Cinchona Alkaloids Catalyzed Asymmetric Reactio - American

Supporting Information for:

A Mechanistic Rationale for the 9-Amino(9-deoxy)epi Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones Antonio Moran,1 Alex Hamilton,1 Carles Bo,1,2 and Paolo Melchiorre1,3*

1

ICIQ - Institute of Chemical Research of Catalonia, Avenida Països Catalans 16 - 43007 Tarragona, Spain URV- Dept. de Química Física i Inorgànica, Universitat Rovira i Virgili, Marcel.li Domingo - 43007 Tarragona, Spain 3 ICREA - Institució Catalana de Recerca i Estudis Avançats, Passeig Lluís Companys 23 - 08010 Barcelona, Spain 2

*To whom correspondence should be addressed. E-mail: [email protected]

Supporting Information

Steric control element

Cooperation of Covalentand Noncovalent-Based Modes of Catalysis H-Bonding Interactions

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Table of Contents A. General Information

S3

A.1 Complete Gaussian 09 Reference (Ref. 28c in the main text)

S2

A.2 General Procedures and Materials

S3

B. Effect of Additives on the Model Friedel-Craft Alkylation

S4

B.1 Effect of the TFA concentration on the enantiomeric excess B.2 Effect of the TFA concentration on the rate

S4 S5

B.3. Effect of the HMPA on the reaction rates

S6

B.4. Effect of HMPA on the enantiomeric excess B.5 Studying the Effect of HMPA by means of NMR Analysis

S7 S9

C. Effect of acid concentration on the rate of the Friedel-Craft Alkylation D. Kinetic Studies of the Friedel-Craft Reaction.

S11 S11

D.1 Calorimeter experiments. D.2 Kinetic Model for the reaction catalyzed by the 1∙(TFA)2.3 combination

S11 S17

D.3 Kinetic Model for the reaction catalyzed by the 1∙(TFA)2 combination D.4 Effect of water on the rate of the Friedel-Craft Alkylation

S18 S20

D.5 Eyring analysis

S22

E. Computational Investigations

S27

E.1 Computational Details

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E.2 Computational Approaches to Study the Conformational Behaviour of Amine 1a E.3 Computational Approaches to Study the Conformation of the Iminium Ion A

S27 S29

E.4 Computational Study of the Carbon-Carbon Bond Formation Transition States E.5 Geometries and Energies of Calculated Stationary Points

S30 S31

A. General Information A.1 Complete Gaussian 09 Reference (Ref. 29c in the main text). Frisch, M. J.; Trucks, G. W.; Schlegel, H.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02, Gaussian Inc., Wallingford CT 2009.

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A.2 General Procedures and Materials. The 1H and 13C NMR spectra were recorded at 400 MHz and 500 MHz for 1H or at 100 MHz and 125 MHz for 13C, respectively. The chemical shifts (δ) for 1H and 13C are given in ppm relative to residual signals of the solvents (CHCl3 @ 7.26 ppm 1H NMR, 77.0 ppm 13C NMR). Coupling constants are given in Hz. When necessary, 1H and 13C signals were assigned by means of g-COSY, g-HSQC and g-HMBC 2D-NMR sequences. When 2D-NMR was not performed, carbon types were determined from DEPT 13C NMR experiments. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; qn, quintet; m, multiplet; bs, broad signal. High-resolution mass spectra (HRMS) were obtained from the ICIQ High Resolution Mass Spectrometry Unit on Waters GCT gas chromatograph coupled time-of-flight mass spectrometer (GC/MS-TOF) with electron ionization (EI). The authors are indebted to the team of the Research Support Area at ICIQ. General Procedures. All the reactions were set up under air and using freshly distilled solvents, without any precautions to exclude moisture, unless otherwise noted - open air chemistry on the benchtop. Chromatographic purification of products was accomplished using force-flow chromatography (FC) on silica gel (35-70 mesh). For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of ceric ammonium molybdate or basic aqueous potassium permangante (KMnO4), and heat as developing agents. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Materials. Commercial grade reagents and solvents were purchased from Sigma Aldrich, Fluka, and Alfa Aesar and used as received, without further purification. Otherwise, where necessary, they were purified as recommended.1 Hexamethylphosphoric triamide (HMPA) was purified by distillation under vacuum and stored over 4Å molecular sieves under argon to avoid the presence of water. Note that the presence of water within HMPA may affect the rate of the model reaction. Freshly distilled TFA was used for all the kinetic runs in the calorimetry and others kinetic studies. The chiral primary amine catalyst, 9-amino-9deoxyepiquinine 1a, was prepared from commercially available quinine following the literature procedure.2 Determination of the Enantiomeric Purity. HPLC analysis on chiral stationary phase was performed on an Agilent 1200-series instrumentation. Daicel Chiralpak IA column with i-PrOH/hexane as the eluent was used. HPLC traces were compared to racemic samples prepared using TFA as a catalyst (Brønsted-acid catalyzed racemic pathway). Determination of the Product Concentration and Yield from HPLC Analysis. The yield of the model reaction was determined using 1,3,5-trimethoxybenzene as the internal standard by HPLC analysis on a Daicel Chiralpak IA column: 90/10 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 215 nm: τmajor = 7.9 min, τminor = 9.2 min. The concentration of the reaction product, 4-(2-methyl-1H-indol-3-yl)octan2-one (4a), was determined directly from the area of the product peak, the area of 1,3,5-trimethoxybenzene in the HPLC spectra (detector @ 215 nm) and the known concentration of the internal standard making use of the following equation (see Figure S1 for the calibration curve):

[Product ]  0.7237 

1 2

Area Product HPLC peak at 215 nm  [Internal Standard] Area Internal Standard HPLC peak at 215 nm

W. L. F. Armarengo, D. D. Perrin, In Purification of Laboratory Chemicals, 4th ed.; Butterworth Heinemann: Oxford, 1996. C. Cassani, R. Martín-Rapún, E. Arceo, F. Bravo, P. Melchiorre, Nat. Protoc. 2013, 8, 325.

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Figure S1. Calibration curve for the determination of the concentration of 4-(2-methyl-1H-indol-3-yl)-octan-2-one (4a) in the presence of 1,3,5-trimethoxybenzene as the internal standard by HPLC analysis; IS: Internal Standard.

B. Effect of Additives on the Model Friedel-Craft Alkylation. B.1 Effect of the TFA concentration on the enantiomeric excess of the model reaction. The reaction of 2a (0.24 M) and enone 3a (0.21 M) catalyzed by amine 1a (0.04 M) in toluene at 45 °C was repeated over a range of concentrations of TFA. The correlation between the enantioselectivity of the process and the amount of TFA, as detailed in Figure S2, clearly indicates that the optical purity of the product 4a is affected by high acid concentrations. This was rationalized (and confirmed by control experiments reported in Table S1, page S6) on the basis of a non-stereoselective acid-catalyzed background reaction. It is known, indeed, that strong Brønsted acids can catalyze the Friedel-Craft reaction of indoles with enones.3

Figure S2. Plot of enantiomeric excess vs [TFA]/[1a] for the Friedel-Craft alkylation of 3-octen-2-one 3a with 2-methylindole 2a @ 45 C0. Reaction conditions: [1a]= 0.04 M; [2a]= 0.240 M; [3a]= 0.213 M; [TFA]= 0.023-0.096 M.

All the reactions were carried out in freshly distilled toluene with a known concentration of the internal standard (1,3,5-trimethoxybenzene), without any precaution to exclude air and moisture (open air chemistry on the benchtop). Reactions were performed at 45 ºC in a 2 mL ordinary vial equipped with a Teflon-coated 3

a) Zhou, W.; Xu, L.-W.; Li, L.; Yang, L.; Xia, C.-G. Eur. J. Org. Chem. 2006, 5225-5227. b) Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.F.; He, L.-N.; Tang, C.-C. Eur. J. Org. Chem., 2008, 1406-1410. c) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593–596.

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stir bar and a plastic screw cap. The reaction mixtures with different initial concentration of freshly distilled trifluoroacetic acid (TFA) were prepared by mixing 200 μL of a stock solution of 9-amino(9-deoxy)epiquinine (1a, 0.080 M) and 2-methylindole (2a, 0.480 M), different amounts of a freshly prepared stock solutions of TFA (0.210 M) and the needed amount of toluene to bring the total volume of the mixture to 0.350 μL. The reaction was started by adding 50 microliters of a freshly prepared stock solution of 3-octen2-one (3a, 1.750 M). After 2 hours a 10 microliter sample from the reaction mixture was taken and dissolved in 1 mL of an 80/20 hexane/i-PrOH mixture and subjected to HPLC analysis. The enantiomeric excesses were determined by HPLC analysis.

B.2 Effect of the TFA concentration on the rate of the model reaction. The presence of an acid-promoted racemic pathway was confirmed by initial rates measurements for the Friedel-Craft alkylation with different initial concentration of TFA with respect to amine 1a.

Figure S3. Plot of initial reaction rates vs [TFA]/[1a] for the Friedel-Craft Alkylation in toluene @ 45 ºC. Reaction conditions: [1a]= 0.04 M; [2a]= 0.240 M; [3a]= 0.200 M; [TFA]= 0.027-0.162 M. Comments to Figure S3: The rate is strongly dependent on the ratio [TFA] / [1a]. The continuous increase of the rate while adding TFA is ascribable to the higher free acid concentration and the resulting fast background Brønsted acid-promoted pathway, which greatly affects the overall stereoselectivity (see Figure S2) and reactivity of the process.

Initial rates measurements for the Friedel-Craft alkylation with different initial concentration of TFA. All reactions were carried out with a known concentration of the internal standard. The reaction mixtures with a different initial concentration of TFA were prepared by mixing 200 μL of a stock solution of 9-amino(9-deoxy)epi-quinine (1a, 0.080 M) and 2-methylindole (2a, 0.480 M) with different amounts (00.150 μl) of a freshly prepared stock solutions of distilled TFA (0.426 M) and the needed amount of toluene to bring the total volume of the system to 0.350 μL. The reaction was started by adding 50 microliters of a freshly prepared stock solution of 3-octen-2-one (3a, 1.680 M). During the first 2-20 minutes (conversion lower than 10 % with a linear concentration increase), six samples were collected from the reaction mixture, dissolved in 1 mL of an 80/20 hexane/i-PrOH mixture and subjected to HPLC analysis. The concentration of the product at different reaction times was determined by HPLC analysis. The initial rates were obtained by linear regression of the data.

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Table S1. Ability of acids characterized by different strengths to promote a background non-stereoselective pathway.

acid p-TSA CCl3COOH TFA 2-OH-C6H4CO2H 4-NO2-C6H4CO2H N-Boc-D-Phenylglycine 2,6-(OCH3)2-C6H4CO2H

Time 20 minutes 20 minutes 20 minutes 24 hours 24 hours 24 hours 24 hours

Yield (%) 90 86 93 36 7 10 7

General reaction conditions: reactions performed on a 0.2 mmol scale using 40 mol% of the acid, 1.2 equiv. of 2a and [3a]= 0.2 M in toluene. Note that no amine 1a was used.

The results in Table S1 clearly indicate that only strong acids, such as TFA, are able to promote a background non-stereoselective Friedel-Crafts reaction. B.3 Effect of the HMPA on the reaction rates. The presence of an acid-promoted racemic pathway that competes with the stereoselective aminocatalytic regime would preclude the possibility for a mechanistic study, since both the rate and the enantiomeric excess of the reaction are altered. We reasoned that the presence of an additive characterized by a strong hydrogen-bond-accepting ability4 could greatly reduce the rate of the acid-catalyzed background process by sequestering the free TFA that is not engaged in electrostatic (acid-base) interactions with the basic moieties of the amine 1a. Extensive studies revealed that hexamethylphosphoric triamide (HMPA) greatly inhibited the Brønsted acid-promoted pathway (Scheme S1a, reaction rate reduced 40 times). On the contrary, HMPA has a minimal influence on the organocatalytic regime (Scheme S1b).

Scheme S1. Effect of the HMPA (1.75 ratio with respect to [TFA]) on the rates of a) the Brønsted acid-catalyzed pathway, and b) the organocatalytic reaction; rates extrapolated from initial rate measurements. Prior to use, HMPA was distilled under vacuum and stored over 4Å molecular sieves under argon to avoid the presence of water. Note that the presence of water within HMPA may affect the rate of the model reaction (See Section D.4 for details).

From the results depicted in Scheme S1a, it is clear that HMPA greatly inhibited the Brønsted acidpromoted pathway while minimally affecting the organocatalytic regime. This result brings about important mechanistic implications, since it excludes the possibility for a chiral acid-catalyzed pathway to be operative in the enantioselective reaction. Indeed, a mechanism where the protonated ammonium salt of 1a may act as a chiral acid could be envisaged. However, the small reduction of 4

a) Anslyn, E. V.; Dougherty, D. A. in Modern Physical Organic Chemistry, University Science Book (2005), chapter 3, pages 145-155. b) Kamlet, M. J.; Abboud, J.-L M.; Abraham, M. H.; Taft, R. W. J. Org. Chem. 1983, 48, 2877-2887.

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the reaction rate of the organocatalytic reaction when using HMPA is not consistent with this noncovalent mode of catalysis. This supports a covalent mode of catalysis for amine 1a through iminium ion formation in the model Friedel-Crafts alkylation (see Figure S4 for the two possible pathways).

Figure S4. The two distinct modes of catalysis that might be operative in the model reaction - Kinetic data support a covalent activation mode via iminium ion formation.

B.4.1 Effect of HMPA on the enantiomeric excess. The ability of HMPA to suppress the acid-catalyzed pathway provided a reliable catalytic system for our mechanistic studies. Indeed, repeating the [TFA]/stereoselectivity correlation studies in the presence of a 1.75 constant ratio between [HMPA] and [TFA] led to a more consistent profile of the enantioselectivity (ee in the range of 80-84% ee, Figure S5). The data should be compared to the results in Figure S2.

Figure S5. Plot of the enantiomeric excess vs [TFA]/[1a] for the model Friedel-Craft Alkylation @ 45 0C. Reaction conditions: [1a]= 0.04 M; [2a]= 0.240 M; [3a]= 0.200 M; [TFA]= 0.027-0.162 M; [HMPA]= 0.049-0.286 M. HMPA dried over molecular sieves was used.

Reaction mixtures with different initial concentrations of TFA and HMPA (constant ratio [HMPA]/[TFA]=1.75) were prepared by mixing 200 μL of a stock solution of 9-amino(9-deoxy)epi-quinine (1a, 0.080 M) and 2-methylindole (2a, 0.480 M), different amounts (0-0.150 μL) of a freshly prepared stock solutions of distilled TFA (0.426 M) and HMPA (0.755 M) and the needed amount of toluene to bring the total volume of the system to 0.350 μL. The reaction was started by adding 50 microliters of a freshly prepared stock solution of 3-octen-2-one (3a, 1.600 M). A 10 microliter sample was taken from the reaction mixture and dissolved in 1 mL of an 80/20 hexane/i-PrOH mixture. The enantiomeric excesses were determined by HPLC analysis.

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B.4.2 Effect of HMPA concentration on the enantiomeric excess. Figure S6 shows that the best ratio between [HMPA] and [TFA] is 1.75. Upon further increase of the HMPA concentration, the ee of the model reaction remained almost constant.

Figure S6. Plot of the enantiomeric excess vs [HMPA] for the model reaction at 25 C0. Reaction conditions: [1a]= 0.04 M; [2a]= 0.240 M; [3a]= 0.201 M; [TFA]= 0.083 M; [HMPA]= 0-0.240 M. Freshly distilled TFA and HMPA were used.

The reactions were performed at 25 ºC. The reaction mixtures with different initial concentration of hexamethylphosphoramide (HMPA) were prepared by mixing 100 μL of a stock solution of 9-amino(9deoxy)epi-quinine (1a, 0.080 M), 2-methylindole (2a, 0.480 M) and TFA (0.166 M), different amounts (00.050 μL) of a freshly prepared stock solutions of HMPA (0.75 M) and the needed amount of toluene to bring the total volume of the system to 0.150 μL. The reaction was started by adding 50 microliters of a freshly prepared stock solution of 3-octen-2-one (3a, 0.875 M). After 2 hours, a 10 microliter sample was taken from the reaction mixture and dissolved in 1 mL of an 80/20 hexane/i-PrOH mixture and subjected to HPLC analysis. The enantiomeric excesses were determined by HPLC analysis. The overall effect of HMPA on the model Friedel-Craft alkylation. The role of HMPA is to suppress the acid-catalyzed pathway, thus providing a reliable catalytic system for our mechanistic studies. HMPA seems to have a minimal influence, if any, on the organocatalytic regime. To challenge the possibility that HMPA may have a direct effect on the stereoselectivity of the cinchonabased primary amine 1a catalyzed Friedel-Crafts reaction, we carried out the experiments detailed in Table S2. We used different acids, within a wide range of pKa, and with a different ability to promote the acidcatalyzed addition of indole 2a to enone 3a (please refer to results detailed in Table S1 @ page S6). The results reported in Table S2 clearly show that the enantioselectivity of the model reaction is affected by the presence of HMPA only when using a combination of chiral amine 1a and an acid that is strong enough to catalyze the reaction by itself (strong acids like TFA, trichloroacetic acid or para-toluenesulfonic acid, see Table S1 @ page S6). The increase of the enantioselectivity when using a strong acid such as TFA and in the presence of HMPA can be ascribed to the suppression of the acid-catalyzed background reaction, which restores the intrinsic stereoselectivity of the amine 1a/acid catalyst combination. These results suggest that HMPA is not affecting the stereoselectivity of the iminium ion-catalyzed process.

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Table S2. Enantioselectivities for the model Friedel-Craft alkylation catalyzed by 1a and different acidic derivatives.

acidic additive p-TSA CCl3COOH CF3COOH 2-OH-C6H4CO2H 4-NO2-C6H4CO2H N-Boc-D-Phenylglycine 2,6-(OCH3)2-C6H4CO2H

Without HMPA

ee (%) 56 76 73 91 93 94 97

With HMPA

ee (%)a 69 88 86 92 93 94 97

General reaction conditions: reactions performed on a 0.2 mmol scale using 20 mol% of amine 1a, 40 mol% of the acid, 1.2 equiv. of 2a and [3a]= 0.2 M in toluene over 24 hours. a Reaction performed in the presence of HMPA (adjusted to keep [HMPA]/[acid] = 1.75).

B.5 Studying the Effect of HMPA by means of NMR Analysis 1 H NMR spectroscopic study, detailed in Figure S7, further indicates that HMPA, acting as a Lewis base, greatly outperforms the ability of the carbonyl oxygen of the enone 3a to interact with TFA. The chemical shift and the shape of the signal of the proton B in 3a is sensitive to the presence of a strong acid like TFA (Figure S7a vs Figure S7b). In the presence of both HMPA and TFA, the shape and the chemical shift of this signal remains unchanged to the one observed in the absence of TFA (Figure S7a vs Figure S7c).

Figure S7a. 1H NMR 500 MHz of 3-octen-2-one (3a) in toluene-d8.

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Figure S7b. 1H NMR 500 MHz of 3-octen-2-one (3a) + 1 equivalent of TFA in toluene-d8.

Figure S7c. 1H NMR 500 MHz of 3-octen-2-one (3a) + 1 equivalent of TFA + 1 equivalent HMPA in toluene-d8.

Figure S7d. Resume of the change of the 1H NMR vinylic proton signal of 3a in the presence of TFA and a mixture of TFA/HMPA.

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C. Effect of the Acid Concentration on the Rate of the Friedel-Craft Alkylation. With consistent experimental conditions in hand, we analyzed the effect of the acid concentration on the rate of the model reaction. Again, the correlation studies carried out in the absence or the presence of HMPA showed strikingly different behaviors (compare Figure S3 @ page S5 with Figure S8 below). The results further confirm the presence of a background reaction altering the kinetic profile when HMPA is absent. Initial rates measurements for the Friedel-Craft Alkylation with different initial concentration of the TFA and in the presence of HMPA. Reaction mixtures with different initial concentrations of HMPA and TFA were prepared by mixing 200 μL of a stock solution of 9-amino(9-deoxy)epi-quinine (1a, 0.080 M) and 2-methylindole (2a, 0.480 M), different amounts (0-0.150 μL) of a freshly prepared stock solutions of HMPA (0.755M) and distilled TFA (0.426 M) and the needed amount of toluene to bring the total volume of the system to 0.350 μL. The reaction was started by adding 50 microliters of a freshly prepared stock solution of 3-octen-2-one (3a, 1.600 M). Six samples from the reaction mixture were collected during the first 2-40 minutes (conversion lower than 10 % with linear concentration increase). After dilution in 1 mL of an 80/20 hexane/i-PrOH mixture, the concentration of the product 4a was determined by HPLC analysis. The initial rates were obtained by linear regression of the data.

Figure S8. Plot of initial reaction rates vs [TFA] / [1a] for the Friedel-Craft Alkylation in toluene at 45 ºC. Reaction conditions: [1a]= 0.04 M; [2a]= 0.240 M; [3a]= 0.200 M; [TFA]= 0.027-0.162 M; [HMPA]= 0.049-0.286 M, adjusted to keep [HMPA]/[TFA] = 1.75. HMPA dried over molecular sieves was used

D. Kinetic Studies of the Friedel-Craft Reaction. D.1 Calorimeter experiments. The progress of the reaction of 2a and 3a, catalyzed by the 1a∙(TFA)2.3 and in the presence of HMPA (1.75 ratio with respect to TFA) at 45 ºC, was in situ monitored in a calorimeter. The reaction progress kinetic analysis (RPKA) was repeated using the catalyst combination 1a∙(TFA)2. These studies revealed very similar kinetic profiles for the two catalytic systems. General Experimental Procedure for Kinetic Studies Using Reaction Calorimetry. Reactions were performed in an Omnical SuperCRC 20-250-2.4 microcalorimeter. The instrument contains a differential scanning calorimeter (DSC), which compares the heat released or consumed in a sample vessel with respect to a reference vessel. The temperature of the DSC was held constant at 45 ºC, ensuring that the reaction would proceed under isothermal conditions. The reaction vessels were 16 mL borosilicate screw-thread vials fit with a black phenolic screw caps and white PTFE septa charged with Teflon stir bars. In a typical calorimetry experiment, a reaction vessel containing a solution of the proper amounts of 9amino(9-deoxy)epi-quinine (1a), 2-methylindole (2a, Sigma-Aldrich), TFA (Sigma-Aldrich) and anhydrous HMPA (Sigma-Aldrich, stored over activated molecular sieves) was placed in the calorimeter. A reference vessel containing the same amount of all the reagents except the 9-amino(9-deoxy)epi-quinine and TFA was prepared too. Two syringes, one for the reaction vessel and another for the reference vessel, containing 3octen-2-one (3a, Alfa Aesar) were placed in the sample injection port of the calorimeter. All the system was S11

allowed to thermally equilibrate for at least 60 minutes. The reaction was initiated by injecting the 3-octen-2one (3a) into the reaction and the reference vessels at the same time. A raw data curve was produced by measuring the heat flow from the sample vessel every 3 seconds during the reaction. When no more heat was developed, a 10 microliter sample from the reaction mixture was taken and dissolved in 1 mL of an 80/20 hexane/i-PrOH mixture and subjected to HPLC analysis. The yield and the enantiomeric excess for the product 4a were determined by HPLC analysis. Due to the delay between the instantaneous moment heat evolved from the reaction vessel and the time the thermophile sensor detects the heat flow, the raw data curve must be calibrated. To accomplish this calibration, a constant amount of current was passed through a resistor in the sample chamber of the calorimeter thereby producing a known quantity of heat. This process results in a response curve, which is then transformed into a square wave allowing for the response time of the instrument to be calculated using the WinCRC software. Application of the response time to the raw data gives a “tau corrected data curve” (plot of heat flow (mJ/s) versus time). The reaction rate and the fraction conversion at any time can be obtained from the “tau corrected” heat flow (eq S1, eq S2). The instantaneous concentrations of reactants/products can all be calculated from the conversion and the initial concentrations of the reactants. For the reaction under study an average heat of reaction of 17.5 ± 1.0 Kcal/mol was obtained.

q  H V  v (eq S1) Eq S1. q is the reaction heat flow, ΔH is the heat of reaction, V is the reaction volume, and v is the reaction rate. The heat of the reaction can be obtained from integration of the observed heat flow versus time curves. t

conversion 

 q(t )dt 0 tf

(eq S2)

 q(t )dt 0

Eq S2. The numerator represents the area under the heat flow to any time point t and the denominator represents the total area under the heat flow curve.

The in-situ calorimetry technique needs to be calibrated with an independent analytical method; therefore the final conversion determined from the heat flow was compared in all cases with the one obtained by HPLC measurements. The overlaying obtained in Figure S9, confirms that the observed heat flow represents an accurate measure of the rate of the reaction under study.

Figure S9. Comparison of fraction conversion vs time for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole at 45 ºC obtained with two independent methods: heat flow and HPLC. [1a] = 0.04, [2a] = 0.304, [3a] = 0.207, [TFA] = 0.080, [HMPA]= 0.164. HMPA dried over molecular sieves was used. S12

Kinetic Studies Using Reaction Calorimetry (Runs reported in Scheme S2 page S17 and in Figure 3 of the main text) a) a

[1a] 0.040

[TFA] 0.093

[2a] 0.304

[3a] 0.207

[HMPA] 0.164

[“excess”] 0.097

b

Yield 0.965

ee % 84.1

c

Heat of reaction 16.9

d

a Concentration in Molar.b Yield were determined by HPLC analysis of the crude mixture. c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol.

Figure S10. Rate vs [3a] for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) @ 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.304 M, [3a] = 0.207 M, [TFA]= 0.093 M, [HMPA]= 0.164 M. HMPA dried over molecular sieves was used.

b) [1] a 0.040

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

0.093

0.367

0.274

0.163

0.093

Yield b 0.970

ee % c 83.6

Heat of reaction d 16.7

a

Concentration in Molar.b Yield were determined by HPLC analysis of the crude mixture. c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol.

Figure S11. Rate vs [3a] for the model Friedel-Craft alkylation in toluene (5 ml) @ 45 ºC. The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.367 M, [3a] = 0.274 M, [TFA] = 0.093 M, [HMPA]= 0.163 M. HMPA dried over molecular sieves was used.

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c) [1a] a 0.035

[TFA] 0.080

a

[2a]

[3a]

[HMPA]

[“excess”]

0.299

0.206

0.144

0.093

Yield b 0.954

ee % c 84.8


b

Concentration in Molar. Yield were determined by HPLC analysis of the crude mixture. c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol.

Figure S12. Rate vs [3a] for the model Friedel-Craft alkylation in toluene (5 ml) @ 45 ºC. The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.035 M, [2a] = 0.299 M, [3a] = 0.206 M, [TFA]= 0.080 M, [HMPA]= 0.144 M. HMPA dried over molecular sieves was used.

d) [1a] a 0.03 a

[TFA] 0.069

[2a]

[3a]

[HMPA]

[“excess”]

0.299

0.207

0.122

0.092

Yield b 0.92

ee % c 83.8


b

Concentration in Molar. Yield were determined by HPLC analysis of the crude mixture. c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol.

Figure S13. Rate vs [3a] for the model Friedel-Craft alkylation in toluene (5 ml) at 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.030 M, [2a] = 0.299 M, [3a] = 0.207 M, [TFA]= 0.069 M, [HMPA]= 0.122 M. HMPA dried over molecular sieves was used.

S14

e) [1a] a 0.040

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

0.092

0.225

0.169

0.163

0.056

Yield b 0.935

ee % c 85.7


a


Figure S14. Rate vs [3a] for the model Friedel-Craft alkylation in toluene (5 ml) at 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.225 M, [3a] = 0.169 M, [TFA]= 0.092 M, [HMPA]= 0.163 M. HMPA dried over molecular sieves was used.

f) [1a] a 0.040

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

0.092

0.249

0.240

0.163

0.010

Yield b 0.90

ee % c 85.1


a


Figure S15. Rate vs [3a] for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) at 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.249 M, [3a] = 0.240 M, [TFA]= 0.092 M, [HMPA]= 0.163 M. HMPA dried over molecular sieves was used.

S15

g) [1a] a 0.040

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

0.092

0.301

0.136

0.162

0.164

Yield b 0.957

ee % c 85.2


a


Figure S16. Rate vs [3a] for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) at 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.301 M, [3a] = 0.136 M, [TFA] = 0.092 M, [HMPA] = 0.162 M. HMPA dried over molecular sieves was used.

h) [1a] a 0.035

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

0.080

0.297

0.267

0.142

0.03

Yield b 0.902

ee % c 84.1


a


Figure S17. Rate vs [3a] for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) at 45 ºC.The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.035 M, [2a] = 0.297 M, [3a] = 0.267 M, [TFA] = 0.080 M, [HMPA] = 0.142 M. HMPA dried over molecular sieves was used.

S16

D.2 Kinetic Model for the reaction catalyzed by the 1a∙(TFA)2.3 combination.

Scheme S2. Reaction progress kinetic profiles measured by reaction calorimetry for the model reaction under the standard conditions: toluene, 45 ºC, using 1a∙(TFA)2.3 as the catalyst and with [HMPA] adjusted to keep [HMPA]/[TFA] = 1.75. HMPA dried over molecular sieves. Note that reaction progress is from right to left. For consistency, all kinetic analyses used data from 10-90% conversion of enone [3a]. (a) “Same excess” experiments, [e] = 0.1 M: checking for catalyst stability. (b) Kinetic experiments at different catalyst concentrations (1520 mol%): probing the reaction order in [1a∙(TFA)2]. (c) and (d) “Different excess” experiments, [e] = 0.1 M, 0.01 M, 0.06 M, 0.17 M: exploring dependence on substrates [2a] and [3a] concentrations. Reaction conditions: a): [1a] = 0.040 M, [TFA]= 0.093 M, [HMPA]= 0.164 M, [2a] = 0.304 M, [3a] = 0.207 M; b) [1a] = 0.040 M, [TFA]= 0.093 M, [HMPA]= 0.163 M, [2a] = 0.367 M, [3a] = 0.274 M; c) [1a] = 0.035 M, [TFA]= 0.080 M, [HMPA]= 0.144 M, [2a] = 0.299 M, [3a] = 0.206 M; d) [1a] = 0.030 M, [TFA] = 0.069 M, [HMPA] = 0.122 M, [2a] = 0.299 M, [3a] = 0.207 M; e) [1a] = 0.040 M, [TFA]= 0.092 M, [HMPA]= 0.163 M, [2a] = 0.225 M, [3a] = 0.169 M; f) [1a] = 0.040 M, [TFA]= 0.092 M, [HMPA]= 0.162 M, [2a] = 0.249 M, [3a] = 0.240 M; g) [1a] = 0.040 M, [TFA]= 0.092 M, [HMPA]= 0.162 M, [2a] = 0.301 M, [3a] = 0.136 M.

Power rate law of the Friedel-Craft Reaction. The power rate law of the Friedel-Craft reaction has been obtained by non-linear least-squares fitting of the experimental results to Eq. S3 (Eq. 1 in the main manuscript) by using the Solver function within Microsoft Excel (Figure S18).5 The observed nearly first order in the catalyst 1a and in the indole 2a is in good agreement with the Reaction Kinetic Analysis.

rate(M min 1 )  k  1  2a  3a (Eq. S-3) x

y

z

k  3.6  0.3, x  1.00  0.05 y  0.98  0.01, z  0.77  0.01

5

Parameters were determined by non-linear least-squares fitting of the data to the rate-law between 10-90% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc. 2010, 5, 267–281.

S17

Figure S18. Rate vs [3a] for the Friedel-Craft Alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) @ 45 ºC. The black lines represent the calculated rate vs [3a] given by eq.S3. Reaction conditions: (a) [1a] = 0.040 M, [2a] = 0.304 M, [3a] = 0.207 M, [TFA]= 0.093 M, [HMPA]= 0.164 M; (c) [1a] = 0.035 M, [2a] = 0.299 M, [3a] = 0.206 M, [TFA]= 0.080 M, [HMPA]= 0.144 M; (d) [1a] = 0.030 M, [2a] = 0.299 M, [3a] = 0.207 M, [TFA]= 0.069 M, [HMPA]= 0.122 M; (e) [1a] = 0.040 M, [2a] = 0.225 M, [3a] = 0.169 M, [TFA]= 0.092 M, [HMPA]= 0.163 M; (f) [1a] = 0.040 M, [2a] = 0.249 M, [3a] = 0.240 M, [TFA]= 0.092 M, [HMPA]= 0.163 M; (g) [1a] = 0.040 M, [2a] = 0.301 M, [3a] = 0.136 M, [TFA] = 0.092 M, [HMPA] = 0.162 M; (h) [1a] = 0.035 M, [2a] = 0.297 M, [3a] = 0.267 M, [TFA] = 0.080 M, [HMPA] = 0.142 M.

D.3 Kinetic Model for the reaction catalyzed by the 1a∙(TFA)2 combination. Repeating the RPKA of the model reaction catalyzed by amine 1a in the presence of 2 equivalents of TFA gave very similar kinetic results. The overlaying obtained in Figure S19, confirms that the observed heat flow represents an accurate measure of the rate of the reaction under study (using 1a∙(TFA)2 catalyst salt combination).

Figure S19. Comparison of fraction conversion vs time for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole at 45 ºC obtained with two independent methods: heat flow and HPLC. [1a] = 0.04, [2a] = 0.239, [3a] = 0.218, [TFA] = 0.080, [HMPA]= 0.140.

S18

Scheme S3. Reaction progress kinetic profiles measured by reaction calorimetry for the model reaction under the standard conditions: toluene, 45 ºC, using 1a∙(TFA)2 as the catalyst and with [HMPA] adjusted to keep [HMPA]/[TFA] = 1.75. Note that reaction progress is from right to left. For consistency, all kinetic analyses used data from 10-90% conversion of enone [3a]. (a) “Same excess” experiments, [e] = 0.1 M: checking for catalyst stability. (b) Kinetic experiments at different catalyst concentrations (15-20 mol%): probing the reaction order in [1∙(TFA)2]. (c) and (d) “Different excess” experiments, [e] = 0.1 M, 0.02 M, 0.06 M, 0.17 M: exploring dependence on substrates [2a] and [3a] concentrations. Reaction conditions: a): [1a] = 0.040 M, [TFA]= 0.080 M, [HMPA]= 0.140 M, [2a] = 0.300 M, [3a] = 0.201 M; b) [1a] = 0.040 M, [TFA]= 0.080 M, [HMPA]= 0.140 M, [2a] = 0.351 M, [3a] = 0.251 M; c) [1a] = 0.035 M, [TFA]= 0.070 M, [HMPA]= 0.120 M, [2a] = 0.300 M, [3a] = 0.201 M; d) [1a] = 0.030 M, [TFA] = 0.060 M, [HMPA] = 0.107 M, [2a] = 0.300 M, [3a] = 0.201 M; e) [1a] = 0.040 M, [TFA]= 0.080 M, [HMPA]= 0.140 M, [2a] = 0.239 M, [3a] = 0.219 M; f) [1a] = 0.040 M, [TFA]= 0.080 M, [HMPA]= 0.140 M, [2a] = 0.258 M, [3a] = 0.195 M; g) [1a] = 0.040 M, [TFA]= 0.080 M, [HMPA]= 0.140 M, [2a] = 0.300 M, [3a] = 0.132 M.

Power rate law of the Friedel-Craft Reaction catalyzed by the 1a∙(TFA)2 combination. The power rate law was obtained by non-linear least-squares fitting of the experimental results to Eq. S4 by using the Solver function within Microsoft Excel (Figure S20). The results indicate a very similar kinetic behavior of the 1a∙(TFA)2.3 catalytic system with the 1a∙(TFA)2 combination, compare Eq S3 in page S17 with Eq S4.

rate(M min 1 )  k  1a  2a  3a (Eq S-4) x

y

z

k  3.1  0.2, x  1.00  0.01 y  0.96  0.01, z  0.81  0.01

S19

Figure S20. Rate vs [3a] for the Friedel-Craft Alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) @ 45 ºC catalyzed by the 1a∙(TFA)2 combination. The black lines represent the calculated rate vs [3a] given by eq.S5. Reaction conditions: (a) [1a] = 0.040 M, [2a] = 0.300 M, [3a] = 0.201 M, [TFA]= 0.080 M, [HMPA]= 0.140 M; (c) [1a] = 0.035 M, [2a] = 0.300 M, [3a] = 0.201 M, [TFA]= 0.070 M, [HMPA]= 0.120 M; (d) [1a] = 0.030 M, [2a] = 0.300 M, [3a] = 0.201 M, [TFA]= 0.060 M, [HMPA]= 0.107 M; (e) [1a] = 0.040 M, [2a] = 0.239 M, [3a] = 0.219 M, [TFA]= 0.080 M, [HMPA]= 0.140 M; (f) [1a] = 0.040 M, [2a] = 0.258 M, [3a] = 0.195 M, [TFA] = 0.080 M, [HMPA]= 0.140 M; (g) [1a] = 0.040 M, [2a] = 0.300 M, [3a] = 0.132 M, [TFA] = 0.080 M, [HMPA] = 0.140 M. Note that here HMPA was not freshly distilled prior of use.

D.4 Effect of water on the rate of the model Friedel-Craft alkylation. The kinetic of the model reaction was investigated using the standard reaction conditions ([1a] = 0.040 M, [2a] = 0.300 M, [3a] = 0.205-0.214 M, [TFA] = 0.092 M, [HMPA]= 0.161 M) but in the presence of two different initial concentrations of water. The progress of the reaction of 2a and 3a was in situ monitored in an Omnical SuperCRC 20-250-2.4 microcalorimeter. For technical details refer to section D.1. The reaction rate and the fraction conversion at any time were obtained as previously described in section D.1.

a´) [H2O] = 0.028 [1a] a 0.040

[TFA] 0.093

[2a] 0.305

[3a] 0.199

[HMPA] 0.161

[“excess”] 0.107

Yield b 0.940

ee % c 84.6



S20

a´´) [H2O] = 0.061 [1] a 0.040

[TFA] 0.092

[2a] 0.304

[3a] 0.204

[HMPA] 0.161

[“excess”] 0.101

Yield b 0.940

ee % c 84.6



.

Comparison of the reaction rates with different amounts of water.

Figure S21. Rate vs [3a] for the Friedel-Craft Alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) @ 45 ºC. Reaction conditions: (a) [1a] = 0.040 M, [2a] = 0.304 M, [3a] = 0.207 M, [TFA]= 0.093 M, [HMPA]= 0.164 M, [H2O] = 0 M; (a´) [1a] = 0.040 M, [2a] = 0.305 M, [3a] = 0.199 M, [TFA]= 0.093 M, [HMPA]= 0.161 M, [H2O] = 0.027 M; (a´´) [1a] = 0.040 M, [2a] = 0.304 M, [3a] = 0.204 M, [TFA]= 0.092 M, [HMPA]= 0.161 M, [H2O] = 0.061 M. HMPA dried over molecular sieves. General Comment: the presence of water slightly reduces the reaction rate but it has no effect on the enantioselectivity of the process. S21

D.5 Eyring Analysis. General Procedure for the Eyring analysis. The model reactions were performed under the same reaction conditions ([1a] = 0.040 M, [2a] = 0.300 M, [3a] = 0.205-0.214 M, [TFA]= 0.092 M, [HMPA]= 0.161 M) at seven different temperatures (between 30 and 60 ºC). The progress of the reaction of 2a and 3a, catalyzed by 20 mol% of 1a∙(TFA)2.3 and in the presence of HMPA (1.75 ratio with respect to TFA), was in situ monitored in an Omnical SuperCRC 20-2502.4 microcalorimeter. For technical details refer to section D.1. The reaction rate and the fraction conversion at any time were obtained as previously described in section D.1. The rate constants were determined by non-linear least-squares fitting to the empirical rate equation [Eq. (1) in the main manuscript], which was experimentally determined by the reaction progress kinetic analysis of the model reaction at 45 C0, as detailed in section D2: rate (M sec-1) = k[1a∙(TFA)2.3]1[2a]0.98[3a]0.77

Rate vs time plots at different temperatures. a) 30.5 0C

a

[1a]a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.093

0.299

0.209

0.161

0.090

0.94

86.2

17.02

0.0244±0.0002

b

c

Concentration in Molar. Yield determined by HPLC analysis of the crude mixture. Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol. e Parameters were determined by non-linear least-squares fitting of the data to the equation rate (M sec-1) = k[1a]1[2a]0.98[3a]0.77 between 10-75% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established for k following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc. , 2010, 5, 267–281.

Figure S22. Rate vs [3a] for the Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene (5 ml) @ 30.5 ºC. The progress of the reaction runs from right to left in these figures. Reaction conditions: [1a] = 0.040 M, [2a] = 0.299 M, [3a] = 0.209 M, [TFA]= 0.093 M, [HMPA]= 0.161 M. The black lines represent the calculated rate vs [3a] given by rate (M sec-1) = k[1a]1[2a]0.98[3a]0.77 with k = 0.0244.

S22

b) 34.3 0C [1a]a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.092

0.300

0.211

0.161

0.088

0.92

86.2

16.95

0.0320±0.0002

a

Concentration in Molar.b Yield determined by HPLC analysis of the crude mixture.c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol. e Parameters were determined by non-linear least-squares fitting of the data to the equation rate (M sec-1) = k[1]1[2a]0.98[3a]0.77 between 10-75% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established for k following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc. , 2010, 5, 267–281.


c) 39.5 0C

a

[1a] a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.093

0.300

0.214

0.161

0.086

0.96

85.4

17.10

0.0418±0.0003

b

c

Concentration in Molar. Yield determined by HPLC analysis of the crude mixture. Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol. e Parameters were determined by non-linear least-squares fitting of the data to the equation rate (M sec-1) = k[1]1[2a]0.98[3a]0.77 between 10-75% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established for k following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc. , 2010, 5, 267–281.


S23

d) 44.4 0C [1a]a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.092

0.300

0.208

0.161

0.092

0.95

84.5

16.98

0.0528±0.0002

a

Concentration in Molar.b Yield determined by HPLC analysis of the crude mixture.c Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol. e Parameters were determined by non-linear least-squares fitting of the data to the equation rate (M sec-1) = k[1a]1[2a]0.98[3a]0.77 between 10-75% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established for k following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc., 2010, 5, 267–281.


e) 49.6 0C [1a]a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.092

0.300

0.206

0.161

0.095

0.95

83.4

17.19

0.0660±0.0003

a



S24

f) 54.4 0C [1a]a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.093

0.300

0.205

0.161

0.095

0.93

82.8

16.66

0.0844±0.0007

a



g) 59.3 0C

a

[1a] a

[TFA]

[2a]

[3a]

[HMPA]

[“excess”]

Yield b

ee % c

Heat of reaction d

ke

0.040

0.093

0.298

0.210

0.161

0.088

0.96

81.2

16.86

0.1030±0.0008

b

c

Concentration in Molar. Yield determined by HPLC analysis of the crude mixture. Enantiomeric excess (ee) values were determined by HPLC analysis on a commercially available chiral stationary phase.d Heat of reaction in kcal/mol. e Parameters were determined by non-linear least-squares fitting of the data to the equation rate (M sec-1) = k[1a]1[2a]0.98[3a]0.77 between 10-75% yield by using the Solver function within Microsoft Excel. The confidence intervals at 99% confidence level have been established for k following the procedure described in: G. Kemmer, S. Keller, Nat. Protoc., 2010, 5, 267–281.


S25

Eyring Plot. T (K) 303.6 307.5 312.6 317.5 322.8 327.6 332.5

k 0.0244 0.0320 0.0418 0.0528 0.0660 0.0844 0.1030

ln (k/T) -9.43 -9.17 -8.92 -8.70 -8.50 -8.26 -8.08

1/T 0.003293 0.003252 0.003199 0.003149 0.003098 0.003053 0.003008

Figure S29. Top: Tabulated data for the Eyring plot. Bottom: Eyring plot for the model Friedel-Craft alkylation of 3-octen-2-one with 2-methylindole in toluene catalyzed by 20 mol% of 1a∙(TFA)2.3 and in the presence of HMPA (1.75 ratio with respect to TFA). The experiments were performed at seven different temperatures (between 30 and 60 ºC).

Using the slope (-4628) and the intercept (5.859) obtained from the linear fit of the data in Figure S34, and the constant R (ideal gas constant) = 1.9859 cal/molK, kB (Boltzmann Constant) = 3.30 x 10-24 cal/K, and h (Planck constant) = 1.58 x 10-34 cals, we calculated the following activation parameters: 6

H≠ = 9.2 ± 0.2 kcal/mol S≠ = -35.6 ± 0.7 cal/molK

The confidence intervals for H and S have been established following the procedure described in: G. Lente, I. Fábian, A. J. Pöe New J. Chem., 2005, 29, 759–760. When the rate constants were determined by non-linear least-squares fitting to the rate law obtained by imposing the steady-state approximation to the concentration of the iminium ion A (see [Eq. (2)] in the main text, eq S4 in the SI, as detailed @ page S22): 6

≠

≠

rate =

a =k2

k1 k-1

a [1a∙(TFA)2]total [2a] [3a] 1+ c [2a] + b [3a]

; b=

k1 k-1

(eq.S4)

k1

k2 ;

c =0

;

k2=

k-1 k1

=

a b

k-1 ≠

≠

≠

assuming c = 0 (as found @ 45 ºC) and obtaining k2 from (a/b), similar values of H and S were obtained (H = +9.9±0.3 ≠ 2 kcal/mol; S = -34.7±1.0 cal/molK; R = 0.995).

S26

E. Computational Investigations E.1 Computational Details. Geometry optimizations employed the metahybrid DFT functional M06-2X7 functional and the 6-31G(d) basis set with Gaussian09.8 Thermochemical corrections were obtained from frequency calculations at the same level for a state of 1 atm and 318.15 K. Single-point energies of solvation in Toluene were computed with SMD method at the same level and were used in conjunction with the thermochemical corrections to obtain the free energies. For the C-C bond forming step, the energies of the related transition states were refined with single-point calculations including the solvent effect at the M06-2X/6-311++G(d,p) level. The conformational studies of the amine 1a and the iminium ion A (Section E.2 and E.3 of the Supporting Information) employed the dispersion corrected BP86-D functional,9 and the TZP basis set as implemented in the Amsterdam Density Functional ADF2009.01 program.10 E.2 Computational Approaches to Study the Conformational Behaviour of Amine 1a It has been established that cinchona alkaloids adopt four energetically preferred conformations, two open and two closed forms (Scheme S4).11 They differ for the relative orientation of the quinuclidine and the quinoline moieties as a result of the rotation around the torsional angles 1 and 2.

Scheme S4. The four energetically preferred conformations of amine 1a.

Extensive conformational analysis was conducted using molecular mechanics, with subsequent DFT optimizations to determine the structures. Geometries were fully optimized with the dispersion corrected

7

Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241. Gaussian 09, Revision A.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J., Gaussian Inc., Wallingford CT 2009. 9 a) A. D. Becke, Phys. Rev. A 1988, 38, 3098. b) J. P. Perdew, Phys. Rev. B 1986, 34, 7406; c) J. P. Perdew, Phys. Rev. B 1986, 33, 8822. d) S. Grimme, J. Comp. Chem. 2006, 27, 1787. 10 a) G. T. Velde, F. M. Bickelhaupt, E. J. Baerends, C. F. Guerra, S. J. A. Van Gisbergen, J. G. Snijders and T. Ziegler, J. Comput. Chem., 2001, 22, 931–967. b) C. F. Guerra, J. G. Snijders, G. te Velde and E. J. Baerends, Theor. Chem. Acc., 1998, 99, 391–403. 11 a) Bürgi, T.; Baiker, A. J. Am. Chem. Soc. 1998, 120, 12920–12926. b) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069–8076. c) Prakash, G. K. S.; Wang, F.; Ni, C.; Shen, J.; Haiges, R.; Yudin, A. K.; Mathew, T.; Olah, G. A. J. Am. Chem. Soc. 2011, 133, 9992–9995. It has been shown how modulation of the solvent polarity directly reflects on the ability of a cinchona catalyst to induce a preferred handedness in the product formed during an asymmetric transformation, see: d) Aune, M.; Gogoll, A.; Matsson, O. J. Org. Chem. 1995, 60, 1356–1364. 8

S27

BP86-D functional,12 and the TZP basis set as implemented in the Amsterdam Density Functional ADF2009.01 program.13 DFT methods, used to calculate the relative energies of the four different conformations of amine 1a, established the anti-open as the most populated ground-state conformation. As depicted in Figure S35, the energy difference between the open and the closed conformations is approximately of 6 kcal·mol-1, while the relative energy difference between the anti and syn conformations is very small (0.6 kcal·mol-1). From the calculations alone it is difficult to distinguish between the two. These trends are in agreement with previous computational studies on the conformation of related cinchona alkaloid species.14 Note that, in the presence of one and two molecules of trifluoroacetic acid, the anticonformation becomes more stable than the syn-conformer.

Figure S35. Optimized geometries and energies at BP86-D/TZP of the four possible catalyst conformations. Relative energies given in kcal·mol-1. The three energy values are referred to: the free amine 1a, and the complexes with 1 or 2 equivalents of TFA, respectively: 1a∙TFA, and 1a∙(TFA)2, respectively.

12

a) A. D. Becke, Phys. Rev. A 1988, 38, 3098. b) J. P. Perdew, Phys. Rev. B 1986, 34, 7406; c) J. P. Perdew, Phys. Rev. B 1986, 33, 8822. d) S. Grimme, J. Comp. Chem. 2006, 27, 1787. 13 a) G. T. Velde, F. M. Bickelhaupt, E. J. Baerends, C. F. Guerra, S. J. A. Van Gisbergen, J. G. Snijders and T. Ziegler, J. Comput. Chem., 2001, 22, 931–967. b) C. F. Guerra, J. G. Snijders, G. te Velde and E. J. Baerends, Theor. Chem. Acc., 1998, 99, 391–403. 14 H. Caner, P. Ulrich Biedermann, I. Agranat, CHIRALITY, 2003, 15, 637.

S28

E.3 Computational Approaches to Study the Conformational Behaviour of the Iminium Ion A Iminium Ion Conformation. 1a Conf.1)

C=N Bond2)

C=C Bond3)

N=C-C=C Bond4)

Erel (kcal/mol)

Syn

E

E

s-trans

1.35

Anti

E

E

s-trans

0.00 (A-i)

Syn

E

E

s-cis

5.83

Anti

E

E

s-cis

3.61 (A-ii)

Syn

Z

E

s-trans

2.27

Anti

Z

E

s-trans

0.90 (A-iii)

Syn

Z

E

s-cis

6.53

Anti

Z

E

s-cis

4.65 (A-iv)

Legend for the Table: the topological parameters identifying the conformations of the iminium ion A are given in this order: 1) syn-anti geometry of the cinchona scaffold. See Section E.1 2) E/Z for the C=N bond configuration 3) E/Z for the C=C double bond configuration 4) s-cis or s-trans N=C-C=C single bond conformation.

Figure S36. Optimized geometries and energies at BP86-D/TZP of the lowest energy anti-open iminium ion intermediate (A). Associated TFA and selected hydrogen atoms have been omitted for clarity. Relative energies given in kcal·mol -1. General comment: In agreement with the general LUMO lower theory of iminium ion catalysis, the energy of the iminium ion LUMO is approximately 1 eV lower compared that of the free ketone substrate.

To understand how the iminium ion structure controls the enantioselectivity of the system is important to obtain an accurate description of the three-dimensional conformational space accessible for the iminium ion intermediate (A). Using DFT methods we optimized and evaluated the relative energies of the 16 different possible open (with respect to the cinchona) geometries. The 16 conformations of the iminium ion intermediate (A) arise from the combination of 4 structural motifs; the configuration of the C=N bond (E/Z), the configuration of the C=C bond (cis/trans), and the conformation of the single C-C bond (s-cis/s-trans) connecting them; this leads to 8 conformations. For all these conformations it is possible to have the syn and anti conformation for the quinoline moiety. In all cases the anti quinoline conformation is the more stable and therefore only these will be discussed. The geometries of all 16 conformations are available in the coordinates section of the Supporting Information. Interconversion between the syn and anti conformers of the iminium ion is unlikely, with a barrier to the rotation of the quinoline of approximately 25 kcal mol-1. The calculations suggest that the additional acid molecule, and the restraints imposed by the resulting iminium ion assembly, hinders this rotation. The calculated lowest energy structure, A-i in Figure S36, has an s-trans geometry, which is significantly more stable. We then focused on the keto-imine E/Z configuration. In general the (E)-isomers are more stable compared to their (Z) counterparts, this trend has previously been reported for other iminium ion structures.15 However due to the relatively small energy difference observed between the E/Z conformations (approximately 1.0 kcal·mol-1) it is difficult, with any degree of confidence, to assign a quantitative reason for this trend. This is where using model systems can help shed light on the structural preferences. To understand each conformational preference we used a highly simplified model system (Figure S37) and then increased the level of complexity until the model results matched the full complex system. 15

Terhorst, J. P; Jorgensen, W. L. J. Chem. Theory Comput. 2010, 6, 2762-2769.

S29

Figure S37. Model complex; (E)-s-trans, (Z)-s-trans, (E)-s-cis. Relative energies given in kcal·mol-1. HOMO shown for each conformation.

Initially we started with the simplest iminium ion structure, then increased the bulk at the ‘catalyst’ position and finally included the TFA counter-ion interactions. Our simplified iminium ion model in the absence of TFA counter-ion showed no energetic preference for the E/Z conformation, the same was also true upon increasing the bulk at the nitrogen of the iminium ion (substituting methyl for isopropyl), suggesting little steric interaction between the substrate and the catalyst. However, on inclusion of the TFA counter-ion the (E)-isomer is stabilized by 1.2 kcal·mol-1 with respect to the (Z)-isomer. This stabilization is due to the more favorable hydrogen bonding between the TFA and alkene CH moiety compared to hydrogen bonding with the methyl group. In the (E)-isomer, the TFA lies in-plane with the iminium ion and substrate, with hydrogen bond distance of 1.38 Å to the iminium NH and 2.02 Å to the alkene CH group. Whereas for the (Z)-isomer the TFA is not in the plane, distorted by 42.0° (with respect to the C=N bond), and with a hydrogen bond distance of 2.14 Å between the TFA and the methyl group. This clearly suggests how the presence of the acid has important implications on the conformation of the iminium ion structure. This concept of CH···O hydrogen bonding influencing conformational preference for enantioselective reactions has been observed before.16 In the full catalyst system the conformation around the C-C single bond favors the s-trans conformation by approximately 3.5 kcal·mol-1, in agreement with the trends seen experimentally and similar reports in the literature.17 For the s-cis conformation the N=C-C=C torsion angle deviates from the ideal planar geometry by approximately 15°, this is not the case in the planar s-trans conformation. This deviation from the planar geometry in the s-cis (gauche) conformation relieves the 1,3-allylic strain experienced between the C=C and C=N bond. The disruption in the orbital conjugation of the HOMO (in the model system) for the s-cis versus s-trans is shown in Figure S37. E.4 Computational Study of the Carbon-Carbon Bond Formation Transition States. The carbon-carbon bond forming step also generates a new stereogenic center. Four transition states, characterized by different facial topicity, for the addition of 2-Methylindole (2a) to the iminium ion A have been located (see Figure S38).18 Of this transition states, TS9-Re, which leads to the experimentally observed product enantiomer, is the lower in energy.

16

Corey, E. J.; Rohde, J. J.; Fischer, A.; Azimioara, M. D. ; Tetrahedron Lett., 1997, 38, 37-40. a) García, J. I.; Mayoral, J. A.; Salvatella, L.; Assfeld, X.; Ruiz-López, M. F.; J. Mol. Struct.(THEOCHEM), 1996, 362, 187-197. b) P. Hsueh, M. Lukowski, H. A. Lindsay, M.C. Milletti, J. Mol. Struct. THEOCHEM, 2007, 806, 223-230. 18 Similar transition states for the reaction of indole with (E)-crotonaldehyde catalyzed by dimethylamine has been described in: R. Gordillo, J. Carter,K. N. Houk, Adv. Synth. Catal., 2004, 346, 1175. 17

S30

Figure S38. Optimized transition state structures for the addition of indole 2a to the (a) Re and (b) Si face of the iminium ion assembly A. Selected bond distances are in Å. Dihedral angles are in degrees. Relative free energies given in kcal·mol -1; M06-2X/6311++G(d,p)/SMD//M06-2X/6-31G(d).

E5. Geometries and Energies of Calculated Stationary Points Underneath the coordinates for the species below are listed the EM06-2X/6-31G(d), Toluene= -270.4295769 following energies in Hartrees:

M06-2X /6-31G(d) electronic energy (EM06-2X/6-31G(d)) BP86-D /TZP electronic energy (EBP86-D/TZP) M06-2X /6-31G(d) Gibbs free energy at 318.15 K (G M06-2X/6-31G(d), 318K) M06-2X/6-31G(d) single-point energy in Toluene (EM06-2X/6-31G(d), Toluene) M06-2X/6-311++G(d,p) single-point electronic energy (EM06-2X/6311++G(d,p)) M06-2X/6-311++G(d,p) single-point energy in Toluene (EM06-2X/6311++G(d,p), Toluene) M06-2X /6-31G(d) entropy at 318.15 K in cal/(Mol∙K) (S M06-2X/631G(d), 318K)

Iminium Ion Formation (with TFA)

C H C H C C H H H O C H H H

-1.29616000 -1.06749600 -0.29340700 -0.48808300 1.14854400 1.54089700 1.14226800 1.14226300 2.62866900 1.98990100 -2.74789600 -3.25109000 -2.88659100 -3.25101500

0.31443300 1.38026500 -0.56763000 -1.63841900 -0.20859000 1.25668000 1.76484500 1.76485500 1.32458500 -1.08430900 -0.04882900 0.36740700 -1.13254800 0.36709400

3a (Enone)

TFA

EM06-2X/6-31G(d)= -270.4210177 G M06-2X/6-31G(d), 318K= -270.3356200

EM06-2X/6-31G(d)= -526.6055303 G M06-2X/6-31G(d), 318K= -526.599197

0.00001000 0.00004600 -0.00002200 -0.00005500 0.00000000 -0.00000900 -0.88383800 0.88381200 -0.00000100 0.00001700 0.00000200 -0.87982300 -0.00018100 0.88001700

S31

EM06-2X/6-31G(d), Toluene= -526.6090304 C O O H C F F F

-0.93012800 -1.48773900 -1.51061700 -2.47442100 0.59921700 0.98934600 1.18209400 0.98930800

0.16008600 1.21793800 -1.03995400 -0.90007400 -0.00071300 -0.67610500 1.18799200 -0.67633400

0.00000200 0.00000500 0.00000000 0.00000000 0.00000000 1.08191300 -0.00013900 -1.08178100

Water EM06-2X/6-31G(d)= -76.37337803 G M06-2X/6-31G(d), 318K= -76.370928 EM06-2X/6-31G(d), Toluene= -76.3776736 S M06-2X/6-31G(d), 318K= 45.6 O H H

0.00000000 0.00000000 0.11843600 0.00000000 0.76223500 -0.47374400 0.00000000 -0.76223500 -0.47374400

1aTFA (Anti-open TFA ) EM06-2X/6-31G(d)= -1542.826211 G M06-2X/6-31G(d), 318K= -1542.4220920 EM06-2X/6-31G(d), Toluene= -1542.850367 C C C C C C C H C H C H C H H C H C C C C H H C H H C H H H H H H C H C H

-0.46939800 -1.92359900 -3.00686000 -2.22165600 -2.84298100 -4.32312200 -3.56937700 -1.41738100 -3.94182900 -1.84772600 -5.43532600 -3.80077800 -5.25617800 -6.42428700 -6.09063000 -0.01235200 0.19499400 -0.98359300 1.97040800 1.13129600 -0.16844800 -1.64063900 -1.63129200 0.99649300 2.25906400 2.88211300 0.43749900 0.54401400 2.13374400 -0.80922000 1.52186500 -0.34510400 1.15374300 0.51844500 0.07858200 0.59620300 1.03416800

-0.31925400 -0.17976200 -0.67199000 0.47585100 -1.37698500 -0.43384800 0.65574200 0.83845800 -1.81523500 -1.56942800 -0.90389200 1.17918900 -1.57354300 -0.70600500 -1.93855500 1.00201200 1.67354500 1.67234100 2.17080500 0.25803700 2.37744900 0.92911800 2.36733100 3.18775500 2.46877000 2.00719000 1.28928100 -0.65700600 -0.01647700 3.04752900 3.69373900 0.80237800 1.72759700 4.24172700 3.89198400 5.54829500 5.93558800

1.06399900 1.48165300 0.69264500 2.65437500 -0.53491800 1.17885500 3.03641900 3.28666100 -1.23621300 -0.91368900 0.42322000 3.96229300 -0.74998700 0.82304800 -1.33943400 0.40966800 1.25010800 -0.58175000 -0.40815700 -1.66466700 -1.67855500 -1.04789800 -0.04045700 -1.06121900 0.60368800 -0.98633400 -2.57425200 -1.55176200 -1.99942200 -2.25815400 -1.87964700 -3.16440200 -3.27685600 -0.09974700 0.83538400 -0.33108400 -1.24808500

H O C H H H N H N H H H N C O O C F F F

0.22796800 -3.89178900 -2.61819300 -2.79221100 -2.06251600 -2.03178800 -4.59174500 -0.38306800 0.35704200 -0.02686300 1.30461400 1.98951300 1.30345300 3.93330400 4.17906000 2.85801100 5.01825700 4.57750700 5.32453800 6.13814100

6.27728100 -2.48945000 -2.77580200 -3.31659500 -1.85289200 -3.40025900 0.22644700 -1.12822800 -0.55195800 -1.33633400 -0.81873100 0.12733300 0.84031800 -0.80894700 -0.04596700 -0.90533100 -1.81225400 -3.07114100 -1.63542800 -1.68797300

0.38326800 -2.41010700 -2.94375600 -3.87340400 -3.15663000 -2.25902500 2.33540300 0.32302500 2.24669100 2.76942500 1.97619300 0.23082600 -0.29811800 0.04880300 -0.88062700 0.72567800 0.49589600 0.35387400 1.78817100 -0.21354100

5 EM06-2X/6-31G(d)= -2339.91448 G M06-2X/6-31G(d), 318K= -2339.3631800 EM06-2X/6-31G(d), Toluene= -2339.940077 C N C C C C C C C N C C C C C C C C C C C O C C C C H H H H H H H H H H H H H H H

-0.08963000 0.48522100 -0.75835800 -0.99522600 0.14740700 1.38725600 1.50446200 1.02267300 2.08536800 0.40445000 -0.28022500 0.77839400 2.62672400 1.47541100 1.77529200 3.91550000 4.17041100 -1.87381200 -2.33066500 -3.15072500 -3.38643300 -4.68668400 -4.96779200 0.01919900 -0.79918300 -1.84967400 -0.98569500 2.28644200 2.49095900 1.74970900 -0.88456300 -0.97971000 0.92323300 0.44827000 2.86190500 1.01958200 1.78898500 2.82542800 2.70082800 1.18251300 4.71601300

-0.67818600 3.16121400 2.64138600 1.41968800 0.65904300 1.21641300 2.47915800 -1.73447100 -3.30895500 -3.09936300 -3.63378400 -4.00298400 -4.00544400 -4.04418800 -1.83090000 -3.36651000 -2.72229100 3.38585800 1.00100100 2.96457400 1.76428200 1.46454200 0.31406500 3.59383700 4.26938600 2.06160100 -1.10355400 0.69087800 2.91738700 -1.59859100 -4.48088700 -2.86950200 -5.08770200 -3.66999700 -5.04092700 -5.03537200 -3.75403900 -3.39014800 -1.25436800 -1.40182400 -3.44819700

-0.37845400 -2.33835900 -2.13745300 -1.45474400 -1.05023800 -1.24347200 -1.87602900 -0.55410200 -2.19000700 -0.31042900 -1.53593400 -2.58619000 -0.91527200 0.11660700 -1.89529400 -0.45821100 0.67648500 -2.61554600 -1.20113100 -2.37977100 -1.65103100 -1.45306200 -0.66773100 1.41516600 0.59728000 2.32166300 -0.84101400 -0.94015500 -2.01297500 0.25033700 -1.20319000 -1.87210900 -2.63731700 -3.57416900 -1.19426700 0.17961800 1.12079000 -2.99192300 -1.82419500 -2.71271100 -1.19474900

S32

H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H H H H N C O

3.43974700 5.14950100 -1.66897200 -2.51476000 -4.01363400 -6.05386300 -4.53997600 -4.57027000 1.06172600 -1.83465200 -1.96059900 -2.46375600 -2.17862800 -0.38376500 -2.66743200 -2.83170100 -1.66758800 -3.78166200 -3.48652700 -4.97692500 -3.90125800 3.16274600 2.60233100 2.83975500 4.42141200 5.49922600 4.62229700 4.27952000 -0.38329600 -0.50286600 -1.01262300 0.66158000 1.91757900 -0.79683600 0.40116000 -0.42671700 -0.40386600 0.43222200

-2.57243100 -2.29043300 4.29834000 0.09269900 3.52221700 0.23549000 -0.59299300 0.43268500 3.89199400 3.94401600 1.23224900 2.91222300 1.72935300 -3.05880000 -2.59290600 -2.32900900 -3.10839000 -2.12956500 -0.88265000 -2.06595100 -2.90809400 1.09770500 0.02677700 2.19836700 1.29570900 1.47984300 0.22515900 2.35844400 5.47424000 5.30050700 6.32988800 5.72863300 2.08291100 -1.23330000 -0.09858600 -0.40877500 2.46129200 1.86190600

1.46559200 0.85453100 -3.16748900 -0.63806700 -2.72931200 -0.62796800 -1.10704100 0.34637700 1.50934100 0.48294600 3.01854800 2.63378200 1.33189000 0.43386700 0.74303500 -0.45129000 1.32322400 1.70932200 2.13931900 1.11039200 2.78293000 1.54263000 1.58771200 2.15848700 0.67627100 1.43675700 -0.09421600 -0.12094200 -0.18074300 -1.25418500 0.08936500 0.01185200 2.60019700 1.48456800 1.52343500 1.01601700 2.25466100 2.93948000

TS5 EM06-2X/6-31G(d)= -2339.902955 G M06-2X/6-31G(d), 318K= -2339.3471560 EM06-2X/6-31G(d), Toluene= -2339.929397 Imaginary frequency: -150.7 cm-1 C N C C C C C C C N C C C C C C C C C C

-0.07526000 -0.05106700 -1.22185400 -1.28981300 -0.05467300 1.11606900 1.06361800 1.06904500 1.78165500 0.84885800 -0.09091500 0.59064800 2.85947000 2.18776700 1.29380400 4.08007500 4.61012200 -2.43066900 -2.55353500 -3.63459600

-0.35155900 3.53118600 2.92554500 1.64144200 0.97236500 1.61568900 2.89582800 -1.28211700 -2.95578000 -2.65024300 -3.50852900 -3.89617800 -3.31649300 -3.30957500 -1.51035900 -2.44260000 -1.59409600 3.64428600 1.10828000 3.12738000

-0.61548100 -2.53762400 -2.19655400 -1.59223000 -1.34462700 -1.66301800 -2.26555800 -1.03002200 -2.73727300 -0.40846000 -1.21592900 -2.53469300 -1.68228300 -0.28381900 -2.53163300 -1.84370800 -0.96771700 -2.41765400 -1.21508600 -2.03315300

C O C C C C H H H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H H H H N C O

-3.70024600 -4.93859700 -5.05054800 0.04048700 -0.77187200 -1.91349800 -1.01429600 2.08591600 1.98989600 1.99509900 -0.33404100 -1.01086800 0.92975100 -0.12424200 3.17052800 2.01323900 2.75084300 2.20336600 2.03194800 0.36760900 4.54910200 4.20521200 5.49296400 -2.35287000 -2.62608900 -4.56482100 -6.11306100 -4.66465100 -4.50257700 1.11626700 -1.84925200 -2.05835900 -2.32439600 -2.43529100 0.36011300 -2.46537500 -2.73976100 -1.34687400 -3.66511200 -3.68331000 -4.83915200 -3.59412500 3.22270100 2.77816600 2.67950000 4.61719200 5.12844100 5.48715400 4.51596300 -0.29548300 -0.68399700 -0.65972700 0.79575400 1.32644100 -0.54426800 0.94389900 -0.02966100 -0.44966900 0.29331200

1.84408400 1.43772000 0.18114000 2.71591600 3.63926600 1.26348300 -0.86489400 1.17582500 3.40465500 -0.92332800 -4.36272100 -2.93524400 -4.93736100 -3.80063700 -4.34792400 -4.32152200 -2.74794700 -3.07613300 -0.78997300 -1.34104200 -2.54772600 -1.41973100 -1.01763000 4.61900700 0.12360300 3.66555100 0.03904000 -0.63534900 0.18106200 2.87476300 3.47076600 0.26272600 1.99003400 1.35898900 -2.54830000 -2.39321500 -2.05968300 -2.61133600 -2.49946400 -1.41993300 -2.52101700 -3.58258700 0.71352900 -0.36833900 1.56243000 1.10055900 2.18021400 0.09273300 1.34498000 4.94897400 5.12273300 5.76350500 4.99447200 1.27037900 -0.83131400 -0.14719100 -0.09587700 1.53859300 1.04364500

-1.41983000 -1.07044000 -0.41582300 1.47617000 0.94754700 2.35600700 -0.83318100 -1.43810300 -2.52632100 -0.57112100 -0.58072500 -1.34431500 -2.51291600 -3.35664900 -1.89416300 0.08878300 0.46425800 -3.73939900 -2.89083400 -3.09543300 -2.82318100 0.02482800 -1.22529500 -2.88933600 -0.76755100 -2.18336500 -0.22195200 -1.03313900 0.53492100 1.50055500 0.93046600 2.76308000 3.06619800 1.40244400 0.50424600 0.81894000 -0.34388100 1.35225200 1.79406700 2.60767900 1.15523200 2.56839400 1.89304600 1.47615000 2.64295700 1.35215500 1.92986100 1.49948900 0.02864300 0.40605900 -0.60142900 1.04353400 0.37361300 2.99731400 1.33487600 1.16465900 0.83951000 2.20517800 3.13277500

6 EM06-2X/6-31G(d)= -2339.919075 G M06-2X/6-31G(d), 318K= -2339.3606440 EM06-2X/6-31G(d), Toluene= -2339.945868 C

-0.15503000 -0.11968700 -0.38629800

S33

N C C C C C C C N C C C C C C C C C C C O C C C C H H H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C

0.50836500 -0.75266500 -1.04425500 0.06512500 1.33547200 1.50420800 0.75213200 1.02236800 0.42744600 -0.71094900 -0.24015800 2.17351600 1.67903500 0.74128200 3.45869600 4.19181400 -1.83231200 -2.39855000 -3.12545800 -3.41485800 -4.72711800 -5.06872300 0.25961000 -0.47910400 -1.79070000 -1.19471500 2.20952100 2.50546600 1.77403500 -1.00891900 -1.53898000 -0.02669600 -1.02975500 2.33691200 1.42341700 2.39427300 1.29709400 1.50745500 -0.22375900 3.78700000 3.94381800 5.09545300 -1.58217500 -2.64214200 -3.96133800 -6.15720700 -4.66484100 -4.68960700 1.34654200 -1.56530300 -2.05101400 -2.11613600 -2.30280400 0.06137300 -2.58639600 -2.96098600 -1.41760100 -3.67119700 -3.40526500 -4.88831900 -3.70059000 3.38798300 2.77470500 2.98217700 4.81077100 5.49945400 5.51746000 4.71596600 0.08908000

3.92098500 3.42021400 2.08547900 1.27202800 1.79048400 3.12659800 -1.10828500 -2.39461400 -2.55193600 -3.08968200 -3.24549000 -3.08019400 -3.34642400 -0.99852900 -2.29772400 -1.72768400 4.29436400 1.65197500 3.86848400 2.53116500 2.22185100 0.90683900 2.21178000 3.30474400 0.73965600 -0.42893500 1.20962000 3.54748900 -0.97151600 -4.03019300 -2.38775000 -4.29352200 -2.91018100 -4.05570200 -4.39655900 -3.03430800 -2.31611400 -0.28093800 -0.62143000 -2.20814300 -1.74797100 -1.18447800 5.30700100 0.63785500 4.52165900 0.86688900 0.15966500 0.68561100 2.28648900 3.22236100 -0.26757500 1.44590200 0.96317600 -2.62779800 -2.16007700 -1.44703100 -2.53436300 -2.67679400 -2.27053100 -2.23787900 -4.01560800 0.10155100 -0.76033800 0.76125400 0.39505100 1.21623600 -0.73380700 0.96687800 4.68332400

-1.76285900 -1.68844900 -1.29037800 -0.92789100 -1.01795400 -1.44541200 -1.13358500 -3.25066800 -0.80010600 -1.63009600 -3.08133900 -2.46956500 -1.02477400 -2.66705800 -2.60726700 -1.65460100 -2.00292800 -1.22554300 -1.91911800 -1.52435700 -1.47192900 -1.06234200 1.88366400 1.70355600 2.31147700 -0.49629900 -0.72556400 -1.51080200 -0.77462000 -1.16192400 -1.50976500 -3.31611100 -3.75935100 -2.94593700 -0.86630200 -0.26047300 -4.30636400 -2.96722400 -3.02943800 -3.64387200 -0.59715500 -1.91305600 -2.30234400 -0.93025000 -2.14691200 -1.06674900 -1.75412900 -0.05843000 1.92617200 1.65781400 2.64630400 3.07740300 1.37138200 0.17126600 0.89808900 -0.04107900 1.20691600 1.87142500 3.12141600 1.54944900 1.87526000 1.78597300 1.09392900 2.74631100 1.26070800 2.04214200 1.10611100 0.03966500 1.55015100

H H H H H H N C O

-0.25546300 -0.23727800 1.18208600 1.25351800 -0.30725900 1.19445600 0.15315100 -0.28410400 0.28283500

5.14737700 5.32549800 4.66253100 0.49450800 -1.07646700 -0.36840600 -0.21059300 0.83644400 0.31332600

0.62021100 2.37617900 1.54137700 3.30789200 1.42903300 1.20932300 1.08739200 2.17369900 3.32292800

TS6 EM06-2X/6-31G(d)= -2339.906367 G M06-2X/6-31G(d), 318K= -2339.3508720 EM06-2X/6-31G(d), Toluene= -2339.933983 Imaginary frequency: -80.2 cm-1 C N C C C C C C C N C C C C C C C C C C C O C C C C H H H H H H H H H H H H H H H H H H H H H H H H

-0.97584600 -4.39428500 -4.59710100 -3.54460000 -2.21415700 -2.03289900 -3.15239200 -0.19732800 0.23210500 1.21429100 1.24731200 0.87568800 1.32255300 2.05579700 -0.86726100 0.73881200 0.69781400 -5.94641900 -3.87884300 -6.24159500 -5.19367900 -5.61262200 -4.62495800 -1.46484400 -2.74473700 -1.39898800 -1.27602700 -1.02978500 -3.00631000 -0.06202700 2.25149700 0.54572500 1.76828800 0.18234800 2.04008300 3.00844000 2.24113000 -0.18778300 -1.47072600 -1.54311500 0.30088400 1.10427100 0.24075500 -6.72175100 -3.09338800 -7.26187500 -5.15730600 -4.02377400 -3.96334300 -0.88223400

0.25943500 -2.39240800 -1.07118700 -0.11734600 -0.61028200 -1.95166000 -2.80106900 0.21603500 1.66640000 0.72015900 2.20946500 2.78104900 0.61704800 0.26973100 1.00442400 -0.56644700 -1.83536700 -0.63425700 1.24835400 0.67451000 1.62977700 2.89634300 3.88873600 -1.61198900 -1.72099600 0.91687300 1.29278800 -2.37321500 -3.86312100 -0.82499100 2.49737300 2.49840600 3.16575400 3.61792800 1.10339600 0.79565300 -0.79218900 2.08162400 0.31851600 1.77076800 -0.30999200 -2.18477400 -2.59010800 -1.38732500 1.98754600 1.02655900 4.81677200 4.00660500 3.64943100 -2.50857700

0.16502500 0.60709400 0.37284200 0.25662700 0.37253500 0.62640300 0.73475800 1.49352600 3.47049300 1.34382900 1.24388500 2.62905900 3.81363500 2.50563400 2.62842300 4.54897400 4.14804400 0.23670200 0.01688100 0.00116800 -0.11185100 -0.35046700 -0.51801100 -2.42438600 -2.76939800 -2.73346500 -0.03482800 0.68989400 0.92164400 1.77964000 0.92656800 0.45753100 3.13285100 2.50820100 4.48729600 2.40617500 2.34860300 4.39130300 3.22768900 2.22651100 5.51479100 3.20038300 4.78023500 0.33070100 -0.07079600 -0.10809200 -0.72410800 0.39250100 -1.36009300 -2.19649200

S34

H H H H H C O O C F F F C O O C F F F C H H H H H H N C O

-3.32388300 -0.75056000 -1.63939900 -2.32681600 1.62652200 3.10423300 1.98061500 3.32215100 4.17291600 5.38554700 4.11575200 3.94674400 2.20854700 1.45595400 1.92501000 3.67883700 4.52653000 4.05213500 3.83165400 -3.48402400 -4.32937800 -3.88905300 -2.82837600 0.99741200 1.29432900 0.31781400 -0.09782200 -0.65776300 0.47436700

-0.82324100 1.78792200 0.83746600 1.05465200 0.27866200 1.31216700 1.56316700 0.45096700 2.36968700 1.90688300 2.78001600 3.43066500 -2.23904500 -2.01323400 -2.25773900 -2.53839400 -2.23415800 -1.84540800 -3.84046300 -3.02288500 -3.03760100 -3.17828400 -3.86469000 -1.20809200 0.85228600 -1.06528500 -0.16458000 -0.33808700 -0.43659200

-2.98728000 -2.59155300 -3.79551200 -2.17123100 0.50606100 -1.27364300 -1.88511600 -0.44990700 -1.59545300 -1.33750300 -2.85545000 -0.79655900 -0.36855500 0.61611600 -1.57375200 0.00654000 -0.97367600 1.09896500 0.29692900 -2.85920400 -2.16171100 -3.86543500 -2.61893700 -2.83177800 -1.68046300 -0.66430400 -0.93029000 -2.30669300 -3.14033800

7 EM06-2X/6-31G(d)= -2339.922386 G M06-2X/6-31G(d), 318K= -2339.3632510 EM06-2X/6-31G(d), Toluene= -2339.946904 C N C C C C C C C N C C C C C C C C C C C O C C C C H H H H H

0.83576100 5.07425500 4.65612200 3.29338300 2.33117900 2.78201500 4.16236400 0.22328200 0.56578100 -0.66557100 0.14609500 0.66786800 -0.93186200 -1.66660200 1.17925100 -1.12196500 -1.81491000 5.64788600 2.96578900 5.31357000 3.95809300 3.75510400 2.42826800 -0.67960100 -0.21998900 1.40494500 0.66170800 2.06986800 4.51743900 -0.45390200 -0.50300000

1.06302200 1.83055300 0.61753400 0.30332100 1.32374800 2.55638600 2.76079800 0.86117200 -0.24380200 -0.36173700 -1.61258200 -1.65986300 0.08060300 -0.26154900 0.72577300 1.49050100 2.47790900 -0.38195600 -0.97925600 -1.61149900 -1.91062100 -3.14026100 -3.48211600 3.44076600 4.41497700 2.00831700 0.13281800 3.36099500 3.73275800 1.69818500 -2.44857000

0.17927000 0.71465100 0.26683000 -0.00352400 0.25711200 0.66523700 0.88018600 1.60197200 3.82700800 1.62215900 1.79564100 3.24242500 4.04300300 2.73412300 2.80550700 4.54861300 3.98708200 0.05140400 -0.53440500 -0.43362900 -0.74984400 -1.26675400 -1.63110500 -2.29547500 -3.07271500 -2.57826600 -0.37662200 0.82244000 1.21801500 1.79070800 1.53173700

H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H H H H N C O

0.96031000 0.08422300 1.70569300 -1.30095200 -2.16524200 -2.40512900 1.10198000 1.34057300 2.15724700 -0.61257100 -2.35546200 -1.87157600 6.67566600 1.94904800 6.05749400 2.47850700 1.76698200 2.02095600 -1.67951800 0.77707600 1.82538200 1.27474400 2.10943300 -1.19536200 -1.05751100 -0.11863300 -1.90942400 -1.13714000 -0.68257100 -2.38396600 -0.37914600 -3.32659500 -2.62972500 -3.23457500 -4.52279500 -4.84536900 -4.24123200 -5.58502700 -0.98867100 -0.45128400 -1.12595600 -1.97513100 -2.29657200 -0.43409500 -0.82079000 0.14095100 0.04943100 -0.80525800

-1.56831900 -2.36493100 -2.00397300 -0.59624000 -1.23249600 0.47605800 -0.18025600 1.71719700 0.34540300 1.68670900 2.37249400 3.45153800 -0.11821900 -1.20400600 -2.38079800 -4.48697600 -3.48582800 -2.78695200 3.52344400 4.33312500 1.02259000 2.07450100 2.77156100 -0.47096300 -2.01803500 -1.45123100 -1.54203200 -3.55489500 -4.12839800 -3.97624100 -4.01467100 0.69174600 1.28537000 0.70655700 -0.13446000 -1.11814900 -0.64944300 0.67021800 5.65755500 6.55283000 5.75035400 5.65445200 1.03298500 0.21409400 2.21133500 2.18960000 2.17499700 1.11202400

1.06720000 3.84369500 3.24389400 4.82497400 2.77931700 2.42780200 4.77853700 3.23649800 2.49414800 5.49314900 3.04936400 4.46275300 0.27832900 -0.83741100 -0.61218100 -2.04879000 -0.75534600 -2.37134200 -1.86203500 -3.50303400 -2.35173700 -3.66043300 -2.24013200 0.72275000 -1.20351800 -1.79798800 -0.42205200 -1.36103600 -0.22154900 -1.55246400 -2.35907600 -0.53015900 0.27600700 -1.81940400 -0.02817200 -0.85081700 1.17375200 0.11100600 -3.41064800 -3.07873700 -4.49354700 -2.93919500 -2.08934300 -2.18134400 -0.11750600 -0.45355400 -1.90884800 -2.38249100

TS7 EM06-2X/6-31G(d)= -2339.905434 G M06-2X/6-31G(d), 318K= -2339.3487400 EM06-2X/6-31G(d), Toluene= -2339.932577 Imaginary frequency: -174.3 cm-1 C N C C C C C C C N C

0.55352100 4.40371400 4.33931700 3.11963600 1.91654000 2.00629000 3.27475800 -0.07777300 0.31078600 -0.92262300 -0.06796100

0.92410400 2.75900800 1.49151700 0.83937900 1.57078000 2.86036900 3.41255000 0.62997500 -0.52290800 -0.62465300 -1.84848700

0.21887400 1.00884700 0.52462800 0.18321500 0.40415300 0.87155800 1.15646500 1.61221700 3.80074100 1.59294700 1.73157400

S35

C C C C C C C C C C O C C C C H H H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H H H H N C O

0.44064500 -1.19239300 -1.92161100 0.89711700 -1.42019300 -2.13938800 5.56548100 3.15573400 5.58155500 4.36456800 4.50878700 3.33425200 -1.23121900 -0.97985500 1.14804800 0.64678000 1.10788800 3.34745300 -0.78395100 -0.68117600 0.74944000 -0.13739700 1.48316200 -1.54481800 -2.36533300 -2.69506300 0.85036400 1.04312800 1.87883200 -0.92351300 -2.66831500 -2.22929200 6.47860800 2.24802900 6.50680100 3.66631600 2.64855800 2.80473200 -2.22561100 0.02067300 1.64895700 1.02637000 1.77014700 -1.42682300 -0.38029900 0.53671200 -1.37229900 -0.21928400 0.25658600 -1.37298300 0.65522400 -3.39882100 -2.79170900 -3.33556600 -4.35310300 -4.88560100 -3.69481900 -5.35023500 -2.00417600 -1.69326900 -2.12488500 -2.97455500 -1.80135900 -0.37408100 -1.34818000 -0.36704400 -0.20448500 -0.88425000

-1.92218700 -0.23066200 -0.58728400 0.48195400 1.17287300 2.13919100 0.78876800 -0.47546900 -0.47576500 -1.11280300 -2.34170000 -3.00152900 3.17033500 4.16674600 2.17915200 -0.00730200 3.45212000 4.43107300 1.43364600 -2.69655000 -1.75745300 -2.65127400 -2.25188700 -0.91917900 -1.58353500 0.11550900 -0.46763100 1.46423100 0.12846400 1.38040100 2.01827500 3.10916000 1.30551600 -0.95102700 -1.02166100 -3.94907300 -3.19643200 -2.41320500 3.01838700 4.28688200 1.22725000 2.29009000 2.98944700 -0.69369000 -2.08229300 -1.44439200 -1.65167800 -3.62417800 -4.02839300 -4.25370300 -4.04515100 0.57097000 1.10072100 0.84435900 -0.56758800 -1.21960100 -1.46791700 -0.08176300 5.16513600 6.18331600 5.13385500 4.96791700 0.58321800 -0.09103600 1.78898500 1.79949500 2.21271200 0.70804600

3.18159800 4.02356700 2.71701500 2.79921000 4.53295200 3.96610600 0.34650800 -0.36239200 -0.16246900 -0.53944300 -1.07068100 -1.52094400 -2.22430500 -3.07310300 -2.41712200 -0.34931400 1.02993100 1.53296700 1.83172100 1.43004400 1.01073300 3.75913000 3.18577800 4.80308100 2.75585700 2.41583300 4.75070300 3.25445500 2.46645500 5.48195100 3.02256900 4.44475400 0.62267900 -0.71433800 -0.31458500 -1.94336800 -0.68690600 -2.27617200 -1.80836100 -3.48649600 -2.22325400 -3.49338800 -2.02347300 0.68656800 -1.49829700 -2.06347000 -0.88327100 -1.50624300 -0.30049300 -1.70674800 -2.42327000 -0.53481300 0.44039900 -1.73458500 -0.10508500 -1.12779400 0.66137600 0.65154700 -3.51269600 -3.25427200 -4.60101500 -3.05155300 -2.63138400 -2.69084100 -0.16256400 -0.51730600 -1.76699000 -2.96786300

8 EM06-2X/6-31G(d)= -2339.928121 G M06-2X/6-31G(d), 318K= -2339.3767840 EM06-2X/6-31G(d), Toluene= -2339.955348 S M06-2X/6-31G(d), 318K= 266.4 C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C

0.23682300 1.83502100 2.64866200 2.21620500 0.84484700 0.04369100 0.58753200 -0.77378400 -0.85106600 -1.33949300 -0.38927100 -0.29683200 -2.38161000 -2.62084800 -0.18689000 -2.98979000 -3.67492700 4.00835900 3.15430200 4.89472400 4.47083900 5.44467300 5.12828900 1.58093800 0.99855900 -1.00325300 -0.04465600 -1.63544800 -0.79541000 0.56696500 -0.86629400 0.74594000 -2.81932700 -2.90467600 -3.37362000 -0.64354300 -0.37325700 0.90012800 -2.82490200 -3.89201000 -4.05877900 4.30741100 2.85176700 5.93866600 6.05702800 4.36450300 4.76219000 2.13272600 1.96033000 1.76832000 -1.53345300 1.96719100 2.14456000 0.94653700 3.24897800 3.01663100 3.78917000 4.18434300 -3.89644500

-0.58997600 -3.31523400 -2.81149200 -1.88065100 -1.49592900 -1.99915100 -2.90688100 -1.39697100 -2.94963400 -0.59590900 -0.52841100 -1.92501800 -2.73515900 -1.22862400 -2.69266300 -3.65587700 -3.32775100 -3.23653400 -1.36924200 -2.73487400 -1.76946400 -1.29491000 -0.16172100 1.62466600 -0.17936600 -1.71108200 -3.31257200 -1.63068200 0.22930200 -0.15435600 -1.96559600 -2.14952000 -3.00034900 -0.71457800 -1.01733100 -3.96963600 -3.51073100 -2.60490000 -4.71343900 -2.30348100 -4.10469200 -3.95743700 -0.64380900 -3.03068100 0.12930400 -0.38963600 0.65978100 0.98405200 2.63916000 1.27024500 0.42667100 2.18808200 0.98863100 2.78305000 3.05677300 4.32379600 3.05791700 2.57476100 1.06465200

0.28996900 3.25959300 2.29586600 1.30737100 1.34859000 2.34756200 3.28300200 -0.53530000 -2.48238900 -1.68021700 -2.84020600 -3.48228800 -2.36495600 -2.12990400 -1.12075300 -1.33326800 -0.23996200 2.28939000 0.36664400 1.38329200 0.42569400 -0.37551700 -1.17307700 1.69062900 -0.37910000 2.41944900 4.07029900 0.09472700 -3.51429000 -2.46607000 -4.41708400 -3.72310000 -3.33656400 -3.05132300 -1.37248200 -2.81922400 -0.42063500 -1.24675800 -1.54555100 0.05602000 0.41375800 3.04316600 -0.38117900 1.37601500 -1.66254400 -1.92292200 -0.54826900 1.00182000 1.58117500 2.71170600 -1.41043800 -1.33664500 -1.62827800 -0.93691500 -1.35729600 -1.69332400 -0.11496600 -2.18478600 0.51310400

S36

O O C F F F C H H H H H H N C O C H C H

-3.06683600 -3.68697400 -5.36085900 -6.23676500 -5.52721300 -5.66235400 -1.27094500 -1.21656700 -0.96049400 -2.30562100 -2.25384200 -0.71782100 -1.51710700 -0.45871900 0.10902100 -1.61330200 -0.35898700 0.69810300 -0.78096300 -1.83688500

0.11731000 2.27665400 0.57229200 1.55675500 -0.30044700 -0.07967700 4.86754700 5.02334300 5.80654100 4.65703800 2.36614700 2.37181100 0.53616200 0.55630800 1.58535600 1.99828900 3.76123300 3.89275700 2.65392400 2.53425200

0.62377800 0.41056100 0.48719900 0.32517400 -0.52938800 1.61722600 2.91258900 3.99594300 2.44116100 2.63352400 -0.81777800 -1.26812200 0.81437600 0.89251500 1.44195600 -1.46061500 2.49832200 2.72324100 1.87329900 1.62968000

A EM06-2X/6-31G(d)= -2263.515591 G M06-2X/6-31G(d), 318K= -2262.9902130 EM06-2X/6-31G(d), Toluene= -2263.544445 C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H

-0.94579200 -3.74416800 -4.19885200 -3.35153800 -1.95555800 -1.51415500 -2.45072700 -0.43211600 -0.99676600 0.49215500 -0.26762500 -0.95628000 0.45027600 1.35212000 -1.53299400 0.50296100 1.14874000 -5.60246300 -3.92618200 -6.13443800 -5.28696800 -5.93144400 -5.14808300 -0.95001100 -1.37173000 -0.45318300 -2.10627700 0.18505400 0.46124200 -0.96161500 -0.41377800 -1.96810100 0.76092000 1.90432200 2.06429400 -1.63966600 -1.78958900 -2.44587200 -0.07494300 1.74205600 1.10075700

-0.10501600 -1.83108700 -1.02800800 -0.41566500 -0.67206500 -1.48548100 -2.04374000 -1.23807900 -2.54752600 -0.73270100 -0.18282500 -1.33945900 -3.07826300 -1.87312800 -2.06850600 -4.24898500 -4.33252100 -0.79573400 0.41207700 -0.00135600 0.61314800 1.37991400 2.03024300 2.56696600 0.68903400 -1.69721500 -2.68938700 -1.89505300 0.35685300 0.56212600 -1.59467500 -1.04150700 -3.45030100 -1.51054600 -2.07135100 -3.33476300 -2.90982600 -1.47697000 -5.10970700 -3.52489200 -5.24605900

-0.22121500 -3.04696400 -2.05096000 -1.08519500 -1.20281000 -2.22011100 -3.11800100 0.68049500 2.72206300 1.75336600 2.92197800 3.66650400 2.56317400 2.20731300 1.36288000 1.61069100 0.45002300 -1.98036600 -0.07793100 -1.00903000 -0.04490300 0.86327500 1.84227100 -1.45918900 0.39542400 -2.33789700 -3.92300100 0.06553900 3.53123800 2.53266500 4.58307700 3.95756800 3.54855200 3.07791000 1.40643700 3.12701300 0.71434300 1.51224000 1.95145200 0.02937700 -0.13479900

H H H H H H H H H H C O O C F F F C O O C F F F C H H H H H N C C C H

-6.22306900 -3.29183400 -7.20021900 -5.84405400 -4.61007200 -4.42639300 -0.83033000 -1.00467700 -1.88095900 1.14566100 1.25186300 0.01229200 2.01498100 1.96139500 3.17922400 1.24771100 2.08423500 3.27707100 2.10387300 3.74689400 4.18002700 5.44052400 4.17854700 3.70904400 3.16115300 3.17459700 3.44672100 3.89735000 2.36395900 1.09941900 0.20352800 0.24946200 1.55330300 1.79769400 0.98994000

-1.27591200 0.88587000 0.18877700 2.59419100 1.30302200 2.71557200 3.31892500 3.06407700 2.02387900 0.08450400 2.34081000 2.38287200 1.34314600 3.71151800 3.62322100 4.56276300 4.27484300 -1.13321800 -1.27889900 -0.22011500 -2.34674800 -2.17653900 -2.60257100 -3.45291600 3.92041400 4.43287900 4.65449700 3.11379800 1.39197100 -0.13834400 0.47626800 1.67268700 2.12339600 3.40347000 4.13419400

-2.72955100 0.66089600 -0.93965900 2.46214500 2.46339300 1.38210300 -0.67276700 -2.43002500 -1.29307200 1.42533400 1.31203600 1.36388300 1.34646900 1.19853600 0.66072200 0.43570000 2.40822100 -1.25515800 -0.77547000 -1.91505600 -0.93122400 -1.31061100 0.39339500 -1.53648300 -2.50442000 -3.47246600 -1.74235500 -2.50815100 -1.85404000 -0.93074700 -0.92196500 -1.41932500 -1.87683300 -2.19535000 -2.18820100

C-C Bond Formation (TFA) 2a (Indole) EM06-2X/6-31G(d)= -402.9596847 G M06-2X/6-31G(d), 318K= -402.8359600 EM06-2X/6-31G(d), Toluene= -402.9731052 S M06-2X/6-31G(d), 318K= 90.0 C C C C C C C C H H H H H H N C H H H

-0.23300900 -0.20708600 -1.37191600 -2.58237900 -2.63411400 -1.47575800 1.13474700 1.92520400 -1.32969500 -3.50737900 -3.60036800 -1.52506200 1.49253200 1.44834800 1.11577100 3.41194100 3.76555800 3.76570400 3.87418900

0.76203800 -0.65335500 -1.42452600 -0.75163700 0.65500600 1.41317600 1.20062400 0.08527600 -2.50982400 -1.31975900 1.14979800 2.49829100 2.22075000 -1.98654400 -1.03488700 -0.04852100 -0.58849300 -0.58879700 0.94029900

-0.00012100 0.00006300 0.00004300 -0.00015900 -0.00034100 -0.00032400 -0.00003800 0.00018200 0.00018200 -0.00017900 -0.00050100 -0.00046900 -0.00012800 0.00038800 0.00024700 0.00033800 0.88582500 -0.88490600 0.00020300

S37

9 EM06-2X/6-31G(d)= -2666.510539 G M06-2X/6-31G(d), 318K= -2665.8322090 EM06-2X/6-31G(d), Toluene= -2666.542318 C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O

-0.79927000 0.27110000 0.58266700 0.24799300 -0.42245900 -0.73358300 -0.37379900 -2.31527800 -4.49968100 -2.81822700 -3.04971900 -4.25671300 -5.04988900 -4.10024500 -3.15128600 -5.28734400 -4.72149500 1.28662100 0.60766800 1.63859600 1.29611300 1.69999700 1.46243400 1.90905000 -0.51257900 -1.25220200 -0.62385300 -2.53269900 -3.19030600 -2.12253200 -5.14950300 -4.04914300 -6.02687800 -4.51540800 -3.83234200 -5.22139400 -3.28339800 -2.63849600 -6.01392100 -3.98642400 -4.98200800 1.53107100 0.34351000 2.17904600 1.90120900 0.38758100 1.93934900 1.71769000 2.96154000 1.69730200 -2.13953400 -0.56608600 -0.33784000 -1.43486500 0.31193900 0.42491100 1.55320200 -0.21216000 -1.15959100 -1.83733400 0.05342100

0.91960900 3.54122900 3.90060200 3.12420700 1.89148200 1.54877600 2.40988600 0.69451100 1.60328600 -0.28118500 0.36896800 1.31591500 0.30896900 -0.84939400 1.97828400 0.50702800 -0.13828600 5.12663100 3.60577800 5.55962100 4.78973300 5.32477900 4.57741900 0.23744400 1.28131500 0.62220500 2.13416600 0.21582700 -0.44060100 0.87191700 0.86609300 2.24119300 0.11477200 -1.46801200 -1.49949300 2.41572900 2.40644900 2.72894600 1.29225700 -0.92927300 0.11366500 5.69141400 3.03599700 6.48719600 5.14882600 4.45121400 3.59126100 0.07756200 0.05426900 1.27164100 -1.13886200 -1.88432100 -0.71090900 -2.32962800 -2.96674300 -4.06660500 -2.51135500 -3.32948200 -1.96765400 -1.71401800 -2.16689400

0.47696800 -2.81698400 -1.54561700 -0.39748100 -0.63466400 -1.93172700 -2.98930100 0.41852900 1.17777900 1.44125600 2.76923900 2.66437300 0.52535600 0.91636300 0.53864200 -0.95346700 -1.97047200 -1.36810300 0.89377600 -0.12471400 1.02285500 2.19704900 3.37159900 1.47110900 1.46691600 -2.15997200 -4.01154000 -0.53697000 3.48920900 3.04327700 3.11195300 3.20993100 0.98748200 1.71583100 0.08099300 1.05177000 -0.45780500 1.15564200 -1.16905300 -1.84854900 -2.99393400 -2.26140600 1.77562200 0.03185700 4.18882500 3.54968300 3.31361900 2.53864100 1.24613800 1.20072400 1.63716500 2.96463100 3.28495600 2.16596800 3.63326000 2.88160700 3.86843600 4.81194500 -2.36762200 -1.33470100 -2.47215500

C F F F C H H H H H H N C C C H C C C C C C C H H C H H H N C H H H

-1.98198900 -1.35477400 -3.17575600 -2.21957100 2.83639200 3.83975500 2.82311800 2.10836400 5.41520700 0.67948800 -0.69681900 -0.13070100 1.04212800 1.39961100 2.51873100 3.22995500 4.61509200 4.49532400 3.52293700 3.30042400 5.25388800 2.87135000 4.81356400 6.17471500 1.79518000 3.63610300 1.98016300 5.39290100 3.32409600 2.74243500 3.09675700 3.74492100 2.06030100 3.13930400

-1.90889500 -2.45449500 -2.50110000 -0.60976900 -4.09475300 -4.26208800 -4.47261400 -4.66152200 -2.68412500 -2.73592600 -1.07448100 -0.36996900 -0.71827200 -2.11129700 -2.63912400 -1.99736800 -2.03082800 -0.62201100 -2.40868400 -0.20307900 0.33081400 1.12811300 1.64467500 0.04030100 -1.38075300 2.04215500 1.43426500 2.38654500 3.08307900 -1.30848700 -3.74970900 -4.53072400 -3.95261300 -3.79728800

-3.67720000 -4.71369600 -3.55144700 -3.98160900 1.05468500 0.65061800 2.08335600 0.46992500 -0.86470300 0.02051300 -0.26802100 0.27073300 0.71804600 0.54534000 1.06833500 1.58398600 -1.18617600 -0.94356300 -1.92858100 -1.58601500 -0.24289900 -1.56927800 -0.19804100 0.25559800 -2.54886600 -0.86119200 -2.10832100 0.34321900 -0.82558100 -2.18211600 -2.42623100 -2.02287500 -2.13293500 -3.51947500

TS9 - Re EM06-2X/6-31G(d)= -2666.487218 G M06-2X/6-31G(d), 318K= -2665.8074150 EM06-2X/6-31G(d), Toluene= -2666.51731 EM06-2X/6-311++G(d,p)= -2667.275349 EM06-2X/6-311++G(d,p), Toluene= -2667.308024 S M06-2X/6-31G(d), 318K= 287.9 Imaginary frequency: -374.7 cm-1 C N C C C C C C C N C C C C C C C C C C C

0.49016600 -0.23243600 -0.91778200 -0.73568600 0.21343000 0.89831400 0.64789000 2.00131600 3.79957500 2.35274700 2.16819700 3.21212500 4.66089400 3.78036200 2.63222700 5.24730100 4.98954400 -1.87681900 -1.50959000 -2.61870000 -2.43496300

0.86291800 3.92659700 3.96325400 3.02052200 1.97827700 1.96868200 2.96242600 0.78997900 1.83499300 -0.24628600 0.26335600 1.35805200 0.68428100 -0.59153400 2.13672800 1.06858600 0.54188700 5.00454900 3.15701300 5.10556400 4.16718800

-0.84045200 2.18034500 1.00748400 -0.04653800 0.16977300 1.36508400 2.33448900 -1.10919000 -2.47146900 -2.11217000 -3.49064200 -3.80608800 -1.89124200 -1.91009200 -1.51909500 -0.55376900 0.64102300 0.84467000 -1.23432600 -0.29507400 -1.34873300

S38

O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H C H H N C H C H C C C C C C C H H C H H H

-3.23196400 -3.12714100 -2.23019100 -0.02922800 1.64319500 1.19785400 2.46446200 2.24142400 1.14423400 4.00897900 2.74145600 5.50124800 4.06939200 3.85763300 4.41814400 2.97087600 1.89514000 5.95136700 4.29695900 5.47190100 -1.98994500 -1.37811200 -3.35642100 -3.85753400 -2.12333500 -3.35671600 -1.90545300 -3.15766600 -2.42905000 1.61685000 0.04779900 -0.39815300 1.16252500 -0.72793500 -0.39899000 -2.04529400 -0.47377800 1.89915200 2.02267500 0.88527200 3.21125500 3.16519100 4.27503100 3.43326000 -2.53163100 -3.44693700 -2.43266700 -1.67233700 -1.31405500 -0.41076500 0.72547000 0.06424100 -1.15389900 -4.04910100 -2.55286800 -3.41242200 -3.32809600 -3.69844800 -2.10518900 -2.59398500 -4.80315700 -2.55072500 -4.77269900 -5.67081900 -0.65377900 -3.66021400 -1.69679600 -5.62533500 -3.66202800

4.36795100 3.44909300 -0.22489700 1.05022300 1.20780000 2.93994400 0.44686100 -0.59079300 0.63306900 0.96779700 2.19007800 0.53576300 -1.25548800 -1.16238500 2.72693200 2.67044100 2.77743600 1.90064700 -0.27973900 0.92991500 5.70695400 2.45052200 5.88855900 3.76434400 3.46720400 2.42904400 -0.01945600 -0.79230400 0.72196000 -1.54940600 -2.40037300 -1.40783400 -2.52142300 -3.72476900 -4.59279500 -3.50383700 -4.30060300 -0.97099200 -1.16067600 -0.94544800 -0.60104000 -0.84089100 -1.24224500 0.72373000 -4.46044200 -4.87593000 -4.83465000 -4.83278000 -2.28405800 -2.77016800 -0.87249400 -0.43099300 -0.99326200 -3.22783800 -2.94877500 -2.56039600 -2.43101500 -1.03511300 -2.37519100 -0.26498400 -0.40125200 1.11954500 0.98142100 -0.97320600 -0.91217300 1.73224200 1.69519000 1.49308900 2.81155200

-2.42562700 -3.49210300 -1.13832300 -1.78353800 1.57387400 3.27328500 -0.17936500 -4.17106900 -3.57398600 -4.44950400 -4.33969300 -2.58315400 -2.73082900 -0.98093400 -2.61476200 -0.62751300 -2.02417200 -0.61211400 0.80715200 1.53259200 1.66402600 -2.04262300 -0.43585400 -4.23677500 -3.93383000 -3.15895600 -2.16361700 -1.19133600 -0.62552900 -2.04860400 -2.77285900 -3.31240300 -2.12324300 -2.88046500 -1.92283800 -2.80902300 -4.06192600 2.80588300 1.57966300 3.53199900 3.53939200 4.84793100 3.04157500 3.37456100 0.33469700 0.76311200 -0.68783800 0.89922600 0.04876300 0.41905000 0.32357700 -0.33187400 -0.43311800 2.17684600 0.27975600 -0.26442300 2.03686400 1.81792600 2.77924900 2.21616900 1.24698200 2.08878200 1.10354600 0.92986000 3.05311700 1.51574100 2.43151100 0.66826300 1.38970200

N C H H H

-1.64878200 -1.26651300 -1.86114300 -0.46947800 -0.77709300

-1.13367100 -3.48744100 -4.38775400 -3.71206000 -3.18912600

2.77477900 3.30157600 3.46367000 2.58068100 4.23167800

TS9 – Si EM06-2X/6-31G(d)= -2666.487694 G M06-2X/6-31G(d), 318K= -2.665,8049520 EM06-2X/6-31G(d), Toluene= -2666.519212 EM06-2X/6-311++G(d,p)= -2667.274216 EM06-2X/6-311++G(d,p), Toluene= -2667.30838 Imaginary frequency: -359.4 cm-1 C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H

1.44239200 4.58033800 4.78239800 3.80047700 2.55039200 2.35994400 3.40695400 1.35876800 2.51324200 0.50368200 1.28800300 2.30535800 1.23332700 0.03312000 2.70969100 1.29649700 0.46463300 6.04874900 4.09437600 6.31851200 5.32843300 5.70697400 4.74607100 0.75624800 1.66459100 1.40691000 3.26004300 0.82536000 0.56749900 1.77822100 1.95307400 3.24437500 1.17411800 -0.43990000 -0.72730200 3.38114000 3.06754000 3.46225700 2.14257300 -0.40618900 0.63600300 6.77980100 3.34292600 7.27503800 5.23253400 4.44052500 3.84872500 1.14843600 0.35948900 1.60172200

0.51030500 1.02634900 0.20700600 -0.04021000 0.62990800 1.43505600 1.60499100 1.82823100 3.12590900 1.67300400 1.03551400 2.05800400 3.99223400 3.02887400 2.41189900 5.02625600 5.18898000 -0.43580900 -0.93920200 -1.28430500 -1.54785700 -2.42530900 -2.76099300 -2.05479400 -0.29690700 1.93457800 2.25037800 2.55869700 0.69399800 0.15364000 2.52347600 1.54484200 4.53547700 2.88390600 3.36680000 3.75064100 3.10063200 1.62090800 5.70870700 4.56301900 5.98765000 -0.22630800 -1.17651300 -1.78759900 -3.47999500 -1.87786600 -3.20038000 -2.18124900 -3.00771300 -1.78953300

-0.64836500 -3.60995900 -2.54474700 -1.54264400 -1.68859900 -2.78644500 -3.71836300 0.13571900 1.93534200 1.37404300 2.48582500 3.01836000 1.88583700 1.81723900 0.58886700 0.78593700 -0.24091600 -2.43870000 -0.47603200 -1.40657200 -0.41798900 0.53599700 1.52273200 -1.62251100 0.05481500 -2.94188400 -4.58257200 -0.48029700 3.23158000 2.07408700 3.94532600 3.24466200 2.83853800 2.79067600 1.11891100 2.16570400 -0.18041300 0.69490200 0.88157000 -0.42841500 -0.95583600 -3.21263400 0.27040300 -1.31091100 2.18140100 2.09551600 1.07703500 -0.60741800 -1.96649100 -2.26807500

S39

H C O O C F F F C O O C F F F C H H H H C H N C H C H C C C C C C C H H C H H H N C H H H

-0.35145400 0.53334400 1.73545600 -0.30471500 -0.01200100 -1.30261000 0.67134800 0.04539700 -2.35529500 -1.64974100 -2.13635000 -3.60509900 -4.39246400 -3.19443300 -4.35780900 -3.02531200 -2.42231400 -3.57223400 -3.74375200 -2.14944300 -1.53617700 -0.54334400 0.14668500 -0.26740400 -3.52920700 -2.09442000 -1.41125100 -3.33705900 -4.34310300 -2.47578500 -3.89273700 -5.51959900 -4.58331800 -6.21052000 -5.89130700 -2.06783000 -5.74493000 -4.21396400 -7.12976500 -6.29767400 -2.73154500 -1.36391700 -1.17737300 -0.44512900 -1.63091300

1.09718800 -1.92229300 -2.07635900 -1.15205200 -2.73175000 -3.07406700 -3.85312800 -1.97936700 2.05459900 2.36762300 1.21529600 2.95387500 2.59544300 4.21481500 2.97492300 -2.19725800 -1.96524400 -3.12462100 -1.38567000 -0.19257800 -1.09080000 1.02000500 0.25217600 -0.95429900 -4.11352900 -2.30599000 -3.15066200 -3.17986900 -2.14723900 -3.11923500 -1.39116400 -1.77788400 -0.28725800 -0.66413500 -2.35366600 -1.59851500 0.07301300 0.27263100 -0.36259400 0.94370100 -2.00933600 -4.04845000 -4.73183400 -3.50684500 -4.64073000

1.15865300 1.94635400 1.68004500 1.42287500 3.14797800 2.96676600 3.37460000 4.26042600 0.04074000 -0.94429000 0.93500400 0.20247700 1.22510900 0.44240900 -0.90002600 -3.89465300 -4.77919700 -4.08786800 -3.75519100 -2.27781000 -2.21785100 -1.23959700 -1.25269400 -1.67420900 -1.91461200 -2.70657500 -2.78622800 -1.39698800 -1.17023400 -0.26483700 -0.07778400 -1.82320700 0.40963000 -1.36090400 -2.66599200 1.09237600 -0.26227400 1.25814900 -1.85318300 0.07525900 0.41559900 0.07378600 -0.75800200 0.30628900 0.95470700

10 EM06-2X/6-31G(d)= -2666.498316 G M06-2X/6-31G(d), 318K= -2665.8195040 EM06-2X/6-31G(d), Toluene= -2666.526492 C N C C C C C C C N C C C C

-1.02948900 0.08471200 0.24531000 -0.08810200 -0.63190100 -0.79702200 -0.41976100 -2.51844900 -4.76980800 -2.98547700 -3.27489100 -4.50470700 -5.25774800 -4.23199500

-0.30433000 -4.16298200 -3.94734900 -2.72439400 -1.68022400 -1.93738400 -3.18212600 -0.04491400 -0.58005900 1.23121500 1.06428700 0.15030900 0.46492100 1.62812000

-0.71765800 1.00041300 -0.33178200 -0.98269400 -0.17480500 1.16711700 1.71396500 -0.43477200 -1.35905900 -1.03180800 -2.47382900 -2.68105200 -0.32408200 -0.34258800

C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H H N C C H C C C C C C C H H

-3.44637100 -5.50703000 -4.94012700 0.78813300 0.14120500 1.00768400 0.69050800 0.97593900 0.74922600 1.58115400 -0.88814800 -1.23923000 -0.53869700 -2.62275400 -3.42448200 -2.37812300 -5.38586900 -4.31573800 -6.22519000 -4.63555000 -3.97087500 -5.53055700 -3.60267300 -2.98726500 -6.24318900 -4.19911500 -5.20624300 1.02186500 -0.09638200 1.42627400 1.07880500 -0.31510500 1.32598300 0.87104300 2.52164300 1.75797900 -1.98392000 -0.53631100 -0.52020400 -1.39862100 0.52364500 0.65778600 1.71280000 0.18004800 0.03813800 0.05254600 0.99413700 -1.24281700 -1.45777900 -1.15573700 -2.30274200 3.47242200 4.54531000 2.96867200 3.09415500 -0.46829500 -0.26630300 1.04888900 3.19385600 3.54690500 4.05049000 4.07151400 3.34013300 3.29876500 4.60777600 2.99180400 4.32538100 5.21497100 1.82836900

-1.19649000 -0.19165800 0.07194200 -5.01582100 -2.60695600 -4.87692400 -3.65133800 -3.62428600 -2.41224400 0.44656400 -0.27893600 -1.18501200 -3.35870300 0.09130000 2.06258600 0.66688100 0.73467000 -0.56991200 0.84416700 2.49348400 1.96676700 -1.35667800 -1.89305200 -1.76604700 -0.99657100 0.85175100 -0.49605500 -5.93600300 -1.68079800 -5.67651100 -2.57862200 -2.14709400 -1.59203000 0.57756200 0.90336900 -0.62404800 2.46331600 3.23782500 2.42906100 3.33156400 4.35272800 4.90605000 3.87488300 5.32020400 -0.09161700 0.88374000 -0.93369800 -0.44966600 -1.76856500 -0.02965800 0.13179700 3.76323600 3.98246400 4.46169100 3.95016000 0.97216400 0.78556600 1.09537800 2.32775800 2.23272200 1.28794300 -0.05488600 0.93141700 -0.92097700 -0.49412900 -2.21133600 -1.79831700 0.16308100 -0.71270000

-0.88110500 1.01215200 2.18638400 -1.10166300 -2.38343200 -2.44040900 -3.08873000 -4.41309900 -5.10093400 -1.74861900 -1.79952200 1.81367200 2.78019100 0.65003400 -2.89640300 -2.95217100 -2.96986600 -3.48368400 -0.68127500 -0.87763000 0.66332200 -1.48991400 -0.05293000 -1.70118600 0.96774300 2.33095900 3.07198300 -0.57611500 -2.88892100 -3.04282700 -6.12614500 -5.09784100 -4.65528200 -2.57092300 -2.05373700 -1.58999500 -0.93156400 -1.89299500 -2.79516100 -0.92356000 -1.86316400 -0.65813200 -2.24155000 -2.72419300 3.64051200 2.91994300 3.88345700 4.42091900 4.43222400 5.68349600 3.85249000 0.59996300 0.59170600 -0.07077400 1.61022900 0.82875700 -0.15044500 -0.50242300 0.14872400 -0.88454300 0.97937300 0.30533100 2.27105300 1.08349200 -0.89439700 0.68042100 -1.31017800 -1.51206700 3.26600800

S40

C H H H N C H H H C H H

3.51371200 2.37074100 4.72924600 3.28477400 2.90365700 3.07540000 3.92940600 2.20290500 2.85231100 1.73053000 5.04694500 1.20832900

-2.63739200 -2.86038200 -2.16135900 -3.63747500 -0.28198300 1.87122300 2.53117600 2.49037500 1.31243900 1.98878700 1.70833100 2.40996000

-0.54306400 1.29108800 -2.25025500 -0.89906800 2.28571900 3.39908000 3.57273900 3.16270200 4.31097100 0.24411500 1.16458900 1.10413700

4 EM06-2X/6-31G(d)= -673.4262253 G M06-2X/6-31G(d), 318K= -673.1896150 EM06-2X/6-31G(d), Toluene= -673.4430178 C O C H H H C H H C C H H H H C C C C C C C H H C H H H N C H H H

2.32257600 3.17601900 1.54694800 1.64960200 1.89460300 0.48219700 1.95101600 2.84431600 1.18225800 1.44953500 1.13851000 0.33549800 0.81745400 2.02297200 2.27479600 0.28055300 -1.03589200 0.29508100 -1.77825900 -1.66193300 -3.10490200 -2.97575000 -1.12615400 -1.18964200 -3.69303200 -3.65297300 -3.46320200 -4.72238300 -0.94544300 1.39849600 1.44354500 1.25877000 2.36060900

-0.58005400 0.27379400 -0.77378900 -1.80557000 -0.07726800 -0.60916900 -1.46478300 -2.01534600 -2.19253300 -0.56816200 -1.38200100 -2.10375700 -0.72341700 -1.93628500 0.11601800 0.25958800 -0.20677700 1.61529900 0.92822400 -1.46459000 0.84568400 -1.55349500 -2.36224400 2.96514200 -0.40754800 1.73224400 -2.52270000 -0.50760700 2.01612300 2.60845900 2.98412100 3.46631800 2.15251200

1.17640800 1.05706600 2.45523100 2.80904400 3.21876400 2.24635700 -0.00577200 -0.32472600 0.27827900 -1.15433100 -2.41283400 -2.23521700 -3.22481000 -2.74392400 -1.38439600 -0.69098800 -0.32409600 -0.47453800 0.08673800 -0.27722100 0.51629900 0.15140600 -0.57184000 0.21739000 0.54113000 0.82180100 0.18861000 0.87080800 -0.01979500 -0.65474900 -1.68289000 0.01026400 -0.40757900

TS9 – Re´ EM06-2X/6-31G(d)= -2666.477510 G M06-2X/6-31G(d), 318K= -2665.796711 EM06-2X/6-311++G(d,p)= -2667.265475 EM06-2X/6-311++G(d,p), Toluene= -2667.302596 Imaginary frequency: - 385.0 cm-1 C N C C

-1.50009900 -2.88418700 -3.63860400 -3.25102100

-0.06206100 1.06513400 0.24093500 -0.18841600

0.03642200 4.00191400 3.22794100 1.92769400

C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F C H H H C H H N

-2.00216400 -1.24708500 -1.73556300 -1.72846100 -3.44944200 -1.40824400 -2.55368500 -3.70326100 -2.23206500 -1.07802700 -3.13777700 -1.92662900 -0.77485100 -4.87929100 -4.10283300 -5.68504300 -5.29084300 -6.16743400 -5.82907000 -0.49209600 -2.03240500 -0.27726800 -1.14189800 -0.99570300 -2.15383600 -2.82040000 -3.75809000 -4.65696300 -2.52542300 -0.94765500 -0.11729000 -4.32309100 -3.16400700 -3.89371200 -2.78472100 0.12301800 -0.68841600 -5.15128400 -3.80869600 -6.63207400 -6.64824000 -5.72868500 -4.89340600 -1.12216800 0.03581100 -1.13198100 -0.56533900 -0.08567600 -1.20007600 0.39685400 0.83403600 2.12482900 0.72313100 0.48925000 1.78371500 1.27559600 1.87232000 2.38625000 3.62272600 2.46650900 1.63164900 3.55458900 4.24764700 3.00267500 4.12345900 1.77109200 2.28067500 0.55674900 -0.08289900

0.28870200 1.11198900 1.47222800 1.14337500 2.31865200 0.81269700 0.13398600 1.13461100 3.10364800 2.09231000 1.76071000 4.29018700 4.60244500 -0.21319300 -1.07138700 -1.05103200 -1.49099900 -2.32903800 -2.81192800 -2.57784300 -0.92843100 1.48315800 2.12973600 1.90597500 -0.26014700 -0.72879300 1.48083400 0.65135600 3.49788100 1.84436300 2.42580400 2.97641200 2.54478300 1.01394400 4.94870200 4.00248700 5.49415500 0.13345100 -1.41911900 -1.40912200 -3.46234900 -1.98827100 -3.38314800 -2.95281400 -3.43078100 -2.13808100 0.11113200 -2.07399800 -2.32919400 -0.96673900 -3.29714500 -2.96794500 -4.17232500 -3.94921600 2.60328600 2.01879200 2.25697700 4.00555700 4.11163000 4.28784300 4.95672700 -3.59546500 -4.20529700 -4.24981400 -2.88581700 -1.83310900 -1.13805200 0.37516500 -0.37585100

1.43226300 2.23568800 3.51230300 -0.88693300 -2.25818600 -2.31986500 -3.00645100 -3.19719200 -2.80303600 -3.02073500 -0.85876000 -1.92215900 -1.33661300 3.76027900 1.20298800 3.04794900 1.75365300 1.15118500 -0.13166100 0.95877100 -0.36338000 1.90442500 4.14456000 -0.60421300 -3.94378200 -2.39752600 -4.23504800 -2.96337100 -3.78576400 -4.07704500 -2.62331700 -2.21934900 -0.09740100 -0.58444800 -1.77559400 -1.43999000 -0.72430200 4.75177600 0.22103500 3.43769500 -0.43644200 -0.85025300 -0.10805800 0.14347200 1.38238800 1.72926500 -2.43557400 -2.54940200 -2.07103000 -2.90480900 -2.76714400 -2.87464400 -1.75094000 -3.88843700 0.32892200 -0.64640200 1.52638200 0.05208800 0.56403900 -1.25159400 0.62540100 -0.23098300 0.35624700 -0.91178300 -0.83561700 0.05070600 -0.61570900 -0.27515100 0.02004300

S41

C H C H C C C C C C C H H C H H H N C H H H

0.44839900 3.89333300 2.53411600 1.96847300 3.69140500 4.71670500 2.77431900 4.23396900 5.93147200 4.89451400 6.61174600 6.34039600 2.42399300 6.09816600 4.49407500 7.56152700 6.65382800 3.04203300 1.54976700 1.32180400 1.68905700 0.69433200

-1.56599700 -3.17378300 -2.89210200 -3.58554100 -2.23098700 -1.42940300 -1.27952300 -0.11318800 -1.71429200 0.93775600 -0.67626700 -2.72019100 0.75115000 0.62869100 1.94527100 -0.87809000 1.41459200 -0.08419300 -1.52852600 -2.59566200 -1.16912900 -0.99248600

0.36105700 2.61408100 0.63069500 1.25184400 2.11694100 1.44565000 2.65933100 1.42289900 0.82117900 0.79763000 0.19335800 0.82804200 2.13425500 0.17609400 0.81641800 -0.29160600 -0.32466900 2.15960800 3.46433800 3.50459300 4.48930100 3.03555100

TS9 – Si´ EM06-2X/6-31G(d)= -2666.481368 G M06-2X/6-31G(d), 318K= -2665.797218 EM06-2X/6-311++G(d,p)= -2667.2650218 EM06-2X/6-311++G(d,p), Toluene= -2667.3009602 Imaginary frequency: - 380.7 cm-1 C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H

-1.25624900 -3.89351600 -4.06308600 -3.24046300 -2.18737100 -2.02379900 -2.90246100 -1.66339100 -3.26711900 -0.86910300 -1.45943400 -2.78190200 -2.33230000 -0.88006300 -3.15034000 -2.68133900 -1.90982400 -5.12849400 -3.49410800 -5.35833900 -4.52936600 -4.85887800 -4.07025100 0.46874800 -1.31482400 -1.21569500 -2.77499200 -1.38117200 -0.70760100 -1.59456500 -2.65272000 -3.51357800 -2.50079300 -0.43110200 -0.22717000

0.52380800 0.20731400 -0.63460600 -0.62660800 0.33441500 1.16273600 1.06503100 1.83208200 2.87769800 2.10299300 1.39899300 2.08839600 4.10268400 3.58641500 1.96975200 4.91215100 5.19445700 -1.57477800 -1.56840600 -2.46419400 -2.46824200 -3.41153600 -3.49535800 -1.68559700 -0.31063800 1.88999900 1.72774800 2.64467100 1.42961200 0.36123600 2.76084800 1.32810700 4.74959600 3.73630100 4.03119600

0.48049700 3.92555400 2.87357200 1.70882800 1.67693000 2.76386400 3.86239100 -0.21371400 -1.80657600 -1.46994500 -2.65486100 -3.02929200 -1.64539900 -1.71443600 -0.57105800 -0.41830100 0.62939800 2.95914600 0.66816900 1.95391600 0.79675800 -0.11297500 -1.28304400 1.27118500 -0.22423900 2.78469200 4.71627400 0.46206300 -3.44565400 -2.36747200 -3.88441200 -3.31799600 -2.51678600 -2.69827000 -0.96591100

H H H H H H H H H H H H H H H H O C O O C F F F C H H N C H C C C C C C C C H H C H H H N C H H H C H H H H C C O F F F

-4.30050900 -3.67673000 -3.59611300 -3.70277700 -0.88023900 -2.29968100 -5.73881900 -2.86619700 -6.16100400 -4.48683700 -4.12285700 -3.02230700 0.21783700 1.21020500 -0.44079300 0.13882900 0.44172000 1.97385400 1.12449400 1.84283400 3.38244000 4.24158600 3.33014000 3.90802800 2.23405200 2.45933700 0.46576700 0.12205100 0.97499600 5.46308200 3.23676200 4.54142300 3.99972800 4.16462800 3.20427400 4.01429100 2.42954300 3.24484400 4.61501100 2.81532200 2.46346400 1.83108000 3.25050100 1.87454700 3.33554700 4.43928400 4.95462500 5.06229700 3.49575500 4.23608600 3.70413200 5.02605400 4.68801300 2.92146000 0.58600000 -0.67224300 1.60349400 -0.80810500 -1.82586400 -0.61620600

3.21061300 2.39114400 0.98887500 5.29574100 4.85554500 5.79692300 -1.55381600 -1.58546000 -3.19258100 -4.31544200 -2.56587600 -3.70514300 -1.97352800 -2.39268700 -1.76350500 1.82976200 -0.53603500 3.12188400 3.33666400 2.50365700 3.68431100 3.53128000 4.98365000 3.04355700 0.12010100 1.18332800 1.65788500 0.69076300 -0.27388900 -1.32399500 -0.70771900 -1.57345500 -2.92450800 -0.91574200 -2.94078800 -4.04674400 -4.03193700 -5.14891700 -4.06210900 -1.46847900 -5.14032000 -4.00151400 -6.03347700 -6.01585000 -1.69457900 0.48035200 1.02982200 0.50117300 0.98839600 -0.01210600 0.37052700 -0.68276700 0.84651000 -1.68628000 -1.52456800 -2.41608500 -1.97810000 -2.88197800 -1.76858600 -3.47672900

-1.94079300 0.28919500 -0.78095300 -0.43052600 0.73371400 1.44395300 3.85574200 -0.21506400 2.00161000 -1.86752300 -1.86077900 -1.04401900 0.24523700 1.64549700 1.87853400 -1.34747400 -1.73517800 -0.14840300 0.74923700 -1.21973500 0.16604700 -0.84441800 0.47057500 1.23416200 1.70153700 1.63745600 0.94528900 0.89394700 1.27939800 1.42065100 2.25838000 0.91061000 0.80060100 -0.29437300 -0.35758700 1.63002800 -0.73526600 1.26900000 2.53530200 -1.84768000 0.10432600 -1.63850400 1.89815600 -0.14912600 -0.97800300 -0.71352500 0.07601500 -1.61385600 -0.95177400 3.15667200 4.03507000 3.50186400 2.65031600 2.61130100 -2.47558800 -2.67028800 -3.02977400 -3.90800100 -2.36140800 -1.83644600

Iminium Ion Conformation 1) Underneath the coordinates for the species below are listed the following energies in kcal mol-1: BP86-D /TZP electronic energy (EBP86-D/TZP) 2) Name of the different conformations

S42

1a Conf. Syn-Anti

-

C=N Bond E/Z

-

C=C Bond E/Z

-

N=C-C=C Bond s-cis/s-trans

Syn-E-E-s-trans EBP86-D/TZP= -14749.96 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O

-5.914522 -2.231611 -2.607396 -3.823640 -4.646409 -4.247425 -3.039118 -5.601268 -4.740027 -6.816813 -7.008418 -5.868171 -5.240548 -6.625548 -4.437269 -4.197269 -4.294755 -1.739619 -4.130597 -2.045227 -3.250520 -3.444861 -4.665682 -7.279365 -6.404442 -4.873011 -2.728763 -5.371409 -8.002703 -7.033949 -6.227252 -5.498331 -5.385049 -7.446331 -6.736628 -3.839273 -3.507651 -4.329818 -3.252863 -5.199786 -3.449796 -0.825206 -5.058951 -1.385366 -4.647319 -5.542406 -4.721065 -6.852600 -8.185213 -6.536539 -7.768797 -8.684780 -7.534449 -9.354124 -9.386186 -10.738222 -9.098741 -8.950672 -8.193889 -7.094128 -9.343396

6.548999 5.066977 6.363116 6.934669 6.075709 4.765990 4.306755 7.582480 7.717360 7.849484 6.765263 6.858956 9.190228 9.172689 7.180821 10.080335 10.781681 7.191910 8.295991 8.509201 9.070301 10.386442 10.975528 5.046424 5.673007 4.091451 3.269669 8.548618 6.936570 5.808776 7.314964 5.850254 9.533108 9.265707 9.947728 7.673601 7.602536 6.084369 10.111880 10.799703 11.375066 6.741869 8.733333 9.152062 12.020101 10.462407 10.915933 4.534665 4.514748 5.011204 7.882791 4.262376 4.178005 5.258653 2.883627 2.934803 2.505212 1.881260 10.394876 9.797909 9.920863

0.502493 -1.284538 -1.491850 -0.970358 -0.183878 0.013013 -0.558117 1.594073 3.933473 2.463028 3.495285 4.536611 3.848754 3.152171 2.520255 3.213652 2.079470 -2.258570 -1.243568 -2.496241 -1.985552 -2.287435 -1.802386 -1.638067 0.969558 0.602432 -0.404876 1.131361 3.928178 2.955521 5.472136 4.768990 4.887330 3.875142 2.386371 4.559960 2.113396 2.552275 3.769475 1.465490 1.726055 -2.645514 -0.886763 -3.079810 -2.128308 -2.223738 -0.706041 -0.769369 -1.947150 -2.452560 1.896850 1.063759 1.560388 0.680043 0.772800 0.881299 -0.524598 1.580554 -0.222836 -0.011886 -0.344228

C F F F H H H N C O C H C H C C C C H C H C H H H

-8.043381 -9.189402 -7.081916 -7.654284 -9.370682 -9.276708 -7.103862 -6.896588 -7.585286 -9.189302 -9.375148 -9.206480 -8.598121 -8.756544 -10.437376 -10.850199 -11.088248 -11.873614 -10.381743 -12.110790 -10.777160 -12.503973 -12.190250 -12.603448 -13.306411

11.947988 -0.391620 12.623267 -0.150736 12.458492 0.436212 12.233521 -1.676433 8.414038 0.699213 6.827822 1.084340 8.163289 -0.285174 7.133546 -0.423344 6.475496 -1.333677 7.775432 1.437718 6.708426 -3.015024 5.677920 -3.338733 7.221343 -2.024478 8.246103 -1.683120 7.410322 -3.710382 8.717491 -3.360064 6.752307 -4.777253 9.339271 -4.069230 9.237066 -2.522460 7.380649 -5.486412 5.739363 -5.041434 8.677307 -5.134337 10.344596 -3.788350 6.861850 -6.309586 9.171867 -5.684094

Syn-E-Z-s-trans EBP86-D/TZP= -14741.11 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H

-5.992023 -2.544193 -2.932460 -4.068477 -4.800016 -4.389516 -3.260328 -5.566834 -4.436904 -6.676565 -6.712103 -5.461502 -4.984694 -6.442537 -4.292044 -4.048886 -4.301859 -2.163758 -4.393063 -2.486893 -3.609107 -3.827897 -4.952652 -7.398015 -6.463520 -4.954426 -2.940823 -5.413164 -7.653570 -6.773989 -5.721964 -5.038939 -5.013859 -7.172436 -6.666078 -3.466685 -3.426275 -4.157208

6.475644 4.736025 6.009320 6.660515 5.908941 4.621747 4.079577 7.597910 7.965592 7.924316 6.939594 7.152178 9.415391 9.309018 7.297532 10.259935 10.864472 6.730156 7.992420 8.019934 8.662399 9.944172 10.616816 4.859078 5.655312 4.023784 3.059564 8.523158 7.130037 5.936925 7.692221 6.177591 9.852334 9.457309 10.007503 7.996583 7.686683 6.210659

0.656969 -1.354952 -1.658696 -1.057149 -0.091553 0.202452 -0.451993 1.616988 3.811110 2.596804 3.738761 4.624338 3.651189 3.132523 2.428651 2.817817 1.652190 -2.617164 -1.434840 -2.960627 -2.362981 -2.773969 -2.175537 -1.325676 1.235219 0.921162 -0.222234 1.050174 4.270395 3.295345 5.547673 4.907060 4.663819 3.938861 2.318849 4.324472 1.874637 2.552089

S43

H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-3.044218 -5.275360 -3.520850 -1.307438 -5.257100 -1.900672 -4.967713 -5.891655 -4.837672 -7.248962 -8.205783 -6.455433 -7.699278 -8.747981 -7.558472 -9.466702 -9.422584 -10.778584 -9.056594 -9.021642 -8.397013 -7.247721 -9.526528 -8.325834 -9.534768 -7.616507 -7.668291 -9.393067 -9.260009 -7.248373 -7.035932 -7.703218 -9.117124 -9.360168 -10.283891 -8.787879 -9.206478 -8.879558 -7.502176 -9.809114 -7.067149 -6.778935 -9.372707 -10.876873 -8.001190 -5.998993 -10.100503 -7.660044

10.350994 10.818667 11.440174 6.222027 8.491216 8.580615 11.621478 10.091152 10.670984 4.382729 4.364160 4.744816 7.878803 4.262887 4.246007 5.210263 2.845077 2.885659 2.256312 2.009850 10.205313 9.665560 9.683963 11.755092 12.350978 12.346082 12.043656 8.320162 6.743040 8.044508 7.004191 6.307501 7.710362 6.701669 7.239264 7.003558 7.842060 5.803263 5.621808 5.147602 4.767162 6.184861 4.282231 5.309541 4.086483 4.642978 3.765761 3.420379

3.247229 1.155681 1.152330 -3.061007 -1.005189 -3.689514 -2.608757 -2.400778 -1.083105 -0.346974 -1.873843 -1.881963 2.142925 1.623692 2.030040 1.206913 1.528954 1.554344 0.338667 2.526357 -0.097184 -0.028072 -0.001942 -0.322282 -0.376899 0.691891 -1.489421 1.104970 1.546876 -0.145047 -0.237608 -1.128139 1.842708 -2.989832 -3.224640 -1.795241 -1.229961 -4.034510 -4.277911 -4.869641 -5.288776 -3.685814 -5.872492 -4.708550 -6.081430 -5.470794 -6.499487 -6.875591

Anti-E-E-s-trans (A-i) EBP86-D/TZP= -14751.31 kcal/mol C N C C C C C C C N C C C C C C

-5.899899 -2.320375 -2.708723 -3.868189 -4.626269 -4.205614 -3.053321 -7.086221 -8.668910 -8.409069 -8.879109 -9.269344 -9.425621 -9.427508 -7.178371 -8.857561

6.465932 5.265748 6.573296 7.062489 6.099403 4.779707 4.411503 5.763876 6.059996 6.166263 7.506885 7.373260 4.870937 5.112109 6.019782 3.546959

0.492869 -1.681842 -1.681794 -0.977529 -0.252605 -0.251390 -0.978657 -0.176711 -2.086785 0.446585 -0.062331 -1.552656 -1.421707 0.110768 -1.695085 -1.877690

C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H

-8.251973 -1.915672 -4.180421 -2.228786 -3.363010 -3.552512 -4.650707 -4.156072 -6.078374 -4.762064 -2.726252 -7.001824 -9.723771 -8.064953 -10.363676 -8.874039 -10.468443 -10.394718 -9.165385 -8.778134 -6.645164 -6.695342 -8.955407 -8.109345 -7.874113 -1.047535 -5.038569 -1.619577 -4.622510 -5.609205 -4.541850 -4.478381 -4.034122 -3.182910 -8.366699 -6.647074 -6.607195 -6.985670 -6.096708 -6.690916 -4.747052 -6.217970 -7.850482 -7.319640 -8.047337 -8.286216 -9.033627 -9.016135 -7.182147 -8.301640 -7.931507 -6.452177 -5.841270 -5.121253 -8.560565 -4.596779 -3.842580 -5.289155 -6.051112 -4.756403 -5.746900 -3.883015 -5.839462 -6.451725 -3.977847 -3.125512 -4.955379 -6.607784 -3.294118

2.611880 7.503771 8.449674 8.840258 9.323260 10.671817 11.195057 7.692870 7.550510 4.024742 3.368243 4.685663 7.787999 8.221174 7.361505 8.230421 4.926233 5.494774 4.221248 5.996847 5.215094 6.976467 3.379316 2.700651 1.701717 7.115604 8.838481 9.561042 12.280307 10.787173 10.939931 8.265158 8.380969 7.234176 6.285725 9.650534 9.495859 8.867678 11.036054 11.471574 10.911868 12.027730 3.603216 3.819912 4.396056 2.111074 1.921182 1.661839 1.311043 6.009232 7.521471 5.199577 6.035601 6.605474 6.740274 6.523146 7.303834 6.085530 5.312675 6.034126 5.090747 6.523440 4.648014 4.717692 6.074316 7.259781 5.132624 3.922908 6.457272

-1.137925 -2.413269 -1.015051 -2.432634 -1.717054 -1.780444 -1.005629 2.505492 0.496860 0.308951 -0.982113 0.010175 0.580207 0.121037 -1.672400 -2.116126 -1.777024 0.461559 0.692044 -3.177687 -2.218839 -1.955315 -2.956847 -0.056878 -1.607508 -2.946273 -0.470145 -2.979004 -1.144598 -1.359705 0.057844 1.628372 3.347950 2.261726 1.547417 2.264038 1.017444 3.187283 2.771420 3.907611 3.038052 1.842688 3.373603 2.241820 4.321899 3.579781 4.692352 2.512875 3.681693 3.588184 3.096919 2.149114 1.897328 2.841509 2.963408 5.252583 5.121379 4.167599 4.283725 6.609187 6.971672 7.605479 8.287992 6.226871 8.921852 7.328401 9.264707 8.559485 9.680519

S44

H

-5.034159

4.778651 10.294022

Anti-E-Z-s-trans EBP86-D/TZP= -14742.25 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F

-5.896829 -2.106424 -2.621640 -3.858311 -4.556815 -4.010894 -2.789421 -6.982295 -8.444927 -8.367253 -8.889587 -9.171021 -9.161697 -9.288518 -6.985804 -8.473163 -7.861853 -1.888969 -4.302445 -2.333588 -3.544815 -3.866407 -5.053426 -4.291922 -6.167209 -4.522552 -2.361938 -6.841439 -9.790510 -8.140281 -10.251575 -8.801766 -10.178359 -10.301228 -9.013503 -8.473147 -6.360705 -6.557015 -8.481414 -7.804730 -7.392757 -0.960435 -5.214508 -1.773565 -5.129196 -5.943194 -4.974875 -4.823169 -3.964471 -3.411720 -8.408913 -6.989999 -6.889203 -7.347674 -6.508309 -6.824857 -5.134290 -7.011159 -7.921780 -7.252539 -8.223428 -8.446099 -9.152205

6.534598 5.562273 6.820450 7.233829 6.247168 4.979171 4.684612 5.689015 5.670498 6.054861 7.296665 6.981351 4.502250 4.900559 5.787349 3.185413 2.377876 7.777270 8.576671 9.069518 9.480313 10.793067 11.250501 7.977489 7.597873 4.207941 3.681790 4.642052 7.582629 8.083531 6.872129 7.803511 4.440547 5.246937 4.094891 5.487454 4.979798 6.748837 2.901902 2.587672 1.454134 7.446166 8.913793 9.811089 12.319578 10.718459 11.084924 8.613245 8.573684 7.578938 6.301104 9.787625 9.518475 9.080615 11.240094 11.634347 11.300173 12.172930 3.860407 3.982771 4.724552 2.400658 2.252060

0.509615 -1.405699 -1.517015 -0.901237 -0.148404 -0.037110 -0.680806 -0.166471 -2.191395 0.327514 -0.352086 -1.839222 -1.449810 0.044609 -1.706277 -1.724068 -0.850813 -2.277182 -1.046158 -2.406883 -1.776548 -1.946671 -1.264338 2.422463 0.438752 0.543566 -0.597324 0.131184 0.206207 -0.196682 -2.019575 -2.468732 -1.873446 0.288316 0.734088 -3.273830 -2.110367 -2.034797 -2.783256 0.221295 -1.194879 -2.742749 -0.557901 -2.977577 -1.486270 -1.633145 -0.181078 1.700718 3.279060 1.893568 1.414964 2.090270 0.865139 3.065356 2.453132 3.707909 2.343266 1.591529 3.477698 2.404445 4.328241 3.702749 4.844591

F F H H H N C O C H C H C C C C H C H C H H H

-9.266068 -7.415139 -8.503355 -8.164452 -6.465636 -5.871534 -5.174414 -8.725050 -4.652454 -5.129037 -5.409302 -6.356626 -3.281107 -2.301364 -2.901126 -0.995592 -2.571293 -1.598127 -3.646429 -0.643058 -0.246788 -1.321895 0.380192

2.039586 1.506898 6.207610 7.706172 5.359253 6.202343 6.852184 6.870255 6.734978 6.517669 6.465261 5.941772 7.223459 6.892821 7.993946 7.361784 6.239559 8.475940 8.226854 8.163866 7.091952 9.088063 8.528858

2.660643 3.731013 3.449491 2.886784 2.240990 1.943865 2.849195 2.737615 5.322329 6.283275 4.225360 4.389875 5.417034 4.458121 6.536822 4.586685 3.627924 6.656699 7.299980 5.680567 3.840896 7.516029 5.782340

Syn-E-E-s-cis EBP86-D/TZP= -14745.48 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H

-5.973223 -2.355244 -2.813611 -4.011228 -4.728959 -4.243583 -3.059180 -5.610497 -4.492520 -6.725543 -6.739010 -5.491498 -5.080996 -6.527914 -4.322725 -4.151759 -4.375096 -2.055395 -4.401575 -2.443315 -3.623920 -3.901188 -5.070578 -7.185843 -6.395052 -4.788005 -2.681958 -5.494697 -7.683275 -6.788304 -5.763465 -5.039927 -5.138411 -7.274315 -6.748380 -3.524011 -3.474097 -4.141106 -3.174442 -5.321412 -3.601070

6.404908 5.658233 6.936201 7.279689 6.200668 4.914434 4.691379 7.138305 6.708288 7.056152 5.724293 5.621820 8.097600 8.160097 6.610613 9.205545 10.152535 7.982913 8.643481 9.294311 9.632324 10.966477 11.340909 5.400741 5.414032 4.073709 3.672441 8.208293 5.693973 4.949756 5.766942 4.624791 8.124862 8.000346 9.103136 6.572098 7.210598 5.561794 9.176539 10.244048 10.884557

0.441746 -1.869540 -1.728260 -1.001993 -0.407787 -0.560152 -1.296591 1.741581 3.938994 2.761534 3.469549 4.378094 4.321327 3.763684 2.410507 3.882866 2.966502 -2.326604 -0.902373 -2.209771 -1.488039 -1.434169 -0.681587 -1.985334 0.692760 -0.123769 -1.418688 1.537624 4.028637 2.692919 5.434953 4.276347 5.422485 4.552504 3.252274 4.438383 2.053789 2.125921 4.378637 2.427186 2.730034

S45

H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-1.155498 -5.313385 -1.866803 -5.120177 -5.978658 -4.987081 -6.907728 -7.977296 -6.288107 -7.745087 -8.765571 -7.619072 -9.466289 -9.417797 -10.774223 -9.093873 -8.964140 -8.373007 -7.321717 -9.521615 -8.161130 -9.310439 -7.335441 -7.555420 -9.458154 -9.297023 -7.312937 -7.042721 -7.641350 -9.157259 -9.444375 -9.258451 -8.702424 -8.943807 -10.529836 -10.880646 -11.262163 -11.930238 -10.323670 -12.315226 -10.989699 -12.652250 -12.192996 -12.873969 -13.476458

7.702920 -2.874450 8.918479 -0.379704 10.102826 -2.660520 12.433068 -0.726060 10.900220 -1.117613 11.002242 0.360851 4.653117 -1.233216 4.996662 -2.625788 5.606614 -2.593455 7.142852 2.312203 3.998270 0.415955 3.813548 0.891774 5.043581 0.323105 2.737950 -0.273021 2.720755 -0.191397 2.746287 -1.617385 1.558914 0.233981 10.180528 1.331034 9.623451 0.894357 9.710514 1.485346 11.677276 1.757344 12.313499 2.081116 11.729889 2.855018 12.398022 0.765296 7.938584 1.636059 6.318578 1.268637 8.073244 0.124988 7.137712 -0.274289 6.676147 -1.354143 7.050503 1.967325 8.390615 -1.471806 8.684279 -0.437947 7.389907 -2.015056 7.010857 -3.008623 9.102698 -2.118388 8.906761 -3.473847 10.038561 -1.352678 9.622733 -4.040190 8.194542 -4.084083 10.752268 -1.924753 10.186912 -0.306920 10.546374 -3.267116 9.466040 -5.087358 11.470078 -1.322881 11.103055 -3.716322

Syn-E-Z-s-cis EBP86-D/TZP= -14742.10 kcal/mol C N C C C C C C C N C C C C C C C C

-5.908975 -2.291013 -2.895645 -4.092580 -4.656614 -4.023291 -2.846204 -5.718560 -4.649312 -6.852893 -6.672125 -5.456336 -5.498567 -6.901796 -4.390689 -4.771788 -5.146351 -2.302020

6.617751 5.816617 7.036857 7.393695 6.391664 5.165498 4.924806 7.672589 7.922747 7.607592 6.478862 6.784156 9.225420 8.912441 7.544718 10.390520 11.122051 8.008360

0.650347 -1.637643 -1.735214 -1.015278 -0.173719 -0.084141 -0.829155 1.754358 4.000347 2.759605 3.743085 4.650515 4.084572 3.502581 2.527551 3.457703 2.403462 -2.589823

C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-4.635390 -2.835826 -4.000200 -4.414494 -5.467139 -7.176885 -6.174878 -4.443370 -2.349976 -5.786978 -7.617032 -6.569967 -5.784502 -4.833369 -5.615863 -7.653182 -7.257673 -3.697314 -3.649699 -4.007146 -3.820035 -6.073681 -4.515383 -1.402654 -5.556486 -2.378810 -5.644258 -6.386834 -5.138422 -6.581482 -7.993580 -6.514965 -7.858732 -8.269959 -7.100267 -9.147489 -8.697994 -10.021863 -8.435658 -8.011958 -8.991767 -7.769057 -10.020900 -9.228093 -10.365376 -9.336784 -8.203526 -9.612497 -9.223883 -7.503643 -7.088107 -7.726132 -9.236538 -9.482873 -10.564149 -9.041447 -9.755563 -8.724962 -7.405197 -9.381189 -6.770909 -6.889826 -8.731164 -10.401584 -7.429078 -5.755303 -9.246112 -6.923584

8.697951 -1.157247 9.269021 -2.705164 9.627510 -1.968238 10.915291 -2.133519 11.354446 -1.248190 4.811527 -1.282351 5.659843 1.133349 4.381191 0.549823 3.953213 -0.757138 8.678088 1.327045 6.417646 4.298899 5.553955 3.161681 7.085414 5.657174 5.883879 4.750462 9.449351 5.158484 8.789666 4.293206 9.665878 2.792130 8.074514 4.526514 8.207505 2.059672 6.512727 2.473391 10.627333 3.947557 10.945160 1.851416 11.940800 2.052769 7.719531 -3.133806 8.970658 -0.648552 10.025302 -3.344506 12.406390 -1.493747 10.776199 -1.397746 11.251882 -0.204358 4.379615 -0.470571 4.131382 -1.549897 4.932638 -2.158135 7.433366 2.294438 3.776760 1.389654 3.943558 1.807776 4.610223 1.027212 2.279454 1.170692 2.063631 1.380772 1.934713 -0.140007 1.407883 1.954479 9.871263 0.399345 9.522939 0.423185 9.169141 0.463573 11.421170 0.373607 11.773111 -0.278470 11.869539 1.665725 12.116990 -0.198959 7.725656 1.315458 6.149088 1.563343 7.957697 0.026440 6.990917 -0.166641 6.156951 -0.947129 7.073238 1.977358 7.643997 -2.044495 7.711423 -2.188054 6.505018 -1.465303 5.695337 -1.292099 8.758539 -2.608298 8.615591 -3.083031 9.993110 -2.790026 9.670913 -3.734622 7.659442 -2.977445 11.059559 -3.411817 10.108642 -2.420961 10.896235 -3.898304 9.542436 -4.107952 12.013847 -3.527958 11.721849 -4.402411

S46

Anti-E-E-s-cis (A-ii) EBP86-D/TZP= -14747.70 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F

-5.917219 -2.350388 -2.841274 -3.999439 -4.644907 -4.122690 -2.979074 -7.068365 -8.612658 -8.417582 -8.916887 -9.260622 -9.355397 -9.394949 -7.133519 -8.744091 -8.100484 -2.162370 -4.421404 -2.580962 -3.712252 -4.011176 -5.114063 -4.056889 -6.153222 -4.593521 -2.570183 -6.950975 -9.787187 -8.134453 -10.350462 -8.870336 -10.391690 -10.381007 -9.121756 -8.688608 -6.567350 -6.670242 -8.838291 -7.959227 -7.689530 -1.294233 -5.274294 -2.058919 -5.178589 -6.050210 -4.940701 -4.557464 -3.680851 -3.206273 -8.401576 -6.702363 -6.756757 -7.008026 -6.079036 -6.131890 -4.745892 -6.682331 -8.078046 -7.224463 -8.542033 -8.661902 -9.264462 -9.606571 -7.711459

6.495138 5.470823 6.743095 7.173011 6.189956 4.908253 4.597192 5.727358 5.923856 6.105724 7.416339 7.234631 4.733961 5.011936 5.933582 3.415802 2.528359 7.697376 8.528451 9.003502 9.430098 10.755556 11.223516 7.795415 7.567797 4.139242 3.583590 4.659808 7.684281 8.162366 7.191824 8.085678 4.754853 5.370299 4.138484 5.829240 5.128033 6.893942 3.211331 2.657796 1.618400 7.352834 8.876025 9.743258 12.300700 10.727874 11.021542 8.447399 8.396995 7.329696 6.270304 9.610624 9.476567 8.826225 10.986360 11.220954 11.023188 12.038022 3.567891 3.830856 4.302862 2.115181 1.714092 2.075225 1.192993

0.583241 -1.701186 -1.738840 -0.996882 -0.194167 -0.156966 -0.924379 -0.075323 -2.037557 0.496992 -0.060695 -1.556905 -1.361398 0.164803 -1.606288 -1.776784 -1.011455 -2.550484 -1.074307 -2.609077 -1.853664 -1.959684 -1.155223 2.330928 0.576751 0.459810 -0.898765 0.148919 0.552375 0.130783 -1.706820 -2.132993 -1.738449 0.487474 0.765174 -3.129028 -2.092388 -1.887053 -2.849870 0.065094 -1.452638 -3.112541 -0.494841 -3.216783 -1.338447 -1.453955 -0.088886 1.604945 3.165423 1.802696 1.594388 2.395280 1.145662 3.327979 2.839378 4.171182 2.478135 2.212960 3.232816 2.335701 4.134611 3.147130 4.290673 2.146987 2.835087

H H H N C O C H C H C C C C H C H C H H H

-8.498005 -7.966089 -6.348705 -5.778134 -4.954504 -8.624714 -5.658864 -6.554058 -4.814482 -3.969013 -5.520638 -4.399390 -6.554670 -4.319054 -3.587638 -6.469536 -7.420622 -5.353739 -3.449458 -7.273557 -5.285113

5.996495 7.510413 5.266037 6.103631 6.711846 6.764497 5.508672 5.132897 6.324977 6.787139 5.095516 5.422865 4.313783 4.981122 6.018713 3.873566 4.067537 4.205375 5.235970 3.271305 3.860925

3.594072 3.171601 2.307909 2.002924 2.833436 2.974290 4.897932 4.399102 4.212029 4.722921 6.280690 7.077837 6.844922 8.394352 6.658468 8.165627 6.227666 8.942333 9.001742 8.590175 9.975637

Anti-E-Z-s-cis EBP86-D/TZP= -14743.25 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H

-6.111333 -2.569813 -2.956512 -4.106387 -4.858785 -4.449484 -3.302183 -7.329606 -8.899958 -8.629094 -9.035513 -9.443249 -9.704147 -9.702179 -7.411811 -9.187858 -8.608217 -2.174954 -4.423213 -2.495375 -3.622704 -3.825097 -4.933712 -4.275836 -6.258475 -5.005376 -2.977114 -7.295583 -9.859786 -8.188580 -10.538242 -9.019826 -10.743033 -10.649302 -9.493650 -9.013527 -6.912272 -6.891593 -9.303038 -8.447505 -8.267868 -1.312387 -5.271440

6.542193 5.248066 6.555523 7.071886 6.137527 4.814700 4.420911 5.870333 6.158739 6.362318 7.699333 7.517301 5.032785 5.348745 6.074172 3.665961 2.751066 7.456857 8.455281 8.789571 9.299788 10.640863 11.190506 7.778934 7.630879 4.082269 3.376821 4.798114 8.052516 8.381236 7.543636 8.332426 5.111091 5.800324 4.474221 6.054652 5.229195 6.999998 3.443240 2.893407 1.804245 7.049607 8.866074

0.565908 -1.609519 -1.655061 -0.955387 -0.188431 -0.152694 -0.873973 -0.075177 -1.996126 0.532529 -0.036058 -1.516711 -1.279458 0.239130 -1.602600 -1.667444 -0.882461 -2.434381 -1.046190 -2.509290 -1.801172 -1.928158 -1.185581 2.465537 0.560950 0.435243 -0.846670 0.150284 0.597193 0.112174 -1.627898 -2.120631 -1.641713 0.561418 0.863163 -3.083423 -2.095261 -1.900270 -2.734834 0.190526 -1.306124 -2.962013 -0.502291

S47

H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-1.898549 -4.916450 -5.883964 -4.829804 -4.582725 -4.096311 -3.325015 -8.566515 -6.602341 -6.704417 -6.923507 -5.869715 -5.925404 -4.531662 -6.357593 -8.288178 -7.709275 -8.445159 -8.973627 -8.872519 -10.309773 -8.480295 -8.511660 -8.005423 -6.704107 -6.030946 -5.252388 -8.693161 -5.383617 -5.578780 -5.333334 -5.374421 -5.164822 -4.362611 -5.760536 -4.201784 -3.850723 -5.611896 -6.379196 -4.835344 -3.571202 -6.106034 -4.711205

9.487686 12.267428 10.755325 10.989414 8.353025 8.454263 7.272961 6.531236 9.779974 9.612248 9.037588 11.119086 11.424487 11.014170 12.188353 3.931677 4.123940 4.716396 2.528776 2.019762 2.658459 1.593528 6.305448 7.776041 5.355673 6.143964 6.723965 7.052560 5.119179 5.080167 6.354327 7.226622 3.823274 3.665151 2.681975 2.410059 4.527122 1.428534 2.797549 1.288932 2.303615 0.560936 0.307860

-3.097124 -1.380337 -1.531088 -0.110218 1.584033 3.310230 2.218434 1.629573 2.391870 1.151141 3.356553 2.780636 4.099130 2.451884 2.089724 3.449031 2.334336 4.406704 3.590665 4.847950 3.307514 2.733061 3.664772 3.174352 2.289370 1.987456 2.858215 3.023541 4.816270 5.891037 4.266641 4.923446 4.176367 3.029719 4.748625 2.447144 2.600013 4.155081 5.639958 2.999836 1.563174 4.592965 2.539240

Syn-Z-E-s-trans EBP86-D/TZP= -14749.04 kcal/mol C N C C C C C C C N C C C C C C C C C C C

-5.916758 -2.078188 -2.580286 -3.848531 -4.591077 -4.064322 -2.810703 -5.740893 -4.905166 -6.977645 -7.006854 -5.898436 -5.612380 -6.980557 -4.530661 -4.708772 -4.909440 -1.797606 -4.282919 -2.230354 -3.482772

6.414184 5.570143 6.839637 7.210380 6.171559 4.892651 4.640619 7.302272 7.195613 7.256807 6.006229 6.103667 8.577342 8.470668 6.930244 9.695907 10.552262 7.848962 8.562093 9.151061 9.515533

0.403055 -1.475943 -1.507601 -0.932848 -0.298811 -0.276622 -0.879105 1.643143 3.994893 2.518906 3.362348 4.436590 4.127528 3.406460 2.522496 3.663373 2.656355 -2.137809 -1.009465 -2.193127 -1.621883

O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-3.804621 -5.059554 -8.482472 -6.312257 -4.625793 -2.399020 -5.651380 -8.017936 -6.871903 -6.325655 -5.387892 -5.805040 -7.806222 -7.203102 -4.006519 -3.670482 -4.268413 -3.777304 -5.808712 -4.160060 -0.843157 -5.245531 -1.635601 -5.142494 -5.900159 -5.077582 -8.757384 -8.054284 -9.389170 -7.926115 -8.206375 -6.969137 -9.006037 -8.894182 -9.598251 -9.766199 -7.997811 -8.631935 -7.427872 -9.686059 -8.742806 -10.002544 -8.259782 -7.980518 -9.548095 -9.238812 -7.221988 -6.924421 -7.487198 -9.310533 -7.676146 -8.296978 -7.166125 -6.512310 -7.460310 -6.902132 -7.845650 -6.723723 -6.646343 -7.652237 -8.292143 -7.089016 -6.312927 -7.946083 -6.946629

10.838042 -1.732087 11.233697 -1.148130 7.241534 -2.295975 5.428631 0.715614 4.085151 0.198437 3.627829 -0.865501 8.351001 1.340434 5.949418 3.785751 5.154218 2.681929 6.358547 5.418672 5.134623 4.527051 8.729250 5.203113 8.333304 4.116617 9.332029 2.766954 7.183696 4.625786 7.535341 2.203773 5.868133 2.390227 9.770682 4.236651 10.540406 2.034167 11.310868 2.423620 7.548762 -2.570665 8.855138 -0.600894 9.930744 -2.670132 12.312267 -1.314143 10.708891 -1.624892 11.008104 -0.071960 8.160622 -1.763449 7.497567 -3.277885 6.645600 -2.465012 7.239526 1.946724 3.585615 0.716918 3.579010 0.950248 4.538570 0.540008 2.171095 0.648610 1.946090 1.801296 2.067007 -0.388904 1.147592 0.523919 9.948469 0.288336 9.537058 0.300142 9.318295 0.077265 11.476524 0.619156 11.954542 0.568694 11.710306 1.883944 12.221262 -0.241000 7.700731 0.792809 6.099972 1.002342 8.018721 -0.232859 7.027363 -0.481085 6.436927 -1.512736 6.996684 1.455748 4.462211 -2.954040 5.033594 -3.650321 5.087092 -1.857868 4.538931 -1.185039 3.071302 -3.295273 2.149685 -2.379353 2.615828 -4.575210 0.820167 -2.748191 2.468532 -1.367420 1.286308 -4.944856 3.323882 -5.276870 0.386267 -4.031453 0.111613 -2.028312 0.947346 -5.939006 -0.658126 -4.313606

Syn-Z-Z-s-trans EBP86-D/TZP= -14741.53 kcal/mol S48

C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H

-5.855900 -2.025145 -2.571238 -3.852245 -4.550001 -3.975338 -2.720132 -5.626703 -4.680799 -6.822870 -6.823916 -5.659568 -5.370912 -6.770961 -4.377536 -4.479825 -4.711736 -1.820795 -4.335506 -2.297714 -3.565977 -3.931378 -5.222629 -8.714722 -6.235055 -4.500612 -2.273701 -5.541549 -7.811387 -6.755579 -6.033311 -5.151163 -5.512385 -7.565703 -7.013086 -3.753674 -3.529945 -4.126731 -3.526864 -5.632829 -3.966111 -0.855644 -5.310552 -1.729868 -5.343642 -6.019105 -5.276879 -8.496923 -8.893511 -9.632301 -7.819284 -8.639165 -7.488875 -9.455331 -9.133702 -10.412773 -8.337380 -9.059442 -8.578050 -7.402377 -9.680212 -8.595923 -9.788707 -7.653056 -8.291298 -9.476191 -9.304139 -7.231889

6.356585 5.710856 6.961903 7.269811 6.186289 4.927069 4.735858 7.201159 7.042002 7.144564 5.883664 5.946772 8.425542 8.341326 6.805190 9.545490 10.412065 8.017797 8.606475 9.304789 9.606299 10.917908 11.249677 7.326290 5.359455 4.083896 3.737881 8.255564 5.837957 5.043351 6.180431 4.973031 8.558509 8.200077 9.214412 7.011817 7.412838 5.744759 9.609625 10.411740 11.167008 7.764803 8.852345 10.120379 12.327486 10.704232 10.996653 8.387475 7.138529 7.079829 7.154394 3.885473 3.842441 4.845547 2.508245 2.529406 2.120524 1.526347 9.984059 9.497169 9.403981 11.551192 12.087511 12.092108 11.970455 7.835857 6.198316 7.955855

0.471085 -1.497748 -1.484346 -0.897448 -0.286704 -0.309416 -0.929025 1.735139 4.039513 2.661895 3.486651 4.503950 4.230761 3.569919 2.546751 3.745225 2.753675 -2.076017 -0.935490 -2.088428 -1.514370 -1.590646 -1.046305 -1.845663 0.754473 0.145238 -0.951247 1.449233 3.964293 2.784033 5.512783 4.546194 5.316742 4.313799 2.954180 4.627227 2.199996 2.380943 4.283423 2.163726 2.498422 -2.514908 -0.524229 -2.537355 -1.191341 -1.572523 0.021609 -1.667956 -2.909985 -1.292575 2.139455 0.481885 0.971763 0.359544 -0.097775 -0.557054 -1.145948 0.846245 0.552295 0.545729 0.564404 0.498413 0.830758 1.331220 -0.773038 1.217365 1.181735 0.027711

N C O C H C H C C C C H C H C H H H

-6.932358 -7.594307 -9.210205 -7.702741 -7.046485 -7.153282 -6.188004 -9.014361 -10.191707 -9.112838 -11.426841 -10.127232 -10.346483 -8.206851 -11.506772 -12.334494 -10.409446 -12.476120

6.994573 6.477670 7.035220 4.548377 3.783642 5.246522 4.884800 4.619165 4.860006 4.352984 4.887724 4.968795 4.409775 4.122965 4.681601 5.057216 4.228283 4.708664

-0.309212 -1.324782 1.757669 -2.962225 -3.389848 -1.925959 -1.578141 -3.589409 -2.850705 -4.973811 -3.496961 -1.766700 -5.618554 -5.538681 -4.880342 -2.916258 -6.692223 -5.381133

Anti-Z-E-s-trans (A-iii) EBP86-D/TZP= -14750.41 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H

-5.835102 -2.382053 -2.729880 -3.860732 -4.615816 -4.232266 -3.119982 -7.066847 -8.747836 -8.345672 -8.823200 -9.298546 -9.483213 -9.395031 -7.239080 -8.960640 -8.316767 -1.914306 -4.134872 -2.175035 -3.286572 -3.414821 -4.541926 -5.117565 -5.997964 -4.785188 -2.827445 -6.984311 -9.625308 -7.990214 -10.397965 -8.924821 -10.543469 -10.335665 -9.115445 -8.917201 -6.749212 -6.757243 -9.132175 -8.101072 -7.982266 -1.066168 -4.973483 -1.541647 -4.470753 -5.485762

6.399285 5.121934 6.440282 6.945203 5.996260 4.666573 4.277454 5.693779 5.966121 6.129221 7.463234 7.301048 4.804542 5.082295 5.910619 3.461871 2.539918 7.366185 8.342205 8.713721 9.210729 10.569198 11.092819 6.280115 7.484826 3.919578 3.224674 4.620619 7.775531 8.168191 7.302585 8.138314 4.867604 5.486596 4.200049 5.879818 5.083171 6.851771 3.265985 2.657659 1.611784 6.965511 8.742093 9.429778 12.181649 10.734722

0.430342 -1.903891 -1.865930 -1.130819 -0.383822 -0.416615 -1.194561 -0.148051 -1.978482 0.534042 0.018861 -1.444067 -1.244797 0.278778 -1.667351 -1.700817 -0.977101 -2.578507 -1.136988 -2.545523 -1.806393 -1.794620 -1.056728 4.169178 0.418027 0.157514 -1.230440 0.063079 0.700277 0.139880 -1.501099 -2.050675 -1.542484 0.674536 0.865534 -3.060183 -2.197903 -1.981554 -2.765956 0.088819 -1.444530 -3.133921 -0.570277 -3.070190 -1.141182 -1.495024

S49

H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-4.504495 -5.778630 -4.132662 -5.567944 -8.258106 -6.576994 -6.450892 -6.951456 -6.233132 -7.376679 -5.430523 -5.599597 -7.712599 -7.100183 -7.895047 -8.373924 -8.831143 -9.446604 -7.516185 -8.154281 -7.828349 -6.271836 -5.696740 -4.977605 -8.434747 -3.473893 -3.608889 -4.118166 -4.025278 -2.654487 -2.366061 -2.154308 -1.616552 -2.729126 -1.399217 -2.380676 -1.131401 -1.412329 -1.023200 -0.543796

10.788882 5.411507 6.073770 7.131300 6.270337 9.597537 9.392495 8.839076 11.049170 11.714714 11.031455 11.808907 3.607640 3.799311 4.389387 2.190463 1.890724 2.145166 1.199967 5.958385 7.499423 5.180068 6.025267 6.683874 6.697473 8.558803 8.369284 7.756782 7.960248 9.706211 10.074003 10.508704 11.213211 9.462316 11.647494 10.231589 12.004351 11.485755 12.262022 12.898246

-0.001823 4.281132 4.610777 4.703879 1.641004 2.406488 1.174614 3.341495 2.909089 3.253078 4.012883 1.968570 3.368170 2.271247 4.324607 3.462840 4.697870 2.600658 3.085748 3.644228 3.178945 2.162028 1.851093 2.734158 3.032534 3.223660 4.291786 2.331820 1.269286 2.889279 1.555737 3.937153 1.283912 0.730506 3.663177 4.968850 2.336162 0.247860 4.482060 2.120126

Anti-Z-Z-s-trans EBP86-D/TZP= -14743.40 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C

-5.877964 -2.398433 -2.762169 -3.884428 -4.633427 -4.236976 -3.118607 -7.087446 -8.690321 -8.392524 -8.847913 -9.268341 -9.451719 -9.429077 -7.195130 -8.906440 -8.300047 -1.981525 -4.171412 -2.271969 -3.369263 -3.543026 -4.636192 -5.260335

6.402110 5.211200 6.524463 7.003894 6.028447 4.703908 4.344992 5.726714 6.032091 6.153387 7.495798 7.355699 4.856883 5.110629 5.978330 3.522843 2.585535 7.471429 8.397065 8.812890 9.285509 10.637555 11.138270 5.892591

0.463008 -1.873439 -1.810968 -1.045717 -0.327218 -0.387508 -1.171742 -0.194062 -2.085449 0.442935 -0.070915 -1.552227 -1.401426 0.129065 -1.712919 -1.856496 -1.120150 -2.534774 -1.012460 -2.490231 -1.712736 -1.716630 -0.918365 4.177209

H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-6.033549 -4.786741 -2.809889 -7.020474 -9.673364 -8.017266 -10.364935 -8.876731 -10.498822 -10.386559 -9.169974 -8.814743 -6.677543 -6.705792 -9.024884 -8.136688 -7.943348 -1.140505 -4.992840 -1.672190 -4.603107 -5.595849 -4.527205 -5.575967 -4.346980 -6.062514 -8.344596 -6.552174 -6.503911 -6.992266 -5.943705 -6.034453 -4.609872 -6.559745 -7.893046 -7.235944 -8.186317 -8.408835 -9.065171 -9.273599 -7.379923 -8.336496 -7.926586 -6.400766 -5.798321 -5.079439 -8.558081 -3.280708 -2.481653 -4.120440 -3.959186 -3.260126 -4.438358 -2.007582 -4.359329 -5.402641 -1.935074 -1.094137 -3.112857 -5.274675 -0.963037 -3.057230

7.487389 3.937608 3.297550 4.647307 7.801285 8.194419 7.352780 8.204380 4.922077 5.506692 4.219456 5.962649 5.165716 6.928700 3.348588 2.679862 1.666766 7.091798 8.776619 9.544359 12.227554 10.748019 10.845777 4.844819 5.982177 6.435833 6.284685 9.500000 9.330481 8.759328 10.874839 11.100590 10.944373 11.916927 3.536456 3.732168 4.335667 2.062121 1.822218 1.782940 1.169098 5.907668 7.457520 5.094279 5.946538 6.495405 6.691880 8.208523 8.749898 7.523046 7.695018 8.362790 8.496008 8.463017 8.667665 8.517828 8.606231 8.405248 8.704552 8.786063 8.656146 8.833544

0.498226 0.163764 -1.224695 -0.008076 0.585228 0.091835 -1.649856 -2.130962 -1.742152 0.491334 0.711752 -3.174303 -2.239975 -1.984556 -2.932519 -0.042587 -1.589707 -3.115220 -0.407904 -3.032743 -1.020542 -1.290611 0.135620 4.092082 4.776897 4.697294 1.552051 2.508347 1.267317 3.430114 2.974770 4.308066 2.645124 2.341489 3.251107 2.179244 4.162969 3.383491 4.539750 2.352658 3.297089 3.529713 3.151988 2.101455 1.862110 2.818468 2.945081 3.325921 2.809403 2.497243 1.434497 4.774400 5.538147 5.420572 6.919643 5.029117 6.804621 4.824822 7.558096 7.500934 7.296944 8.640406

Syn-Z-E-s-cis EBP86-D/TZP= -14744.78 kcal/mol C N

-6.066697 6.380251 0.399426 -2.260223 5.422516 -1.488354

S50

C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O

-2.721561 -3.972243 -4.748780 -4.256656 -3.013168 -5.825328 -4.987656 -7.058583 -7.166042 -6.058460 -5.589010 -6.970045 -4.645672 -4.612413 -4.764161 -1.908195 -4.352204 -2.291858 -3.521594 -3.795550 -5.026236 -8.053675 -6.529882 -4.841930 -2.632798 -5.654850 -8.181143 -7.069222 -6.468117 -5.622287 -5.757492 -7.793197 -7.144123 -4.087651 -3.739842 -4.474706 -3.669495 -5.670885 -3.963338 -0.967930 -5.292414 -1.672620 -5.071654 -5.892739 -5.043782 -8.785188 -7.311874 -8.555986 -8.005144 -8.369960 -7.129687 -9.020477 -9.216314 -9.373222 -10.453623 -8.596091 -8.599798 -7.423415 -9.666602 -8.659231 -9.904540 -8.155499 -7.883334 -9.604120 -9.368354 -7.291690 -7.005795 -7.338670 -9.412307

6.707992 7.115182 6.094131 4.801716 4.514980 7.186931 6.918831 7.190500 5.906419 5.889346 8.342679 8.359875 6.681304 9.409770 10.319010 7.695923 8.485256 9.014436 9.417111 10.753234 11.184364 8.094981 5.418322 4.010108 3.490119 8.238930 5.886869 5.079292 6.143816 4.882323 8.469348 8.241377 9.262083 6.815289 7.223902 5.607004 9.393022 10.397852 11.028558 7.365971 8.812249 9.777009 12.268152 10.702295 10.937827 8.548882 8.867397 7.762964 7.265945 3.613600 3.451081 4.654512 2.298814 2.018958 2.379577 1.217259 10.076999 9.606378 9.489836 11.622027 12.135675 11.917045 12.288519 7.863928 6.252759 8.084194 7.145084 6.950289 7.127294

-1.507188 -0.920249 -0.296791 -0.275895 -0.883821 1.688495 4.027060 2.571504 3.357959 4.435996 4.218054 3.514712 2.541824 3.780704 2.811865 -2.132318 -0.971589 -2.168376 -1.574964 -1.654988 -1.047246 -2.371059 0.676977 0.194816 -0.875942 1.434414 3.774744 2.642126 5.425614 4.494613 5.300990 4.231194 2.918764 4.647378 2.237551 2.366502 4.339842 2.205162 2.596130 -2.574502 -0.537604 -2.641772 -1.191457 -1.524737 0.024577 -1.686942 -2.635314 -3.286633 2.007747 0.842570 1.008769 0.587632 1.003702 2.338335 0.458728 0.438846 0.455212 0.561457 0.183139 0.710076 0.639537 1.949635 -0.204311 0.856181 1.018635 -0.043230 -0.446614 -1.708157 1.500291

C H C H C C C C H C H C H H H

-6.789041 -6.811101 -7.050255 -7.158183 -6.565056 -6.402801 -6.507248 -6.193264 -6.429009 -6.304293 -6.639930 -6.146617 -6.062941 -6.272722 -5.986620

4.546887 4.370285 5.797209 5.954086 3.358393 3.382311 2.120395 2.199181 4.332934 0.936338 2.110916 0.973417 2.222668 -0.016456 0.047957

-2.027802 -0.954931 -2.503509 -3.578288 -2.822088 -4.225595 -2.142591 -4.926471 -4.760711 -2.850568 -1.058146 -4.241181 -6.009311 -2.320820 -4.797116

Syn-Z-Z-s-cis EBP86-D/TZP= -14730.85 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H H H H H H H H H H H H H H H H H H H H H H H

-5.802559 -2.649641 -2.952536 -3.950363 -4.683925 -4.343607 -3.318093 -5.268268 -4.437259 -6.401167 -6.853717 -5.746391 -4.583664 -5.911614 -4.232578 -3.343799 -3.226643 -2.227033 -4.145407 -2.446452 -3.401252 -3.500859 -4.454667 -8.438258 -6.364846 -4.895242 -3.058390 -4.831171 -7.810562 -7.076171 -6.013044 -5.625593 -4.681678 -6.710838 -5.812349 -3.583139 -3.224718 -4.363505 -2.448425 -4.068160 -2.258179 -1.487579 -4.857118 -1.894706 -4.385854 -5.472394 -4.225309 -8.227127 -8.448217

6.536939 6.376600 7.570916 7.732196 6.561588 5.359348 5.310217 6.490114 4.796572 6.288764 4.852909 3.984442 5.958568 6.689414 5.369077 6.821525 8.097614 8.716041 9.012664 9.947648 10.097809 11.363525 11.563167 9.160921 5.605542 4.450364 4.355071 7.464260 4.836974 4.560339 3.712097 3.054761 5.490442 6.416535 7.780197 4.165405 5.786499 4.565669 6.293920 8.692259 8.598769 8.572844 9.143862 10.831092 12.619674 11.327366 10.926125 9.685099 9.859519

0.124919 -2.881187 -2.294879 -1.263140 -0.904140 -1.499662 -2.466519 1.565464 3.214618 2.554482 2.582607 3.222729 4.239896 3.919513 1.797199 4.258083 3.876508 -2.729377 -0.675693 -2.167265 -1.121538 -0.626225 0.431787 -0.728851 -0.057607 -1.251969 -2.931398 1.815414 3.116918 1.549850 4.255454 2.647947 5.233836 4.620339 3.906440 3.494673 1.670276 1.054779 4.607118 3.510373 3.922874 -3.517389 0.136014 -2.489696 0.705632 0.083867 1.297212 0.213190 -1.575906

S51

H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-9.442735 -7.348603 -10.404585 -9.756627 -10.201663 -11.635247 -12.792334 -11.464743 -11.826831 -7.000448 -6.192399 -8.246834 -6.327970 -7.006219 -5.039609 -6.286939 -8.615426 -9.261912 -6.790490 -6.768712 -7.489759 -8.622085 -7.231971 -7.071109 -7.393109 -7.500169 -7.320081 -7.956914 -6.785078 -8.020239 -8.449774 -6.826951 -6.316406 -7.441728 -8.557875 -6.397509 -7.498997

8.707766 6.910513 5.472843 4.685808 6.711477 4.902771 5.536845 5.080063 3.571475 10.177454 9.361606 10.191133 11.350818 11.663495 11.072188 12.474232 8.508564 7.193701 8.272436 7.637474 8.031564 7.510243 6.336902 6.371691 7.556047 8.391540 4.995037 4.707201 3.929274 3.395444 5.510606 2.625838 4.147095 2.357399 3.204779 1.811940 1.331219

-0.643667 2.384805 0.808199 1.520803 0.581951 0.015425 0.362728 -1.333029 0.218429 2.586915 2.042046 2.560152 3.385188 4.512794 3.749391 2.600568 2.440537 1.699273 0.888143 0.036660 -0.985594 2.447737 -2.934743 -4.016565 -2.352075 -3.050733 -2.394280 -1.170425 -3.152512 -0.694890 -0.620218 -2.666962 -4.113974 -1.434127 0.234446 -3.252752 -1.067244

Anti-Z-E-s-cis (A-vi) EBP86-D/TZP= -14746.66 kcal/mol C N C C C C C C C N C C C C C C C C C C C O C C H H H

-5.904352 -2.788232 -2.938897 -3.933847 -4.776296 -4.597069 -3.595478 -7.204363 -8.670156 -8.456710 -8.687619 -9.060234 -9.629068 -9.623494 -7.218165 -9.278415 -8.846675 -2.051183 -3.989049 -2.114190 -3.074775 -2.991822 -3.834719 -5.818907 -5.824901 -5.228013 -3.459032

6.391510 5.225446 6.535700 7.000313 6.010373 4.685675 4.343942 6.180572 7.351071 6.564521 8.055012 8.490822 6.150198 5.858868 6.938327 4.984967 3.771275 7.490799 8.376774 8.817007 9.264466 10.580763 11.010597 5.034659 7.431009 3.907471 3.297832

0.517274 -2.295011 -1.942816 -1.013009 -0.427800 -0.782575 -1.720033 -0.283506 -1.942095 0.470457 0.451621 -0.983786 -1.690472 -0.167334 -1.631282 -2.586064 -2.228193 -2.516532 -0.666447 -2.164569 -1.212036 -0.879140 0.213823 4.081093 0.863501 -0.346969 -2.006619

H H H H H H H H H H H H H H H H H H H H H H H H C O O C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-7.306993 -9.487543 -7.767539 -10.138642 -8.516436 -10.640217 -10.522809 -9.522051 -8.756162 -6.813704 -6.579136 -9.384205 -8.710937 -8.615969 -1.312172 -4.696181 -1.423154 -3.587439 -4.898477 -3.629303 -6.606715 -4.954513 -6.205905 -8.454059 -6.407950 -6.206866 -6.969183 -5.874835 -6.906666 -5.191960 -5.024401 -8.465465 -7.685366 -8.683660 -9.292596 -10.003304 -10.183978 -8.493898 -8.600446 -8.031604 -6.652462 -5.950823 -5.375562 -8.732114 -3.394337 -3.328170 -4.370047 -4.394258 -2.368551 -2.346681 -1.384537 -1.372455 -3.104826 -0.407911 -1.411059 -0.401000 -1.371419 0.342563 0.358497

5.103739 8.240247 8.520717 8.697104 9.410427 6.492415 6.248558 4.793964 7.674078 6.276574 7.834992 5.209561 3.466595 3.024691 7.125963 8.727665 9.550423 12.063655 10.905110 10.416149 4.309860 4.534113 5.763580 6.299374 9.007471 9.205103 8.058458 10.122346 10.843147 9.575164 11.003885 3.155080 3.591773 3.594435 1.904980 1.333189 2.290054 0.943693 5.344062 6.894543 4.747709 5.558348 5.819627 6.277905 7.177416 6.639766 6.827514 7.255938 8.185079 9.043595 8.340917 10.032532 8.948629 9.328709 7.687286 10.178076 10.698975 9.442771 10.956927

-0.470048 1.180337 0.831929 -1.065584 -1.243040 -1.968561 0.326725 0.070672 -2.988270 -2.408932 -1.578405 -3.653911 -1.186634 -2.990415 -3.230197 0.082477 -2.581498 0.380189 -0.046514 1.117260 3.842431 4.542389 4.811344 1.543913 3.242445 2.023617 3.859213 4.219587 4.741685 5.282132 3.625238 2.213076 1.308759 3.360594 1.753135 2.748909 0.776970 1.207988 3.335657 3.393192 1.695218 1.735460 2.888250 3.010514 2.243320 1.299798 3.117743 4.121782 2.445469 3.564887 1.445173 3.672515 4.340509 1.557469 0.569935 2.670613 4.535955 0.774740 2.758320

Anti-Z-Z-s-cis EBP86-D/TZP= -14730.29 kcal/mol C N C C C

-6.140525 -3.143039 -3.075824 -4.037918 -5.069343

6.512045 5.716486 6.860294 7.215429 6.268911

0.449393 -2.607768 -1.867330 -0.853877 -0.598117

S52

C C C C N C C C C C C C C C C C O C C H H H H H H C F F F C O O C F F F H H H N C O C H C H C C C C H C H C H H H

-5.137035 -4.161142 -7.439183 -8.547411 -8.569587 -8.421730 -8.676502 -9.769296 -9.870852 -7.238454 -9.690477 -9.618660 -1.990050 -3.911412 -1.870552 -2.842476 -2.619667 -3.641339 -6.383899 -5.872147 -5.929191 -4.214814 -7.815759 -9.146882 -7.414243 -5.877215 -7.071446 -5.233529 -5.126450 -9.607140 -8.856553 -9.604193 -10.655174 -11.571748 -11.333280 -10.018009 -8.999133 -7.913825 -7.461544 -6.425915 -5.659702 -8.790867 -3.105864 -2.256765 -4.264877 -4.132586 -2.738242 -3.511028 -1.477689 -3.012216 -4.475728 -1.011268 -0.878028 -1.774100 -3.576639 -0.048612 -1.401124

5.128706 4.897679 6.862779 8.693443 7.368032 8.838649 9.653738 7.729603 7.139990 7.896619 6.722638 5.390271 7.749155 8.451022 8.926839 9.288126 10.487078 10.930326 3.214926 7.326908 4.394626 3.993842 5.927339 9.051199 8.977587 9.519628 9.963465 8.870473 10.625582 3.837372 4.348781 4.014422 2.830509 2.419539 3.390094 1.716657 5.609314 6.805414 5.089422 5.321473 4.339732 6.576966 4.791387 4.215280 4.077414 3.001448 6.113752 6.862040 6.611639 8.063371 6.489814 7.835478 6.022395 8.556705 8.620441 8.219930 9.501429

-1.380211 -2.371413 -0.324140 -1.624726 0.552176 0.857301 -0.429771 -1.602577 -0.172967 -1.454730 -2.726458 -2.635024 -2.113639 -0.163111 -1.419297 -0.440378 0.171307 1.088584 2.402940 1.143097 -1.214586 -2.984678 -0.759174 1.653843 1.271471 4.909646 5.398944 5.922511 4.615506 1.696415 0.809122 2.933139 1.110538 2.013640 0.059945 0.629924 3.142132 3.431556 1.355268 1.281728 1.703997 2.994134 1.372943 0.990722 1.431994 1.265733 1.832178 2.743732 1.424253 3.244242 3.096161 1.890723 0.727174 2.817286 3.987916 1.551886 3.215170

H H H H H H H H H H H H H H H H H H H H H C O O

-9.678762 -7.934927 -10.662749 -10.641144 -10.062172 -8.533096 -6.971739 -6.412498 -9.680301 -9.620857 -9.559628 -1.266843 -4.620642 -1.044308 -3.300892 -4.602512 -3.777083 -6.666890 -5.717866 -7.301036 -8.628107 -6.112920 -5.898607 -6.495331

10.109509 10.461717 8.352851 7.648166 6.062654 9.245857 7.357940 8.584163 7.181211 4.854911 4.781760 7.462274 8.720217 9.614991 11.900593 11.040263 10.218191 2.456055 2.741832 3.562038 6.880365 8.589587 9.116996 7.426637

-0.418689 -0.505035 -1.777690 0.421513 -0.157408 -2.573711 -2.373780 -1.211166 -3.722449 -1.680966 -3.539517 -2.877518 0.617438 -1.602232 1.465272 0.562599 1.912912 1.654424 3.135740 2.895697 1.545113 3.660453 2.545004 3.960876

S53

S54

Cinchona Alkaloids Catalyzed Asymmetric Reactio - American

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