Decarboxylation Facilitated by Carbocation Formation and

Henry B. Wedler, T. Newman, and Dean J. Tantillo. Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 9561...
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Decarboxylation Facilitated by Carbocation Formation and Rearrangement during Steam Distillation of Vetiver Oil Henry B. Wedler, T. Newman, and Dean J. Tantillo* Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States S Supporting Information *

ABSTRACT: Density functional theory (DFT) calculations are used to probe the validity of mechanistic proposals for the conversion of isozizanoic acid to 12norisoziza-5-ene, a reaction that occurs during steam distillation of vetiver oil. While this conversion corresponds overall to a simple decarboxylation, a multistep mechanism involving carbocation intermediates is supported by the computational results.

V

Scheme 1. Proposed Mechanism for the Decarboxylation of Isozizanoic Acid during Steam Distillation7 a

etiver oil is an essential oil extracted from the roots of the vetiver plant (Chrysopogon zizanioides).1 In recent years, vetiver has been used as an effective termite repellant.2 Because of its very strong odor, researchers have delivered vetiver oil to mosquitos to allow dogs to track the insects when performing a study on malaria.3 Perhaps ironically, the essential oil is also widely used in Western perfumes and cologne due to its strong fixative property.4 Vetiver root oil also is used as the most prominent flavor in khus syrup, which is used in Indian cooking as a dessert flavoring.5 The strong odor of vetiver oil is due in large part to the multitude of terpenes and terpenoids it contains, many of which are known for their strong aromas.6−8 Vetiver oil is most commonly extracted from the plant via steam distillation, a process that occurs at or above 100 °C.4,7 These high temperatures can allow various rearrangements involving carbocations to occur.9−12 One such rearrangement was examined by Filippi, who investigated the transformation of isozizanoic acid to 12-norisoziza-5-ene via nigritene and 6-epinigritene. This rearrangement was proposed after both nigritene and 6-epi-nigritene were observed as major products after steam distillation.7 The proposed mechanism for this transformation (Scheme 1) involves a carbocation rearrangement, triggered by protonation, followed by decarboxylation and by another protonation-triggered carbocation rearrangement. This mechanism is unusual because decarboxylations do not typically require accompanying rearrangements in order to occur.13−17 We employed quantum chemical calculations to investigate the viability of the proposed mechanism.12 We also compared and contrasted the two rearrangements (Int1 → Int2 and Int4 → Int5), which differ only by the presence/absence of a carboxylate; that is, the second is the reverse of the first, without carboxylate. All calculations were performed using the Gaussian09 software suite.18 The mPW1PW91 density functional theory (DFT) method was employed, along with the 6-31+G(d,p) basis set.19,20 This method has been used successfully to examine the details of terpene-forming carbocation rearrangements.10,11,21,22 All optimizations were performed in water using the SMD (solvent model, density) solvent continuum © 2016 American Chemical Society and American Society of Pharmacognosy

a

Note that zwitterionic forms of Int1 and Int2 are shown here, but various protonation states were examined.

model.23−26 Reported energies of minima and transition state structures (TSSs) are free energies, except for energies for structures in Figure 2 in water; attempts at optimizing the TSS and product of this step in water failed (the reverse reaction is likely barrierless, as described below), so single-point energies Received: April 19, 2016 Published: September 22, 2016 2744

DOI: 10.1021/acs.jnatprod.6b00348 J. Nat. Prod. 2016, 79, 2744−2748

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models of all minima and TSSs using a 3-D printer. To do so, all structures were converted to STL format (3-D printer input) using the AsteriX-BVI software suite developed by Lounnas et al.31−34 AsteriX-BVI provides unique textures on atoms of each element (H, C, O, etc.) and annotates bond lengths, bond angles, and dihedral angle measures in Braille on the models. A visualization of a sample structure generated with AsteriX-BVI is shown at the left-hand side of Figure 1, and a photograph of the physical model 3-D printed from this structure is shown at the right-hand side of Figure 1. Only the rearrangement of the carbocation derived from protonation of isozizanoic acid on the β-face is discussed here. Protonation on the α-face, generating a nigritene intermediate as opposed to a 6-epi-nigritene intermediate, led to qualitatively similar results (see Supporting Information for details). The first chemical step after protonation is a 1,2-alkyl shift, which changes the carbocation skeleton dramatically (Scheme 1). The structures involved in this step are shown in Figure 2 (CO2H form) and Figure 3 (CO2− form; examined for comparison only, since this protonation state is unlikely in the absence of an enzyme). In both cases, the C-1−C-10 bond is broken and the C-5−C-10 bond is formed via a TSS containing a three-center two-electron bonding array.

Figure 1. 3-D printable structure of 12-norisoziza-5-ene annotated with Braille-labeled bond lengths in picometers (left) and photograph of printed physical model (right).

Figure 2. Alkyl shift from Int1 (top) to Int2 (bottom) for the CO2H form of Int1, during which the C-1−C-10 bond is broken and the C5−C-10 bond is formed. The position of the formal charge in reactant and product and the three-center two-electron delocalized bonding array in the TSS are highlighted in green. In the TSS, the C-1−C-10 distance is 1.98 Å, the C-5−C-10 distance is 1.75 Å, and the C-1−C-5 distance is 1.41 Å. Figure 3. Alkyl shift from Int1 (top) to Int2 (bottom) for the CO2− form of Int1, during which the C-1−C-10 bond is broken and the C5−C-10 bond is formed. The position of the formal charge in reactant and product and the three-center two-electron delocalized bonding array in the TSS are highlighted in green. In the TSS, the C-1−C-10 distance is 1.84 Å, the C-5−C-10 distance is 1.84 Å, and the C-1−C-5 distance is 1.40 Å.

on gas-phase-optimized structures are reported. Energies along intrinsic reaction coordinate (IRC)27−29 diagrams are electronic energies. Structure drawings were produced using the CYLview software.30 One of the authors of this Note, H.B.W., is completely blind. H.B.W. made this research accessible by printing physical 2745

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The structures shown in Figure 2 were optimized in the gas phase, and single-point calculations were performed in water (using the SMD continuum model; see the Supporting Information). These SMD(water)-mPW1PW91/6-31+G(d,p)//mPW1PW91/6-31+G(d,p) calculations predict a low barrier (5.2 kcal/mol), consistent with previous work on other 1,2-alkyl shifts.12 Int2 is predicted to be essentially isoenergetic with the associated TSS (0.3 kcal/mol above it), indicating that conversion of Int2 back to Int1 is barrierless. Int2 is a minimum in the gas phase, but the 1,2-alkyl shift TSS is selectively stabilized in water, since it has a larger dipole moment than does Int2 (5.3 vs 5.0 D). Rearrangement of the conjugate base form of isozizanoic acid (Figure 3) was also examined, since Int2 must be deprotonated before (or during) decarboxylation (vide inf ra). The predicted barrier for rearrangement of Int1 changes only slightly upon deprotonationfrom 5.2 to 3.7 kcal/molbut Int1 and Int2 are now predicted to be nearly isoenergetic (Int2 is 0.2 kcal/ mol higher in energy than Int1). The forming and breaking bonds in the TSS for rearrangement are also essentially the same length, while they were unequal, i.e., the TSS was later, for the CO2H form (consistent with the latter reaction being endothermic). Decarboxylation of the CO2− form of Int2 was then examined. The TSS for this decarboxylation is shown in Figure 4. The hyperconjugation in Int2 (the C-2−C-12 distance is

Figure 5. Free energy surface for conversion of Int1 to 6-epi-nigritene + CO2 in kcal/mol.

IRC calculations; see Supporting Information for details), and the transition state structure for this process is shown in Figure 6. Although concerted, proton transfer to water and C−C bond

Figure 6. Transition state structure for concerted decarboxylation and proton transfer.

cleavage occur asynchronously, with proton transfer leading. The predicted barrier for this process is over 20 kcal/mol, but, based on the results described above for decarboxylation of the zwitterionic form of Int2, it appears that most of the activation energy is associated with the proton transfer event. The second half of the proposed mechanism (Scheme 1) generates 12-norisoziza-5-ene from 6-epi-nigritene by a rearrangement that is essentially the reverse of the first rearrangement, but without attached CO2. After the protonation of C-2 to form a carbocation (protonation on C-1 would form a secondary rather than tertiary carbocation),12 a 1,2-alkyl shift ensues. Here, the C-5− C-10 bond breaks and the C-1−C-10 bond forms (Figure 7). The geometries of Int4, Int5, and the TSS that connects them are very similar to those of the analogous structures shown in Figure 3. However, the predicted barrier for the 1,2-shift is only 0.8 kcal/mol, and this reaction is predicted to be exergonic by 2.8 kcal/mol. The energetic differences between the reactions without and with CO2 attached reflect the absence of hyperconjugation between the C-2−C-12 bond and the carbocation center in the former (replaced with weaker C−H ↔ p hyperconjugation). Deprotonation of Int5 at C6 yields the final product, 12-norisoziza-5-ene. Overall, none of the reactions of carbocations examined here are predicted to have substantial barriers. First, this provides support for the mechanism proposed by Filippi.7 Second, this implies that protonation (perhaps by benzoic acid, which is a major component of vetiver oil35) is rate-determining and has a barrier high enough to require heating of the sort associated with steam distillation.

Figure 4. TSS for decarboxylation of Int2. C-1, C-2, and C-12 are highlighted in green. In the TSS, the C-2−C-12 distance is 1.97 Å and the C-1−C-2 distance is 1.38 Å. The O−C−O angle is 143°, partway toward the 180° angle in CO2.

1.64 Å) points to the key structural feature that promotes decarboxylation: the formally empty p-orbital at the carbocation center (C-1) provides the sink for the electron density in the C2−C-12 bond that is left behind as the CO2 departs. It is the rearrangement that brings together and aligns the sink and source of electron density. Decarboxylation of Int2 leads to 6-epi-nigritene and CO2. This step is quite exergonic (by approximately 21 kcal/mol, based on separated products; Figure 5) and is also driven forward (experimentally) by the irreversible departure of CO2. The overall energetics of 6-epi-nigritene formation (carboxylate form) are summarized in Figure 5. Once protonation occurs, rearrangement and decarboxylation are predicted to occur with little to no barrier; that is, the free energy surface corresponding to these chemical events is rather flat, spanning an energy window of less than 4 kcal/mol. Since formation of the zwitterionic form of Int2 is unlikely, i.e., the carboxylate is likely to be protonated, the possibility of coupled deprotonation of the carboxylic acid and decarboxylation was examined. These two processes are predicted to be concerted when a water molecule is used as base (confirmed via 2746

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biosynthetic relevance and may find applications in the synthesis of fine chemicals.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00348. Computational details (PDF) 3-D structures (MOL)



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS We gratefully acknowledge support from the National Science Foundation (CHE-0449845, CHE-0957416, CHE-1361807, CHE-030089 [XSEDE], GRFP for H.B.W. and T.N.) and the United States Department of Education (GAANN fellowship to H.B.W.). We thank S. Cohen for helpful comments.



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Figure 7. Alkyl shift from Int4 (top) to Int5 (bottom), during which the C-5−C-10 bond is broken and the C1−C-10 bond is formed. The position of the formal charge in reactant and product and the threecenter two-electron delocalized bonding array in the TSS are highlighted in green. In the TSS, the C-1−C-10 distance is 1.82 Å, the C-5−C-10 distance is 1.86 Å, and the C-1−C-5 distance is 1.40 Å.

Protonation of alkene π-bonds is quite difficult. In biological settings, enzymes with specialized arrays of amino acid side chains are used to accomplish this feat.36,37 In solution, the difficulty of protonation is reflected in pKa’s of carbocations (associated with deprotonation reactions that produce alkenes), which are generally in the range of −20.38 In the gas phase, proton affinities of alkenes have been experimentally determined to be approximately 170 kcal/mol; other weak bases with gas-phase proton affinities between 165 and 175 kcal/mol include trifluoroethanol, trifluoroacetic acid, formaldehyde, and HCN.39 All of these data are consistent with protonation being the rate-determining step of the decarboxylation process described herein. In summary, the structures of carbocation-containing species involved in the conversion of isozizanoic acid to 12-norisoziza5-ene were described, and it was shown that the barriers for the rearrangements that interconvert them are very low. Thus, as long as protonation of the olefinic π-bonds in isozizanoic acid and the nigritenes can occursomething that requires elevated temperaturesthe reaction should be rapid. The originally proposed mechanism (Scheme 1)7 is thus consistent with the conversion of isozizanoic acid to 12-norisoziza-5-ene occurring in vetiver oil during steam distillation. The unusual means by which decarboxylation is triggered in this system not only is relevant to the chemistry of vetiver oil but may also have 2747

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