Solution Structures of Lithium Enolates of Cyclopentanone

Supporting Information

Solution Structures of Lithium Enolates of Cyclopentanone, Cyclohexanone, Acetophenones and Benzyl Ketones. Triple Ions and Higher Lithiate Complexes Kristopher J. Kolonko, Margaret M. Biddle, Ilia A. Guzei and Hans J. Reich,* Department of Chemistry, University of Wisconsin 1101 University Avenue Madison, Wisconsin 53706 [email protected]

Table of Contents S1. General Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 S2. Synthesis 1,3-Bis-(4-fluorophenyl)-2-propanone (5F-H) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Phenyl-2-(4-fluorophenyl)ethanone (6F-H) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,3-Diphenyl-2-(trimethylsilyloxy)-1-propene (5H-Si) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,3-Bis-(4-fluorophenyl)-2-(trimethylsilyloxy)-1-propene (5H-Si) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Phenyl-2-(4-fluorophenyl)-1-(trimethylsilyloxy)ethene (6F-Si)) . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3 4 4 4

S3. NMR Characterization of Enolate Structures General Preparation of Samples for Multinuclear NMR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . 5 HMPA Titration of the Lithium Enolate of Cyclopentanone (1-Li) . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 HMPA Titration of the Lithium Enolate of Cyclohexanone (2-Li) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 HMPA Titration of the Lithium Enolate of 4-Fluoroacetophenone (3F-Li) . . . . . . . . . . . . . . . . . . . . . 8 HMPA Titration of the Lithium Enolate of Acetophenone (3H-Li) . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 TMEDA Titration of the Lithium Enolate of 4-Fluoroacetophenone (3F-Li) . . . . . . . . . . . . . . . . . . . 10 PMDTA Titration of the Lithium Enolate of 4-Fluoroacetophenone (3F-Li) . . . . . . . . . . . . . . . . . . . 11 HMPA Titration of Lithium 4-Fluorophenolate (4F-Li) in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . 12 HMPA Titration of Lithium 4-Fluorophenolate (4F-Li) in Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Kinetic and Thermodynamic Isomers of 1,3-Diphenyl-2-propanone Lithium Enolate (5H-Li) . . . . . 14 1 H NOE of the E and Z Isomers of Enol Silyl Ether of 1,3-Diphenyl-2-propanone . . . . . . . . . . . . . . 15 PMDTA Titration of the Lithium Enolate Z-5H-Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 TMTAN Titration of the Lithium Enolate Z-5H-Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 HMPA Titration of the Lithium Enolate Z-5H-Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Kinetic and Thermodynamic Enolates of 1,3-Bis-(4-fluorophenyl)-2- propanone (5F-Li) . . . . . . . . 19 1 H NOE of the of Enol Silyl Ether Isomers of 1,3-Bis-(4-fluorophenyl)-2- propanone (5F-Si) . . . . . 20 Variable Temperature NMR Study of Dimers of Lithium Enolate E/Z-5F-Li . . . . . . . . . . . . . . . . . . 21 Variable Concentration Study of the Lithium Enolate Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . 22 Variable Temperature Study of Monomer Dimer Equilibrium of Lithium Enolate Z-5F-Li . . . . . . . 23 P4-tBu Titration of 1,3-Bis-(4-fluorophenyl)-2- propanone (5F-H) . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Variable Temperature Study of Phenyl Ring Rotation in Z-5F-P4H . . . . . . . . . . . . . . . . . . . . . . . . . 25 Variable Temperature Study of Phenyl Ring Rotation in Z-5F-Li . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 TMEDA Titration of Lithium Enolate Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 TMTAN Titration of Lithium Enolate Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 PMDTA Titration of Lithium Enolate Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 PMDTA Titration of Lithium Enolate E/Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 HMPA Titration of Lithium Enolate Z-5F-Li at -130 °C in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . 31 HMPA Titration of Lithium Enolate Z-5F-Li at -140 °C in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . 32 S-1

P4 Enolate Titration of Lithium Enolate Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixing Studies of P4 Enolate Generated Quadruple Ions of Z-5F and Z-6F . . . . . . . . . . . . . . . . . . . Dilution Study of Triple ion – Quadruple Ion Equilibrium for Z-5F . . . . . . . . . . . . . . . . . . . . . . . . . Variable Temperature Study of Quadruple Ion and Triple Ion of Z-5F . . . . . . . . . . . . . . . . . . . . . . . Variable Temperature Study of Z-5F-Li with 6 Equiv. HMPA in THF/Et2O . . . . . . . . . . . . . . . . . . . HMPA Titration of Lithium Enolate E/Z-5F-Li in THF/Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HMPA Titration of Lithium Enolate E-5F-Li at -105 °C in Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . HMPA Titration of Lithium Enolate E-5F-Li at -125 °C in Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . HMPA Titration of Lithium Enolate Z-5F-Li at -140 °C in Et2O/Me2O . . . . . . . . . . . . . . . . . . . . . . . Dilution study of Lithium Enolate Z-5F-Li in Et2O with 6 Equiv. of HMPA . . . . . . . . . . . . . . . . . . . HMPA Titration of Lithium Enolate of 1,2-Diphenylethanone (6H-Li) in THF/ Et2O . . . . . . . . . . . . Kinetic and Thermodynamic Deprotonation of 1-Phenyl-2-(4-fluorophenyl)ethanone (6F-H) . . . . . NOESY Study of Z-1-Phenyl-2-(4-fluorophenyl)-1-(trimethylsilyloxy)ethene (6F-Si) . . . . . . . . . . . HMPA Titration of Lithium Enolate 6F-Li in THF/ Et2O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P4 Titration of 1-Phenyl-2-(4-fluorophenyl)ethanone (6F-H) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P4 Enolate Titration of Z Dimer of Lithium Enolate 6F-Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33 34 35 36 37 38 39 40 41 42 43 44 45 47 48 49

S4. Crystallographic Section (Summary) PMDTA Solvate of the Lithium Enolate of 1,3-Diphenyl-2-propanone (Z-5H-LiAPMDTA) . . . . . . 50 Lithium Enolate ((Z-5F-Li)2A(OEt2)2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 S5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 S6. NMR Spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 O

O

N P[N(CH3)2]3

O

tBu

N

X

1-H

2-H

X

X

O

5H-H (X=H) 5F-H (X=F) O

6H-H (X=H) 6F-H (X=F)

4F-H

3H-H (X=H) 3F-H (X=F)

Li

X

O

X

Li

O

6H-Li (X=H) 6F-Li (X=F)

S-2

P[N(CH3)2]3 P[N(CH3)2]3

t Bu-P4 X

(X=H) (X=F)

5H-Li 5F-Li

N

N P

OH

F

Si(CH3)3

X

O

5H-Si 5F-Si X

(CH3)3Si

X

(X=H) (X=F)

O

6F-Si

F

S1. General Experimental. All reactions requiring a dry atmosphere were performed in glassware flame-dried or dried overnight in a 110 °C oven, sealed with septa and flushed with dry N2. Tetrahydrofuran (THF) and Et2O were freshly distilled from sodium benzophenone ketyl under N2. Commercially available starting materials and reagents were obtained from Aldrich Chemical Company and included: n-butyllithium, diisopropylamine, phosphazene base P4-tBu (1-tert-butyl-4,4,4-tris(dimethylamino)2,2-bis[tris(dimethylamino)-phosphoranylidenamino]-2Ê5,4Ê5-catenadi(phosphazene)) 1 M solution in hexanes, cyclohexanone (1-H), cyclopentanone (2-H), 4-fluorophenol (4F-H), 4-fluoroacetophenone (3FH), acetophenone (3H-H), and 1,3-diphenyl-2-propanone (5H-H), 1,3-bis-(4-fluorophenyl)-2- propanone (5F-H) and 1-phenyl-2-(4-fluorophenyl)ethanone (6F-H) were prepared according to previously published procedures.[S1] Low-temperature NMR spectra were acquired on a Bruker AVANCE spectrometer using a 10 mm broadband probe at the following frequencies: 360.131 MHz (1H), 90.556 MHz (13C), 338.827 MHz (19F), 139.96 (7Li) and 145.785 MHz (31P). All spectra were taken with the spectrometer unlocked. 13C NMR spectra were referenced internally to the C-O carbon of THF (* 67.96), Et2O (* 66.57) or Me2O (* 60.25). Lorentzian multiplication (LB) of 2-6 Hz was applied to 13C NMR spectra. 31P NMR spectra were referenced externally to 1.0 M PPh3 in THF (* -6.00) or internally to free HMPA (* 26.40). 19F NMR spectra were acquired without proton decoupling and were referenced internally to CFCl3 (* 0.0), 1,3difluorobenzene (* -110.8), or 1,2-difluorobenzene (* -140). 7Li spectra were referenced externally to 0.3 M LiCl/MeOH standard (* 0.00 ppm) or internally to free +Li(HMPA)4 (* -0.40). Probe temperatures were measured internally with the 13C chemical shift thermometer: 10% 13C enriched (Me3Si)3CH.[S2] S2. Synthesis 1,3-Bis-(4-fluorophenyl)-2-propanone (5F-H): (See reference [S3] for an X-ray structure of 5FH) 4-Fluorophenylacetic acid (4.135 g, 26.8 mmol), 4-(dimethylamino)pyridine (3.53 g, 28.8 mmol), Nethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCIAHCl) (5.00 g, 26.0 mmol) and 80 mL of dichloromethane were added to a 250 mL round bottom flask. The solution was stirred for four days at room temperature, and 100 mL of 10% HCl solution was added. The organic layer was separated, washed with 10% HCl twice, saturated NaHCO3 once, dried over MgSO4 and the solvent was removed under vacuum. The resulting solid was recrystallized from ethanol to yield 2.35 g (74%) of 5F-H. Melting Point 62-64 ºC. 1H NMR (300 MHz, CDCl3), * 3.69 (s, 4H), 6.99 (t, J = 8 Hz, 4H), 7.09 (dd, J = 5.5, 8.8, 4H). 13C NMR (75.4 MHz, CDCl3), * 48.4 (s), 115.8 (d, JCF = 21.5 Hz), 129.7 (d, JCF = 3.2Hz),131.2 (d, JCF = 7.8 Hz), 162.2 (d, JCF = 246.6 Hz), 205.3 (s). 19F NMR (282 MHz, CDCl3) * -116 (tt, JFH = 5.5, 8.8 Hz). HRMS (EI) (m/z): calcd. for C15H12F2O (M+) 246.0856; found 246.0860. 1-Phenyl-2-(4-fluorophenyl)ethanone (6F-H). Prepared according to literature procedure.[S4] 1H NMR (300 MHz, CDCl3), * 4.262 (s, 2H), 7.02 (t, J = 8 Hz, 4H), 7.23 (dd, J = 5.5, 8 Hz, 2H), 7.47 (t, J = 8 Hz, 2H), 7.57 (t, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 2H). 13C NMR (75.4 MHz, CDCl3), * 44.7 (s), 115.7 (d, JCF = 21.5Hz), 128.7 (s), 128.9 (s), 130.4 (d, JCF = 3.3Hz), 131.3 (d, JCF = 8.1Hz), 133.5 (s), 136.7 (s), 162.16 (d, JCF = 246.6Hz), 197.7 (s). 19F NMR (282 MHz, CDCl3) * -116.56 (tt, JFH = 5.5, 8.8 Hz). HRMS (EI) (m/z): calcd. for C15H12F2O (M+) 214.0789; found 214.0795.

S-3

1,3-Diphenyl-2-(trimethylsilyloxy)-1-propene (5H-Si). 1,3-Diphenyl-2-propanone (380 µL, 0.78 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2. After 10 min at -78 °C for 10 min Et3N (84 µL, 0.6 mmol) and Me3SiCl (160 µL, 1.2 mmol) were added. The sample was diluted with cold (ca 0 °C) pentane, washed with cold saturated NaHCO3, dried over MgSO4, and the solvent was removed under vacuum. The enol silyl ether mixture 5H-Si was dissolved in d6-benzene and 1H, 19F and 13C NMR and HRMS spectra were obtained. Z Isomer: 1H NMR (299.73 MHz, CDCl3), * 0.04 (s, 9H), 3.63 (s, 2H), 5.32 (s, 1H), 7.01-7.4 (m, 10H). 13C NMR (90.56 MHz, CDCl3), * 1.01 (s), 49.3 (s), 110.4 (s), 125.8 (s), 126.7 (s), 128.2 (s), 128.3 (s), 128.6 (s), 129.4 (s), 136.8 (s), 138.2 (s), 152.03 (s). E Isomer: 1H NMR (299.73 MHz, CDCl3), * 0.06 (s, 9H), 3.53(s, 2H), 5.87 (s, 1H), 7.01-7.3 (m, 10 H). 13C NMR (75.37 MHz, CDCl3), * 0.45(s), 38.6 (s), 110.8 (s), 110.4 (s), 126.0 (s), 126.4 (s), 110.4 (s), 128.5 (s), 128.7 (s), 129.1 (s), 137.3 (s), 138.7 (s), 153.1(s). HRMS (ESI) (m/z): calcd. for C18H22OSi (M+) 282.1435; found 282.1436. 1,3-Bis-(4-fluorophenyl)-2-(trimethylsiloxy)-1-propene (5F-Si): 1,3-Bis-(4-fluorophenyl)-2propanone (380 µL, 0.78 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared 0.1 M solution of LiNiPr2 in 3:2 THF/Et2O. Et3N (84 µL, 0.6 mmol) and Me3SiCl (160 µL, 1.2 mmol) were added at -78 °C. The sample was diluted with cold (ca 0 °C) pentane, washed with cold saturated NaHCO3, dried over MgSO4, and the solvent was removed under vacuum. 1H, 19F and 13C NMR and HRMS were obtained on the resulting enol silyl ether mixture. Z Isomer: 1H NMR (360.16 MHz, CDCl3), * 0.07 (s, 9H), 3.41 (s, 2H), 5.29(s, 1H), 6.89 (t, J = 8.6 Hz, 2H), 6.95 (J = 8.6 Hz, 2H), 7.17 (dd, J = 8.8, 5.5 Hz, 2H), 7.38 (dd, J = 8.8, 5.5 Hz, 2H). 13C NMR (90.56 MHz, CDCl3), * 0.98 (s), 43.0 (s), 109.4 (s), 114.9 (d, JCF = 21 Hz), 115.4 (d, JCF = 21 Hz), 129.8 (d, JCF = 8 Hz), * 130.8 (d, JCF = 8 Hz), 132.7 (d, JCF = 3 Hz), 133.7 (d, JCF = 3 Hz), 151.5 (s), 161.0 (d, JCF = 246 Hz), 161.9 (d, JCF = 246 Hz). 19F NMR (338.82 MHz, CDCl3) * -117.16 (tt, JFH = 8.6, 5.5 Hz), -117.06 (tt, JFH = 8.6, 5.5 Hz). E Isomer: 1H NMR (300 MHz, CDCl3), * 0.07 (s, 9H), 3.46 (s, 2H), 5.83 (s, 1H), 6.89-6.976 (m, 4H), 7.12 (dd, J = 8.8, 5.5 Hz, 4H). 13C NMR (75.37 MHz, CDCl3), * 0.41(s), 37.6 (s), 109.5 (s), 115.3 (d, JCF = 21 Hz), 115.4 (d, JCF = 21 Hz), 130.3 (d, JCF = 8 Hz), 130.5 (d, JCF = 8 Hz), 133.2 (d, JCF = 3 Hz), 134.2 (d, JCF = 3 Hz), 153.0 (s), 161.5 (d, JCF = 246 Hz), 161.8 (d, JCF = 246 Hz). 19F NMR (338.82 MHz, CDCl3) * -117.30 (tt, JFH = 8.6, 5.5 Hz), -117.66 (tt, JFH = 8.6, 5.5 Hz). HRMS (ESI) (m/z): calcd. for C18H20OF2Si (M+) 318.1247; found 318.1241. 1-Phenyl-2-(4-fluorophenyl)-1-(trimethylsiloxy)ethene (6F-Si): Freshly prepared LiNiPr2 (0.29 M , 4 mL) in 3:2 THF/Et2O was added to a solution of 1-phenyl-2-(4-fluorophenyl)ethanone (0.247 g, 1.15 mmol) at -78 °C. The solution was allowed to warm to 0 °C for 1h, and Me3SiCl (160 µL, 1.2 mmol) was added. The sample was diluted with cold (ca 0 °C) pentane, washed with cold saturated NaHCO3, dried over MgSO4, and the solvent was removed under vacuum. 1H and 13C NMR and HRMS were obtained on the resulting enol silyl ether. Z Isomer: 1H NMR (299.87 MHz, CDCl3), * 0.02 (s, 9H), 6.04(s, 1H), 6.95 (t, J = 8.6 Hz, 2H), 7.27 (m, 3H), 7.51 (m, 2H), 7.57 (dd, J = 8.8, 5.5 Hz, 2H). 13C NMR (75.37 MHz, CDCl3), * 0.87 (s), 109.5 (s), 115.13 (d, JCF = 21 Hz), 126.3 (s), 128.3 (s), 128.3 (s), 130.3 (d, JCF = 8 Hz), 132.9 (d, JCF = 3 Hz), 139.7 (s), 150.8 (s), 161.3 (d, JCF = 246 Hz).19F NMR (282 MHz, CDCl3) * -116.30 (tt, JFH = 8.6, 5.5 Hz). E Isomer: 1H NMR (300 MHz, CDCl3), * 0.07 (s, 9H), 5.83 (s, 1H), 6.89-6.976 (m, 4H), 7.12 (dd, J = 8.8, 5.5 Hz, 4H). HRMS (ESI) (m/z): calcd. for C17H19OFSi (M+) 286.1184; found 286.1190.

S-4

S3. NMR Characterization of Enolate Structures General Preparation of Enolate Samples for Multinuclear NMR Spectroscopy. Lithium diisopropylamide was prepared fresh by the following procedure. Solvent was added (typically 1.8 mL of THF and 1.2 mL of Et2O) including 1-2 :L of 10% 13C enriched (Me3Si)3CH as a shift thermometer[S2] to a dried thin-walled 10 mm NMR tube that had been stored under vacuum, fitted with septa, and flushed with N2 or Ar. Silicon grease was applied to the interface between the tube and the septa before securing with parafilm for a better seal, as well as to the top of the septa to seal needle punctures. The NMR tube was cooled to !78 °C under positive N2 or Ar pressure and diisopropylamine (42 :L, 0.30 mmol) and nBuLi (120 :L, 2.5 M) were added to the solution. The solution was warmed to 0 °C in an ice bath for 5 min, and then cooled to !78 °C under positive N2 or Ar pressure. The carbonyl compound was added by syringe either neat or as a solution in the desired solvent. Samples free of diisopropylamine were prepared from either crystalized material or from cleavage of the enol silyl ether. Experiments run using these samples did not differ from those containing diisopropylamine. Samples were stored at -78 °C. The spectrometer probe was cooled to 95%) based on NOE correlations observed.

S-20

Variable Temperature NMR Study of Dimers of Lithium Enolate E/Z-5F-Li. 1,3-Bis-(4fluorophenyl)-2- propanone (500 µL, 0.58 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. 13C, 19F, and 7Li spectra were acquired at -129 °C. 13C, 7Li, and 19F spectra were obtained at -130 °C, -95 °C, -45 °C, 0 °C, and 22 °C. The sample was cooled to -133 °C and 13C, 7Li, and 19F spectra were acquired. Spectra are shown in Figure S-16. H O Li Ar 13

Temp.

Ar

Li

EE

Li

Ar

Ar

EZ 13

7

C Li O C=C

Li O C=C

19

Li

EZ

Ar =

O Li

H

Ar

H

H

Li O

O

O Ar

Ar

H

Li

O

C

Ar

Ar

H

Ar

Ar

F

Ar EE/EZ/ZZ 1:3.3:3

ZZ

F

ZZ

EE

-133°C

22°C

0°C EZ

EE

ZZ -45°C

-95°C ZZ

EE

EZ

EZ

EE

ZZ

-129°C 168

166

98

94

0.6

0.1

EE/EZ/ZZ 1:1.7:0.8 -122.5

ZZ

EZ

-123.5

EE

-124.5

Figure S-16. A variable temperature NMR study of the dimers of 5F-Li in 3:2 THF/Et2O. Over the course of the experiment, total ca 4 h (ca 40 min for each set of spectra), the ratio of E and Z isomers changed only slightly (from 52:48 to 36:64).

S-21

Variable Concentration Study of the Lithium Enolate Z-Q5F-Li in THF/Et2O. A 10 mm NMR tube was sealed with a septa, purged with Ar, and cooled to -78 °C, and 3.5 mL of THF/ Et2O were added. From a crystalized solution (See Crystallography section of Supplemental Information) of the lithium enolate of 1,3-bis-(4-fluorophenyl)-2- propanone (0.5 mL, 0.5 M solution in Et2O, 0.12 mmol) was added at -78 °C. An internal standard, 1,3-difluorobenzene (8 µL), was added and 13C, 7Li, and 19F spectra were acquired at -120 °C of the 0.072 M sample. This sample was warmed to room temperature, 1.0 mL was removed by syringe and placed in a dry, purged 10 mm NMR tube sealed with a septum containing 3.0 mL of THF/ Et2O. More internal standard, 1,3-difluorobenzene (6 µL), was added and 13C, 7Li, and 19F spectra were acquired at -120 °C of the 0.012 M sample.. From the original sample 0.5 mL was removed by syringe and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 3.5 mL of THF/ Et2O. More internal standard, 1,3-difluorobenzene (7 µL), was added and 13C, 7Li, and 19F spectra were acquired at -120 °C of the 0.006 M sample. Spectra are shown in Figure 6 and S-17. F

O

F

H

O Li

H

-120 °C

H

Li

Log [Monomer]

F

-3.2

F

F 3:2 THF/Et O 2

2

Li

O

-3.4 -3.6 -3.8 y = 0.57(±0.02)x - 2.49(±0.04) R2=0.9993

-4.0 19

F

F

-2.4 -2.2 -2.0 -1.8 -1.6 -1.4 -1.2 Log [Dimer]

Z-M-PMDTA

PMDTA Monomer

Keq= [D]/[M]2

ZZ-D Monomer

Monomer

ZZ-D

0.006M

2.03E+05

0.012M

2.08E+05

0.072M

1.43E+05

EZ-D EE-D Dimer Mixture

-118

-120

-122

-124

-126

-128

ppm

Figure S-17. Variable concentration study of the lithium enolate of 1,3-bis-(4-fluorophenyl)-2propanone (5F-Li). Increasing amounts of monomer were observed in the 19F NMR spectra as the sample was diluted. The signal is very similar in chemical shift to that of the PMDTA solvated monomer (top spectrum) and a log plot of dimer and monomer concentration supports this assignment.

S-22

Variable Temperature Study of Monomer Dimer Equilibrium of Lithium Enolate Z-5F-Li. 1,3Bis-(4-fluorophenyl)-2- propanone (1.0 mL, 0.32 M solution in 3:2 THF/ Et2O, 0.31 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for several hours. 13C and 19F spectra were acquired at 211 K, 204 K, 189 K, 182 K, 178 K, 165 K, 162 K, and 143 K. Spectra are shown in Figure S-18. -3.6 3:2 THF/Et 2O

Li

O-R

Li

2 R-O Li

F

ΔH = -3.8 kcal/mol

-3.7 ΔG

R-O

-3.8

F

R=

ΔG = ΔH - TΔS = RT ln(Keq) y =-3.84(±0.03) + 1.7x10 -4 (±1.6x10-4)x R2=0.4156

-3.9 -4.0 19

ΔS = -0.2 eu

F

130 140 150 160 170 180 190 200 210 220 Temperature (K)

Temperature

Temperature -62 °C

211.1 K

Keq = [Dimer] / [Monomer] 2

% Monomer

8.65E+03 M-1

4.9%

204.1 K

-69 °C

1.21E+04 M-1

4.2%

189.1 K

-84 °C

2.64E+04 M-1

2.8%

182.1 K

-91 °C

3.72E+04 M-1

2.4%

178.1 K

-95 °C

4.77E+04 M-1

2.1%

165.1 K

-108 °C

1.18E+05 M-1

1.4%

162.1 K

-111 °C

1.40E+05 M-1

1.3%

-130 °C

6.70E+05 M-1

0.6%

ZZ Dimer

Z Monomer

143.1 K -124

-125

-126

-127

ppm

Figure S-18. Variable temperature study of the monomer-dimer equilibrium of the lithium enolate of 1,3bis-(4-fluorophenyl)-2- propanone (5F-Li) observed by 19F NMR spectra. The signal is similar in chemical shift to that of the PMDTA solvated monomer (see experiment) and a plot of the association constant (Keq = [Dimer] / [Monomer]2), converted to Gibb’s free energy ()G°), versus temperature gave the entropy and enthalpy of dimerization ()H = -3.8 ± 0.1 kcal/mol, )S = 0.17 ±0.16 eu).

S-23

P4-tBu Titration of 1,3-Bis-(4-fluorophenyl)-2-propanone (5F-H). A solution of 1,3-bis-(4fluorophenyl)-2-propanone (74.8 mg , 0.3 mmol) in 3 mL of 3:2 THF/Et2O was prepared in a 10 mm NMR tube sealed with a septum, purged with Ar. 13C, 1H, 19F and 31P NMR spectra were obtained at -130 °C with 0, 0.1, 0.25, 0.4, 0.5, 0.75, and 1.0 equiv. of P4-tBu added as a 1 M solution in hexanes. Spectra are shown in Figure S-19. +

Ar F

0.5 Equiv. P4-t Bu Ar

O H O

Ar

O Ar

5F-P4H

Ar

5F-H

Ar =

H-Dimer 1

Equiv. P4-t Bu

13

H

19

C Li O C=C

H-Dimer

F

F

P4 Enolate

Li O C=C P4 Enolate

1 H-Dimer

H-Dimer

H-Dimer

P4 Enolate

0.75

0.5

0.4

0.25

0.1

0 19

18

174

171

168

165 ppm

95

90

85 -118

-122

-126

-130

Figure S-19. P4-tBu titration of 0.1 M 1,3-bis-(4-fluorophenyl)-2- propanone (5F-H) in 3:2 THF/Et2O at -130 °C. The addition of less than a half of an equivalent of P4-tBu produces a dimeric enolate species which is bridged by a low barrier hydrogen bond (* 18.4). The 13C signals at * 165.1 (C-O carbon) and * 94.1 ($-carbon) are similar to those of the lithium enolate (5F-Li)2 * 168.6 (C-O carbon) and * 96.2 ($carbon). Upon the addition of a full equivalent of P4-tBu a “naked” enolate was produced which has substantially shifted C-O carbon (* 173.1) and $-carbon (* 87.3 ), compared to the lithium enolate.

S-24

Variable Temperature Study of Phenyl Ring Rotation in Z-5F-P4H. A solution of 1,3-bis-(4fluorophenyl)-2-propanone (55.0 mg , 0.22 mmol) was prepared using the general procedure for sample preparation in 3:1 Me2O/Et2O. P4-tBu (1.0 equiv.) was added as a 1 M solution in hexanes and 13C, 1H, and 19F NMR spectra were obtained at -95 ºC, -83 ºC, -77 ºC, -71 ºC, -64 ºC, -54 ºC, and -41 ºC. Rates were determined by simulation of the coalescence of two doublets (J(C,F) = 7 Hz) with WINDNMR.[S5] Spectra with simulated fits are shown in Figure 7 and S-20. Simulation data is presented in Table S-1. Table S-1. Data for Simulation of the 13C Spectra of the rotation of the conjugated phenyl ring of 5FP4H.(Fig. S-20). Temperature °C -94.5 -82.9 -77.2 -70.9 -64 -53.6 -41 13888 13889.3 13889.3 13889.3 13892.7 13893.5 13896.9 va /Hz 13786.6 13787.9 13787.9 13787.9 13791.3 13792.1 13795.5 vb /Hz 42 126 243 513 954 2428 5818 kab + kab / sec-1 %a 50 50 50 50 50 50 50 2 2 2 2 2 2 2 Waa /Hz 2 2 2 2 2 2 2 Wba /Hz 21 63 121.5 256.5 477 1214 2909 kab / sec-1 b )G‡ / kcal/mol 9.19 9.40 9.43 9.45 9.53 9.62 9.79 a b Line width in the absence of exchange. kab = kba since %a = %b +

F

13 H-P4-tBu

O

3:1 Me2O/Et2O

F

C

C -41 °C

C H

-54 °C

5F-P4H

-64 °C Aryl Ring Rotation 10.5

-71 °C

10.0 -77 °C

ΔG

9.5 ΔG = ΔH - TΔS y =7.4(±0.16) + 0.010(±0.001)x R2=0.9848

9.0 8.5

-83 °C

ΔH = 7.4 kcal/mol

8.0

ΔS = -10 eu

-95 °C

7.5

A

160

170

180 190 200 210 Temperature (K)

220

230

124.5

124.0

123.5

B

123.0 ppm

122.5

122.0

121.5

Figure S-20. DNMR study of the conjugated phenyl ring rotation of Z-5F-P4H. The upper lines are simulations using WINDNMR, using the “DNMR-dddd” option with three of the four coupling constants set to 0 to simulate two coalescing doublets.[S5]

S-25

Variable Temperature Study of Phenyl Ring Rotation in Z-5F-Li. A solution of the lithium enolate of 1,3-bis-(4-fluorophenyl)-2-propanone was prepared by the addition of 1,3-bis-(4fluorophenyl)-2-propanone (255.5 mg , 1.0 mmol) to a 0.17 M solution of lithium diisopropylamide in 2:1 Me2O/Et2O at -78 ºC. 13C, 1H, and 19F NMR spectra were obtained at -146 ºC, -142 ºC, -137 ºC, -131 ºC, -125 ºC, -115 ºC, and -104 ºC. Rates were determined by simulation of the coalescence of two doublets (J(C,F) = 7 Hz) with WINDNMR.[S5] Spectra with simulated fits are shown in Figure 7 and S-21. Simulation data is presented in Table S-2. Table S-2. Data for DNMR Simulation of the rotation of the conjugated phenyl ring of the lithium enolate 5F-Li.(Fig. S-21). Temperature °C -146 -142 -137 -131 -125 -115 -104 14117.3 14117.3 14121.6 14122.7 14124.8 14115.1 14119.4 va /Hz 13925.9 13929 13932.3 13933.4 13935.5 13925.8 13930.1 vb /Hz 222 354 738 1935 4505 13205 31015 kab + kab / sec-1 %a 50 50 50 50 50 50 50 7 7 7 5 5 3 3 Waa /Hz a 7 7 7 5 5 3 3 Wb /Hz 111 177 369 967.5 2252.5 6602.5 15507.5 kab / sec-1 b )G‡ / kcal/mol 6.03 6.11 6.16 6.17 6.19 6.29 6.47 a Line width in the absence of exchange. b kab = kba since %a = %b 13

F

C

C -104°C

C F

H

Li O

O Li

H

F -115°C

C C 2:1 Me2O:Et2O F

-125°C

ZZ-(5F-Li)2 Aryl Ring Rotation 7.5

-131°C

7.0

ΔG

6.5 6.0 5.5 5.0 4.5

-137°C ΔG = ΔH - TΔS y = 4.9(±0.14) + 0.009(±0.001)x R2=0.9708

-142°C

ΔH = 4.9 kcal/mol

-146°C

ΔS = -9 eu

A

B

115 125 135 145 155 165 175 185 195 205 215 130

Temperature (K)

128

126 ppm

124

Figure S-21. DNMR study of the conjugated phenyl ring rotation of the lithium enolate Z-5F-Li. The upper lines are simulations using WINDNMR, using the “DNMR-dddd” option with three of the four coupling constants set to 0 to simulate two coalescing doublets.[S5]

S-26

TMEDA Titration of Lithium Enolate Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for 4 h. 13C, 7Li, and 19F spectra were obtained at -135 °C with 0, 0.25 (13 µL), 0.5 (22 µL), 1 (44 µL), 2 (88 µL), 4 (176 µL), and 6 equiv.(264 µL) of TMEDA added. From the ending solution 1 mL was removed and placed in a dry, sealed, and Ar purged 10 mm NMR tube containing 3 ml of 3:2 THF/ Et2O. 13C, 7Li, and 19F spectra were obtained at -135 °C. Spectra are shown in Figure 8 and S22. F F

F

F O

+

O Li

H

H

H

Li

N

N

Li

3:2 THF/Et2O

O F

-135°C

F

H O F

Li

N

N

TMEDA

ZZ-(5F-Li)2

(5F-Li)2 (TMEDA)1

F

[(5F-Li)2 (TMEDA)1]

Keq (avg) =

TMEDA Equiv. 7Li 4X dilution

13

C

[(5F-Li)2] [TMEDA]

= 7.26 M 19

D-TMEDA

F

1

(avg) D-TMEDA

D-TMEDA Keq

Li O C=C

Li O C=C

7.37

D-TMEDA

6

7.29

4

7.55

2

7.33

1

7.13

0.5

7.11

0.25

7.16 (ZZ) Dimer

(ZZ) Dimer

(ZZ) Dimer

(ZZ) Dimer

0 0.9

0.4

-0.1

172

170

168

99 ppm

94

89

-118

-120

-122

-124

Figure S-22. TMEDA titration of Z-5F-Li in 3:2 THF/ Et2O at -130 °C. Formation of a mono TMEDA solvated dimer was observed as the concentration of TMEDA was increased (D = dimer).

S-27

TMTAN Titration of Lithium Enolate Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for 4 h. 13C, 7Li, and 19F spectra were obtained at -130 °C with 0, 0.5 (23 µL), and 1 equiv.(46 µL) of TMTAN added. Spectra are shown in Figure 8 and S-23. F

F N

F

H

Li O Li

H

H

-130°C TMTAN

O

O

3:2 THF/Et2O

F

N

N

Li

F

N TMTAN

N N

F Z-(5-Li)1 TMTAN

ZZ-(5-Li)2 13

7

C

19

Li

F M-TMTAN

Equiv. TMTAN

M-TMTAN Li O C=C

Li O C=C

1

M-TMTAN M-TMTAN 0.5

ZZ Dimer ZZ Dimer

ZZ Dimer

ZZ Dimer

Ketone 0 168

166

100

95

90

85

1.2

0.8 ppm

0.4

0.0

-117 -119 -121 -123 -125 -127

Figure S-23. TMTAN titration of the lithium enolate of Z-1,3-bis-(4-fluorophenyl)-2- propanone (5F-Li) in 3:2 THF/ Et2O at -130 °C. Dissociation of the dimer to a TMTAN solvated monomer was observed as the concentration of TMTAN was increased (M = monomer).

S-28

PMDTA Titration of Lithium Enolate Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (800 µL, 0.38 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for several hours. 13C, 7Li, and 19F spectra were obtained at -130 °C with 0, 0.5 (31 µL), 1 (62µL), 2 (124µL) and 4 equiv. (248 µL) of PMDTA added. Spectra are shown in Figure 8 and S24. F

F

N F

H

Li O

-130°C

O Li

H

F

O N

N

N

H

PMDTA

3:2 THF/Et2O

Li

F

PMDTA

N N

F

ZZ-(5F-Li)2

Z-(5F-Li)1 PMDTA 7

13

C M-PMDTA

M-PMDTA Li O C=C

4

19

Li

Equiv. PMDTA

F

M-PMDTA

M-PMDTA

Li O C=C

2

1

0.5

ZZ Dimer

ZZ Dimer

ZZ Dimer

ZZ Dimer

Ketone 0 170

168

166

95

90

85 1.5

1.0

0.5

0.0 -116 -118 -120 -122 -124 -126 -128 ppm

Figure S-24. PMDTA titration of 5F-Li in 3:2 THF/ Et2O at -130 °C. Dissociation of the dimer to a PMDTA solvated monomer was observed as the concentration of PMDTA was increased (M = monomer).

S-29

PMDTA Titration of Lithium Enolate E/Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. 13C, 7Li, and 19F spectra were obtained at -130 °C with 0, 0.5 (13 µL), 1 (52 µL), and 2 equiv. (312 µL) of PMDTA added. The sample was allowed to warm to room temperature (ca 25 °C) for 15 min after which 13C, 7Li, and 19F spectra were obtained at 130 °C . Spectra are shown in Figures 10 and S-25. Ar H Ar

Li O Li

Ar

H

Ar Ar

Ar

PMDTA -130°C

H

Li

+ Ar

O

H

O

O Li

Li

Ar =

F

Ar

C

EE 19

Li

Z-M-PMDTA

Li O C=C

Ar

Li

N

N

Z-Monomer-PMDTA

F Z-M-PMDTA

Li O C=C

EE-D

Equiv. PMDTA

O

H

7

Z-M-PMDTA

+

O

Ar

EZ-(5F-Li)2

EE-(5F-Li)2 13

Warmed to RT for 15 mins

O

Ar

H

N

Li

3:2 THF/Et2O

Ar

H

Ar

Ar

EE-D Z-M-PMDTA

EE-D EZ-D

EZ-D

EZ-D

EZ-D

2

1

0.5 EE-D

EE-D EZ

EE-D

EE-D

ZZ-D

0 169

167

165 98

93

88 ppm

1.0 0.8 0.6 0.4 0.2 0.0

-120

-125

Figure S-25. PMDTA titration of the EE and EZ dimers of 5F-Li in 3:2 THF/ Et2O at -130 °C. Formation of the Z PMDTA solvated monomer was observed but no PMDTA solvated E monomer was detected (D = dimer; M = monomer).

S-30

HMPA Titration of Lithium Enolate Z-5F-Li at -130 °C in THF/Et2O. 1,3-Bis-(4fluorophenyl)-2- propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for several hours. 13C, 7Li, 19F and 31P spectra were obtained at -130 °C with 0, 0.25 (13 µL), 0. 5 (26 µL), 1 (52 µL), 2 (104 µL), 6 equiv. (312 µL), and 10 equiv. (520 µL) of HMPA added. Spectra are shown in Figures 11 and S-26. 'Phenyl F'

'Benzyl F' Li

F

F

O

3:2 THF/Et2O -130°C

13

13

C

R O

Li Li

Li

h

7

C

Li

O R R O

NMe2

O R

R O-Lih2

O=P

h

D-h1

H ZZ-(5F-Li)2

Equiv. HMPA

h

HMPA

D-h2

Li

M-h2

NMe2 NMe2

HMPA

19

F

+

Li-h4

Li O C=C

QI

Triple Ion

Li O C=C

10 QI+ M-h3

M-h2

M-h3

6 M-h2

M-h2

4

M-h2

M-h2

M-h2

M-h2

M-h2

M-h2

M-h2

2 D-h2

D-h2

D-h2

D-h2

D-h2

D-h2

D-h2

1 D-h2

D-h2

0.5 D-h1

D-h1

D-h1

D-h1

D-h1

0.25 h0

D-h1

h0

h0

'Benzyl F'

h0

'Phenyl F'

0 172

170

168

98

93

88

1.0

0.5

0.0 ppm

-0.5

-120

-124

-128

Figure S-26. HMPA titration of 5F-Li in 3:2 THF/ Et2O at -130 °C. Sequential solvation of the dimer was observed as HMPA was increased up to 1 equiv. Above 1 equiv. of HMPA dissociation to a HMPA solvated monomer was observed. Above 4 equiv. of HMPA the solution becomes more complex with the formation of a significant amount of +Li(HMPA)4. Two lithiate structures correlate with the formation of free Li+, a triple ion with a lithium to enolate ratio of 1:2, and a quadruple ion with a lithium to enolate ratio of 1:3. These species were generated and identified separately in the P4 enolate titration of lithium enolate 5F-Li (h = HMPA; D = dimer; M = monomer; QI = quadruple ion).

S-31

HMPA Titration of Lithium Enolate Z-5F-Li at -140 °C in THF/Et2O. A 10 mm NMR tube was sealed with a septa, purged with Ar, and cooled to -78 °C, and 1 mL of THF and 1 mL of Me2O were added. From a crystalized solution (See X-ray section) of the lithium enolate of 1,3-bis-(4-fluorophenyl)2- propanone (1 mL, 0.12 M solution in Et2O, 0.12 mmol) was added at -78 °C. 13C, 7Li, and 19F spectra were acquired at -130 °C. 13C, 7Li, 19Fand 31P spectra were obtained at -130 °C with 0, 0.25 (13 µL), 0. 5 (26 µL), 1 (52 µL), 2 (104 µL), 6 equiv. (312 µL), 10 equiv. (520 µL), 15 equiv. (780 µL), and 20 equiv. (1040 µL) of HMPA added. Spectra are shown in Figure S-27. h F O

F

Li

HMPA

R O

1:1:1 THF/Me2O/Et2O -140 °C

0.04 M

Equiv. HMPA

5F-Li +

Li Li

D-h1

O R R O h

7

Li

19

F

13

C

Li D-h2

(R-O)2H Li(HMPA)4+ H-Dimer

Li-h4

Li

O R h

-148°C

M-h3

(R-O)3Li

2

2Li(HMPA)4+ QI

H-Dimer M-h3 QI

H-Dimer

QI

M-h2

M-h2

O=P

M-h2

-150°C

20

NMe2

R O-Lih2

M-h3 QI

Li O C=C

NMe2 NMe2

HMPA

1

H H-Dimer

15 M-h2

M-h2

10 M-h2

6 M-h2 D-h2

4 M-h2

D-h2

2 D-h2

D-h2

D-h1

1 D-h2

D-h1

0.5 D-h1

D-h1

D-h0

0.25 D-h1

Ketone

D-h0

0 0.5

0.0

-0.5

172

170

168

166 ppm -118

-122

-126

-130

19

18

Figure S-27. The HMPA titration of 0.1 M 5F-Li in 1:1:1 THF/Me2O/Et2O at -140 °C. Sequential solvation of the dimer was observed as the concentration of HMPA was increased up to one equiv. Above one equiv. dissociation to a HMPA solvated monomer was observed. Above four equiv. of HMPA the solution became more complex with the formation of a significant amount of separated Li(HMPA)4+. Two ionic structures correlate with the formation of free Li+, a triple ion with a lithium to enolate ratio of 1:2, and a quadruple ion with a lithium to enolate ratio of 1:3. These species were generated and identified separately in the P4 enolate titration of lithium enolate 5F-Li (Page S-33) (h = HMPA; D = dimer; M = monomer; QI = quadruple ion pair).

S-32

P4 Enolate Titration of Lithium Enolate Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (900 µL, 0.64 M solution in 3:2 THF/ Et2O, 0.6 mmol) was added at -78 °C to 3 mL of a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O (0.3 mmol). The sample was allowed to warm to room temperature (ca 25 °C) for several h to equilibrate to the Z isomer. 13C, 19F, and 7Li spectra were acquired at -125 °C of the Z-lithium enolate as well as after the addition of 0.5 (15 µL) and 1 equiv. (30 µL) of P4-tBu (1.0 M solution in hexanes) to generate the P4 enolate in the presence of the lithium enolate at ratios of 0.5:1 and 1:1. 13C, 19F, and 7Li spectra were acquired with the addition of another 0.5 equiv. of 5F-P4H (0.5 mL of a 0.3 M solution in 3:2 THF/ Et2O, 0.3 mmol) at -125 °C and -115 °C bringing the ratio of P4 enolate to lithium enolate to 1.5:1. 13C, 19F, and 7Li spectra were acquired with the addition of another 0.5 equiv. of P4 enolate of 5F-P4H (0.5 mL of a 0.3 M solution in 3:2 THF/ Et2O, 0.3 mmol) at -115 °C. Spectra are shown in Figure 12 and S-28. R-O

Li

O-R

Li

1 Equiv. P4 Enolate

P4H+

-2

R-O Li O-R

3:2 THF/Ether

(ZZ)-Dimer

Triple Ion TI

13

C

2.0 Equiv QI P4 Enolate

Li O C=C

F

R=

+

R-O P4H

O-R Quadruple Ion QI

P4 Enolate 19

Li

F

Li O C=C

P4 Enolate

QI -115 °C

1.5 Equiv P4 Enolate

TI

TI

TI

TI

-115 °C

1.5 Equiv P4 Enolate 1.0 Equiv P4-t Bu

F

O-R

R-O Li

7

13

C

2 P4H+

-125°C TI

QI

TI

QI

TI

QI

-125°C ?

0.5 Equiv. P4-t Bu

Ketone TI

-125°C ZZ Dimer

ZZ Dimer

Ketone:Li Dimer 1:1 172

170

168 96 ppm

92

88

2.0

1.5

1.0

0.5

ZZ Dimer

Ketone

0.0

-118

-122

-126

-130

Figure S-28. The generation of the “naked” enolate in the presence of lithium enolate results in formation of complex lithiate species. The addition of a sub-stoichiometric amount of P4 to a solution of 1:1 ketone and enolate (1:1 5F-H : 5F-Li) produced a complex solution which appears to be in rapid exchange. Addition of a full equivalent of P4 (1:1 5F-P4H : 5F-Li) produced a solution which is mostly triple ion (TI). As the ratio of 5F-P4H to 5F-Li was further increased a new species appeared, leaving only small amounts of the triple ion at two equivalents of 5F-P4H. We assigned the quadruple ion (QI) structure (RO)3Li2- (P4H+)2 to this species.

S-33

Mixing Studies of P4 Enolate Generated Quadruple Ions of Z-5F and Z-6F. Spectrum A: 1Phenyl-2-(4-fluorophenyl)ethanone (800 µL, 0.38 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2. The sample was allowed to warm to ca 25 °C for two h after which 1-phenyl-2-(4-fluorophenyl)ethanone (1265 mg, 0.6 mmol) and P4tBu(0.6 mL, 1 M, hexane) were added. Spectrum E: 1,3-bis-(4-fluorophenyl)-2- propanone (900 µL, 0.64 M solution in 3:2 THF/ Et2O, 0.6 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2. The sample was allowed to warm to ca 25 °C for several h. Two equivalents of P4 enolate of 1,3-bis-(4-fluorophenyl)-2- propanone (1.0 mL, 0.3 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added and 13C, 19F, and 7Li spectra were acquired at -125 °C. Spectra B, C, and D: appropriate ratios of solutions of the quadruple ions generated for spectra A and E were mixed in 10 mm NMR tubes sealed with septa and purged with Ar. 13C, 1H and 19F NMR spectra were obtained at -130 °C. Spectra are shown in Figure 12 and S-29.

R-O

Li Li

O-R

-2

3:2 THF/Ether -130°C

F

2 P4H+

P4H+

2 Equiv. P4 Enolate

R-O P4H+

R-O Li

R-O Li O-R

O-R Quadruple Ion 5F-QI / 6F-QI

Triple Ion 5F-TI / 6F-TI

5F

Ph 19

Li

5F-QI

F

Ratio of Enolates 5F : 6F E) 1 : 0

F

R=

P4 Enolate 5F-P4H / 6F-P4H

5F-QI 7

F

R=

O-R

6F 5F-P4H

5F-TI 5F-TI

QI Mixed TI Mixed

D)

2:1

C)

1:1 QI Mixed

B)

1:2 6F-QI

6F-TI

6F-QI

6F-P4H

6F-TI

A)

0:1 2.5

2.0

1.5

1.0

0.5

-120

0.0

-125

-130

ppm

Figure S-29. Individual solution of the quadruple ions (5F)3Li+2 and (6F)3Li+2 were generated by the addition of of 2 equiv of 5F-P4H to 5F-Li or 2 equiv of 6F-P4H to 6F-Li (Spectra E and A). When solutions of the two quadruple ions were mixed in several ratios, two new sets of signals were observed in the 19F and 7Li NMR spectra in addition to those of the homo-aggregates. The new signals are due to the formation of the 2:1 and 1:2 mixed quadruple ions (5F)1(6F)2Li+2 and (5F)2(6F)1Li+2 (Spectra B, C, and D). Small amounts of the triple ions and mixed triple ion were also formed.

S-34

Dilution Study of Triple Ion–Quadruple Ion Equilibrium of Z-5F. 1,3-Bis-(4-fluorophenyl)2- propanone (1.00 mL, 0.97 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2 (0.3 mmol). The sample was allowed to warm to ca 25 °C for several hours, cooled to -78 °C, and 1,3-difluorobenzene (8 µL) was added. P4-tBu (600 µL, 1.0 M solution in hexanes, 0.6 mmol) was added to produce a solution of ca 2:1 5F-P4H to 5F-Li. 13C, 7 Li, and 19F spectra were obtained at -115 °C. 2X Dilution: This sample was warmed to ca 25 °C, 2.0 mL was removed via syringe and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 2.0 mL of 3:2 THF/ Et2O and 1,3-difluorobenzene internal standard (4 µL). 13C, 7Li, and 19F spectra were acquired at -115 °C. 4X Dilution: From the original sample 1.0 mL was removed via syringe and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 3.0 mL of 3:2 THF/ Et2O and 1,3difluorobenzene (6 µL). 13C, 7Li, and 19F spectra were acquired at -115 °C. 8X Dilution: From the original sample 0.5 mL was removed via syringe and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 3.5 mL of 3:2 THF/ Et2O and 1,3-difluorobenzene (7 µL). 13C, 7Li, and 19F spectra were acquired at -115 °C. Spectra and results are shown in Figure 13 and S-30. Log [TI] + Log [P4 Enolate]

3:2 THF/Ether, -115 °C 2 P4H+

+

P4H -4.0

R-O P4H

+

Keq

-2

O-R

R-O Li

+ R-O Li O-R

O-R

5F-P4H

-4.5

5F-TI

5F-QI

y = 0.90(±0.05) x -2.5(±0.1)

-5.0

Keq =

[5F-QI] [5F-TI] [5F-P4H]

-2.8 -2.6 -2.4 -2.2 -2.0 -1.8 -1.6 -1.4 Log [QI] 7

19

Li

F Keq

8X Dilution

163 M-1

187 M-1

4X Dilution

2X Dilution 5F-QI

2.0

1.5

1.0

5F-QI

Total Enolate Concentration 0.2M

5F-TI

2.5

209 M-1

0.5

0.0

-120

5F-P4H

5F-TI -122

-124

-126

193 M-1 -128

-130

ppm

Figure S-30. Dilution study of the quadruple ion equilibrium of 5F in 3:2 THF/ Et2O at -115 °C. Concentrations were determined by 19F NMR against an internal standard, 1,3 difluorobenzene. Due to overlap of QI and TI signals the ratios of these species were determined using lineshape simulation using WinDNMR.[S5] Variable Temperature Study of Z-5F-Li with 6 Equiv. HMPA in THF/Et2O. 13C, 7Li, and 19F spectra were acquired at -115 °C, -125 °C, and -140 °C of the sample at the end of experiment titled P4 Enolate Titration of Z Dimer of Lithium Enolate of 1,3-bis-(4-fluorophenyl)-2- propanone (5F-Li) which had been stored at -78 °C for 12 h. Spectra are shown in Figure S-31.

S-35

t Bu

N P+

N

P4H+

H R-O P4H+

-2

3:2 THF/Ether

O-R

R-O Li

+ R-O Li O-R

O-R

N

5F-P4H

N ((CH3)2N)3P P(N(CH3)2)3 ((CH3)2N)3P +

2 P4H+

5F-TI

5F-QI F

F

R=

H P4-t Bu

MW = 634.7 N

7

QI

13

Li

C

Hexanes

19

P(N(CH3)2)3

Linewidth at half height

F

QI 5F-P4H

QI : TI

TI

-115 °C

16 Hz 17 Hz

QI

TI TI -125 °C

25 Hz 10 Hz QI

m-diflurobenzene (reference) 120 Hz 24 Hz

4

3

TI

-140 °C 2

1 ppm

0

-1

39

37

35 ppm

33

-115

-120 -125 ppm

QI

-130

-135

Figure S-31. 7Li, 13C, and 19F NMR spectra of a sample consisting of ca 2:1 ratio of 5F-P4H to 5F-Li.. The linewidth of the 7Li and 19F NMR signals assigned to QI broadened significantly more than the signals assigned to TI upon cooling to -140 °C (HMPA titration conditions). The source of this broadening is unknown. One possibility is a slowing of some ion pair association processes between the quadruple ion and the P4H+ counterion ion. 13C NMR signals assigned to the P4H+ counterion ion were also found to broaden at -140 °C.

S-36

Variable Temperature Study of Z-5F-Li with 6 equiv. HMPA in THF/Et2O. 1,3-Bis-(4fluorophenyl)-2- propanone (850 µL, 0.35 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared solution of 0.1 M LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for several hours. 13C, 7Li, 19F and 31P spectra were obtained at -125 °C. HMPA was added (0.32 mL, 6.0 Equiv.) and 13C, 7Li, 19F and 31P spectra were obtained at -125 °C, -135 °C, and -140 °C. HMPA was added (0.48mL, 15.0 Equiv. total) and 13C, 7Li, 19F and 31P spectra were obtained at -125 °C, -135 °C, and -140 °C. Spectra are shown in Figure S-32. Li

R-O

Li

O-R

F

6 Equiv. HMPA

R O-Lih2 +

3:2 THF/Et2O

(R-O)2Li Li(HMPA)4+ +

M-h2

TI

2

2Li(HMPA)4+

QI

F

R=

(R-O)3Li

(R-O)2H Li(HMPA)4+ H-Dimer

5F

H-Dimer +

Li-h4

7

Li

M-h2 + M-h3 TI

-140 °C

QI

19

F

M-h2

M-h3

-134 °C

-125 °C 15 Equiv. HMPA M-h2 + M-h3

QI M-h2

TI

M-h3

-140 °C

-134 °C M-h2 + M-h3 -125 °C 6 Equiv. HMPA Lithium Dimer

Lithium Dimer

-125 °C Lithium Enolate Dimer 2.0

Ketone

1.5

1.0 0.5 ppm

0.0

-0.5

-118

-120

-122

-124 ppm

-126

-128

-130

Figure S-32. 7Li and 19F NMR spectra of a sample of lithium enolate 5F-Li with 6 equiv. and 15 equiv. of HMPA at -125 to -140 °C. Coalescence of the 19F NMR signals attributed to M-(HMPA)2, QI, and M(HMPA)3 was observed over this temperature range.

S-37

HMPA Titration of Lithium Enolate E/Z-5F-Li in THF/Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2. 13C, 7Li, 19F and 31P spectra were obtained at -130 °C with 0, 0.25 (13 µL), 0. 5 (26 µL), 1 (52 µL), 2 (104 µL), and 6 equiv. (312 µL) of HMPA added. Spectra are shown in Figure S-33. H

H

Ar

Li O Li

O

Ar +

13

H

Li Li

Ar

HMPA -130°C

O

O

Ar

(EE)-D-h2

3:2 THF/Et2O

Ar

+

(Z)-M-h2

Ar Ar =

(EZ)-(5F-Li)2

(EE)-(5F-Li)2

Equiv. HMPA

Ar

H Ar

7

C

Li

(EE)-D-h2

F

(Z)-M-h2

19

(Z)-M-h2 (EE)-D-h2

F

Li O C=C

6 (EE)-D-h2

(Z)-M-h2

4

(Z)-M-h2

2

(EZ)-D-h2

1 (EZ)-D-h1

(EZ)-D-h2

(EE)-D-h1

(EE)-D-h1

0.5 (EE)-D-h1

0.25 (EE)-D-h1

(EZ)

(EE)

0 172

170

168

166

164 ppm

(EE)

0.5

(EZ)

(EZ)

0.0

-0.5

-124

(EE)

-126

-128

-130

Figure S-33. HMPA titration of the EE and EZ dimers of 5F-Li in 3:2 THF/ Et2O at -130 °C. Sequential solvation of the EE and EZ dimer was observed as the concentration of HMPA was increased up to one equiv. Above one equiv. of HMPA formation of the Z HMPA solvated monomer was observed but formation of the E HMPA solvated monomer was not (h = HMPA; D = dimer; M = monomer).

S-38

HMPA Titration of Lithium Enolate E-5F-Li at -105 °C in Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (Et2O) of freshly prepared LiNiPr2. 13C, 7Li, 19F and 31P spectra were obtained at -105 °C with 0, 0.25 (13 µL), 0.5 (26 µL), 0.75 (39 µL), and 1 equiv. (52 µL) of HMPA added. The sample was quenched with the addition of Et3N (84 µL, 0.6 mmol) and Me3SiCl (160 µL, 1.2 mmol). The resulting enol silyl ether was determined to be a 85:15 mixture of E and Z isomer. Spectra are shown in Figure 15 and S-34. F

Li

O

R H

h

Li O Li O R

HMPA Et2O -105 °C

0.1M

R

Li

Li

O R

h

O Li Li O R O

R

Li

h1

R

h

HMPA

O Li R

h

O Li Li O R

R HMPA

h2

h

h3

h4

7

13

Li

h4 C

h4

19

h

h

O Li Li O R

h OLi Li O R R h h4

Li O R O Li

R

C F

F

Equiv. HMPA

O

R

h

HMPA

Free HMPA 31

h4

P

F

1 h3

h3

h4 h3

h3

h4

h4

0.75 h2

h2

h2

h2

h3

h3

0.5 h1

h1

h1

h1 h

2

h2

0.25 h0

h0 h0

0 166

164

162

160

0.8

ppm

R

h h O Li Li O R

O TMSCl

C

E

+

C

154

152

150

112

Ar

E/Z 85:15

5F-Si Z

Z

156

SiMe3

110

27

Ar =

O

H Ar

13

h4

SiMe3

Ar

h OLi Li O R R h

13

-118 -120 -122 -124 -126

0.3

25

23

F

Ar E

H

19

F

Z

E

108

106

-116

-117

-118

-119

Figure S-34. HMPA titration of the tetramer of E-5F-Li in Et2O at -105 °C. Sequential solvation of the E tetramer was observed as the concentration of HMPA was increased up to one equiv. Quenching the solution with Me3SiCl resulted in an enol silyl ether a mixture of 85:15, E and Z isomers. (h = HMPA)

S-39

HMPA Titration of Lithium Enolate E-5F-Li at -125 °C in Et2O. 1,3-Bis-(4-fluorophenyl)-2propanone (450 µL, 0.65 M solution in Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (Et2O) of freshly prepared LiNiPr2 in Et2O. 13C, 7Li, 19F and 31P spectra were obtained at -122 °C with 0, 0.25 (13 µL), and 0.5 (26 µL) equiv. of HMPA and at -105 °C with 0.5, 0.75 (39 µL), 1 (52 µL), 2 (104 µL), 3 (156 µL), 4 (208 µL) and 6 equiv. (312 µL) of HMPA. The sample was quenched with Et3N (84 µL, 0.6 mmol) and Me3SiCl (160 µL, 1.2 mmol). Spectra are shown in Figure S-35. F

O

Li

R H

h

1 Equiv.

HMPA

-122 to -105 °C

h OLi Li O R R h

Et2O

0.1 M

Equiv. 13 HMPA C

F Li O C=C Temp. (Z)-M-h3 Triple Ion

6

h O Li R >1 Equiv. Li O

(E)-h4

7

(Z)-M-h3

+ (Z) Triple Ion

19

F

Li

(Z)-M-h3

Triple Ion

(Z)-M-h3 Triple Ion

Triple Ion

(E)-h4

-105 °C

4

Triple Ion

(E)-h4

-105 °C (Z)-M-h2

2 -105 °C C F

1

-105 °C (E)-h3

(E)-h3 (E)-h4

0.75

-105 °C

(E)-h2

(E)-h2

(E)-h2

(E)-h1

(E)-h3

0.5

-105 °C

(E)-h2

0.5

(E)-h2

(E)-h1

(E)-h1

-122 °C

0.25 -122 °C

0

(E)-h0

(E)-h0

(E)-h0

-122 °C 172 170 168 166 164 162 160 ppm

1.0

0.5

0.0

-0.5

-118 -120

-122

-124

-126 -128

-130

Figure S-35. HMPA titration of the tetramer of E-5F-Li in Et2O at various temperatures from -122 to 105 °C. Sequential solvation of the E tetramer was observed as the concentration of HMPA was increased up to one equivalent. Above one equivalent, the tetra-HMPA solvated E tetramer was converted to triple ion and Z HMPA-solvated monomer with the solution consisting largely of these two species at six equivalents of HMPA . Quenching the sample with Me3SiCl resulted in exclusively (>95%) Z enol silyl ether. (h = HMPA)

S-40

HMPA Titration of Lithium Enolate Z-5F-Li at -140 °C in Et2O/Me2O. 1,3-Bis-(4fluorophenyl)-2- propanone (450 µL, 0.65 M solution in Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (Et2O) of freshly prepared LiNiPr2. The solution was allowed to warm to room temperature for several hours. The sample was cooled to -78 °C and via cannula ca 0.5 mL of Me2O was added. 13C, 7Li, 19 F and 31P spectra were obtained at -133 °C with 0, 0.25 (13 µL), 0.5 (26 µL), 1 (52 µL), 1.5 (78 µL), 2 (104 µL), 4 (208 µL) and 6 equiv. (312 µL) of HMPA added. Spectra are shown in Figure S-36. F O

Li

-140°C HMPA 6:1 Et2O/Me2O

0.1 M

Equiv. HMPA 7 Li 6

-130 °C

6

-145 °C

R O

Li Li

O R

R O

13

Li-h4

C

Li

O R

Li

h

h

D-h1

Z-5F-Li +

NMe2

h

F

D-h2

O=P

R O-Lih3 M-h3

HMPA

19

Li O C=C

F

QI

NMe2 NMe2

31

M-h3

P Free HMPA

M-h3

+

Li-h4

QI

QI

4

M-h3

+

Li-h4

M-h3

2 M-h3

1.5

M-h3 Free HMPA

D-h2 D-h2

D-h2

1 D-h2

D-h2

D-h2

D-h1+ D-h2

0.5 D-h1

D-h1

D-h1

D-h1

0.25 D-h1

D-h1 D-h0 D-h0

D-h0

0 1.0

0.5

0.0

-0.5

172

170

168

-120

-125

-130

28

26

Figure S-36. HMPA titration of Z-5F-Li in Et2O at -140 °C. Sequential solvation of the dimer was observed as the concentration of HMPA was increased up to one equiv. Above one equiv. of HMPA the solution became more complex with the formation of a number of broad signals. The addition of >4 equiv. of HMPA produces a solution consisting of the previously identified tris-HMPA monomer and quadruple ion (h = HMPA; D = dimer; M = monomer).

S-41

Dilution study of Lithium Enolate Z-5F-Li in Et2O with 6 equiv. of HMPA. 1,3-Bis-(4fluorophenyl)-2- propanone (1.13 mL, 0.80 M solution Et2O, 0.3 mmol) was added at -78 °C to a 0.3 M solution of freshly prepared LiNiPr2 in Et2O. HMPA (6 equiv., 120 µL) was added and the sample was allowed to warm to room temperature (ca 25 °C) for 15 min. 13C, 7Li, and 19F spectra were obtained at 125 °C. From this sample 1 mL was removed and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 2.0 mL of Et2O. 13C, 7Li, and 19F spectra were obtained at -125 °C. From the original sample 0.5 mL was removed and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 2.5 mL of Et2O. 13C, 7Li, and 19F spectra were obtained at -125 °C. From the original sample 0.2 mL was removed and placed in a dry, purged 10 mm NMR tube sealed with a septa containing 3.8 mL of Et2O. 13 C, 7Li, and 19F spectra were obtained at -125 °C. Spectra are shown in Figure S-37. -1.0 Ar

H

2

H

Ar Ar

+

H

-125 °C

O Li O Li-h4

5F-TI

Et2O

O h3Li

Ar =

Log [Triple Ion]

Ar

Ar

F

Ar M-h3

19

F NMR Concentration

-1.5 -2.0 -2.5 -3.0 y = 2.01(±0.16)x - 0.59(±0.24) R2=0.9939

-3.5 -4.0

-2.2 -2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 Log [Monomer]

6 Equiv. HMPA -125 °C Et2O 7

13

Li

13

C

19

C

F

H-Dimer TI

Li O C=C

Li O C=C

0.007 M

M-h3

0.036 M

0.075 M

TI 0.22 M

0.8

0.4

0.0

-0.4

172

170

97

168

92

87

-118 -120 -122

-124 -126

-128 -130

ppm

Figure S-37. Variable concentration experiment of an Et2O solution of the lithium enolate of 5F-Li containing 6 equiv. of HMPA at -125 °C. Based on the integration of 19F NMR spectra the triple ion decreased and the amount of tris-HMPA monomer increased as the solution was diluted (h = HMPA).

S-42

HMPA Titration of Lithium Enolate of 1,2-Diphenylethanone (6H-Li) in THF/ Et2O. 1,2Diphenylethanone (480 µL, 0.62 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution of freshly prepared LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for 2 h, recooled to -130 °C and 13C and 7Li spectra were acquired. 13C, 7Li and 31P spectra were obtained at -130 °C with 0.25 (13 µL), 0.5 (26 µL), 0.75 (39 µL), 1 (52 µL), 2 (104 µL), 4 (208 µL) and 6 equiv. (312 µL) of HMPA added. Spectra are shown in Figure S-38. Li

h

O

HMPA

Li

R O

Li

3:2 THF/Et2O -135°C

13

Li

M-h2

31

C

O=P

R O-Lih2

D-h2 13

C

NMe2 O R h

D-h1

Li

Li

h

5H-Li 7

R O

O R

NMe2 NMe2

HMPA Free HMPA

P

M-h2

Equiv. HMPA 6

Li O C=C

Li O C=C

4 M-h2

2 M-h2 D-h1

1

M-h2

M-h2

D-h2 D-h2

0.5 D-h1

D-h1 D-h0

0.25 D-h1 D-h0

D-h0

D-h0

0 1.2

0.8

0.4

0.0

-0.4 167 166 165 164 163 96 94 92 90 88 29 ppm

28

27

26

25

Figure S-38. HMPA titration of the lithium enolate of 0.1 M 6H-H in 3:2 THF/Et2O at -130 °C. Solvation of the dimer by HMPA was observed, followed by dissociation to monomer upon increasing the concentration of HMPA (D = 4-center dimer, M = monomer, hn = number of coordinated HMPA molecules).

S-43

Kinetic and Thermodynamic Deprotonation of 1-Phenyl-2-(4-fluorophenyl)ethanone (6FH). Kinetic Conditions: 1-Phenyl-2-(4-fluorophenyl)ethanone (400 µL, 0.67 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution of freshly prepared LiNiPr2 in 3:2 THF/Et2O and 13C, 19 F and 7Li spectra were acquired at -130 °C. The sample was quenched with the addition of Me3SiCl (100 µL, 0.8 mmol) and 13C, 19F and 7Li spectra were acquired at -130 °C. Thermodynamic Conditions: An identical sample was allowed to warm to room temperature (ca 25 °C) for several hours after which the sample was cooled and 13C, 19F and 7Li spectra were acquired at -130 °C. The sample was quenched with the addition of Me3SiCl (100 µL, 0.8 mmol) and 13C, 19F and 7Li spectra were acquired at -130 °C. Spectra are shown in Figure S-39. ZZ Dimer Major

F

O

Ph

LDA 3:2 THF/Et2O

Ph

EZ Dimer Minor

Ar

Ar

Li O

+

Li

Ph

Ar

Time Heat

O

O

Ph

Ar =

Li

SiMe3 H

Ph F

O +

Me3SiCl / Et3N

13

Li

C

SiMe3 O

SiMe3

Ar

H

Ph

Ph

Ar

H

E

1:3.5

Ph

Ar

Ar

Me3SiCl / Et3N

O

7

Ph

Li

O

ZZ Dimer Ar Li O O Li

Ph

O +

Ar Ph H

Ar

Z

E-6F-Si

C F

19

C O

F

SiMe3

95

Z-6F-Si

Z Enol Silyl Ether

Me3SiCl Quench C F C O

Thermodynamic Enolate

ZZ Dimer

C F

Z Enol Silyl Ether Z Enol Silyl Ether

Z Enol Silyl Ether

E Enol Silyl Ether

E Enol Silyl Ether

E Enol Silyl Ether

Me3SiCl Quench C O

ZZ Dimer

C F

EZ Dimer

Kinetic Enolate

C O

0.5

0.0 166

162

158 C O

154

150 110 ppm

106

102

98

94

-117 -119 -121 -123 -125

O C=C

Figure S-39. Deprotonation of 1-phenyl-2-(4-fluorophenyl)ethanone (6F-H) with 0.1 M LiNiPr2 in 3:2 THF/Et2O under kinetic and thermodynamic conditions. Samples were quenched with Me3SiCl for further analysis of the resulting enol silyl ether.

S-44

NOESY Study of Z-1-Phenyl-2-(4-fluorophenyl)-1-(trimethylsilyloxy)ethene (6F-Si). Z-1Phenyl-2-(4-fluorophenyl)-1-(trimethylsilyloxy)ethene was synthesized and isolated as described in the synthesis section. A sample was prepared in dry CDCl3 and selective 1H NOESY experiments were run irradiating Ha (Figure S-40) and the Me3Si protons (Figure S-41) using standard Varian pulse sequences. The mixing time (time for NOE buildup) was varied to distinguish real NOEs from artifacts (Figure S-40) and to determine relative distances CH3d Hc

1

H

3.9% NOE

Si O

Hc

5.0% NOE

Hb

F

Ha

Hb

Z-6F-Si

3.2% NOE

1 H NOESY 1D 25 °C CDCl3

No Change in NOE Hd = Artifact 0.26% NOE Mix Time = 1000 ms

3.8% NOE 0.28% NOE Mix Time = 800 ms

2.0% NOE

2.4% NOE

0.24% NOE Mix Time = 500 ms

Hd Hb

Ha

Hc

7

6

5

4

3

2

1

0

ppm

Figure S-40. Selective 1H NOESY experiments of 6F-Si were preformed with varying mix times to distinguish artifacts observed from the intense (CH3)3Si signal when the vinyl proton signal was selectively inverted.

S-45

Title 6

Si O

150

He Hb

F 1

He Ha 1

H NOESY 1D 25 °C CDCl3

Hb

Z-6F-Si

H

% NOE x 100

CH3d

slope = ca( 1 / ) = average distance from H d Hb

100

slope = 0.08 He 50 slope = 0.03 Ha

0 1.61% NOE 0.8% NOE

slope = 0.16

300

0.31% NOE

400

500

600 700 Mixing Time

800

900

1000

Mix Time = 1000 ms 1.27% NOE

0.55% NOE

0.24% NOE Mix Time = 800 ms

0.51% NOE

1.15% NOE

0.2% NOE Mix Time = 700 ms

0.38% NOE

0.82% NOE

0.17% NOE Mix Time = 500 ms

0.25% NOE

0.56% NOE

0.11% NOE Mix Time = 350 ms

Hd He

Hb

7

Ha

6

5

4

3

2

1

0

ppm

Figure S-41. Selective 1H NOESY experiments of 6F-Si were preformed with varying mix times to determine the relative distance from (CH3)3Si based on the observed NOE when the (CH3)3Si signal, Hd, was selectively inverted. The measurement of relative distances was made from a plot of the percent NOE versus mixing time where the slope of the line for Ha, Hb, and He are proportional to 1/r6, where r is equal to the average distance from Hd.

S-46

HMPA Titration of Lithium Enolate 6F-Li in THF/ Et2O. 1-Phenyl-2-(4fluorophenyl)ethanone (800 µL, 0.38 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a freshly prepared 0.1 M solution of LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for 2 h, was cooled to -130 °C. 13C, 7Li, 19F and 31P spectra were obtained at -130 °C with 0, 0.25 (13 µL), 0.5 (26 µL), 0.75 (39 µL), 1 (52 µL), 2 (104 µL), 4 (208 µL) and 6 equiv. (312 µL) of HMPA added. Spectra are shown in Figure S-42. Li

F

O

h

HMPA -130°C

Li

R O

3:2 THF/Et2O

Li

R O

O R

Li Li

13

13

Equiv. HMPA 6

C

C

R O-Lih1

R O-Lih2

M-h1

M-h2

h

h D-h1

6F-Li

O R

D-h2

7

19

Li

F

M-h2

M-h2

M-h2 M-h2 Li O C=C

M-h2

4 M-h2

M-h2 M-h1

M-h2

D-h2 M-h1

2 D-h1 D-h2

1

M-h2 D-h2

D-h1

D-h1

D-h1

M-h1 D-h2 D-h1

D-h2

0.5

D-h1

D-h1

D-h0

D-h1 D-h0

0.25 D-h1

D-h0 Li O C=C

0

168

166

164

98

94

90

86

D-h0

D-h0

0.8

0.3

-0.2

-122

-124

-126

-128

-130

ppm

Figure S-42. HMPA titration of 0.1 M 6H-Li in 3:2 THF/Et2O at -130 °C. Solvation of the dimer by HMPA was observed but this enolate dissociates to monomer easily with both mono-HMPA monomer and bis-HMPA monomer observed with half an equivalent of HMPA (D = 4-center dimer, M = monomer, hn = number of coordinated HMPA molecules).

S-47

P4 Titration of 1-Phenyl-2-(4-fluorophenyl)ethanone (6F-H). A solution of 1-phenyl-2-(4fluorophenyl)ethanone (82 mg , 0.38 mmol) was prepared in a 10 mm NMR tube sealed with a septa, purged with Ar, containing 3 mL of 3:2 THF/Et2O. 13C, 1H and 19F NMR spectra were obtained at -130 °C. P4-tBu was added as a 1 M solution in hexane and 13C, 1H, 19F and 31P NMR spectra were obtained at -130 °C with 0.3, 0.6, 0.9, and 1.2 equiv. of P4-tBu. Spectra are shown in Figure S-43. Ph F

O

0.5 Eq

O H O

+

3:2 THF/Et2O

Ar Ph Ar

-130°C

6F-H

+

Ar

P4-t Bu

6F-P4H

Ph H-Dimer

1

13

H

Equiv. P4-t Bu

13

C 6F-P4H

O H O

C

H-Dimer

H-Dimer

19

F

6F-P4H

Li O C=C

Li O C=C

1.2

6F-P4H

H-Dimer

H-Dimer

0.9

0.6

0.3

0 19

18

17 170

165

160 100

95

90

85

-120

-125 -130 ppm

-135

Figure S-43. P4-tBu titration of 0.1 M 6F-H in 3:2 THF/Et2O at -130 °C. The addition of less than 0.5 equivalent of P4-tBu produced a dimeric enolate species which is bridged by a low barrier hydrogen bond (* 18.2). The 13C signals at * 162.1 (C-O carbon) and * 96.5 ($-carbon) are similar to those of the lithium enolate * 163.9 (C-O carbon) and * 95.3 ($-carbon). Upon the addition of a full equivalent of P4-tBu thea “naked” enolate 6F-P4H was produced, with substantially shifted C-O carbon (* 168.0) and $-carbon (* 87.1), compared to 6F-Li.

S-48

P4 Enolate Titration of Z Dimer of Lithium Enolate 6F-Li. 1-Phenyl-2-(4fluorophenyl)ethanone (800 µL, 0.38 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution of freshly prepared LiNiPr2 in 3:2 THF/Et2O. The sample was allowed to warm to room temperature (ca 25 °C) for 2 h and recooled to -130 °C. 13C, 19F and 7Li spectra were acquired on this sample, and after the addition of 1-phenyl-2-(4-fluorophenyl)ethanone (635 mg, 0.3 mmol) and P4tBu(0.3 mL, 1 M, hexane), as well as after the addition of 1-phenyl-2-(4-fluorophenyl)ethanone (540 mg, 0.25 mmol) and P4-tBu(0.25 mL, 1 M, hexane) . Spectra are shown in Figure S-44. R-O

Li Li

O-R

-2

R-O Li O-R

3:2 THF/Ether -130 °C

ZZ-(6F-Li)2

2 P4H+

P4H+

P4 Enolate

F

R=

Triple Ion TI

O-R

R-O Li

R-O P4H+

O-R Quadruple Ion QI

P4 Enolate

Ph 7

13

Li

C

P4 Enolate

13

C

P4 Enolate

QI QI

19

F

QI

TI

2.0 Equiv. P4 Enolate

TI

TI

1.2 Equiv. P4 Enolate

P4 Enolate QI

TI

TI

QI

QI

QI

Li - dimer

Li - dimer

Li O C=C

Li O C=C

2.5 2.0 1.5 1.0 0.5 0.0

168

166

Li - dimer

Li - dimer

164 ppm

94

92

90

88

86

-125

-130

Figure S-44. The generation of the P4 enolate 6F-P4H in the presence of lithium enolate 6F-Li results in formation of complex ionic species. Addition of a full equivalent of 6F-P4H to the lithium enolate produced a solution which is mostly triple ion (TI). Past one equiv of P4 enolate a new species appeared at the expense of the TI, which reached 49% of the total at two equivalents of 6F-P4H leading to the assignment of the quadruple ion structure (6F)3Li-2 (P4H+)2.

S-49

S4. Crystallographic Section (Summary) A full reporting of the crystallographic data is presented in the second section of the Supplemental Information. Reported here is a summary of this data which includes the synthetic procedures used to generate crystals suitable for X-ray diffraction study and ORTEP diagrams of the respective molecules. PMDTA Solvate of the Lithium Enolate of 1,3-Diphenyl-2-propanone (5H-LiAPMDTA). 1,3Diphenyl-2-propanone (410 µL, 0.73 M solution in 3:2 THF/ Et2O, 0.3 mmol) was added at -78 °C to a 0.1 M solution (3:2 THF/Et2O) of freshly prepared LiNiPr2. The solution was allowed to warm to room temperature (ca 25 °C) for several hours after which the sample was recooled to -78 °C and 2.0 equiv. (124 µL) of PMDTA added. Upon standing for several days at -78 °C crystals formed.

Figure S-45. Lithium enolate of 1,3-diphenyl-2-propanone PMDTA solvate (5H-LiAPMDTA). All H atoms have been omitted.

S-50

Lithium Enolate ((Z-5F-Li)2A(OEt2)2). 1,3-Bis-(4-fluorophenyl)-2- propanone (0.768 g, 3.2 mmol) was placed in a 15 mL conical vial, dissolved in 1 mL of Et2O and cooled to 0 °C. Diisopropylamine (0.46 mL, 3.3 mmol) and 2 ml of Et2O was placed in to a flame dried and argon purged 5 mL round bottom flask and cooled to -78 °C. n-Butyllithium (1.5mL, 3.2 mmol) was added and the solution was warmed to 0 °C for 5 min. The freshly prepared lithium diisopropylamide (LiNiPr2) was added to a conical flask by cannula at 0 °C and the flask was shaken to mix the reactants. The solution was allowed to warm to room temperature for 30 min and cooled to -20 °C. Upon standing overnight at 20 °C crystals formed. Crystals for X-ray diffraction study could be removed or a solution of crystalized enolate could be prepared by removing the solvent via cannula, and placing the crystals under vacuum for 2 min. The flask was then back filled with argon and the crystals were dissolved in 5 mL of 3:2 THF/ Et2O to make up a 0.6 M solution. [S3]

Figure S-46. A molecular drawing of (5F-Li)2(OEt2)2 shown with 30% probability ellipsoids. The minor components of the disordered atoms and the H atoms are omitted.

S-51

S5. References [S1]

Kolonko, K. J.; Reich, H. J. J. Amer. Chem. 2008, 130, 9668-9669.

[S2]

Sikorski, W. H.; Sanders, A. W.; Reich, H. J. Magn. Reson. Chem. 1998, 36, S118 -S124.

[S3]

Guzei, I. A.; Kolonko, K. J.; Reich, H. J. Acta Cryst. 2007, E63, o4094.

[S4]

Denney, D. B.; Denney, D. Z.; Pastor, S. D. Phosphorus Sulfur Silicon Relat. Elem. 1985, 22, 191-197. DNMR simulations were performed with a version of the computer program WINDNMR (Reich, H. J. J. Chem. Educ. Software 1996, 3D, 2; http://www.chem.wisc.edu/areas/reich/plt/windnmr.htm)

[S5]

S5. Spectra

S-52

3.69

7.12 7.10 7.09 7.07 7.03 7.00 6.97

(1H, CDCl3, 300 MHz) F

F

O

5F-H S-53

7.15

7.10

7.05 ppm

7.00

6.95

4.00

7.35

1

H 10

9

8

7

6

5 ppm

4

3

2

1

0

48.4

115.9 115.7

131.2 131.1 129.7 129.7

163.9 160.6

205.3

(13C, CDCl3, 75 MHz) F

O

F

S-54

5F-H

13

C

220 210 200 190 180 170 160 150 140 130 120 110 100 90 ppm

80

70

60

50

40

30

20

10

0

-116.00

(19F, CDCl3, 282 MHz) F

F

O

S-55

5F-H

-115.90-115.95-116.00-116.05-116.10-116.15

19

F

-111

-113

-115 ppm

-117

-119

7.60

( H, CDCl3, 300 MHz) F

4.27

8.03 8.02 8.00 8.00 7.61 7.58 7.56 7.50 7.48 7.45 7.26 7.26 7.24 7.23 7.21 7.05 7.02 7.00

8.0

1

7.55

7.50

7.25

7.45

7.20

7.15

7.05

7.00

S-56

O

6F-H 1.79

1.75 2.06 1.69 2.00 0.86

1

H 10

9

8

7

6

5 ppm

4

3

2

1

0

44.7

115.9 115.6

136.7 133.5 131.3 131.2 128.9 128.7

163.7 160.5

197.6

(13C, CDCl3, 75 MHz) F

O

S-57

6F-H

13

C

215

200

185

170

155

140

125

110 ppm

95

80

65

50

35

20

5

-116.42

(19F, CDCl3, 282 MHz) F

O

S-58

6F-H

-116.25-116.30-116.35-116.40-116.45-116.50-116.55

19

F

-112

-114

-116 ppm

-118

-120

0.06 0.04

3.64 3.53 3.44

5.32

5.87

7.26 7.25 7.24 7.24 7.23 7.22 7.21 7.17 7.05

(1H, CDCl3, 300 MHz) (CH3)3Si O

5H-Si

S-59

7.45

7.40

7.35

7.30

7.25

7.20

7.15

7.10

7.05

7.00

6.95

20.63

6.90 14.95

2.09 2.11

1.23

1

H 0.61

9

8

7

6

1.00

5

4 ppm

3

2

1

0

(13C, CDCl3, 75 MHz) (CH3)3Si O

5H-Si

S-60

13

C x

x

215 200 185 170 155 140 125 110 ppm 95 80 65 50 35 20 5

x = 5H

1.2 1.0 0.5

38.6

49.3

77.7 77.2 76.8

110.8 110.4

153.1 152.0 138.6 138.2 137.3 136.9 134.2 129.7 129.4 129.1 128.9 128.8 128.7 128.6 128.5 128.3 128.2 127.3 126.7 126.4 126.0 125.8

7.40

7.35

7.20

7.30

7.15

3.47 3.42

5.30

5.83

7.42 7.40 7.39 7.37 7.20 7.14 7.12 7.11 7.09 7.09 6.99 6.98 6.97 6.96 6.96 6.95 6.94 6.93 6.93 6.92 6.90 6.90

7.45

7.10

7.00

7.05

6.95

6.90

6.85

(1H, CDCl3, 300 MHz) F

(CH3)3Si

F

O

33.04

S-61 28.29

5F-Si (E/Z 2.5:1)

3.50

3.45

3.40

3.35

4.86 1.08

1

H

2.49

2.04

10

9

8

7

6

1.00

5 ppm

4

3

2

1

0

(13C, CDCl3, 75 MHz)

F (CH3)3Si O F

5F-Si

(E/Z 2.5:1)

S-62

13

C

210 200 190 180 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 10 0

1.2 1.0 0.4

37.6

43.3

77.6 77.2 76.8

163.5 163.4 163.1 162.7 160.3 160.2 159.8 159.4 153.0 151.5 134.2 134.1 133.8 133.2 133.1 132.8 130.8 130.7 130.5 130.4 130.3 129.8 129.7 115.6 115.5 115.4 115.3 115.2 115.1 114.8 109.5 109.4

F

(CH3)3Si

-117.68

-117.07 -117.18 -117.31

(19F, CDCl3, 282 MHz) F

O

5F-Si

(E/Z 2.5:1)

S-63 -117.00-117.05-117.10-117.15-117.20-117.25-117.30-117.35

-117.60-117.65-117.70-117.75

19

F -111.0

-113.0

-115.0 ppm

-117.0

-119.0

0.10

3.44

5.32

7.44 7.44 7.42 7.40 7.23 7.21 7.18 7.01 6.99 6.96 6.92 6.89

12.36

(1H, CDCl3, 300 MHz) (CH3)3Si

F

F

O

5F-Si (Z) S-64

7.45

7.40

7.35

7.30 ppm

7.25

7.05

7.20

7.00

6.95 ppm

6.90

4.02

2.05

2.03 1.92 1.00

1

H 10

9

8

7

6

5 ppm

4

3

2

1

0

43.0

109.4

115.5 115.3 115.0 114.8

151.5 133.8 133.7 132.8 132.7 130.8 130.7 129.8 129.7

163.2 162.4 160.5 159.7

(13C, CDCl3, 90 MHz) (CH3)3Si

F

O

F

5F-Si S-65

(Z)

13

C

210 200 190 180 170 160 150 140 130 120 110 100 90 ppm

80

70

60

50

40

30

20

10

0

-117.09 -117.19

(19F, CDCl3, 338 MHz) (CH3)3Si

F

O

F

S-66

5F-Si (Z) -117.00 -117.05 -117.10 -117.15 -117.20 -117.25 ppm

19

F

x

-111

-113

-115 ppm

-117

-119 x = 5F-H

0.00 -0.01

1.50

6.03

6.95

7.52 7.50 7.50 7.30 7.27 7.20

(1H, CDCl3, 300 MHz) F

O

Si(CH3)3 Ph

6F-Si

S-67

7.65

7.60

7.55 ppm

7.50

7.45

7.35

7.30 7.25 ppm

7.00

6.95 ppm

6.90 8.84

4.18 3.94

2.13

1

1.00

H 10

9

8

7

6

5 ppm

4

3

2

1

0

0.9

109.6

115.3 115.0

139.7 132.9 132.9 128.4 128.3 126.3

150.8

162.9 159.6

(13C, CDCl3, 75 MHz) F

O

Si(CH3)3 Ph

6F-Si

S-68

13

C

210 200 190 180 170 160 150 140 130 120 110 100 90 ppm

80

70

60

50

40

30

20

10

0

-116.29

(19F, CDCl3, 282 MHz) F

O

Si(CH3)3 Ph

6F-Si

S-69 -116.20-116.25-116.30-116.35-116.40 ppm

19

F

-110

-112

-114

-116 ppm

-118

109.4

116.0 115.7 115.4

134.8 133.7 131.6 131.5 130.1 130.0

152.5

163.5 162.6 160.9 159.9

(13C, 3:2 THF/Et2O, 90 MHz) F

162.2

131.5 TMS

Enol Silyl Ether -120 C

115.5

Other NMR Signals

F

O 133.7

19

F = -117.61 ppm F = -117.22 ppm

161.2

19

115.8 134.8

152.5

109.4

130.1

S-70

46.3

5F-Si

13

C 170

X

165

160

155

150

145

140

135

130 125 ppm

120

115

110

105

100

95

90

85

101.0

115.7 115.4 115.1 114.9

129.4

131.6

135.3 135.2

155.0

159.0

163.4 161.7 160.8

(13C, 3:2 THF/Et2O, 90 MHz) F

162.1

Enol ( H-P4-tBu // BF4) -120 C +

115.0

131.6 H

F

O 135.2

Other NMR Signals

160.3

19

F = -119.62 ppm F = -117.87 ppm 1 H = 9.739 ppm

19

115.5 135.3

155.0

101.0

129.4

S-71

50.6

13

C

X

X

X

X X 170

165

160

155

150

145

140

135

130

125

120

115

110

105 100 95 90 85 X = 1,3-difluorobenzene

96.1

115.3 115.1 114.2 114.1

126.0

131.6

139.5

156.9

160.3 159.5

163.0

168.5

137.6

Lithium Dimer -135 C

(13C, 3:2 THF/Et2O, 90 MHz) F

161.6

131.6

114.2 Li

Other NMR Signals

F

O 139.5

19

F = -123.89 ppm F = -119.07 ppm

158.4

19

115.2 137.6

168.5

S-72

96.1

126.3

48.2

Z-5F-Li

13

C 170

X

165

160

155

150

145

140

135

130

X

125

120

115

110

105

100

95

90

85

94.3

114.8 114.6 114.3 114.3

126.9 126.9 126.8

131.9 131.9

157.1

163.0 160.3 159.7 159.7

165.1

139.6 138.4

Hydrogen Dimer -120 C

(13C, 3:2 THF/Et2O, 90 MHz) +

H-P4-t Bu

F

161.6

131.9

Other NMR Signals

O

19

F = -123.90 ppm F = -119.53 ppm 1 H = 18.398 ppm

114.6-114.3

H

19

F

O 139.6

158.4

S-73

114.8 138.4

165.1

50.65

94.3

126.9

13

C X

170

165

160

155

150

145

140

135

130 125 ppm

120

115

X 110

105 100 95 90 85 X = 1,3-difluorobenzene

Lithium PMDTA Monomer -135 C

PMDTA F

161.6

131.1

114.0

Li

91.8

115.0 114.7 114.0 114.0

125.2 124.1

131.1

139.7

141.7

155.9

158.5

160.2

162.9

169.0

(13C, 3:2 THF/Et2O, 90 MHz)

Other NMR Signals 19

F = -126.37 ppm F = -119.67 ppm

F

O 141.7

19

157.2

114.8 S-74

139.7

169.0

91.8

125.2 + 124.1

48.2

Z-5F-Li

13

C 170

165

160

155

150

145

140

135

130 125 ppm

120

115

110

105

100

95

90

85

87.1

114.0 113.8 113.5 113.3 113.1 112.9

123.1 122.2

131.1

144.1

154.0

156.5

159.8

162.4

173.2

140.4

P4 Enolate

(13C, 3:2 THF/Et2O, 90 MHz) F

161.1

131.1

+

H-P4-t Bu

-120 C

113.4 + 113.0

Other NMR Signals

F

O 144.1

19

F = -130.24 ppm F = -121.12 ppm

155.3

19

113.9 140.4

173.2

87.1

123.1 + 122.2

S-75

50.4

5F-P4

13

C

X X

175

170

165

160

155

150

145

140

135

130 125 ppm

120

115

110

X 105 100 95 90 85 X = 1,3-difluorobenzene