comprised of the reaction of pyrylium (7a) with aromatic compounds given that the dihydropyran (1) would undergo the reaction at ambient temperature.Even though 4H-pyrans (3) was given by the p-toluenesulfonic acid catalyzed reaction, the reaction of 1 carried out in trifluoroacetic acid with aromatic compounds [6] resulted in the failure of the formation of 3.These experimental evidences provide us with compatible conclusion as to the above calculated prediction.
Finally, we examined the reaction of dihydropyran (5) with aromatic compounds giving butadiene derivatives (6) shown in Scheme 1.As for this reaction, an alternative pathway including the reaction of 6-cation (9b) with aromatic compounds directly affording 2H-pyrans (10) is possible in addition to the pathway via pyrylium (7b) illustrated in Scheme 2. To elucidate such alternative pathway, we considered as to figuring out dihydropyran (5), 4-cation (8b), and 6-cation (9b).The results are summarized in Figure 4.  Based on the energy values for 5, 8b, and 9b, the ionization process from 5 to 6-cation (9b) is estimated to require ca.20 kcal/mol more energy [26] compared with such ionization to 4-cation (8b).The exclusive formation of 8b from 5 in trifluoroacetic acid is attributed to this value.Hence, the reaction of 5 with aromatic compounds giving 6 does not proceed along the pathway via 9b.In other words, butadiene derivatives (6) are assumed to be derived from pyrylium (7b) which formed via 4-cation (8b) along the pathway shown in Scheme 2 as we reported previously [16,27].This de-alcoholization step from 8b to 7b is an endothermic process, however the required external energy no more than 13 kcal/mol suggests that 8b is easily converted to 7b in refluxing trifluoroacetic acid.
The proposed most reasonable and interesting mechanisms based on our DFT calculations for the acid catalyzed reactions of dihydropyrans (1 and 5) with aromatic compounds are summarized in Scheme 3.

Conclusions
On the basis of DFT calculation results, we have achieved a comprehensive explanation regarding the mechanisms for the reactions of dihydropyran (1) with aromatic compounds under different acidic reaction conditions.The reaction in the presence of p-toluenesulfonic acid giving 4H-pyrans (3) and butadiene derivatives (4) proceeding in refluxing acetonitrile is reasonably explained by the thermodynamically controlled reaction of pyrylium (7a) with aromatic compounds.Meanwhile, the reaction in trifluoroacetic acid affording dihydropyrans (2) at ambient temperature can be interpreted as a result of the reaction of 4-cation (8a) with aromatic compounds.Our study also illustrated the selective formation of butadiene derivatives (6) from dihydropyran (5) by the reaction in refluxing trifluoroacetic acid in which the thermodynamically controlled attack of aromatic compounds to pyrylium (7b) was comprised.

Scheme 3 .
Proposed most reasonable mechanisms for the acid catalyzed reactions of dihydropyrans (1 and 5) with aromatic compounds.