Steric Effects in the Computational Modeling of Cyclization Reactions of Dieneynones

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1 Steric Effects in the Computational Modeling of Cyclization Reactions of Dieneynones Kim Anh Hoang Faculty Mentor: Dr. Benjamin Gherman McNair Scholars Journal s Volume 17 Abstract Enediynes can undergo Bergman cyclization and generate a diradical intermediate. They can be used as potential antitumor drugs due to their ability upon cyclization to abstract hydrogen atoms from and cleave DNA. The enediyne core was modified by insertion of a carbonyl group and changing one of the two alkynes into an alkene to give a dieneynone. Previous computational research studying reactivity of unsubstituted dieneynones suggested that experimental study would yield a mixture of products. Substituents were added at the C1 and C7 positions to disfavor reaction pathways involving these positions. Computational chemistry results show not only that the substituents raise the activation and reaction energies of those pathways, but also that alternative cyclization pathways become more favorable. Introduction & Literature Review Cancer is a large family of diseases which are also known as malignant tumors. Cancer involves abnormal cell growth with the potential to spread to other parts of the body. In 2014, approximately 585,720 Americans were expected to die of cancer, adding up to nearly 1,600 people per day.1 Cancer is the second most common cause of death in the United States (exceeded only by heart disease), and accounts for nearly 1 in every 4 deaths annually.2 There have been many experimental studies conducted in order to find the most effective way to cure this illness. Various methods have been used, with computational chemistry at the forefront of anticancer research because of its safety, high accuracy, and unparalleled efficiency. Chemists in other fields, such as organic chemistry and biochemistry, are able to interpret and predict experimental results with computational data. From that data, they can determine the best way to obtain the highest yield for reactions without having to go through costly and timeconsuming laboratory protocols. In 1987, the discovery of two new classes of antitumor agents, Calicheamicins and Esperamicins, aroused the interest of scientists in these chemical and biological compounds.3,4 Both Calicheamicins and Esperamicins use the principle of Bergman cyclization5 and use enediynes as their core.6 They have 47

2 California State University, Sacramento the ability to deliver the prodrug molecule to a DNA strand, activate it, and then abstract hydrogen atom(s) from the sugar backbone of DNA (Figure 1). In the beginning of the process, the sugar moiety of Calicheamicin moves nearby and then binds to the minor groove of the double-stranded nucleic acid. A nucleophile then activates the molecule by initiating a nucleophilic substitution reaction with the trisulfide group, resulting in a thiolate anion which bonds to the bridgehead alkene. The molecule is then ready for the Bergman cyclization now that the distance between the carbon atoms involved in the cyclization has been decreased. Bergman cyclization occurs and a diradical is produced. After the cyclization step, the diradical can abstract hydrogen atom(s) from purine or pyrimidine of the DNA, which causes the double helices to cleave and eventually leads to cell death. Figure 1: Mechanism of how Calicheamicin cleaves DNA Enediynes are organic compounds containing two carbon-carbon triple bonds and a carbon-carbon double bond. The simplest enediyne is 5, (Z)-hexa-3-en- 1,5-diyne (Figure 2). Enediynes can undergo Bergman cyclization thermally and generate an active diradical intermediate, para-benzyne (6), when heated to 200 C. This is followed by hydrogen atom abstraction from a donor (e.g., cyclohexadiene) to create 7.5 Generally, acyclic enediynes (e.g., 5) require elevated temperatures to go through Bergman cyclization due to their high activation barriers.7 Photocyclization of the acyclic enediynes requires ~ nm wavelength light.8,9 On the other hand, cyclic enediynes (cf., Figure 1) have 48

3 McNair Scholars Journal s Volume 17 lower activation energies and therefore can go through the cyclization reaction under significantly lower temperatures. This difference in activation energies is ascribed to the shortness of the distance (the cd distance; Figure 3)10 between the terminal alkynyl carbons. While the distance in cyclic enediynes is Å, acyclic enediynes are found to have longer cd distances (>3.31 Å).11 Owing to this shorter distance, the cyclization reactions of cyclic enediynes can occur at temperatures as low as 40 C. Photo-activated Bergman cyclization has been of interest to pharmaceutical chemists, due to the potential application in the design of new enediyne-based antitumor drugs. In 1994, Turro and coworkers reported the photosensitized reaction of an aromatic enediyne to yield a cyclized naphthyl product via a 1,4-dehydronaphthalene diradical intermediate, which was expected from a thermal Bergman rearrangement (Figure 4).12 Figure 2: Thermal Bergman cyclization Figure 3: Denoted cd bond distance Figure 4: Photo-activated Bergman cyclization Besides the importance of enediynes in designing antitumor drugs, they can also be used in material science and polymer chemistry as polymerization initiators. 49

4 California State University, Sacramento More specifically, due to their formation of highly reactive aromatic diradicals from Bergman cyclization, enediynes are used both as monomers and initiators in vinyl synthesis.13,14 Enediynes also play a role in material science as highly tunable fluorophores15 and precursors to highly conjugated aromatic polymers.16 By using quantum chemistry software, computational chemists are able to test the cyclization pathways of enediynes with various groups, such as carbonyl, hydroxyl, carboxyl, and alkyl groups, attached to the enediyne moiety. In some cases, the modified enediynes and dieneynes can take different cyclization pathways rather than the Bergman cyclization. Obtained by inserting a carbonyl group into an enediyne and attaching a benzene ring to the terminal alkyne carbon, diarylacetylenes undergo the complicated [4+2] cycloaddition but not Bergman cyclization (Figure 5). Rodríguez et al. examined how the reaction is affected by the nature of the tether linking the diarylacetylene moiety to the other reacting acetylene. Bergman cyclization does not occur due to the hybridization of the tether connecting the reacting alkynes, which is determined to have pronounced effect on the course of the reaction.17,18 Figure 5: 2-propynyldiarylacetylenes undergo thermal intramolecular [4+2] cycloaddition to give benzo[b]fluorene The cyclization reactivity of natural anticancer compounds like Calicheamicins is ascribed to an increase in ring strain upon Michael-addition of the intermediate thiolate. This is why the Bergman cyclization in Calicheamicins can occur at physiological temperature. Besides the effect of ring strain, substituents can also significantly change the activation energy for cyclization of enediynes.10,19 Enediynes with substituents may be easier to develop for anticancer applications since their cyclization reactivity is easier to control than by modifying ring strain. By properly choosing substituents, the organic synthesis chemist may be able to raise or lower the activation energy for enediyne cyclization. The information obtained from these cyclization reactions could help determine which enediynes are most reactive at physiological temperatures. For example, 50

5 McNair Scholars Journal s Volume 17 in work by Gherman and Spence, arenediynes bearing naphthyl substituents were examined.9 Depending upon the attachment point of the naphthyl group to enediyne or the presence/absence of an electron-donating subgroup on the naphthyl substituents, the cyclization reactivity for the enediyne could be favored or blocked. Enediynones and Dieneynones The aim of this project is to study the cyclization reactivity of compounds similar to those from Rodríguez et al.17 An enediynone (such as in Figure 5) first differs from the typical enediyne (Figure 2) by insertion of a carbonyl group. The position of the carbonyl group is important; König et al. demonstrated that the main effect of a carbonyl at the enediyne termini was actually to disfavor Bergman cyclization.20 Next, the enediynone can be modified by changing one of the two alkyne groups into an alkene to give a dieneynone (Figure 6). Dieneynone systems used for the computational calculations in this work are free from the strain effect because its moieties are not surrounded by a ring.21 These novel dieneynone compounds have a wider range of cyclization reactivity than enediynes and can undergo cyclization along four different pathways, generating new diradical intermediates with simultaneous formation of a 5-, 6-, or 7-membered ring (Figure 7). Previous computational research studying reactivity of unsubstituted dieneynones (R=R =H) suggested that experimental study would yield a mixture of cyclization products, difficult to isolate from one another.21 By adding substituents to provide steric bulk at the alkene and alkyne termini, it is intended to disfavor cyclization pathways involving those positions to give more readily analyzable product mixtures. Phenyl and naphthyl groups are chosen as substituents because they are aromatic and should also stabilize the product diradicals via resonance. 51

6 California State University, Sacramento Figure 6: Enediyne, enediynone, and dieneynone Figure 7: C2-C6, C1-C6, C2-C7, and C1-C7 cyclization pathways of dieneynones Density functional theory (DFT) calculations are used to determine the energetics of the four reaction pathways of phenyl and naphthyl monosubstituted and disubstituted dieneynones to determine the reaction pathways that are preferred in each case. Empirical dispersion corrections are included within DFT to account for dispersion interactions between substituents which occur upon cyclization. By determining the activation energies and reaction energies for the cyclization pathways of the substituted dieneynones, it can be demonstrated that substituents can be used to create selectivity among the cyclization pathways. Dispersion Dispersion forces are intramolecular and intermolecular forces present between all types of molecules and atoms. They are the result of oscillations in the electron distribution within molecules and atoms.22 The magnitude of the dispersion force is dependent on how difficult or easily the electrons in the molecules or atoms can move in response to a neighboring dipole (i.e., how polarizable the molecules or atoms are). This in turn depends on the size of the electron cloud.22 Since naphthyl is bigger than phenyl which is larger than a hydrogen atom, so it is expected that dispersion interactions should be greatest with naphthyl rings, lesser with phenyl 52

7 McNair Scholars Journal s Volume 17 rings, and lowest with hydrogen atoms. Using these groups as substituents will have varying effects on the energetics for dieneynone cyclization reactions. A specific form of dispersion that plays a potentially important role in affecting the calculation of cyclization energies for substituted dieneynones is π-π stacking, the interactions between the π clouds of nearby aromatic rings.23 During cyclization, aromatic substituents on the dieneynone can become relatively close to one another, suggesting that dispersion interactions between substituents increase as a result of cyclization. In order to test this factor, a model for studying polar π interactions between arenes spaced at van der Waals distances ( Å) was developed on the basis of peri-diarylbiphenylenes (Figure 8). The result showed that dispersive effects are seen to be an important factor in the proper theoretical treatment of arene interactions.24 Additional research conducted by Roy et al. also showed that π-stacking plays an important role in lowering the activation barrier for enediyne reactivity when nucleobase substituents are added to the termini.25 Figure 8: Geometry of (peri) 1,8-biphenylenes Dispersion In Density Functional Theory Since electron dispersion forces play an important role in determining the structure and properties of molecules, theoretical chemists need to account for it in their calculations. However, it is very challenging using density functional theory (DFT) - the most widely used electronic structure technique - because standard DFT fails to give accurate results for molecules with prominent long-range dispersion interactions between chemical groups.26,27 A variety of techniques, including empirical dispersion correction methods, double-hybrid functionals, and long-range corrected functionals, have been developed towards solving this challenge.28,29 Gherman and co-workers tested several of these new methods to find the best way to include dispersion for enediyne cyclization reactions within DFT calculations, such as using long-range corrected functionals (e.g., ωb97x30 and ωb97xd31), double-hybrid functionals (e.g., B2PLYP32 and B2PLYP-D33), and empirical dispersion corrections (e.g., B3LYP-D2).34 Long-range corrected functionals include not only a dependence on the local electron density when calculating the 53

8 California State University, Sacramento exchange-correlation energy as in standard DFT methods, but they also include a dependence on the long-range electron density which is necessary for capturing long-range interactions such as dispersion.31,33 Double-hybrid functionals combine standard DFT methods and perturbation theory (most commonly MP2 or 2nd-order Møller-Plesset perturbation theory) to give a more precise way of accounting for electron correlation, which is useful for describing dispersion effects.35 Empirical dispersion corrections, which were first developed in 2006 by Grimme et al., are based upon standard DFT methods with an added empirical correction term to specifically account for dispersion energies.34 The results from Gherman and co-workers36 showed that dispersion lowered all activation and reaction energies with B2PLYP-D and B3LYP-D2, in accordance with predictions. B2PLYP-D and B3LYP-D2 also both gave the anticipated trend that dispersion increases as the alkyne substituent groups become bulkier, while ωb97x and ωb97xd did not follow this trend. In terms of computational expense, B2PLYP-D, which includes the time-intensive MP2 perturbation theory in its calculation, was less favorable than the quicker B3LYP-D2 method. Therefore, B3LYP-D2 was chosen for the present research to measure dispersion interactions for the combination of its accuracy and computational efficiency. Connection to the Present Research This study involves using DFT computational methods, including corrections for dispersion energy, to study the cyclization of dieneynones. Standard DFT energies (not including dispersion) are first calculated. Second, energies with both B3LYP (does not have dispersion) and B3LYP-D2 (includes dispersion energies) are computed. The difference between those results (B3LYP-D2 energies minus B3LYP energies) represents the dispersion energy contribution and is added to the standard DFT energies to obtain a dispersion-corrected DFT energy. The size of the dispersion energies are compared as the size and number of substituents are varied. The data can be examined to show how dispersion affects reaction pathway preference. By obtaining the more accurate cyclization reaction energies for the dieneynones, the ability of substituents to favor or disfavor reaction pathways can be confirmed. Subsequently, the organic synthesis laboratory can use these findings to decide which dieneynones to synthesize for further experimental study. Methodology Gaussian 03 and Gaussian 09 quantum chemistry programs37,38 were used to carry out the calculations for the dieneynone cyclization reactions. mpw1pw9139,40 density functional and 6-31(d,p) basis set were chosen for the geometry optimization calculations due to the method s accurate reproduction for the crystal structure of arenediynes.9 By using the combination 54

9 McNair Scholars Journal s Volume 17 of mpw1pw91 density functional and cc-pvtz basis set,41 the single-point electronic energies for the optimized geometries were obtained. In order to confirm that the optimized structures were stationary points, and obtain free energies at 25 C for all of the structures, vibrational frequency calculations were used. For the dieneynone reactants, calculations were carried out with restricted wave functions, while the transition states and diradical products from the cyclization reactions used broken-symmetry unrestricted wave function calculations.42,43 Both singlet and triplet states were calculated for the transition states and products. Data showed the singlet states to be consistently lower in energy, therefore all reaction energies were calculated based on the singlet states.44 After the thermal cyclization pathway energies using mpw1pw91 were obtained, a combination of B3LYP45 and B3LYP-D246 DFT methods were used to obtain dispersion energies for all of the structures. All of the same calculation procedures were used as with mpw1pw91, but with both B3LYP and B3LYP-D2 density functionals. B3LYP is a standard density functional in that it does not account for dispersion interactions. The D2 part in B3LYP-D2 represents an empirical a posteriori correction term proposed by Grimme47 to account for dispersion forces. By subtracting the B3LYP energies from the B3LYP-D2 energies, dispersion energies for each structure were obtained.48 The dispersion energies are then added to the mpw1pw91 energies to get a dispersion-corrected free energy for each structure (eq. 1). mpw1pw91 + dispersion correction = mpw1pw91 + (B3LYP-D2 B3LYP) (1) Results and Discussion Reaction Energetics Free energies of activation and free energies of reaction are given in Tables 1 and 2, respectively, for each of the four cyclization pathways for the unsubstituted, mono-substituted (C1 or C7 position), and disubstituted (both C1 and C7 positions) dieneynones with phenyl and naphthyl substituents. According to the calculations, addition of aryl substituents to the C1 and C7 positions raises the activation energies and reaction energies for pathways involving those positions, while lowering the energies of the pathways involving the unsubstituted positions. Figure 9 shows the reaction coordinates when phenyl is added to C1 position. In this case, the C1-C7 and C1-C6 pathways have the greatest activation and reaction energies. The same trend applies when adding phenyl to the C7 terminus; C1-C6 and C2-C6 became the pathways that have the lowest energetic barriers (Figure 10). On average, the difference between the pathways 55

10 California State University, Sacramento involving the substituted versus unsubstituted position is ~4.5 kcal/mol for the C1-phenyl case and ~8.2 kcal/mol for the C7-phenyl case. These results show that steric bulk at the C1 and C7 positions can affect the reaction energies, creating a larger difference in activation and reaction energies than seen with the unsubstituted dieneynone. H C1- Phenyl C7- Phenyl C1C7- Diphenyl C1- Naphthyl C7- Naphthyl C2-C C1C7- Dinaphthyl C2-C C1-C C1-C Table 1: Activation energies (ΔG, kcal/mol) for all of the dieneynones and four different pathways H C1- Phenyl C7- Phenyl C1C7- Diphenyl C1- Naphthyl C7- Naphthyl C2-C C1C7- Dinaphthyl C2-C C1-C C1-C Table 2: Reaction energies (ΔGrxn, kcal/mol) for all of the dieneynones and four different pathways 56

11 McNair Scholars Journal s Volume 17 Figure 9: Reaction coordinates for C1-phenyl substituted dieneynone Figure 10: Reaction coordinates for C7-phenyl substituted dieneynone Dispersion Effects Table 3 gives the dispersion contribution, calculated as the B3LYP-D2 energy minus the B3LYP energy, to the activation energies and reaction energies. These values in Table 3 were obtained by averaging the dispersion contribution to the activation energies and reaction energies. The dispersion effects on the reaction energetics range from kcal/mol with the unsubstituted dieneynone to as much as kcal/mol with the naphthyl-disubstituted dieneynone. 57

12 California State University, Sacramento Unsubstituted C1 Substituent C7 Substituent C1 & C7 Substituents H Phenyl Naphthyl Phenyl Naphthyl Phenyl Naphthyl C2-C C2-C C1-C C1-C Table 3: Dispersion contribution to reaction energetics (kcal/mol) size Table 4 shows the average dispersion effect on the reaction energetics for the cases of zero, one, and two phenyl or naphthyl substituents at the C1 and C7 positions. In all cases, dispersion is a favorable effect and lowers the activation and reaction energies. The dispersion effect increases from unsubstituted (i.e., H substituent) to the phenyl substituted cases due to the size increase from H to phenyl and the π-stacking interaction that is present with phenyl substituents. However, the increase in substituent size does not make a significant difference to the dispersion energies in going from the phenyl to the naphthyl cases. Increasing substituent size further from phenyl to naphthyl only slightly further increases the dispersion effect by kcal/mol. 58 Unsubstituted C1 Substituent C7 Substituent C1 & C7 Substituents H Phenyl Naphthyl Phenyl Naphthyl Phenyl Naphthyl Average Table 4: Average dispersion energy contribution per substituent (kcal/mol) Dispersion effects increased with the number of substituents. The smallest values of dispersion energies were found in the unsubstituted case. Dispersion contributions to reaction energetics were larger in the monosubstituted cases, with those energies being similar between C1 and C7 positions. The largest values of dispersion energies were obtained with the disubstituted cases. However, the effect in the disubstituted cases is less than what would be obtained from adding the two monosubstituted cases together. Dispersion effects were largest for the C1-C7 pathway and smallest for the C2- C6 pathway (Table 5). These differences are due to the spatial proximity of the substituents in the different cyclization products. For example, looking at the dinaphthyl cases (Figure 11), the substituents are farthest away from each other in the C2-C6 product and closest in the C1-C7 product. The substituents are at roughly equivalent distances in the C1-C6 and C2-C7 products, consistent with the similar effect of dispersion on those two pathways.

13 McNair Scholars Journal s Volume 17 Dispersion Energies C2-C C2-C C1-C C1-C Table 5: Average dispersion energy contribution per reaction pathway (kcal/mol) C1-C6 C2-C7 C2-C6 C1-C7 Figure 11: Three dimensional structures of the C1-C6, C1-C7, C2-C6, and C2-C7 transition states for case of dinaphthyl substituentssubstituent Effects The effect of substituents on the reaction energies is larger than on the activation energies (Table 6 & Table 7). This can be attributed to a greater interaction between substituents in the products versus the transition states as the substituents approach each other more in the product structures. For instance, the average effect on activation energies from C1 phenyl and C7 naphthyl is respectively 4.2 kcal/mol and 4.7 kcal/mol while average effect on reaction energies from C1 phenyl and C7 naphthyl is 6.7 kcal/mol and 7.2 kcal/mol. 59

14 California State University, Sacramento ΔΔG vs. H C1 Substituent C7 Substituent C1 & C7 Substituents Phenyl Naphthyl Phenyl Naphthyl Phenyl Naphthyl C2-C C2-C C1-C C1-C Table 6: Substituent effects on activation energies for the four different pathways (kcal/mol) 60 ΔΔGrxn vs. H C1 Substituent C7 Substituent C1 & C7 Substituents Phenyl Naphthyl Phenyl Naphthyl Phenyl Naphthyl C2-C C2-C C1-C C1-C Table 7: Substituent effects on reaction energies for the four different pathways (kcal/mol) As shown in red in Tables 6 & 7, energies for pathways not involving substituents decrease in energy relative to the unsubstituted case. In contrast, energies for pathways at substituent positions increase in energy relative to the unsubstituted case, as shown in blue in Tables 6 & 7. For instance, with a C1 substituent, C1- C6 and C1-C7 pathways increase in energy versus the unsubstituted pathway, while C2-C7 and C2-C6 pathways decrease in energy versus the unsubstituted case. Energies in black reflect the cases under disubstitution in which one reaction position is substituted but the other reaction position is not. In these cases, the reaction energies (in black) are very close to the energies seen with the unsubstituted dieneynone. For activation energies, reaction pathways involving unsubstituted positions are lowered more than reaction pathways involving substituted positions are raised. For example, in C1 monosubstituted cases, activation energies for pathways without substituents are lowered by kcal/mol, whereas pathways with substituents are raised by kcal/mol. A similar trend is seen with C7 substituents and both activation and reaction energies. However, with C1 substituents, in the case of reaction energies, the pattern is opposite with pathways involving substituents being raised more than the alternative pathways being lowered in energy. Furthermore, the effects on activation and reaction energies relative to the unsubstituted case are larger for C1 substitution compared to C7 substitution. As seen in Tables 6 & 7, there is ~1 kcal/mol bigger effect for C1 substitution on activation energies and ~2 kcal/mol bigger effect for C1 substitution on reaction energies.

15 McNair Scholars Journal s Volume 17 For the disubstituted case, reaction energies and activation energies calculated from computational modeling of the C2-C6 pathway were determined to be significantly decreased relative to the unsubstituted case (shown in red in Tables 6 & 7) as this pathway involves neither of the substituted positions. In contrast, the C1-C7 pathway with the disubstituted dieneynones has a significantly increased reaction energy and activation energy barrier as compared to the unsubstituted case (shown in blue in Tables 6 & 7). This is consistent with this pathway having reactivity at both the C1 and C7 positions. Interestingly, under disubstitution, the C2-C7 and C1-C6 pathways reaction and activation energies are nearly unchanged compared to the unsubstituted case. These pathways each involve a reaction between one of the substituted termini and one non-terminal alkyne/ alkene carbon. Tables 8 & 9 assess the additivity of the dispersion effects in going from the monosubstituted to the disubstituted dieneynones. Both phenyl and naphthyl substituent cases showed that the difference for the disubstituted cases versus unsubstituted cases was approximately equal to the two monosubstituted C1 and C7 cases summed together. In most cases, though, the energy change for disubstituted versus unsubstituted cases is slightly smaller than the sum of the monosubstituted cases, except for the case with the C2-C6 activation energies. ΔΔG vs. H (kcal/mol) C1-Phenyl + C1-Naphthyl + C7- C1C7-Diphenyl C1C7-Naphthyl C7-Phenyl Naphthyl C2-C C2-C C1-C C1-C Table 8: Comparison of ΔΔG (C1-C7) versus ΔΔG (C1) + ΔΔG (C7) (kcal/mol) ΔΔGrxn vs. H (kcal/mol) C1-Phenyl + C1-Naphthyl + C7- C1C7-Diphenyl C1C7-Naphthyl C7-Phenyl Naphthyl C2-C C2-C C1-C C1-C Table 9: Comparison of ΔΔGrxn (C1-C7) versus ΔΔGrxn (C1) + ΔΔGrxn (C7) (kcal/mol) 61

16 California State University, Sacramento For the case of substitution at both of the C1 and C7 positions with either phenyls or naphthyls, the resulting changes in activation and reaction energies are quite significant. First, if there are no termini involved in the pathway, i.e., the C2-C6 pathway, then activation and reaction energies can drop by ~10 kcal/ mol versus the C2-C6 pathway for the unsubstituted dieneynone. On the other hand, if both termini are involved in the pathway, i.e., the C1- C7 pathway, then activation and reaction energies can rise ~10 kcal/mol versus the C1-C7 pathway for the unsubstituted dieneynone. Reactivity differences of that size suggest that disubstitution can be used to effectively both block a reaction pathway and strongly favor a different reaction pathway. Overall, there is not a large difference in either activation energies or reaction energies between phenyl-substituted and naphthyl-substituted dieneynones. The average difference in activation energies upon changing from phenyl to naphthyl substituents ranges from 0.4 kcal/mol in the case of C7 substitution to 1.0 kcal/mol for C1,C7 disubstitution. Similarly, the average difference in reaction energies upon changing from phenyl to naphthyl substituents ranges from 0.5 kcal/mol in the case of C7 substitution to 0.8 kcal/mol for C1,C7 disubstitution. The only large differences occur along the C2-C6 reaction pathway in the case of C1,C7 disubstitution, in which phenyl and naphthyl reaction energetics differ by kcal/mol. The difference in activation energies between naphthyl- and phenyl-substituted dieneynones generally correlates with the difference in activation energies between naphthyl-substituted and unsubstituted dieneynones (Figure 12). A similar qualitative relationship can be seen with reaction energies as well (Figure 13). In each case of activation or reaction energies, the larger the effect of the naphthyl substituent(s) on reaction pathway energy, the greater the difference there is in the reaction pathway energies between the naphthyl- and phenyl-substituted dieneynones. Figure 12: ΔΔG between naphthyl-substituted and phenyl-substituted dieneynones plotted against ΔΔG between naphthyl-substituted and unsubstituted dieneynones. 62

17 McNair Scholars Journal s Volume 17 Figure 13: ΔΔGrxn between naphthyl-substituted and phenyl-substituted dieneynones plotted against ΔΔGrxn between naphthyl-substituted and unsubstituted dieneynones. Conclusion Adding phenyl and naphthyl substituents to dieneynones has been demonstrated to be an effective way to affect the activation and reaction energies for cyclization to favor some pathways while disfavoring others. It is predicted then that product mixtures from cyclization of dieneynones with sterically bulky substituents will be less complex, making their experimental analysis and separation easier. Future work will test the potential of applying substituents to affect the cyclization of enediynones to see if similar reactivity trends can be obtained as here with the dieneynones. 63

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