SUPPORTING INFORMATION

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1 SUPPORTING INFORMATION thium Hexamethyldisilazide-Mediated Enolization of Highly Substituted yl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities Kyle A. Mack, Andrew McClory, Haiming Zhang, * Francis Gosselin, and David B. Collum * Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York , United States dbc6@cornell.edu I. NMR Spectroscopic Studies Table 1. Figure 1. Figure 2. Figure 3. Table 2. Figure 4. Figure 5. Figure 6. 6 NMR chemical shifts for different species in THF/hexane mixtures at 80 C. 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in neat THF at 80 C after aging. 6 spectra of 0.10 M [ 6, 15 N]HMDS and 0.10 M ketone with varying amounts of THF in hexane cosolvent at 80 C after aging. Job plot showing the relative integration of the 6 resonances versus the measured mole fraction (X E ) ref 15 of E-enolate for 0.10 M mixtures of E-enolate and Z-enolate at 80 C at varying THF concentrations in hexane. 6 and 15 N NMR chemical shifts for different species in 0.60 M DMEA/toluene at 100 C. 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 80 C after aging. 6 spectra of 0.10 M [ 6, 15 N]HMDS and M ketone with varying amounts of DMEA in toluene cosolvent at 80 C after aging. Unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 100 C. S6 S7 S8 S9 S10 S11 S12 S13 S1

2 Figure 7. Figure 8. Figure 9. Figure 10. Figure 11. Unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 100 C. 15 N-decoupled unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with M ketone in 0.60 M DMEA/tol at 100 C. 6 -decoupled unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with M ketone in 0.60 M DMEA/tol at 100 C. 15 N-decoupled unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with 0.10 M ketone in 0.60 M DMEA/tol at 100 C. 6 -decoupled unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with 0.10 M ketone in 0.60 M DMEA/tol at 100 C. S14 S15 S16 S17 S18 II. IR Rate Studies Figure 12. Figure 13. Figure 14. Plot of initial rate vs. THF concentration in hexane for the enolization of 1 (0.010 M) by HMDS (0.10 M) at 0 C measured with IR spectroscopy (1687 cm 1 ). Plot of initial rate vs. THF concentration in toluene for the enolization of 1 (0.010 M) by HMDS (0.10 M) at 0 C measured with IR spectroscopy (1687 cm 1 ). Plot of initial rate vs. HMDS concentration in 2.0 M THF/hexane for the enolization of 1 (0.010 M) at 0 ºC measured with IR spectroscopy (1687 cm 1 ). S19 S20 S21 Figure 15. Plot of initial rate vs. HMDS concentration in neat THF (12.2 M) for the enolization of 1 (0.010 M) at 0 ºC measured with IR spectroscopy (1687 cm 1 ). S22 Figure 16. Plot of k obsd vs. HMDS concentration in 1.10 M 3 N/toluene for the enolization of 1 ( M) at 0 ºC measured with IR spectroscopy (1671 cm 1 ). S23 Figure 17. Plot of k obsd vs. 3 N concentration in toluene for the enolization of 1 ( M) with HMDS (0.10 M) at 0 C measured with IR spectroscopy (1671 cm 1 ). S24 Figure 18. Plot of k obsd vs. HMDS concentration in 1.10 M 3 N/hexane for the enolization of 1 ( M) at 0 ºC measured with IR spectroscopy (1671 cm 1 ). S25 S2

3 Figure 19. Plot of k obsd vs. 3 N concentration in hexane for the enolization of 1 ( M) with HMDS (0.10 M) at 0 C measured with IR spectroscopy (1671 cm 1 ). S26 Figure 20. Figure 21. Figure 22. Figure 23. Figure 24. Plot of k obsd vs. DMEA concentration with toluene cosolvent for the enolization of 1 ( M) by HMDS (0.10 M) at 40 C measured with IR spectroscopy (1671 cm -1 ). Plot of k obsd vs. HMDS concentration in 0.60 M DMEA/toluene for the enolization of 1 ( M) at 40 ºC measured with IR spectroscopy (1671 cm 1 ). Plot of k obsd vs. HMDS concentration in neat DMEA (9.2 M) for the enolization of 1 ( M) at 40 C measured with IR spectroscopy (1687 cm -1 ). Plot of k obsd vs. DMEA concentration with hexane cosolvent for the enolization of 1 ( M) by HMDS (0.10 M) at 40 C measured with IR spectroscopy (1671 cm -1 ). Plot of k obsd vs. HMDS concentration in 0.60 M DMEA/hexane for the enolization of 1 ( M) at 40 ºC measured with IR spectroscopy (1671 cm 1 ). S27 S28 S29 S30 S31 III. Derivations Derivation 1. HMDS-mediated enolization: THF S32 Derivation 2. HMDS-mediated enolization: DMEA/hexane S33 Derivation 3. HMDS-mediated enolization: DMEA/toluene S35 IV. Ground state computations Chart 1. Table 3. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/THF-mediated enolizations at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). S38 S39 S3

4 Table 4. Table 5. Table 6. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/ 3 N-mediated enolizations at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/DMEA-mediated enolizations at 40 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/DMEA-mediated enolization of 3-pentanone at 40 C with free energies (Hartrees), corrected MP2 energies (kcal) and cartesian coordinates (X, Y, Z). S53 S60 S67 V. Transition state computations Chart 2. Table 7. Table 8. Table 9. Table 10. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for transition states of HMDS/THF-mediated enolizations of 1-(4-fluorophenyl)-2-butan-1-one (ketone) at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for transition states of HMDS/ 3 N-mediated enolizations of 1-(4-fluorophenyl)-2-butan-1-one (ketone) at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for transition states of HMDS/DMEA-mediated enolizations of 1-(4-fluorophenyl)-2-butan-1-one (ketone) at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for transition states of HMDS/DMEA-mediated enolizations of 3-pentanone (3-pent) at 40 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). S68 S69 S74 S78 S81 S4

5 VI. Intrinsic reaction coordinate (IRC) computations Table 11. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for the forward and reverse IRC calculations of HMDS/DMEA-mediated enolization transition structures at 40 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). S84 VIII. References S5

6 I. NMR Spectroscopic Studies Table 1. 6 NMR chemical shifts for different species in THF/hexane mixtures at 80 C. Species δ (ppm) A 2 S AS EE 0.19 EZ 0.03 ZZ 0.13 THF N N THF N (THF) 3 O F A 2 S 2 AS 3 ketone R (THF) 2 O O (THF) 2 R R (THF) 2 O O (THF) 2 R R (THF) 2 O O (THF) 2 R EE EZ ZZ S6

7 A 2 S 2 AS 3 A B EZ ZZ C D EE ppm Figure 1. 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in neat THF at 80 C after aging at rt for 1 hr: a) No ketone, 0.10 M HMDS in 6.0 M THF/hex; b) M ketone; c) M ketone; d) 0.10 M ketone. This figure shows the independence of E/Z selectivity on the HMDS:ketone ratio. S7

8 EE EZ A ZZ B C D ppm Figure 2. 6 spectra of 0.10 M [ 6, 15 N]HMDS and 0.10 M ketone with varying amounts of THF in hexane cosolvent at 80 C after aging at rt for 48 hr: a) 3.0 M THF/hex; b) 4.5 M THF/hex; c) 6.0 M THF/hex; d) neat THF. This figure shows the dependence of E/Z selectivity on the concentration of THF. S8

9 1.0 Relative Integration EE EZ ZZ χ E Figure 3. Job plot showing the relative integration of the 6 resonances versus the measured mole fraction (X E ) ref 15 of E-enolate for 0.10 M mixtures of E-enolate and Z-enolate at 80 C at varying THF concentrations in hexane (see Figure 2). The left side of the plot cannot be filled in, as there exists a solubility problem with respect to enolate. The right side of the plot is the limit of THF concentration (neat). S9

10 Table 2. 6 and 15 N NMR chemical shifts for different species in 0.60 M DMEA/toluene at 100 C. Note that species without chemical shifts could not be characterized at the given temperature due weak signal. 6 δ (ppm) 15 N δ (ppm) Species at 100 C at 100 C A 2 S AS 2 T/AS A 2 S(ketone) 0.85, A 2 (ketone) AES AZS DMEA Me Me 3 Si SiMe 3 Si 3 N (DMEA) Me 3 Si N N 3 Me N Me 3 Si SiMe 3 Si 3 Me toluene 3 Si DMEA (DMEA) 3 A 2 S 2 AS 2 T AS 3 O F Me 3 Si Me 3 Si DMEA N N ketone SiMe 3 SiMe 3 Me 3 Si Me 3 Si ketone N N ketone SiMe 3 SiMe 3 ketone A 2 (ketone) A 2 (ketone) 2 DMEA N O DMEA DMEA N O DMEA AES 2 AZS 2 S10

11 AS 3 A A 2 S 2 AES 2 B AZS 2 C D ppm Figure 4. 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 80 C after aging at rt for 1 hr: a) no ketone; b) M ketone; c) M ketone; d) 0.10 M ketone. S11

12 AES 2 A AZS 2 B C ppm Figure 5. 6 spectra of 0.10 M [ 6, 15 N]HMDS and M ketone with varying amounts of DMEA in toluene cosolvent at 80 C after aging at rt for 1 hr: a) 0.60 M DMEA/tol; b) 1.1 M DMEA/tol; c) 5.1 M DMEA/tol. S12

13 A 2 S 2 AS 3 A A 2 S(ketone) B C D A 2 S(ketone) ppm Figure 6. Unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 100 C: a) no ketone; b) M ketone; c) M ketone; d) 0.10 M ketone. S13

14 AS 3 A 2 S 2 A A 2 S(ketone) B C A 2 S(ketone) 2 D ppm Figure 7. Unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with varying amounts of ketone in 0.60 M DMEA/tol at 100 C: a) no ketone; b) M ketone; c) M ketone; d) 0.10 M ketone. S14

15 A 2 S(ketone) A B C D ppm Figure N-decoupled unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with M ketone in 0.60 M DMEA/tol at 100 C: a) fully coupled; b) selective decoupling of 15 N resonance corresponding to HMDS monomer at ppm; c) selective decoupling of 15 N resonance at ppm; d) broadband decoupled. S15

16 A 2 S(ketone) A AS 3 B C D E ppm Figure N-decoupled unaged 6 spectra of 0.10 M [ 6, 15 N]HMDS with M ketone in 0.60 M DMEA/tol at 100 C: a) fully coupled; b) selective decoupling of 6 resonance corresponding to HMDS monomer at 0.36 ppm; c) selective decoupling of the upfield 6 resonance at 0.85 ppm; d) selective decoupling of the downfield 6 resonance at 1.24 ppm; e) broadband decoupled. S16

17 A 2 S(ketone) 2 A 2 S(ketone) A B C ppm Figure decoupled unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with 0.10 M ketone in 0.60 M DMEA/tol at 100 C: a) fully coupled; b) selective decoupling of 15 N resonance at ppm; c) broadband decoupled. Note that the downfield triplet in spectrum b is independent of the two upfield triplets. The loss of coupling is due to the closeness of the 15 N resonances corresponding to the mono- and di-ketone-solvated HMDS dimers (39.90 and ppm, respectively). S17

18 A 2 S(ketone) A 2 S(ketone) 2 A B C ppm Figure decoupled unaged 15 N spectra of 0.10 M [ 6, 15 N]HMDS with 0.10 M ketone in 0.60 M DMEA/tol at 100 C: a) fully coupled; b) selective decoupling of 6 resonance at 0.85 ppm; c) broadband decoupled. Note that the downfield quintet in spectrum b is independent of the upfield quintet. The loss of coupling is due to the closeness of the 6 resonances corresponding to the mono- and di-ketone-solvated HMDS dimers (1.24 and 1.43 ppm, respectively). S18

19 II. IR Rate Studies 70 Initial Rate x 10 4 (M s 1 ) [THF] (M) Figure 12. Plot of initial rate vs. THF concentration in hexane for the enolization of 1 (0.010 M) by HMDS (0.10 M) at 0 C measured with IR spectroscopy (1687 cm 1 ). The curve depicts the result of an unweighted least-squares fit to y = ax n (a = 0.05 ± 0.03, n = 2.8 ± 0.2). [THF] (M) Initial rate (M s 1 ) Initial rate (M s 1 ) Initial Rate avg 10 4 (M s 1 ) ± ± ± ± ± ± 1 S19

20 70 Initial Rate x 10 4 (M s 1 ) [THF] (M) Figure 13. Plot of initial rate vs. THF concentration in toluene for the enolization of 1 (0.010 M) by HMDS (0.10 M) at 0 C measured with IR spectroscopy (1687 cm 1 ). The curve depicts the result of an unweighted least-squares fit to y = ax n (a = 0.18 ± 0.05, n = 2.4 ± 0.1). [THF] (M) Initial rate 10 4 (M s 1 ) S20

21 2.0 Initital Rate x 10 4 (M s 1 ) [HMDS] (M) Figure 14. Plot of initial rate vs. HMDS concentration in 2.0 M THF/hexane for the enolization of 1 (0.010 M) at 0 ºC measured with IR spectroscopy (1687 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax n [a = 4.4 ± 0.2, n = 0.58 ± 0.02]. [HMDS] (M) Initial rate (M s 1 ) Initial rate (M s 1 ) Initial Rate avg 10 4 (M s 1 ) ± ± ± ± ± ± ± 0.01 S21

22 1.4 Initial Rate x 10 2 (M s 1 ) [HMDS] (M) Figure 15. Plot of initial rate vs. HMDS concentration in neat THF (12.2 M) for the enolization of 1 (0.010 M) at 0 ºC measured with IR spectroscopy (1687 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax n [a = 6.3 ± 0.5, n = 1.01 ± 0.04]. [HMDS] (M) Initial rate (M s 1 ) Initial rate (M s 1 ) Initial Rate avg 10 2 (M s 1 ) ± ± ± ± ± ± ± 0.1 S22

23 1.0 k obsd x 10 2 (s 1 ) [HMDS] (M) Figure 16. Plot of k obsd vs. HMDS concentration in 1.10 M 3 N/toluene for the enolization of 1 ( M) at 0 ºC measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax + b [a = 0.60 ± 0.02, b = 0.1 ± 0.1]. [HMDS] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 2 (s 1 ) ± ± ± ± 0.02 S23

24 k obsd x 10 2 (s 1 ) [ 3 N] (M) Figure 17. Plot of k obsd vs. 3 N concentration in toluene for the enolization of 1 ( M) with HMDS (0.10 M) at 0 C measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax n [a = 0.53 ± 0.03, n = 1.00 ± 0.03]. [ 3 N] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 2 (s 1 ) ± ± ± ± ± 0.1 S24

25 k obsd x 10 2 (s 1 ) [HMDS] (M) Figure 18. Plot of k obsd vs. HMDS concentration in 1.10 M 3 N/hexane for the enolization of 1 ( M) at 0 ºC measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax + b [a = ± 0.003, b = 0.02 ± 0.02]. [HMDS] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 2 (s 1 ) ± ± ± ± 0.01 S25

26 k obsd x 10 2 (s 1 ) [ 3 N] (M) Figure 19. Plot of k obsd vs. 3 N concentration in hexane for the enolization of 1 ( M) with HMDS (0.10 M) at 0 C measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax n [a = 0.69 ± 0.01, n = 1.02 ± 0.01]. [ 3 N] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 2 (s 1 ) ± ± ± ± 0.1 S26

27 k obsd x 10 3 (s 1 ) [DMEA] (M) Figure 20. Plot of k obsd vs. DMEA concentration with toluene cosolvent for the enolization of 1 ( M) by HMDS (0.10 M) at 40 C measured with IR spectroscopy (1671 cm -1 ). The curve is fit to the function described in the Derivations section of this supporting information on page 37. [a 0 = 0.1, k 0 = 0.005, k 1 = (8 ± 1) 10 5, k 2 = ± 0.02, k g1 = 100, k g2 = 0.15, k g3 = 14, kk = 162 ± 9] [DMEA] (M) k 1 obsd 10 3 (s 1 ) k 2 obsd 10 3 (s 1 ) k avg obsd 10 3 (s 1 ) ± ± ± ± ± ± ± ± ± 0.04 S27

28 k obsd x 10 3 (M s 1 ) [HMDS] (M) Figure 21. Plot of k obsd vs. HMDS concentration in 0.60 M DMEA/toluene for the enolization of 1 ( M) at 40 ºC measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax + b [a = 0.64 ± 0.02, b = 0.2 ± 0.1]. [HMDS] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 3 (s 1 ) ± ± ± ± 0.04 S28

29 2.0 k obsd x 10 3 (s 1 ) [HMDS] (M) Figure 22. Plot of k obsd vs. HMDS concentration in neat DMEA (9.2 M) for the enolization of 1 ( M) at 40 C measured with IR spectroscopy (1687 cm -1 ). The curve is fit to the function described in the Derivations section of this supporting information on pag 37. [s = 9.23, k 0 = 0.005, k 1 = , k 2 = 11 ± 3, k g1 = 100, k g2 = 0.15, kk = 900 ± 100)] [DMEA] (M) k 1 obsd 10 3 (s 1 ) k 2 obsd 10 3 (s 1 ) k avg obsd 10 3 (s 1 ) ± ± ± ± ± ± 0.06 S29

30 [DMEA] (M) k obsd x 10 3 (s 1 ) Figure 23. Plot of k obsd vs. DMEA concentration with hexane cosolvent for the enolization of 1 ( M) by HMDS (0.10 M) at 40 C measured with IR spectroscopy (1671 cm -1 ). The curve is fit to the function described in the Derivations section of this supporting information on page 34. [a 0 = 0.1, k 0 = 0.005, k 1 = (3 ± 1) 10 5, k 2 = 1.30 ± 0.4, k g1 = 100, k g2 = 0.15, kk = 395 ± 50] [DMEA] (M) k obsd 10 3 (s 1 ) S30

31 k obsd x 10 3 (s 1 ) [HMDS] (M) Figure 24. Plot of k obsd vs. HMDS concentration in 0.60 M DMEA/hexane for the enolization of 1 ( M) at 40 ºC measured with IR spectroscopy (1671 cm 1 ). The curve depicts an unweighted least-squares fit to y = ax + b [a = 0.74 ± 0.02, b = 0.12 ± 0.02]. [HMDS] (M) k obsd (s 1 ) k obsd (s 1 ) avg k obsd 10 3 (s 1 ) S31

32 III. Derivations i. HMDS-mediated enolization: THF To simplify the discussion of the mechanistic model, we introduce the following shorthand: A = a HMDS subunit, and S = THF. As shown below, A 2 S 2 corresponds to disolvated HMDS dimer, and AS 3 corresponds to trisolvated HMDS monomer. THF N N THF 4 THF K eq 2 N (THF) 3 (1) A 2 S 2 AS 3 Given K eq = [AS 3 ] 2 /{[A 2 S 2 ][S] 4 }, and 2[A 2 S 2 ] + [AS 3 ] = [A] 0, one can solve for [A 2 S 2 ] as a function of [A] 0 and [S]: K eq = [ AS 3 ] 2 [ A 2 S 2 ][ S] 4 ([ ] 0 2[ A 2 S 2 ]) 2 [ ][ S] 4 = A A 2 S 2 (2) Rearranging, 4 A 2 S 2 ( ) A 2 S 2 [ ] 2 4[ A] 0 + K eq [ S] 4 2 [ ] + [ A] 0 = 0 (3) Applying the quadratic equation to [A 2 S 2 ] gives: [ A 2 S 2 ] = ( 4[ A] 0 + K eq [ S] 4 ) 4 A ( [ ] 0 + K eq [ S] 4 ) [ A] 0 = 4 [ A ] 0 + K eq [ S] 4 K eq [ S] 2 K eq [ S] 4 +8[ A] (4) S32

33 ii. HMDS-mediated enolization: DMEA/hexane To reduce complexity of the mathematical description of this mechanism, one must separate the equilibria describing the free base from that describing the ketone-solvated base. Under pseudofirst-order conditions, the total mass balance of the ketone-solvated base accounts for a small amount (5%) of the total base titer. By separating the equilibria, one can solve independently for the relevant species and then substitute them as needed. To simplify the discussion of the mechanistic model, we introduce the following shorthand: A = a HMDS subunit, and S = R 3 N. As shown below, A 2 corresponds to unsolvated HMDS dimer, A 2 S 2 corresponds to disolvated HMDS dimer, and AS 3 corresponds to trisolvated HMDS monomer. R 3 N N N 6 R 3 N K G1 N N R 3 N 4 R 3 N K G2 2 N (NR 3 ) 3 (1) A 2 A 2 S 2 AS 3 Given K G1 = [A 2 S 2 ] 2 /{[A 2 ][S]}, K G2 = [AS 3 ] 2 /{[ A 2 S 2 ][S] 4 }, and 2[A 2 ] + 2[A 2 S 2 ] + [AS 3 ] = [A] 0, one can solve for [A 2 S 2 ] as a function of [A] 0 and [S]: [ A] 0 = 2 A 2 [ ] + 2[ A 2 S 2 ] + [ AS 2 T] + [ AS 3 ] [ ] [ S] + 2 [ A 2S 2 2 ] + K G2 [ A 2 S 2 ][ S] 2 [ T] 2 + K G2 K G3 [ A 2 S 2 ][ S] 4 (2) = 2 A 2S 2 K G1 Rearranging to eliminate the square root affords a quadratic expression: [ A] 0 2 A 2S 2 K G1 S [ ] [ ] 2 [ A 2S 2 2 ] 2 ( [ ] [ S ] 2 [ T] 2 + K K3[ A S ] [ S ] ) 4 G2 2 2 = K G2 A 2 S 2 2 (3) This can be solved for [A 2 S 2 ] to provide: 4[ A] 0 4[ A] 0 K G1 [ S] K K [ S 2 G2 G3 ]4 2K G2 K G3 [ S] 3 [ T] K G2 [ S] 2 [ T] [ A] 0 4 K G1 [ S] 8 4 K G1 [ S] 2 + 4[ A] + 4[ A] K G1 [ S] + K K [ S 2 G2 G3 ]4 + 2K G2 K G3 [ S] 3 [ T] + K G2 [ S] 2 [ T] 2 [ A 2 S 2 ] = K G1 [ S] 8 4 K G1 [ S] 2 (4) We know turn to the set of equilibria and mass balance equation that describe the ketonesolvated base. We introduce the following shorthand: A = a HMDS subunit, S = R 3 N, and K = ketone. As shown below, A 2 K corresponds to ketone-complexed HMDS dimer, A 2 KS corresponds to amine-solvated, ketone-complexed HMDS dimer, and A 2 S 2 corresponds to disolvated HMDS dimer. S33

34 N N ketone R 3 N K 1 R 3 N N N ketone R 3 N K 2 R 3 N N N R 3 N ketone (5) A 2 K A 2 KS A 2 S 2 Given K 1 = [A 2 KS]/{[A 2 K][S]}, K 2 = {[A 2 S 2 ][K]}/{[ A 2 KS][S]}, and [A 2 K] + [A 2 KS] + [K] = [K] 0, one can solve for [A 2 KS] as a function of [K] 0, [A 2 S 2 ], and [S]: K [ A 2 KS] = 1 K 2 [ A 2 S 2 ][ K] 0 [ S] [ A 2 S 2 ] + K 1 [ A 2 S 2 ][ S] + K 1 K 2 [ S] 2 (6) Substituting eq 4 into eq 6 gives: [ A 2 KS] = (k0 k1 kg1 s (kg1 kg2 s^6 + 4 a0 (1 + kg1 s^2) - Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]))/( kg1 (kg1 kg2 s^6 + 4 a0 (1 + kg1 s^2) - Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]) + k1 (8 k2 (1 + kg1 s^2)^2 + kg1 s (4 a0 + 4 a0 kg1 s^2 + kg1 kg2 s^6 - Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]))) (7) The form of the rate law is as follows: d[ P] = k [ A 2 KS] (8) dt The fitting function to describe the enolization with HMDS in DMEA/hexane is found by inserting eq 7 into eq 8: d[ P] = k(k0 k1 kg1 s (kg1 kg2 s^6 + 4 a0 (1 + kg1 s^2) - dt Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]))/( kg1 (kg1 kg2 s^6 + 4 a0 (1 + kg1 s^2) - Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]) + k1 (8 k2 (1 + kg1 s^2)^2 + kg1 s (4 a0 + 4 a0 kg1 s^2 + kg1 kg2 s^6 - Sqrt[kg1] Sqrt[kg2] s^3 Sqrt[8 a0 + 8 a0 kg1 s^2 + kg1 kg2 s^6]))) (9) S34

35 iii. HMDS-mediated enolization: DMEA/toluene To reduce complexity of the mathematical description of this mechanism, one must separate the equilibria describing the free base from that describing the ketone-solvated base. Under pseudofirst-order conditions, the total mass balance of the ketone-solvated base accounts for a small amount (5%) of the total base titer. By separating the mass balance equilibria, one can solve independently for the relevant species and then substitute them as needed. To simplify the discussion of the mechanistic model, we introduce the following shorthand: A = a HMDS subunit, S = R 3 N, and T = toluene. As shown below, A 2 corresponds to unsolvated HMDS dimer, A 2 S 2 corresponds to disolvated HMDS dimer, AS 2 T corresponds to disolvated HMDS monomer with one bound toluene, and AS 3 corresponds to trisolvated HMDS monomer. R 3 N N N 6 R 3 N 2 toluene K G1 N N R 3 N 4 R 3 N 2 toluene (1) A 2 A 2 S 2 K G2 2 N AS 3 (NR 3 ) 3 K G3 2 toluene 2 N (NR 3 ) 3 toluene AS 2 T 2 R 3 N Given K G1 = [A 2 S 2 ] 2 /{[A 2 ][S]}, K G2 = [AS 3 ] 2 /{[ A 2 S 2 ][S] 4 }, K G3 = [AS 2 T] 2 [S] 2 / {[ AS 3 ][T] 2 }, and 2[A 2 ] + 2[A 2 S 2 ] + [AS 2 T] + [AS 3 ] = [A] 0, one can solve for [A 2 S 2 ] as a function of [A] 0 and [S]: [ A] 0 = 2 A 2 [ ] + 2[ A 2 S 2 ] + [ AS 3 ] + [ AS 2 T] [ ] [ S] + 2 [ A 2S 2 2 ] + K G2 [ A 2 S 2 ][ S] 4 + K G2 K G3 [ A 2 S 2 ][ S] 2 [ T] 2 (2) = 2 A 2S 2 K G1 Rearranging to eliminate the square root affords a quadratic expression: [ A] 0 2 A 2 S 2 [ ] 1+ K G1 2 1 [ S] 2 ( [ ] [ S ] 4 + K K [ A S ][ S] 2 [ T ] ) 2 G2 G3 2 2 = K G2 A 2 S 2 2 (3) S35

36 This can be solved for [A 2 S 2 ] to provide: 4[ A] 0 1+ [ A 2 S 2 ] = K G1 2 1 [ S] 2 + K [ S G2 ]4 + K G2 K G3 [ S] 3 [ T] + K G2 K G3 [ S] 2 [ T] 2 16[ A] K G1 [ S] 2 + 4[ A] K G1 1 [ S] 2 K G1 2 1 [ S] 2 K [ S G2 ]4 K G2 K G3 [ S] 3 [ T] K G2 K G3 [ S] 2 [ T] 2 2 (4) We now turn to the set of equilibria and mass balance equations that describe the ketone-solvated base. We introduce the following shorthand: A = a HMDS subunit, S = R 3 N, and K = ketone. As shown below, A 2 K corresponds to ketone-complexed HMDS dimer, A 2 KS corresponds to amine-solvated, ketone-complexed HMDS dimer, and A 2 S 2 corresponds to disolvated HMDS dimer. N N ketone R 3 N K 1 R 3 N N N ketone R 3 N K 2 R 3 N N N R 3 N ketone (5) A 2 K A 2 KS A 2 S 2 Given K 1 = [A 2 KS]/{[A 2 K][S]}, K 2 = {[A 2 S 2 ][K]}/{[ A 2 KS][S]}, and [A 2 K] + [A 2 KS] + [K] = [K] 0, one can solve for [A 2 KS] as a function of [K] 0, [A 2 S 2 ], and [S]: K [ A 2 KS] = 1 K 2 [ A 2 S 2 ][ K] 0 [ S] [ A 2 S 2 ] + K 1 [ A 2 S 2 ][ S] + K 1 K 2 [ S] 2 (6) Substituting eq 4 into eq 6 gives: [ A 2 KS] = (k0 k1 s (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) - kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2]))/(8 (1 + 1/(kg1 s^2))^2 (k1 k2 s^2 + (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) - kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2])/(8 (1 + 1/(kg1 s^2))^2) + (1/(8 (1 + 1/(kg1 s^2))^2))k1 s (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) -kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2]))) (7) The form of the rate law is as follows: d[ P] = k [ A 2 KS] (8) dt S36

37 The fitting function to describe the enolization with HMDS in DMEA/toluene is found by inserting eq 7 into eq 8: d[ P] = k(k0 k1 s (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + dt kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) - kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2]))/(8 (1 + 1/(kg1 s^2))^2 (k1 k2 s^2 + (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) - kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2])/(8 (1 + 1/(kg1 s^2))^2) + (1/(8 (1 + 1/(kg1 s^2))^2))k1 s (4 a0 (1 + 1/(kg1 s^2)) + kg2 s^4 + kg2 Sqrt[kg3] s^3 t + kg2 kg3 s^2 t^2 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) -kg2 s^4 - kg2 Sqrt[kg3] s^3 t - kg2 kg3 s^2 t^2)^2]))) (9) A more convenient form of the equation is found instead by writing the [T] as a function of [S] by replacing [T] with (9.41/9.23*(9.23 [S])): d[ P] = k(k0 k1 s (4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^2 + dt kg2 Sqrt[kg3] ( s) s^3 + kg2 s^4 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^ kg2 Sqrt[kg3] ( s) s^3 - kg2 s^4)^2]))/(8 (1 + 1/(kg1 s^2))^2 (k1 k2 s^2 + 1/(8 (1 + 1/(kg1 s^2))^2) (4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^ kg2 Sqrt[kg3] ( s) s^3 + kg2 s^4 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^ kg2 Sqrt[kg3] ( s) s^3 - kg2 s^4)^2]) + 1/(8 (1 + 1/(kg1 s^2))^2)k1 s (4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^ kg2 Sqrt[kg3] ( s) s^3 + kg2 s^4 - Sqrt[-16 a0^2 (1 + 1/(kg1 s^2))^2 + (-4 a0 (1 + 1/(kg1 s^2)) kg2 kg3 ( s)^2 s^ kg2 Sqrt[kg3] ( s) s^3 - kg2 s^4)^2]))) (9) S37

38 IV: Ground State Computations Chart 1 O 1-(4-fluorophenyl)-2-butan-1-one ketone O THF O O EE THF O O THF EE(THF) 2 (THF) 2 O O (THF) 2 EE(THF) 4 O O ZZ THF O O THF ZZ(THF) 2 (THF) 2 O O (THF) 2 ZZ(THF) 4 O O EZ THF O O THF EZ(THF) 2 (THF) 2 O O (THF) 2 EZ(THF) 4 Me N Me Me Me 3 Si Me 3 Si N N ketone SiMe 3 SiMe 3 Me 3 Si Me 3 Si 3 N N N ketone SiMe 3 SiMe 3 Me 3 Si Me 3 Si 3 N N O 3 N Me 3 Si Me 3 Si 3 N N O 3 N 3 N Me N Me Me Me 3 Si Me 3 Si A 2 (ketone) 0 C N N ketone SiMe 3 SiMe 3 Me 3 Si Me 3 Si A 2 (ketone)( 3 N) DMEA N N ketone SiMe 3 SiMe 3 Me 3 Si Me 3 Si AE( 3 N) 2 AZ( 3 N) 2 DMEA N O DMEA Me 3 Si Me 3 Si DMEA N O DMEA DMEA A 2 (ketone) 40 C A 2 (ketone)(dmea) AE(DMEA) 2 AZ(DMEA) 2 O 3-pentanone S38

39 Table 3. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/THF-mediated enolizations at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). (Note: G MP2 includes singlepoint MP2 corrections to B3LYP/6-31G(d) optimized structures.) O = (4-fluorophenyl) Ketone G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C H H H H H C C C C C C C H H F H H O C C H H H H H H S39

40 O THF G = G MP2 = Atom X Y Z Atom X Y Z C H H C H H C H H C H H O O O EE G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C H H H H H C C C C C C C H H F H H O O C C C C S40

41 C C C C H H H H H C C H H H H H C C C C C C H H F H H C H H H H H THF O O THF EE(THF) 2 G = G MP2 = Atom X Y Z Atom X Y Z O C C C C H H H H H C C C C C C H H H H H C C C C C C H H F H S41

42 H O C C C C C C C C H H H H H C C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H O C H H C H H C H H C H H (THF) 2 O O (THF) 2 EE(THF) 4 G = G MP2 = Atom X Y Z Atom X Y Z O C C S42

43 C C H H H H H C C C C C C H H H H H C C C C C C H H F H H O C C C C C C C C H H H H H C C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H O C H H C H H C H H C H H O C H H S43

44 C H H C H H C H H O C H H C H H C H H C H H O O EZ G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C H H H H H C C C C C C C H H F H H O O C C C C C C C C H H H H H C C S44

45 H H H H H C C C C C C H H F H H C H H H H H THF O O THF EZ(THF) 2 G = G MP2 = Atom X Y Z Atom X Y Z O C C C C H H H H H C C C C C C H H H H H C C C C C C H H F H H O C H H C H H C S45

46 H H C H H O C C C C H H H H H C C C C C C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H (THF) 2 O O (THF) 2 EZ(THF) 4 G = G MP2 = Atom X Y Z Atom X Y Z O C C C C H H H H H C C C C C S46

47 C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H O C H H C H H C H H C H H O C C C C H H H H H C C C C C C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H O C H S47

48 H C H H C H H C H H O O ZZ G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C H H H H H C C C C C C C H H F H H O O C C C C C C C C H H H H H C C H H H H H C C C C C C S48

49 H H F H H C H H H H H THF O O THF ZZ(THF) 2 G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C H H H H H C C C C C C C H H F H H O O C C C C H H H H H C C C C C C H H H H S49

50 H C C C C C C H H F H H C H H H H H C H H C H H C H H C H H O C H H C H H C H H C H H O (THF) 2 O O (THF) 2 ZZ(THF) 4 G = G MP2 = Atom X Y Z Atom X Y Z O C C C C H H H H H C C C C C C H H H S50

51 H H C C C C C C H H F H H O C C C C H H H H H C C C C C C H H H H H C C C C C C H H F H H O C H H C H H C H H C H H O C H H C H H C H H C H H O C H H C H H C H H C H H O C H H C H H S51

52 C H H C H H S52

53 Table 4. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/ 3 N-mediated enolizations at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). (Note: G MP2 includes singlepoint MP2 corrections to B3LYP/6-31G(d) optimized structures.) Me N Me Me 3 N G = G MP2 = Atom X Y Z Atom X Y Z C N C H H C H H H C H H C H H H H H C H H H Me 3 Si Me 3 Si N N ketone SiMe 3 SiMe 3 A 2 (ketone) G = G MP2 = Atom X Y Z Atom X Y Z Si C H H H C H H H N Si C S53

54 H H H C H H H C H H H N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C C C C C C C C H H H H H C C H H H H H H C C C C C C H H F H H C H H H S54

55 Me 3 Si Me 3 Si 3 N N N ketone SiMe 3 SiMe 3 A 2 (ketone)( 3 N) G = G MP2 = Atom X Y Z Atom X Y Z Si C H H H C H H H N Si C H H H C H H H C H H H N C H H C H H H C H H C H H H C H H C H H H N Si C H H H C H H H C H H H Si C H H H C H H H S55

56 C H H H O C C C C C C C C H H H H H C C H H H H H H C C C C C C H H F H H C H H H Me 3 Si Me 3 Si 3 N N O 3 N AE( 3 N) 2 G = G MP2 = Atom X Y Z Atom X Y Z N Si C H H H C H H H C H H H Si C H H H C H H H S56

57 C H H H O C C C C C C C H H F H H C C H H C H H H C C C C C C H H H H H N C H H C H H H C H H C H H H C H H C H H H N C H H C H H H C H H C H H H C H H C H H H S57

58 Me 3 Si Me 3 Si 3 N N O 3 N AZ( 3 N) 2 G = G MP2 = Atom X Y Z Atom X Y Z N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C C C C C C C H H F H H C C C C C C C H H H H H C H H C H H H N C H H C H H H C H H S58

59 C H H H C H H C H H H N C H H C H H H C H H C H H H C H H C H H H S59

60 Table 5. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/DMEA-mediated enolizations at 40 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). (Note: G MP2 includes singlepoint MP2 corrections to B3LYP/6-31G(d) optimized structures.) Me N Me Me DMEA G = G MP2 = Atom X Y Z Atom X Y Z C N C H H C H H H C H H H H H H Me 3 Si Me 3 Si N N ketone SiMe 3 SiMe 3 A 2 (ketone) G = G MP2 = Atom X Y Z Atom X Y Z Si C H H H C H H H N Si C H H H C H H H C S60

61 H H H N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C C C C C C C C H H H H H C C H H H H H H C C C C C C H H F H H C H H H S61

62 Me 3 Si Me 3 Si DMEA N N ketone SiMe 3 SiMe 3 A 2 (ketone)(dmea) G = G MP2 = Atom X Y Z Atom X Y Z Si C H H H C H H H N Si C H H H C H H H C H H H C H H H N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C C C C C C C C H H H S62

63 H H C C H H H H H H C C C C C C H H F H H N C H H H C H H C H H H C H H H Me 3 Si Me 3 Si DMEA N O DMEA AE(DMEA) 2 G = G MP2 = Atom X Y Z Atom X Y Z N Si C H H H C H H H C H H H Si C H H H C H H H S63

64 C H H H O C C C C C C C H H F H H C C H H C H H H C C C C C C H H H H H N C H H H C H H C H H H C H H H N C H H H C H H C H H H C H H H S64

65 Me 3 Si Me 3 Si DMEA N O DMEA AZ(DMEA) 2 G = G MP2 = Atom X Y Z Atom X Y Z N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C C C C C C C H H F H H C C C C C C C H H H H H C H H C H H H N C H H H C H H C H H S65

66 H C H H H N C H H H C H H C H H H C H H H S66

67 Table 6. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for relevant ground states of HMDS/DMEA-mediated enolization of 3-pentanone at 40 C with free energies (Hartrees), corrected MP2 energies (kcal) and cartesian coordinates (X, Y, Z). (Note: G MP2 includes single-point MP2 corrections to B3LYP/6-31G(d) optimized structures.) O 3-pentanone G = G MP2 = Atom X Y Z Atom X Y Z C H H C H H C H H C H H O S67

68 V: Transition State Computations Chart 2 Me 3 Si SiMe 3 N H THF O A(ketone)(THF) - Pro E Me 3 Si SiMe 3 N H THF O A 2 (ketone)(thf) - Pro Z Me 3 Si SiMe 3 N H (THF) 2 O A(ketone)(THF) 2 - Pro E Me 3 Si SiMe 3 N H (THF) 2 O A 2 (ketone)(thf) 2 - Pro Z Me 3 Si SiMe 3 N H O SiMe 3 N SiMe 3 3 N A 2 (ketone)( 3 N) - Pro E Me 3 Si SiMe 3 N H O SiMe 3 N SiMe 3 3 N A 2 (ketone)( 3 N) - Pro Z Me 3 Si SiMe 3 N H O SiMe 3 N SiMe 3 DMEA A 2 (ketone)(dmea) - Pro E Me 3 Si SiMe 3 N H O SiMe 3 N SiMe 3 DMEA A 2 (ketone)(dmea) - Pro Z Me 3 Si SiMe 3 N H O H Me SiMe 3 N SiMe 3 DMEA A 2 (3-pentanone)(DMEA) - Pro E Me 3 Si SiMe 3 N H O Me H SiMe 3 N SiMe 3 DMEA A 2 (3-pentanone)(DMEA) - Pro Z S68

69 Table 7. Optimized geometries at the B3LYP level of theory with 6-31G(d) basis set for transition states of HMDS/THF-mediated enolizations of 1-(4-fluorophenyl)-2-butan-1-one (ketone) at 0 C with free energies (Hartrees), corrected MP2 energies (kcal), and cartesian coordinates (X, Y, Z). (Note: G MP2 includes single-point MP2 corrections to B3LYP/6-31G(d) optimized structures.) Me 3 Si SiMe 3 N H THF O A(ketone)(THF) Pro E G = G MP2 = Atom X Y Z Atom X Y Z Si O C C C C C C C H H F H H C C C C C C C H H H H H C H H C H H H N Si C H H H C H H H C H H H O C H H C H H C S69

70 H H C H H C H H H C H H H C H H H H Me 3 Si SiMe 3 N H THF O A(ketone)(THF) Pro Z G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C C H H F H H O N Si C H H H C H H H C H H H Si C H H H C H H H C H H H O C H S70

71 H C H H C H H C H H C C C C C C H H H H H H H C H H H H Me 3 Si SiMe 3 N H (THF) 2 O A(ketone)(THF) 2 Pro E G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C C C C H H F H H O O C H H C H H C H H C H H O C H S71

72 H C H H C H H C H H C C C C C C H H H H H H H C H H H H C H H H Si C H H H C H H H N Si C H H H C H H H C H H H Me 3 Si SiMe 3 N H (THF) 2 O A(ketone)(THF) 2 Pro Z G = G MP2 = Atom X Y Z Atom X Y Z C C C C C C S72