3.2.1. Cannabinoid Structures
To avoid confusion, the structures of all relevant cannabinoids are shown in
Figure 1 and shortly discussed below.
The structures of Δ
9-CBD, Δ
8-CBD, Δ
9-THC, and Δ
8-THC have been extensively discussed before [
6] and originate from CD calculations, as described in the Materials and Methods section. To clarify the discussion, the positions of the carbon atoms C8, C9, and C10 are indicated in Δ
9-CBD. For readers who appreciate the more classical representation of the structures in 2D, Golombek et al., [
2] provide a good overview of all structures in their Figure 4 and a complete numbering of all C-atoms in their Figure 1. Because the C
5 alkyl side chain is not directly important for the ring closure and isomerization reactions of the cannabinoids, a smaller cannabinoid model with a methyl group as the side chain was chosen to reduce the very high number of possible conformers. The same approach was adopted for iso THC, using a model in which the C
5 chain was reduced to a methyl group too. Like Δ
9-THC and Δ
8-THC, the conformational freedom of iso THC is restricted by the ring closure of the phenolic group to the C9 of the (former) cyclohexenyl substituent and shows only 13 conformers, all of them with the newly formed cyclohexane ring in a chair position with three axial substituents: the C-C(Ar)-, the C-O(Ar)-, and the isopropenyl substituent. Only the C-CH
3 at the C9 position is in an equatorial position. The main differences between the conformers are in the position of the remaining phenolic group and the orientation of the isopropenyl substituent. The best conformer, which is in this case the most abundant and lowest energy conformer, accounts for 84.6% of the Boltzmann weights, and the second-best conformer, showing a phenol group pointing to the isopropenyl cyclohexane substituent, accounts for 6.6% of the Boltzmann weights.
3.2.2. The Conversion of Δ9-CBD to Δ8-THC, with pTSA as Brønsted Acid Catalyst
The conversion of Δ9-CBD to Δ8-THC, with pTSA as Brønsted acid catalyst, requires two steps: ring closure and isomerization of the double bond from the Δ9 to the Δ8-position. The order of the two reactions is not clear in advance, so both options will be investigated. For both cases firstly the ring closure reactions will be discussed and next the isomerization reactions. A choice between the options will be made in
Section 3.2.4. Kinetic models: comparison of computational and experimental results.
Ring Closure of Δ9-CBD to Δ9-THC and Δ8-CBD to Δ8-THC Catalyzed by pTSA
Ring closure reactions catalyzed by pTSA are quite rare. A recent example can be found in the pTSA condensation polymerization of dicarboxylic acids and polyols like sorbitol, where it appears as a side reaction on a secondary carbon atom [
20]. Ring closure by a phenol on a tertiary carbon seems possible only because of the intramolecular presence of the phenolic group, the absence of more suitable nucleophiles, and activation of the alkene by pTSA. These conditions are fulfilled by the reaction conditions described above; dry pTSA is used as a catalyst in refluxing toluene.
Figure 2 shows details of the transition states of the ring closure of Δ
9-CBD to Δ
9-THC and Δ
8-CBD to Δ
8-THC catalyzed by pTSA. The corresponding starting complexes are not shown but can be easily imagined from the transition states. The main difference is in the position of the proton on pTSA. In the starting complexes, the H-OSO
2Ar-pCH
3 distance is ~0.990 Å and the H
2C-HOSO
2Ar-pCH
3 distance is ~2.25 Å.
The two transition states look very similar. There is almost complete proton transfer from pTSA to the CH2 of the isopropenyl group; the CH2–HOSO2Ar–pCH3 distance is 1.237 Å and 1.212 Å. This is also visible from the reduced electron density plot (electron density = 0.08 e/au3). Such a plot provides a good indication of the character of the chemical bond. The more visible the electron density, the more covalent the character of the chemical bond, while the absence of electron density indicates a more ionic character. The blue color (positive electrostatic potential) indicates that the transferred particle is a proton. The phenolic O-atom is poised to form a C–O bond with the tertiary C of the isopropenyl group despite the relative long distance between them, which is 2.758 Å and 3.204 Å. The electrostatic potentials on the reduced electron density surface of the tertiary Cs are +1594 and +1544 kJ/mol, which is a clear indication of their carbocation character. Animation of both imaginary frequencies show the right movement of all atoms involved. The H-atom of the phenol group is H-bridged to an O-atom of pTSA with distances of 1.723 Å and 1.746 Å. The activation barriers are 70.5 and 57.5 kJ/mol, the latter of which is a reflection of the relative stability of Δ9-CBD compared to Δ8-CBD, which is 11.8 kJ/mol in favor of Δ9-CBD.
Isomerization of Δ9-CBD to Δ8-CBD and Δ9-THC to Δ8-THC by pTSA
For the isomerization reaction, two mechanisms were considered:
- (a)
a concerted process with simultaneous proton transfers from pTSA to C10 and C8 to pTSA; and
- (b)
a two-step process, starting with proton transfer from pTSA to C10, followed by proton transfer from C8 to pTSA.
These mechanistic proposals for acid-catalyzed isomerization are not new but go back to 1932 [
21,
22], and evidence has been obtained for both cases, depending on specific reaction conditions and catalysts.
Figure 3 shows the details of the transition states of the concerted and two-step processes of the isomerization of Δ
9-CBD to Δ
8-CBD with pTSA.
On first sight, the two transition states look very similar; however, their appearances are deceptive. In the concerted process, proton transfer from pCH3ArSO3H to C10 is almost complete with an SO–H distance of 1.911 Å and a C10–H distance of 1.126 Å, while the SO–HC8 distance is 1.720 Å and the C8–H distance is 1.169 Å. In the two-step process, proton transfer from pCH3ArSO3H to C10 is less complete with an SO–H distance of 1.621 Å and a C10–H distance of 1.199 Å. Note that in this case, the SO–H C8 distance is 2.175 Å and the C8–H distance is 1.112 Å, also quite different from the concerted case. Once again, the imaginary frequencies are low, and the one for the two-step process is even very low, but it shows the correct movement in both cases. The activation barriers are 75.3 and 67.2 kJ/mol. The two-step process is clearly favored over the concerted process. The starting complex for both processes is the same. The activation barriers for the reverse process, the isomerization of Δ8->Δ9 CBD, show significantly higher activation barriers of 93.4 and 81.8 kJ/mol. The reason for that is the higher stabilization enthalpy of the starting complex caused by the H-bridge of the phenol group of Δ8 CBD to an O=S of pTSA, compared to the H-bridge of that phenol group of Δ9 CBD to an HO–S of pTSA.
For the isomerization of Δ9 THC and Δ8 THC again the two previous mentioned options were considered. However, it turned out that for the concerted option, only a true transition state could be established, despite many attempts to locate a transition state for the two-step process. These attempts either led to the transition state of the concerted process or to non-converged structures, which can be described best as intimate ion pairs consisting of the THC C9 cation and the pTSA anion with no imaginary frequency left and a total energy of 1–3 kJ/mol higher than the energy of the transition state of the concerted process. In the concerted process, proton transfer from pCH3ArSO3H to C10 is almost complete with an SO–H distance of 1.836 Å and a C10–H distance of 1.146 Å, while the SO–H C8 distance is 1.755 Å and the C8–H distance is 1.162 Å. The imaginary frequency is i152 cm−1 and its animation shows the correct movement of the proton transfers and the corresponding skeletal adaptation. The activation barriers for the TS Δ9->Δ8 THC and Δ8->Δ9 THC are 95.7 and 103.9 kJ/mol, reflecting the relative stabilities of Δ9 and Δ8 THC.
3.2.3. The Conversion of Δ9-CBD to Δ8-THC, with BF3·Et2O as Lewis Acid Catalyst
Although BF
3·Et
2O is a well-known catalyst, it is difficult to find examples in which either the ring closure of an O-nucleophile or alkene isomerization is described. Closest to the actual BF
3·Et
2O-catalyzed ring closure reactions are the inverse reactions, the B(C
6F
5)
3-catalyzed ring opening of a 2,2-disubstituted oxetane to a homoallylic alcohol and the BF
3·Et
2O catalyzed decomposition of a t-butyldimethylsilyl ether originating from a tertiary alcohol [
23,
24]. The latter is close to Example 2 from Webster et al. [
8,
9], as described in 3.1 Experimental Results. In 2022, an example of alkene isomerization with B(C
6F
5)
3 was published, including a mechanistic description [
25]. They found experimental and computational evidence that the isomerization of 2-propenyl benzene occurs via direct hydride abstraction by B(C
6F
5)
3 leading to a mixed allylic-benzylic carbenium ion and a 1,2-hydride shift to the terminal alkene-B(C
6F
5)
3 complex. They used the M06-2X DFT functional with an extended basis set and a solvation model. Unfortunately, the computational data are not available in their
Supplementary Materials. Attempts to locate similar transition states with BF
3 using either the M06-2X or the B3LYP functional were not successful.
Because electron-deficient BF
3 wants to interact with electron rich systems, the complexation of BF
3 with the alkene and phenol groups of Δ
9 CBD was investigated to obtain an impression of the complexation energy. Results are listed in
Table 1. As a reference, BF
3·Et
2O is listed too.
From
Table 1, it is clear that complexation of BF
3 with a phenol group is favored over complexation with alkenes like the 2-propenyl substituent on the cyclohexene ring, the cyclohexenyl double bond or ethers like in BF
3·Et
2O, BF
3·Δ
9 THC, and BF
3·iso THC. It was observed that complexation of BF
3 with the cyclohexenyl double bond is particularly unfavorable due to steric hindrance of the methyl and 2-propenyl groups on the cyclohexenyl ring. Furthermore, complexation of BF3 with diethyl ether or pyran ethers in the products leads to similar interaction energies. Finally, it was realized that complexation of the Lewis acid BF
3 with a phenol transforms the weakly acidic phenol into a strong Brønsted acid.
Figure 4 shows the simple BF
3·phenol complex with an electron density plot (electron density = 0.002 e/au
3). The latter coincides with the classical vanderWaals size of molecules. On the surface, the electrostatic potential is plotted. There is a clear blue spot on the surface of the phenolic group, which is indicative of a positive electrostatic potential and related Brønsted acidity. The maximum electrostatic potential (MEP) shows a value of +314.7 kJ/mol. Using an earlier derived linear relation [
26] between MEP and pK
a yielded −2.17 as an estimate for the pK
a of the BF
3·phenol complex, which is more acidic than pTSA (MEP = +261.6 kJ/mol); pK
a = −1.34) and slightly less acidic than H
2SO
4 (MEP = +327.0 kJ/mol; pK
a = −2.49).
Thus, reactions starting from a BF
3-phenolic cannabinoid complex were investigated.
Figure 5 shows the details of the transition states of the ring closure to Δ
9-THC and iso THC.
Both transition states show nearly complete proton transfer from the phenol to the CH2 of the 2-propenyl substituent and C8 of the cyclohexenyl substituent. Their O–H, H2–H and O–H, OH–C8 distances are 1.850 Å, 1.142 Å and 1.743 Å, 1.157 Å, and their activation barriers are 80.9 and 82.1 kJ/mol, respectively. The animation of their imaginary frequencies clearly shows the proton transfer process and some skeletal adaptation to the formation of the tertiary carbenium ion, centered on C9. Neither a movement of the phenolic O to the tertiary C9 nor a sign of double bond isomerization are visible. Therefore, so-called energy profiles (EPs) were constructed, starting from the geometry of the transition states and leading to either the geometry of the starting BF3·Δ9-CBD complex, the BF3·Δ9-THC complex, the BF3·iso THC complex, or the double bond isomerized product complexes.
In an EP, a constraint is applied, and this constraint is varied in regular small steps from the start to the final situation. All steps underwent full geometry optimization, applying the constraint. A plot of the (relative) energy versus the steps provides an impression of the feasibility of such a pathway.
Figure 6 shows the case for the BF
3 catalyzed formation of iso THC, starting from Δ
9-CBD.
In
Figure 6, two EPs are combined, both of which start from the geometry of the TS ring closure from Δ
9-CBD to iso Δ
8-THC, as shown in
Figure 5. The first EP is the reverse of the proton transfer from BF
3·Δ
9-CBD to the C10 of the cyclohexane ring. This EP ranges from molecule number 8 to 1, and the ArO–H distance changes in steps of ~0.1 Å from 1.743 Å to 0.993 Å, the ArO–H equilibrium distance (red line). The second EP is the movement of the phenolic O to the C8 of the cyclohexane ring. This EP ranges from molecule number 8 to 22, and the ArO–C8 distance changes in steps of ~0.1 Å from 2.857 Å to 1.475 Å, the ArO–C8 equilibrium distance (green line). The energy curve (blue) does not show additional local maxima or minima. The Δ (E-total energy) from the TS ring closure iso THC to the product iso THC is −133.2 kJ/mol. A very similar EP was determined, showing the formation of Δ
8-CBD, the isomerized double bond product, from the TS ring closure iso THC. This energy curve does not show additional local maxima or minima. However, the Δ(E-total energy) from the TS ring closure iso THC to Δ
8-CBD is −92.0 kJ/mol. Therefore, in principle, fully reversible isomerization is very well possible but at sufficiently high reaction rates, the thermodynamic product, iso THC, will be formed exclusively.
3.2.4. Kinetic Models: Comparison of Computational and Experimental Results
Table 2 provides an overview of all activation barriers related to the conversion of Δ
9-CBD catalyzed by pTSA or BF
3·Et
2O. The table also contains pseudo-first-order rate constants based on the activation barriers only, and in the case of pTSA as catalyst, corrected pseudo-first-order rate constants. The derived rate constants were used in two simple kinetic models describing pTSA-catalyzed conversion of Δ
9-CBD to mainly Δ
8-THC and BF
3·Et
2O-catalyzed conversion of Δ
9-CBD to Δ
9-THC and iso THC.
As discussed in the Materials and Methods section, reaction rates were calculated using:
Thus, k represents a pseudo-first-order rate constant. As all transition state structures contain the catalyst, pTSA or BF
3, the pseudo-first-order rate constants were corrected for the [catalyst]/[substrate] ratio, which is the maximum amount of substrate that can react in time. The activation barriers for pTSA-catalyzed ring closure lead to rate constants that are orders of magnitude too high. It took some time before it was realized that pTSA in an apolar solvent under dry conditions is actually predominantly present as a dimer with a ΔH = −77.5 kJ/mol. The corresponding equilibrium constant K = 3.31 × 10
10 and the fraction pTSA-monomer is 5.50 × 10
−6 only. Correction for this small amount of monomeric pTSA led to the rate constants k
c, listed in the last column of
Table 2.
For the case of catalysis with pTSA, a kinetic model was developed using the k
c values for ring closure Δ
9 THC pTSA, ring closure Δ
8-THC pTSA and two-step isomerization Δ
9->Δ
8-CBD pTSA only. These values are highlighted (green background) in
Table 2. The concerted isomerization of Δ
9-CBD is not operative, as discussed above, and all other values for k
c are too low to play a role. Using the exact values shown in
Table 2, a yield of 73.7% Δ
8-THC at a total conversion of Δ
9-CBD of 99.9% was predicted. It seems that overall selectivity to Δ
8-THC is slightly too low, while the overall conversion is slightly too high. Probably more important is the apparent absence of Δ
8-CBD in the reaction mixture after less than 15 min, which is in line with the experimental observation that Δ
8-CBD was not detected. Furthermore, the high selectivity to Δ
8-THC instead of Δ
9-THC is explained by the lower activation barriers for two-step isomerization from Δ
9-CBD to Δ
8-CBD and ring closure to Δ
8-THC. Adaptations of +2 kJ/mol in the activation barriers of ring closure of Δ
9 THC and ring closure of Δ
8-THC lead to an almost perfect fit, as can be seen in
Figure 7. The fitted selectivity is 84% compared to 86% experimentally. Alternatively, the ΔH of dimerization of pTSA could be adapted, yielding a very similar result. It should be realized that such small adaptations are within the error limit of the calculations.
For the case of catalysis with BF
3·Et
2O, a kinetic model was developed using the k values for ring closure Δ
9 THC BF
3·Et
2O and ring closure iso THC BF
3·Et
2O. These values are highlighted (green background) in
Table 2. Using the exact values of
Table 2, a yield of 61.9% Δ
9-THC and 36.5% iso THC was predicted at a total conversion of Δ
9-CBD of 98.5%. It seems that overall selectivity to Δ
9-THC is slightly too low, while the overall conversion is slightly too high. An adaptation from 80.9 to 81.5 kJ/mol of the activation barrier for ring closure to Δ
9 THC BF
3·Et
2O and an adaptation from 82.1 to 83.5 kJ/mol of the activation barrier for ring closure to iso THC BF
3·Et
2O leads to a perfect fit, with 66.6% Δ
9-THC and 27.6% iso THC and a total conversion of 94.2%.