Cations or Radicals? Inherent Reactivity of Biosynthetic Intermediates

Mar 25, 2016 - ... (5) and 13-Homo-13-oxa-6a,12a-dehydrorotenone (6) Lack the Characteristic Backbone and Are More Oxidized than Their Namesake (1)...
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Cations or Radicals? Inherent Reactivity of Biosynthetic Intermediates in the B‑Ring Formation of Rotenoid Natural Products Adam K. Kirkpatrick and Matthew R. Siebert* Department of Chemistry, Missouri State University, Springfield, Missouri 65897, United States S Supporting Information *

ABSTRACT: Compounds of the rotenoid class are naturally occurring in the Leguminosae and Nyctaginacae families. Rotenoids have found a myriad of uses, for example, in the agricultural industry as an insecticide and piscicide, and as an anticancer therapeutic. The scientific literature questions whether cyclization of the rotenoid B-ring occurs via a pathway containing either cationic or free-radical intermediates. In this work, both propositions are analyzed using DFT (B3LYP and M06-2X) and the G3 composite method in gas- and (implicit) solution-phase. The accuracy of these methods is compared to several experimental C−H bond dissociation energies (BDEs). We find that of the methods surveyed M06-2X provides the most accurate BDEs. Further, there is a clear thermodynamic preference for the free-radical pathway.

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INTRODUCTION Nature produces a myriad of chemicals in its quest to sustain and propagate life. The understanding of the biosynthetic pathway of plant products is a noteworthy field of study, as it provides a grasp for utilization and modification of such compounds. In fact, it has been suggested that insufficient basic knowledge of the pathways by which Nature produces plant products is the largest limiting factor to full utilization of such promising compounds.1 The shikimate pathway is responsible for generation of many biomolecules including the essential amino acids L-phenylalanine, L-tyrosine, and L-tryptophan as well as lignans, coumarins, flavonoids, isoflavonoids, and terpenoid quinones.2 Within the collection of molecules known as isoflavonoids lies a subclass called rotenoids. Rotenoids are a class of organic molecules that generally feature a cis-fused tetrahydrochromeno-[3,4,b]-chromene backbone (1−4, Chart 1; characteristic substructure highlighted in blue). Other natural products formed via the same biosynthetic pathway and that exhibit similar insecticidal properties have also been termed rotenoids despite lack of the cis-tetrahydrochromeno[3,4-b]chromene backbone, for example, 5 and 6, Chart 1.3 Commonly synthesized by the Leguminosae and Nyctaginacae family, the rotenoid class of molecules has agricultural uses as a natural means to kill insects (insecticide) and fish (piscicide).4 Rotenone (1, Chart 1), a secondary metabolite of Leguminosae family (legumes), was first utilized as a fish neurotoxin.4 Given that it is rapidly metabolized by humans (if ingested) rotenone has been used to “chemically fish.”2,4 Rotenone has also been investigated for its anticancer activity; it prevents cells from dividing by inhibiting microtubule formation from tubulin.4 © XXXX American Chemical Society

More recently, rotenone has found use in the rat model of Parkinson’s disease; it was discovered that prolonged exposure to rotenone via injections to the jugular vein of rats caused symptoms similar to that of Parkinson’s disease.5−11 In 2011, research was published studying the effect of pesticides on humans in the agricultural industry (primarily farm workers and their spouses), which concluded that there does exist a positive correlation between rotenone and Parkinson’s disease.9 Deguelin (2, Chart 1), a secondary metabolite of the Leguminosae family, has been shown to display anticancer activity by inhibiting the growth of precancerous and cancerous cells without toxic effects on healthy cells with strictly modulated doses.12 Rotenoids boeravinone G and H (3 and 4, respectively; Chart 1) found in Boerhaavia dif f usa have displayed interesting prospects as inhibitors of the breast cancer resistance protein (ABCG2); effective inhibition of ABCG2 would lead to increased efficacy and decreased resistance to potent chemotherapeutic agents for the treatment of breast cancer.13 Crombie and Whiting succinctly outlined the biosynthesis of the cis-fused tetrahydrochromeno-[3,4,b]-chromene backbone with an emphasis on Nature’s pathway to rotenone (1).4 The essential amino acid L-phenylalanine is converted to (E)cinnamic acid via enzymatic elimination. Malonyl-CoA then adds several malonyl groups to (E)-cinnamic acid, before successive cyclizations take place to yield a flavonoid. Flavonoid/isoflavonoid isomerization followed by hydroxylaReceived: December 17, 2015 Revised: February 23, 2016

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DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A Chart 1. Rotenone (1) and the Rotenoids Deguelin (2), Boeravinone G (3), and Boeravinone H (4) Exhibit a cisFused Tetrahydrochromeno-[3,4,b]-chromene Backbone (in Blue) and Rotenoid Amorphispironone (5) and 13-Homo13-oxa-6a,12a-dehydrorotenone (6) Lack the Characteristic Backbone and Are More Oxidized than Their Namesake (1)

Scheme 1. Select Steps in the Biosynthesis of Rotenoid Natural Productsa

tion and methylation results in intermediate 7-H in Scheme 1. B-ring cyclization (7-H → 9; Scheme 1) occurs by oxidation of the ortho-disposed methoxy carbon (with respect to the chromeno nucleus). Labeling studies (14C) have isolated the methoxy group that is oxidized and thereby incorporated as the methylene into the ring structure, however there is uncertainty about whether this is a cation- or radical-driven process (* = + or •; Scheme 1). Further experiments have shown that a radical driven process is feasible (given the correct sensitizing groups).14,15 From 9, the Leguminosae family incorporates an isoprene unit (forming either 1 or 2). Comparison of the structures of boeravinones G (3) and H (4) to that of rotenone (1) and deguelin (2) reveals that the Nyctaginacae family forms 3 and 4 through a divergent pathway to that of the Leguminosae family that forms 1 and 2. Similar analysis of amorphispironone (5) and 13-homo-13-oxa-6a,12adehydrorotenone (6) compared to 1 and 2 leads to a similar conclusion. In both cases (comparing 1/2 to each of 3/4 and 5/6), derivatization must occur before and/or after B-ring cyclization (7-H → 9; Scheme 1). Further studies are required to determine any similarity between and divergence from the biosynthesis of 1/2 as compared to each of 3/4 and 5/6. Herein we aim to quantify the thermodynamic and kinetic preferences for the biosynthetic formation of the rotenoid Bring using DFT (B3LYP and M06-2X) and the G3 composite method in gas- and (implicit) solution-phase. To assess the energetics inherent in generation of the carbocationic and freeradical intermediates (7+ and 7•, respectively) we will compare heterolytic and homolytic bond dissociation energies (BDEs) of 7-H (Scheme 2). Given that cationic- and radical-based intermediates can differ in their reactivity, such knowledge will pave a way to leverage the natural biosynthesis for further manipulation and utilization of these interesting plant products.

a

Formation of the rotenoid B-ring occurs by oxidation of a methoxy group, however, experiments have not indicated if a cationic (* = +) or radical (* = •) pathway is preferred.

Scheme 2. Heterolytic (Top) and Homolytic (Bottom) Bond Cleavage

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THEORETICAL METHODS Stationary points were optimized using the Gaussian0916 suite. Frequency analyses were used to classify each stationary point as a minimum or transition state structure (TSS) as well as to provide zero-point energy correction (ZPEC). TSSs were further classified by intrinsic reaction coordinate17−19 calculations that were used to determine the minimum-energy pathway between the TSS and the minima directly connected to it via steepest descent along the potential energy surface. Energies reported throughout are electronic energies with unscaled enthalpy correction (that includes ZPEC) added in. Ball and stick molecular graphics were created with CYLView.20 The hybrid density functional theory method B3LYP21−23 was combined with the 6-311+G(d,p) basis set for all optimizations and frequency analyses. Use of the B3LYP density functional is quite ubiquitous due in part to its low computational cost and relative accuracy.24−29 The M06-2X30 density functional was utilized (vide infra) due to reports of increased accuracy.26,28,29 Also tested was the composite B

DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A method Gaussian-3 (G3), a wave function-theory based method that utilizes an admix of computations at Hartree− Fock and post-Hartree−Fock levels.31 Single-point energy calculations were carried out utilizing the B3LYP/6-311+G(d,p) geometries and each of the B3LYP and M06-2X density functionals paired with the 6-311+G(3df,2p) basis set. Energies reported from density functional methods incorporate B3LYP/ 6-311+G(d,p) enthalpy correction. Computation of the homolytic and heterolytic BDEs using full geometry optimizations of one test compound (anisole) with implicit water solvent at each of the B3LYP/6-311+G(3df,2p) and M06-2X/6-311+G(3df,2p) levels of theory provided little improvement at substantially increased computational cost. Only the M06-2X/6-311+G(3df,2p) heterolytic cleavage differed from its single-point relative [M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p)] with that difference being 0.5 kcal/mol, which is less than one standard deviation in magnitude for structures computed herein (vide infra). Benchmark calculations were carried out on a set of compounds (Chart 2) with experimentally determined C−H BDEs (for homolytic cleavage) that share some structural similarity to the rotenoid precursor 7-H. The gas-phase BDE (homolytic cleavage) was computed for each of compounds 10-23 (Chart 2) and compared to experimentally determined values32 using each model chemistry described above. The thermodynamic data was distilled into several mean deviations and standard deviations thereof, see Table 1. Looking at the mean deviations (MD and MPD) between experimental values and those computed herein, we see that the B3LYP functional suffers from rather large mean deviations; the MD is −3.48 kcal/mol (−3.79%) for the 6-311+G(d,p) basis set, while accuracy is not improved with the larger 6311+G(3df,2p) basis set (MD = −3.58 kcal/mol; −3.91%). Comparing the MD/MPD with the MAD/MAPD, we see that B3LYP consistently underestimates the endothermic nature of the homolytic BDEs. Precision with the B3LYP functional is reasonable with standard deviations (σ) of approximately 1.0 kcal/mol suggesting that the deviation leading to underestimation of the BDEs is reasonably systematic. M06-2X/6311+G(3df,2p)//B3LYP/6-311+G(d,p) provides the best accuracy (even better than G3 on our set of 14 compounds) with an MD of −0.70 kcal/mol (MPD = −0.72%). Comparing the mean (MD and MPD) with mean absolute deviations (MAD and MAPD) for M06-2X/6-311+G(3df,2p)//B3LYP/6311+G(d,p), it is apparent that this model chemistry occasionally overestimates the endothermicity of the homolytic BDEs, a feature that influences the standard deviation in the mean deviations (σ). The interpretation is that the M06-2X/6311+G(3df,2p)//B3LYP/6-311+G(d,p), although it is the most accurate model chemistry tested herein, is slightly less precise than B3LYP (albeit a very slight difference in precision). The G3 method tends to overestimate the endothermic nature of the BDEs calculated herein and is the least precise of the methods. Refinement of the G3 method to accurately reproduce radical thermochemistry (G3-RAD)33 has been reported; however, we look to accurately reproduce radical and ionic thermochemistry. For this reason, the G3-RAD approach33 was not tested herein. Overall, the data above suggest that the M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) is the most reliable method tested herein, and although the data for the other methods are presented throughout this

Chart 2. Reference Compounds for Comparison of Experimentally-Determined and Computed Homolytic C−H BDE with Structural Similarity to the Rotenoid Precursor 7Ha

a

Cleaved C−H (and homotopic equivalent) bonds highlighted in blue.

report the M06-2X energetic data are discussed explicitly in the text. The aim below is to compare reaction thermochemistry of radical and ionic pathways shown in Scheme 2. Gas-phase optimization of molecular geometry will carry a disproportionate bias against charge separation of ionic species not present in either of the gas-phase free-radical process or the naturally occurring enzyme-catalyzed process. To overcome this inherent bias, molecular geometries were computed in the condensed-phase using the default settings available in Gaussian09, which include integral equation formalism of the polarizable continuum model (IEFPCM)34−48 and atomic radii from the universal force field (UFF) scaled by 1.1.49 Water was chosen as the solvent to emphasize the stabilization afforded to ionic species. Results presented below utilize the implicit C

DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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Table 1. Mean Deviation (MD), Mean Average Deviation (MAD), Mean Percent Deviation (MPD), Mean Absolute Percent Deviation (MAPD), and Standard Deviations Thereof (σMD, σMAD, σMPD, and σMAPD, respectively) in Computed (Homolytic) BDEs method B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) G3 a

MD ± σMD (kcal/mol) −3.48 −3.58 −0.70 1.53

± ± ± ±

1.00 1.00 1.17 1.23

MAD ± σMAD (kcal/mol) 3.48 3.58 1.08 1.65

± ± ± ±

1.00 1.00 0.80 1.05

MPDa ± σMPD (%) −3.79 −3.91 −0.72 1.71

± ± ± ±

1.12 1.13 1.23 1.37

32 The MPD was computed using calculated (ΔHcalc (ΔHexp rxn ) and experimental rxn ) BDEs in the following form: Deviation =

MAPD ± σMAPD (%) 3.79 3.91 1.15 1.83

± ± ± ±

1.12 1.13 0.80 1.20

calc exp ΔHrxn − ΔHrxn . exp ΔHrxn

Figure 1. IEFPCM (solvent = water) B3LYP/6-311+G(d,p) optimized geometries for each of 7-H and its related product of heterolytic (7+) and homolytic (7•) cleavage. Select distances displayed in angstroms (Å).

Cleavage of the C−H bond in 7-H, results in a decreased distance between the carbon of the reactive intermediate and its oxygen from 1.43 Å (in 7+) to 1.25 and 1.36 Å for the cation (7+) and radical (7•), respectively. This indicates stronger interaction between the oxygen and carbocation-center, compared to that between the oxygen and the radical-center. This is further manifest in a concomitant increase of the distance between the oxygen atom and the aromatic ring from 1.37 Å in 7-H to 1.42 and 1.38 Å for the cation (7++) and radical (7•), respectively, indicating decreased delocalization into the aromatic ring by the oxygen atom (see Figure 1). The

solvent model; gas-phase data can be found in the Supporting Information.

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RESULTS AND DISCUSSION

Generation of Radical versus Ionic Reactive Intermediates. Species appearing in the homolytic and heterolytic bond dissociation reactions (Scheme 2) were calculated. The B3LYP/6-311+G(d,p) geometries for each of 7-H and its related product of heterolytic (7+) and homolytic (7•) cleavage appear in Figure 1. D

DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A Table 2. Computed Homolytic and Heterolytic BDEs for Compounds 7 and 24−28a compound 7-H

24

25

26

27

28

method B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3 B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3 B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3 B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3 B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3 B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) G3

heterolytic cleavage

homolytic cleavage

106.7 105.1

94.6 94.3

112.8

96.7

b 111.5 110.4

b 94.3 94.1

117.8

96.4

116.9 113.0 111.8

98.6 94.0 93.8

118.7

96.2

116.2 111.3 110.0

98.5 93.9 93.7

117.6

96.0

116.7 107.8 106.4

98.6 93.5 93.3

115.3

95.7

114.1 108.8 107.3

98.1 92.8 92.6

115.6

95.0

Chart 3. Bond Dissociation Reactions were Computed for Rotenone Precursor 7-H and Smaller Analogs 24−28 to Elucidate Substituent Effects

The meta-methoxy substituent (26), results in a smaller BDE for both heterolytic and homolytic cleavage reactions, albeit a small deviation (0.2 and 0.4 kcal/mol). The para-methoxy substituent (27) has the largest effect, reducing the BDEs for heterolytic and homolytic cleavage by 2.5 and 0.7 kcal/mol, respectively. We find that the combined effect of all substituents is approximately additive with BDEs for heterolytic and homolytic cleavage that are 2.2 and 1.4 kcal/mol smaller (compare 28 and 24). Overall, the average M06-2X/6-311+G(3df,2p)//B3LYP/6311+G(d,p) heterolytic BDE of 7-H and 24−28 in Table 2 was found to be 116.3 kcal/mol, while that for the homolytic BDE is 96.0 kcal/mol (20.3 kcal/mol lower than that for heterolytic cleavage). As the numbers demonstrate, the homolytic cleavage of the C−H is favored substantially, even with the (implicit) inclusion of a very polar solvent. Formation of the B-Ring. The minimum energy pathway describing formation of the B-ring for rotenoid-class natural products may provide additional insight into the inherent preference for a radical as compared to a cationic mechanism. The B3LYP/6-311+G(d,p) geometries for 7*‡ and 8* (where * = either + or •) appear in Figure 2. Cyclization of the B-ring by progression from 7* (through 7*‡) to 8* is described by a decrease in a methylene-C− methyne-C contact. For the cation (* = +), this contact is initially (in 7+) 3.85 Å, proceeding to 2.06 Å in the TSS (7+‡) before settling at 1.52 Å (in 8+); for the radical (* = •), the same contact starts at 4.35 Å (in 7•) and transitions through 2.27 Å (in 7•‡; illustrating the earlier transition state expected50,51 for a less endothermic reaction) before settling at 1.52 Å in 8•. With the reactive intermediate now formally in the α-position with respect to the carbonyl, the methylene-C−

a

Energies in kcal/mol computed in water using the IEFPCM implicit solvent model. bComputation of radical and cationic derivatives of 7 with the G3 composite method proved intractable on our available system.

average M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) heterolytic BDE of 7-H and 24−28 in Table 2 was found to be 116.3 kcal/mol, while that for the homolytic BDE is 96.0 kcal/mol, showing a strong inclination for the homolytic pathway, even with the (implicit) inclusion of a very polar solvent (water). In an attempt to elucidate substituent effects in the bond dissociation, a series of smaller analogs (24−28; Chart 3) were also investigated. Contacts proximal to the reactive intermediate center did not deviate substantially from that of 7-H, for this reason geometries for each of 24−28 and their related products of heterolytic and homolytic cleavage are relegated to the Supporting Information. The computed homolytic and heterolytic BDEs for 7-H and 24−28 appear in Table 2. Structure 24 will act as the reference point for substituent effects. The M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) BDE is 117.8 and 96.4 kcal/mol for heterolytic and homolytic cleavage, respectively. Addition of an ortho-methyl group (25) as a simulation for the alkyl group of 7-H increases the BDE for heterolytic cleavage by 0.9 kcal/mol, while that for homolytic cleavage is lowered by 0.2 kcal/mol. E

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Figure 2. IEFPCM (solvent = water) B3LYP/6-311+G(d,p) optimized geometries for both cationic (* = +) and radical (* = •) pathways for cyclization to 8* through transition state structure (7*‡). Select distances displayed in angstroms (Å).

O and ipso-carbon−O distances relax to values consistent with where they started (in 7-H) indicating a restored delocalization of the oxygen lone pair into the aromatic ring. The computed relative electronic energies for the cationic and radical pathways appear in Table 3. At the M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) level of theory, the activation barrier for the radical pathway is 3.0 kcal/mol lower than that of the cationic pathway. Additionally, the radical pathway possesses a thermodynamic

preference of 5.6 kcal/mol. A detailed reaction coordinate diagram is presented in Figure 3. The trend of a lower barrier and more exothermic nature for the radical-based pathway is mirrored in the B3LYP results. Overall, the radical pathway for

Table 3. Relative Enthalpies [with Unscaled B3LYP/6311+G(d,p) Enthalpy Correction] of the Radical (* = •) and Cationic (* = +) Pathways for Compounds 7*,7*‡, and 8*

compound 7*

‡

7*

8*

method B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) B3LYP/6-311+G(d,p) B3LYP/6-311+G(3df,2p)// B3LYP/6-311+G(d,p) M06-2X/6-311+G(3df,2p)// B3LYP/6-311+G(d,p)

cationic pathway (* = +)

radical pathway (* = •)

(0.0) (0.0)

(0.0) (0.0)

(0.0)

(0.0)

9.9 9.9

7.4 8.5

10.4

7.4

−23.6 −21.5

−25.4 −24.1

−20.6

−26.2

Figure 3. Reaction coordinate diagram describing B-ring formation of rotenoid natural products via each of cationic (* = +) and radical (* = •) pathways. Energies obtained from the IEFPCM (solvent = water) M06-2X/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) level of theory are displayed in kcal/mol and incorporate unscaled B3LYP/6-311+G(d,p) enthalpy correction. Values for the cationic pathway appear above its dashed line, while those for the radical pathway appear below its solid line. F

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the B-ring formation shows both a kinetic and thermodynamic preference.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.5b12367. Coordinates and energies for all structures discussed herein as well as complete refs 9 and 16. (PDF)

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REFERENCES

(1) Dixon, R. A.; Paiva, N. L. Prospects of Accessing DNA Banks for the Isolation of Genes Encoding Biologically Active Proteins. In Conservation of Plant Genes; Adams, R. P., Adams, J. E., Eds.; Academic Press: San Diego, 1992; pp 99−118. (2) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach, 2nd ed.; John Wiley & Sons, Ltd: New York, 2009. (3) Roark, R. C. Definition of the Word ″Rotenoid″. J. Econ. Entomol. 1940, 33, 416−416. (4) Crombie, L.; Whiting, D. A. Review Article Number 135 Biosynthesis in the Rotenoid Group of Natural Products: Applications of Isotope Methodology. Phytochemistry 1998, 49, 1479−1507. (5) Betarbet, R.; Sherer, T. B.; Mackenzie, G.; Garcia-Osuna, M.; Panov, A. V.; Greenamyre, J. T. Chronic Systemic Pesticide Exposure Reproduces Features of Parkinson’s Disease. Nat. Neurosci. 2000, 3, 1301−1306. (6) Caboni, P.; Sherer, T. B.; Zhang, N.; Taylor, G.; Na, H. M.; Greenamyre, J. T.; Casida, J. E. Rotenone, Deguelin, Their Metabolites, and the Rat Model of Parkinson’s Disease. Chem. Res. Toxicol. 2004, 17, 1540−1548. (7) Greenamyre, J. T.; Cannon, J. R.; Drolet, R.; Mastroberardino, P.G. Lessons from the Rotenone Model of Parkinson’s Disease. Trends Pharmacol. Sci. 2010, 31, 141−142. (8) Klein, A.; Gidyk, D. C.; Shriner, A. M.; Colwell, K. L.; Tatton, N. A.; Tatton, W. G.; Metz, G. A. Dose-Dependent Loss of Motor Function after Unilateral Medial Forebrain Bundle Rotenone Lesion in Rats: A Cautionary Note. Behav. Brain Res. 2011, 222, 33−42. (9) Tanner, C. M.; Kamel, F.; Ross, G. W.; Hoppin, J. A.; Goldman, S. M.; Korell, M.; Marras, C.; Bhudhikanok, G. S.; Kasten, M.; Chade, A. R.; et al. Rotenone, Paraquat, and Parkinson’s Disease. Environ. Health Perspect. 2011, 119, 866−872. (10) Wolf, L. K. The Pesticide Connection. Chem. Eng. News 2013, 91, 11−15. (11) Johnson, M. E.; Bobrovskaya, L. An Update on the Rotenone Models of Parkinson’s Disease: Their Ability to Reproduce the Features of Clinical Disease and Model Gene−Environment Interactions. NeuroToxicology 2015, 46, 101−116. (12) Lee, H.-Y. Molecular Mechanisms of Deguelin-Induced Apoptosis in Transformed Human Bronchial Epithelial Cells. Biochem. Pharmacol. (Amsterdam, Neth.) 2004, 68, 1119−1124. (13) Ahmed-Belkacem, A.; Macalou, S.; Borrelli, F.; Capasso, R.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Pietro, A. Nonprenylated Rotenoids, a New Class of Potent Breast Cancer Resistance Protein Inhibitors. J. Med. Chem. 2007, 50, 1933−1938. (14) Ahmad-Junan, S. A.; Walkington, A. J.; Whiting, D. A. The Mechanism of Biological C-C Bond Formation to Methoxy Groups; Biomimetic Cyclisation Via Alkyloxyl Radicals. J. Chem. Soc., Chem. Commun. 1989, 1613−1615. (15) Ahmad-Junan, S. A.; Walkington, A. J.; Whiting, D. A. Aryloxymethyl Radical Cyclizations Mimicking Biological C-C Bond Formation to Methoxy Groups. J. Chem. Soc., Perkin Trans. 1 1992, 2313−2320. (16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (17) Fukui, K. The Path of Chemical Reactions - the IRC Approach. Acc. Chem. Res. 1981, 14, 363−368. (18) Quapp, W.; Heidrich, D. Analysis of the Concept of Minimum Energy Path on the Potential Energy Surface of Chemically Reacting Systems. Theor. Chem. Acc. 1984, 66, 245−260. (19) Gonzalez, C.; Schlegel, H. B. Reaction Path Following in MassWeighted Internal Coordinates. J. Phys. Chem. 1990, 94, 5523−5527. (20) Legault, C. Y. Cylview, 1.0.562; Université de Sherbrooke, Canada, 2009, http://www.cylview.org (accessed Feb 23, 2016). (21) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789.

CONCLUSION In this report we provide evidence, in the form of electronic structure calculations, that the inherent reactivity of the rotenoid precursor 7-H prefers a radical-based pathway as compared to its ionic counterpoint. This is illustrated in the BDE for homolytic C−H bond cleavage, which we find to be approximately 20 kcal/mol lower than its heterolytic counterpoint. Further, subsequent cyclization via a radical-based pathway proceeds through a lower barrier (by approximately 3 kcal/mol) and to a lower-energy intermediate (by approximately 6 kcal/mol) than the ionic alternative. All of this preference for the radical-based pathway is despite implicit inclusion of water solvent, which is likely a more polar environment than the enzyme that generates rotenoids. However, the model used herein neglects the enzyme, and any site-specific interactions that may be present, meaning that ionic pathways cannot be completely ruled-out. We express great interest in additional research conducted on the rotenoid family that the agricultural and medicinal applications of this family may be developed and acted upon.

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Telephone: (417) 8365367. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the Missouri State University Graduate College for their Faculty Research Grant and Thesis Research Funding; the Missouri State University College of Natural and Applied Sciences and Department of Chemistry for their support of this research; last, we thank the Missouri State University Office of the Provost and Office of Student Development and Public Affairs for sponsoring monthly faculty writing retreats that provided direct support for production of this report.

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ABBREVIATIONS BDE, bond dissociation energy; TSS, transition state structure; G3, Gaussian-3; ZPEC, zero-point energy correction; IEFPCM, integral equation formalism of the polarizable continuum model; UFF, universal force field; MD, mean deviation; MAD, mean absolute deviation; MPD, mean percent deviation; MAPD, mean absolute percent deviation; σ, standard deviation G

DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry A (22) Becke, A. D. Density-Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652. (23) Becke, A. D. A New Mixing of Hartree−Fock and Local Density-Functional Theories. J. Chem. Phys. 1993, 98, 1372−1377. (24) Zheng, J.; Zhao, Y.; Truhlar, D. G. Representative Benchmark Suites for Barrier Heights of Diverse Reaction Types and Assessment of Electronic Structure Methods for Thermochemical Kinetics. J. Chem. Theory Comput. 2007, 3, 569−582. (25) Tirado-Rives, J.; Jorgensen, W. L. Performance of B3LYP Density Functional Methods for a Large Set of Organic Molecules. J. Chem. Theory Comput. 2008, 4, 297−306. (26) Zhao, Y.; Truhlar, D. G. Density Functionals with Broad Applicability in Chemistry. Acc. Chem. Res. 2008, 41, 157−167. (27) Siebert, M. R.; Osbourn, J. M.; Brummond, K. M.; Tantillo, D. J. Differentiating Mechanistic Possibilities for the Thermal, Intramolecular [2 + 2] Cycloaddition of Allene−Ynes. J. Am. Chem. Soc. 2010, 132, 11952−11966. (28) Xu, X.; Alecu, I. M.; Truhlar, D. G. How Well Can Modern Density Functionals Predict Internuclear Distances at Transition States? J. Chem. Theory Comput. 2011, 7, 1667−1676. (29) Bakowies, D. Assessment of Density Functional Theory for Thermochemical Approaches Based on Bond Separation Reactions. J. Phys. Chem. A 2013, 117, 228−243. (30) Zhao, Y.; Truhlar, D. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241. (31) Curtiss, L. A.; Raghavachari, K.; Redfern, P. C.; Rassolov, V.; Pople, J. A. Gaussian-3 (G3) Theory for Molecules Containing First and Second-Row Atoms. J. Chem. Phys. 1998, 109, 7764−7776. (32) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press: Boca Raton, FL, 2003. (33) Henry, D. J.; Sullivan, M. B.; Radom, L. G3-RAD and G3XRAD: Modified Gaussian-3 (G3) and Gaussian-3X (G3X) Procedures for Radical Thermochemistry. J. Chem. Phys. 2003, 118, 4849−4860. (34) Miertuš, S.; Scrocco, E.; Tomasi, J. Electrostatic Interaction of a Solute with a Continuum. A Direct Utilizaion of Ab Initio Molecular Potentials for the Prevision of Solvent Effects. Chem. Phys. 1981, 55, 117−129. (35) Miertus̃, S.; Tomasi, J. Approximate Evaluations of the Electrostatic Free Energy and Internal Energy Changes in Solution Processes. Chem. Phys. 1982, 65, 239−245. (36) Pascual-Ahuir, J. L.; Silla, E.; Tuñon, I. GEPOL: An Improved Description of Molecular Surfaces. III. A New Algorithm for the Computation of a Solvent-Excluding Surface. J. Comput. Chem. 1994, 15, 1127−1138. (37) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Ab Initio Study of Solvated Molecules: A New Implementation of the Polarizable Continuum Model. Chem. Phys. Lett. 1996, 255, 327−335. (38) Barone, V.; Cossi, M.; Tomasi, J. A New Definition of Cavities for the Computation of Solvation Free Energies by the Polarizable Continuum Model. J. Chem. Phys. 1997, 107, 3210−3221. (39) Cancès, E.; Mennucci, B.; Tomasi, J. A New Integral Equation Formalism for the Polarizable Continuum Model: Theoretical Background and Applications to Isotropic and Anisotropic Dielectrics. J. Chem. Phys. 1997, 107, 3032−3041. (40) Mennucci, B.; Tomasi, J. Continuum Solvation Models: A New Approach to the Problem of Solute’s Charge Distribution and Cavity Boundaries. J. Chem. Phys. 1997, 106, 5151−5158. (41) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995−2001. (42) Barone, V.; Cossi, M.; Tomasi, J. Geometry Optimization of Molecular Structures in Solution by the Polarizable Continuum Model. J. Comput. Chem. 1998, 19, 404−417.

(43) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Ab Initio Study of Ionic Solutions by a Polarizable Continuum Dielectric Model. Chem. Phys. Lett. 1998, 286, 253−260. (44) Cammi, R.; Mennucci, B.; Tomasi, J. Second-Order Møller− Plesset Analytical Derivatives for the Polarizable Continuum Model Using the Relaxed Density Approach. J. Phys. Chem. A 1999, 103, 9100−9108. (45) Tomasi, J.; Mennucci, B.; Cancès, E. The IEF Version of the PCM Solvation Method: An Overview of a New Method Addressed to Study Molecular Solutes at the QM Ab Initio Level. J. Mol. Struct.: THEOCHEM 1999, 464, 211−226. (46) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Polarizable Dielectric Model of Solvation with Inclusion of Charge Penetration Effects. J. Chem. Phys. 2001, 114, 5691−5701. (47) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. New Developments in the Polarizable Continuum Model for Quantum Mechanical and Classical Calculations on Molecules in Solution. J. Chem. Phys. 2002, 117, 43−54. (48) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, Structures, and Electronic Properties of Molecules in Solution with the C-PCM Solvation Model. J. Comput. Chem. 2003, 24, 669−681. (49) Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W. A.; Skiff, W. M. UFF, a Full Periodic Table Force Field for Molecular Mechanics and Molecular Dynamics Simulations. J. Am. Chem. Soc. 1992, 114, 10024−10035. (50) Bell, R. P. The Theory of Reactions Involving Proton Transfers. Proc. R. Soc. London, Ser. A 1936, 154, 414−429. (51) Evans, M. G.; Polanyi, M. Inertia and Driving Force of Chemical Reactions. Trans. Faraday Soc. 1938, 34, 11−24.

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DOI: 10.1021/acs.jpca.5b12367 J. Phys. Chem. A XXXX, XXX, XXX−XXX