Among the various pericyclic reactions of heterocyclic compounds, thermal and photoinduced ring opening reactions of spirocyclic compounds, derivatives of spiropyrans and spiro-1,4-oxazines hold a special place. Such reactions define the intramolecular isomerization processes of these bistable compounds, leading to substantial structural changes and switching their physicochemical properties.1 – 3 The key step of these reactions involves cleavage of the relatively weak Cspiro–O bond, followed by conformational changes, generally resulting in opening of pyran ring of the chromene system and the formation of colored isomers with conjugated merocyanine structure. Depending on the structure of the latter, these reactions may be thermally or photochemically reversible. The described properties (bistability) of spirocyclic compounds opens broad possibilities for their applications as optical switches,4 chemosensors,5 – 8 materials for molecular electronics,9 – 11 regulators and markers for enzyme reactions and other dynamic biological processes.12 – 14 Mechanistic study of ring opening reactions in spirocyclic compounds is highly important, as it provides basis for rational design of new thermo- and photochromic compounds and expanding the areas of their practical application.

Despite the relatively long history of experimental and theoretical studies regarding spiropyrans and spirooxazines,15 – 31 many mechanistic details of processes occurring during the conversion of cyclic form to the open merocyanine form both in the ground state and, especially, in the excited states remain unknown. Furthermore, the computational studies in this direction were performed either with model compounds containing isolated fragments of the actual molecules,21 , 22 or, in the majority of cases, with spirobenzopyrans and spirobenzoxazines of indoline series.23 – 31

In the current work, we relied on the density functional theory (DFT), using PBE0 hybrid functional and 6-311+G(d,p) basis set to study thermal ring opening reactions in a wide range of spiropyrans 1–9 and spirooxazines 10–15 with various heterocyclic and 2H-chromene ring systems (Fig. 1) in order to establish the dependence of mechanism and activation parameters of these reactions on the structure of spiroheterocycles, as well as the position and electronic properties of substituents (using the examples of spiro-benzopyrans 1a–c and spironaphthopyrans 2a–c).

Figure 1
figure 1

The structures of studied spiropyrans 1–9 and spirooxazines 10–15.

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The obtained results are expected to provide an opportunity not only to establish mechanistic features of thermal opening reactions of spiropyrans and spirooxazines, but also will serve as the basis for further studies of photophysical and photochemical mechanisms of photochromic transformations in these systems. The energy profiles of the studied reactions on the potential energy surfaces of ground and excited states will provide the most complete mechanistic understanding of these highly important photoinitiated processes and will allow to establish certain structure–activity relationships, indicating the best approaches to the synthesis of desired products.

Calculated energetic characteristics of stationary points on the thermal ring opening reaction pathways of the studied compounds are shown in Table 1 and Figures 2–6.

Table 1 The relative energies (E, kcal/mol) with zero-point energy correction (ZPE) of the structures, corresponding to local minima and transition states (TS) on the routes of ring opening reactions of spiropyrans 1–9 and spirooxazines 10–15, according to PBE0/6-311+G(d,p) calculations in gas phase
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Figure 2
figure 2

The energy profiles of ring opening reactions in Sp-c isomer of spirobenzopyrans 1a–c and spironaphthopyrans 2a–c, according to the data of PBE0/6-311+G(d,p) calculations.

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Figure 3
figure 3

The energy profiles of ring opening reactions in Sp-c isomers of spiropyrans 1a, 2a and spirooxazines 10, 11, 13 according to the data of PBE0/6-311+G(d,p) calculations.

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Figure 4
figure 4

The energy profiles of ring opening reactions in Sp-c isomers of spirooxazines 11–15 according to the data of PBE0/6-311+G(d,p) calculations.

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Figure 5
figure 5

The energy profiles of ring opening reactions of isomers Sp-c of spiropyrans 1a, 6, 7, according to the data of PBE0/6-311+G(d,p) calculations.

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Figure 6
figure 6

The energy profiles of ring opening reactions of isomers Sp-c of spiropyrans 1a, 3, 4, 8, 9, according to the data of PBE0/6-311+G(d,p) calculations.

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As previously established by us26 and later confirmed by other authors,28 the structural flexibility of cyclic spiropyran and spirooxazine isomers, associated with slight conformational changes in the chromene or 1,4-benzoxazine rings (Scheme 1, Het – heterocyclic system) creates two reaction pathways on the potential energy surface for thermal ring opening reactions in these systems. Depending on the initial configuration of the cyclic isomer (Sp-c or Sp-t), the reaction may result in the formation of merocyanine isomers of the starting spirocyclic structures – CTC (cis-trans-cis) or TTC (trans-trans-cis) (Scheme 1).

scheme 1

Scheme 1

The calculated bending angles in the chromene system of cyclic isomers of the studied compounds varied from 149.4° for isomer Sp-t of spiropyran 4 to 169.8° for the analogous isomer of spiropyran 1b. The results of computational modeling showed that the form Sp-c was preferable, except in the case of spiropyrans 2c, 3, 4, 6, 8, 9 and spirooxazine 10. Both cyclic isomers (Sp-c and Sp-t) of spiropyran 5 were a pair of enantiomers, while the respective merocyanines (CTC and TTC) were identical.

The local minima on potential energy surface corresponding to the structures of conformational isomers Sp-c and Sp-t were located at a relatively flattened region, while the relative energy values of these minima were very small (Table 1). Due to the flattened potential energy surface in the vicinity of the cyclic isomers, only one of the possible cyclic forms could be localized for spiropyrans 3, 4, 6–9. Nevertheless, the cleavage of Cspiro–O bond in spiropyran or spirooxazine according to one or the other reaction pathway in any case was preceded by the respective structural transformations of pyran or oxazine ring.

The main common feature of the described reactions was that they occurred in two steps. The first step involved cleavage of Cspiro–O bond, followed by cis-trans isomerization in the second step, associated with rotation of the chromene moiety relative to the central bond of =CH–X= motif (Scheme 1). The potential energy surface regions corresponding to these reaction stages, as a rule, were separated by a flattened area even in the case when the intermediate minimum could not be located in this region (for example, for the benzimidazole spiropyran 5).

Another common feature of the investigated processes was linked to the very low activation energy barriers to the recyclization of cisoid intermediates CCC and TCC (Scheme 1, Table 1). For the thermodynamically and kinetically more stable CCC isomers, the activation energy barriers of the reverse reaction did not exceed 3.8 kcal/mol, while for the majority of TCC isomers (except for the spiropyran 8) the energy barriers were much lower. Furthermore, for spiropyrans 1a,b, 2b, 5, 6 and the spirooxazine 10 the TCC structures could not be located on the potential energy surface. All these facts mean that the cisoid isomers (CCC, TCC) would practically never accumulate during the reaction, and the two-stage process must be kinetically similar to a single-stage reaction. Thus, it is pointless to attempt to identify the limiting, i.e., the slowest stage of the investigated reactions, since the reaction rate will be quite accurately determined by the sum of activation barriers for Cspiro–O bond cleavage and cis-trans isomerization.

By studying the reaction mechanisms of ring opening in unsubstituted and substituted derivatives of spiropyrans and spirooxazines 1a–c and 2a–c containing electron-donating and electron-withdrawing substituents (Fig. 2), we established some correlation between the activation energy barriers of the first and second stage of this reaction.

In those cases when the cleavage of Cspiro–O bond required overcoming a relatively high energy barrier, the subsequent step as a rule had lower activation energy parameters. The main reason determining such energy profile of the investigated reactions was the partial rotation of one moiety of the spiropyran or spirooxazine molecule relative to the other during the stretching and cleavage of Cspiro–O bond.

The high activation energy barrier for bond cleavage corresponded to longer Cspiro–O distance and larger torsion angle between the parts of molecule in the transition state and the intermediate structures. Besides that, an increase of torsion angle can be linked to substantial repulsion between the chromene and heterocyclic moieties in the cisoid intermediate, caused by the presence of bulky substituents in these moieties. Some examples of such systems include the TCC isomers of spiropyrans 1a–c, 2a–c, 6 and spirooxazines 10–15.

Thus, in this case the heterocyclic (Het) and chromene (benzoxazine) parts of the molecules are already sufficiently rotated one relative to the other and provide for the low energy barrier to the subsequent cis-trans isomerization. On the other hand, the cleavage of Cspiro–O bond with low energy barrier occurred at smaller torsion angles between the parts of the molecules. At the same time, in the absence of steric hindrance the possibility arised for effective conjugation between the =CH–X= moiety (Scheme 1) and the π-electron system of the rest of the molecule, resulting in a double bond character in the central part of this motif. This, in turn, led to increased activation energy of the cis-trans isomerization process.

According to the results of calculations (Table 1, Fig. 2), the introduction of electron-donating methoxy substituent in the heterocyclic (Het) part of the molecule and electron-withdrawing nitro substituent in the 2H-chromene part of compounds 1a and 2a (Scheme 1) led to lower activation energy barriers for the cleavage of Cspiro–O bond by 5.8 and 3.2 kcal/mol, respectively. At the same time, the energy barriers to cis-trans isomerization increased by 6.7 and 4.1 kcal/mol (the energy profiles for compounds 1b and 2b are given in Fig. 2). The structures corresponding to intermediates CCC showed a shortening of the central bond in =CH–X= moiety (with X = CH) from 1.393 to 1.376 Å (compounds 1a–c) and from 1.400 to 1.388 Å (compounds 2a–c), indicating enhanced conjugation in this part of the molecule. On the other hand, when the positions of substituents in these systems were switched to the opposite (curves 1c, 2c, Fig. 2), the activation energy barrier for the bond cleavage was increased by 10.2 and 6 kcal/mol, and the energy barrier of the subsequent isomerization step decreased by 9.7 and 4.1 kcal/mol. The opposite effect was also observed as changes of bond lengths in the =CH–X= moieties.

The substituent effect was much more pronounced in the spirobenzopyran system of compound 1a, compared to the spironaphthopyran system of compound 2a. The possible reason for such result is associated with the fact that the extended π-electron system in these compounds allows for partial compensation of structural changes in the molecule via effective redistribution of electron density.

Indeed, according to computer modeling data, the stepwise expansion of π-electron system of the 2H-chromene moiety in the series of spiropyrans 1a, 2a and spirooxazines 10, 11, 13 leads to lowering of activation energy barriers both at the stage of Cspiro–O bond cleavage and the subsequent cis-trans isomerization (Fig. 3). The calculated changes of energy barrier at the first stage of the reaction were 3.4 kcal/mol in spiropyran series, as well as 4.0 and 1.7 kcal/mol in spirooxazine series. The energy barriers to cis-trans isomerization decreased by 1.7 kcal/mol in spiropyran series, as well as by 3.7 and 1.8 kcal/mol in spirooxazine series.

The change from benzene ring to thiophene in the heterocyclic part (Het) of spirooxazine 11 molecule (curve 12, Fig. 4) and aza-substitution in the chromene system of spirooxazine 13 (curves 14, 15) only insignificantly changed the activation parameters of reaction.

In comparison to spiropyrans, derivatives of spirooxazines were generally characterized by higher activation energy values at each step of thermal electrocyclization reaction. This result can be linked to some degree of shortening and, therefore, increased strength of the Cspiro–O bond in spirooxazine ring compared to the analogous spiropyrans.

Based on the obtained results, we can formulate conclusions about the effect of various heterocyclic (Het) and 2H-chromene (benzoxazine) groups with different electron-donating or electron-withdrawing properties in molecules of spiropyrans and spirooxazines, which affect the energy profile of the considered electrocyclic reactions. It was established that changing from benzochromene system in an indoline type spiropyran to coumarin system with stronger electron-withdrawing properties lowered the energy barrier of Cspiro–O bond cleavage by 5 kcal/mol (curve 6, Fig. 5). At the same time, the change of indoline part in compound 6 to a more electron-withdrawing benzochromene system (curve 7, Fig. 5) largely cancelled the effect of previous structural modification.

On the other hand, the change of indoline system in the heterocyclic part of compound 1a to the more electron-withdrawing isobenzofuran and benzoxazine systems (curves 8, 9, Fig. 6) noticeably increased the energy barrier to the cleavage of Cspiro–O bond (by 5.5 and 7.6 kcal/mol, respectively), while the benzoxazole and benzothiazole analogs of compound 1a (curves 3, 4, Fig. 6) had lower activation energy values (by 0.6 and 1.3 kcal/mol, respectively) at this stage of the reaction. For the subsequent cis-trans isomerization of CCC isomers of compounds 3, 4, 8, 9 the energy barriers were higher by 4.2 and 3.4 kcal/mol for spiropyrans 3, 4 and lower by 4.8 and 2.0 kcal/mol for compounds 8, 9. Qualitatively similar results were obtained by variation of substituents with different properties in the series of benzo- and naphthopyrans 1 and 2 (Fig. 1).

In conclusion, it should be noted that the steric factors associated with the presence of bulky substituents in the heterocyclic (Het) and (or) 2H-chromene (1,4-benzoxazine) systems of spiropyrans and spirooxazines, which interfere with the stabilization of cisoid intermediates, largely prevail over the effect of electronic factors at some stages of the reactions. For example, the ring opening in Sp-t isomers of spiropyrans and spirooxazines belonging to indoline series, having two methyl groups in the chromene part that create steric obstacles to the formation of intermediates TCC, often proceeds as a single-step process with a relatively high energy barrier, combining the cleavage of Cspiro–O bond and cis-trans isomerization (Table 1).

Based on the results of our study, we have reached the following general conclusions. Electrocyclic ring opening reaction in spiropyrans and spirooxazines occurs by two routes, as a consequence of structural flexibility in the 2H-chromene (1,4-benzoxazine) system in the spirocyclic form of these compounds, leading to the existence of conformational isomers with similar energy. The reaction proceeds in two stages: dissociation of Cspiro–O bond and cis-trans isomerization of the first intermediate, but its kinetics are similar to a single-stage process, due to the very low energy barriers to recyclization of cisoid intermediates. Increasing the electron-donating properties of the heterocyclic part and the electron-withdrawing properties of the 2H-chromene (1,4-benzoxazine) part decreased the activation energy barrier to the cleavage of Cspiro–O bond and simultaneously increased the barrier to the subsequent isomerization through stronger conjugation in the =CH–X= moiety (X = CH, N) of cisoid intermediates with the π-electron system of the rest of the merocyanine molecule. The extended π-electron systems of chromene and benzoxazine rings in spiropyrans and spirooxazines, respectively, had lower activation barriers for both reaction stages due to the ring fusion and suppressed the influence of the substituents. The steric obstacles to the formation of cisoid intermediates on the reaction pathway of spiropyran and spirooxazine ring opening led to the combination of Cspiro–O bond cleavage and cis-trans isomerization steps in one process. The activation barriers to thermal isomerization of spirooxazines, as a rule, were higher than the respective barriers for structurally analogous spiropyrans.

Computational modeling. The mechanistic pathways of 2H-pyran and 2H-1,4-benzoxazine ring opening in the series of spiropyran and spirooxazine derivatives 1–15 were studied by DFT calculations using GAUSSIAN 09 software suite.32 The PBE0 hybrid functional33 and 6-311+G(d,p) basis set were used in the calculations. The nature of identified stationary points on the reaction routes was confirmed by calculation of the intrinsic Hessian matrix values.