Supporting Information
A Rapid Injection NMR Study of the Reaction of Organolithium Reagents with Esters, Amides and Ketones Kristin N. Plessel, Amanda C. Jones, Daniel J. Wherritt, Rebecca M. Maksymowicz, Eric T. Poweleit, and Hans J. Reich* Department of Chemistry, University of Wisconsin 1101 University Avenue Madison, Wisconsin 53706 [email protected]
Table of Contents
S1. General Experimental ...... S-4
S2. Synthesis ...... S-5 N,N-Dimethyl 2-Deutero-3-fluorobenzamide ...... S-5 1-(3-Fluorophenyl)-1-(4-fluorophenyl)ethan-1-ol ...... S-5 General Tertiary Alcohol Synthesis ...... S-5 General Ketone Synthesis ...... S-6 1-(3-Fluorophenyl)pentan-1-one ...... S-6 5-(3-Fluorophenyl)nonan-5-ol ...... S-6 1-(3-Fluorophenyl)ethanone (5)...... S-6 2-(3-Fluorophenyl)propan-2-ol ...... S-6 (3-Fluorophenyl)(phenyl)methanone ...... S-6 (3-Fluorophenyl)diphenylmethanol ...... S-6 (3-Fluorophenyl)(4-fluorophenyl)methanone (7) ...... S-6 (3-Fluorophenyl)bis(4-fluorophenyl)methanol (8) ...... S-6 1-(3-Fluorophenyl)-3-(4-fluorophenyl)prop-2-yn-1-one ...... S-6 3-(3-Fluorophenyl)-1,5-bis(4-fluorophenyl)penta-1,4-diyn-3-ol ...... S-7
S3. NMR Data and Spectra for Competition Experiments ...... S-8 Competition Experiments of R-Li with ester 1 and Amide 2 ...... S-8 Figure S-1. n-Butyllithium Competition Experiment ...... S-8 Figure S-2. Methyllithium Competition Experiment ...... S-9 Figure S-3. Phenyllithium Competition Experiment ...... S-9 Figure S-4. 4-Fluorophenyllithium Competition Experiment ...... S-10 Figure S-5. 4-Fluorophenylethynylithium Competition Experiment ...... S-11
S4. 4-Fluorophenyllithium ...... S-12 Synthesis of 4-Fluorophenyllithium (9) by Lithium/Tin Exchange...... S-12 Variable Temperature NMR Experiment of 4-Fluorophenyllithium: 9D and 9M Interconversion ...... S-13 PMDTA Titration of 4-Fluorophenyllithium (9) ...... S-15 13C NMR of 9M-P with Excess PMDTA ...... S-16 Association Constant of PMDTA with 4-Fluorophenyllithium ...... S-17 Variable Temperature NMR Experiment of 9D, 9M and 9M-P ...... S-18
S5. Rapid-Injection NMR Experiments ...... S-19 General Preparation of RINMR Samples...... S-19 7Li RINMR of n-BuLi with Ethyl Formate ...... S-20 Products from RINMR of n-BuLi with Ethyl Formate ...... S-22 7Li RINMR of n-BuLi with Acetone...... S-22
S-1 7Li RINMR of n-BuLi with 3-Methoxyacetophenone ...... S-23 7Li RINMR of n-BuLi with N,N-Dimethyl 3-Methoxybenzamide ...... S-24 7Li RINMR of n-BuLi with Methyl Benzoate...... S-25 19F RINMR of 4-Fluorophenyllithium (9) with Ester 1 at -110 ºC ...... S-26 19F RINMR of 4-Fluorophenyllithium (9) with Ester 1 at -97 ºC ...... S-28 Diffusion Ordered NMR Spectroscopy (DOSY)...... S-30 19 F DOSY of Tetrahedral Intermediates 3AArLi and (3)2 ...... S-30 19F RINMR of 4-Fluorophenyllithium (9) with Amide 2 at -110 ºC ...... S-32 19F RINMR Competition Experiments between Amide 2 and Ester 1 ...... S-33 19F RINMR of Excess 4-Fluorophenyllithium (9) with Ester 1 at -120 ºC ...... S-34 19F RINMR of Excess Mixed Dimer 3AArLi with Ester 1 at -120 ºC ...... S-35 19F RINMR of Excess 4-Fluorophenyllithium (9) with Amide 2 at -120 ºC ...... S-36 19F RINMR of Excess Mixed Dimer 3AArLi with Amide 2 at -120 ºC ...... S-37 19F RINMR of PMDTA Complex 9M-P with Ester 1 ...... S-39 19F RINMR of PMDTA Complex 9M-P with Ester 1 with excess PMDTA...... S-40 Long Term Observation of the Reaction of 9M-P with Ester 1 ...... S-41 19F RINMR of 4-Fluorophenyllithium (9) with Ethyl Formate...... S-42 19F RINMR of 4-Fluorophenyllithium (9) with Methyl Trifluoacetate ...... S-43 Lithium alkoxide of 2,2,2-Trifluoro-1,1-bis(4-fluorophenyl)ethan-1-ol (13-Li)...... S-44 2,2,2-Trifluoro-1,1-bis(4-fluorophenyl)-1-methoxy-ethane (13-Me) ...... S-44 Restricted Rotation of Trifluoromethyl Group ...... S-44 19F RINMR of 4-Fluorophenyllithium (9) with S-iso-Propyl 3-Fluorobenzothioate...... S-47 19F RINMR of 4-Fluorophenyllithium (9) with 3,4'-Difluorobenzophenone (7) ...... S-48 19F RINMR of 4-Fluorophenyllithium (9) with Excess 3-Fluoroacetophenone (5) at -115 °C ...... S-49 19F RINMR of 4-Fluorophenyllithium (9) with 3-Fluoroacetophenone (5) at -135 °C ...... S-50 19F RINMR of 4-Fluorophenyllithium (9) with 3-Fluoroacetophenone (5) at -140 °C ...... S-51 19F RINMR of the Reaction of Alcohol 6-OH with 4-Fluorophenyllithium (9)...... S-52 19F RINMR of 2,5-Difluorophenyllithium with Ester 1 at -115 ºC ...... S-53 Lithium Iodide Titration of Amide 2 and Ester 1...... S-54 HMPA Titration of Amide 2 and Ester 1 with 2.0 Equivalents LiI...... S-54
S6. NMR Data and Spectra ...... S-55
S5. References ...... S-82
S-2 2 F2 F N O O 3 N N F Li OEt Li OEt OEt NMe2 OO Li 1 EtO O Li O F EtO Li F3 F3 F F F2 F 12 (3)2 3 ArLi F 3 PMDTA F F F F O HO H C OLi 3 Li Me F Li O F OO O Me Li Li Me F F F F F F F F 5 (6)1 6 ArLi (6)2 6-OH 7
F F N F N N HO Li OLi Li NMe2 Li F F Li F O F Li Li H OEt F F F F 8 9D 9M 9M-P (10)n 11 ArLi F OMe F C R-O CF Ar R H R 3 Ar 3 Me O O Ar F Me Me F Sn + H O O Li 18 Li Li Ar Ar CH3 Sn CH F F Li Li 3 CH R H R F F 3 R H R = H 13-H O O or O O O ? Li R Li R = Li 13-Li F Li 14 19 F R = Me 13-Me 12 ArLi F F 15 ArLi 16 17
S-3 S1. General Experimental. Concentration values of lithium species in experimental procedures are expressed as monomer equivalents independent of the state of aggregation (which is not always known), except in concentration vs time graphs for kinetics experiments, where actual molarities of species indicated are presented (monomer, dimer or tetramer) . 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 diethyl ether (Et2O) were freshly distilled from sodium benzophenone ketyl under N2. Dimethyl ether (Me2O) was distilled via cannula from a graduated conical cylinder containing n-BuLi (for drying). Commercially available starting materials and reagents included: n-butyllithium, s-butyllithium, methyllithium, phenyllithium,4-fluorobromobenzene, ethyl 3- fluorobenzoate, 3-fluorobenzoic acid, acetone, ethyl formate, methyl trifluoroacetate and 4-fluorophenylacetylene. Low-temperature NMR spectra were acquired on a 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 52.99 MHz (6Li). All spectra were taken with the spectrometer unlocked. 13C NMR spectra were referenced internally to the C-O carbon 13 of THF (* 67.96), Et2O (* 66.57) or Me2O (* 60.25). Lorentzian multiplication (LB) of 2-6 Hz was applied to C NMR spectra. RINMR 19F NMR spectra and spectra for characterization were acquired without proton decoupling, 19F NMR spectra for competition experiments proton decoupled. Spectra were referenced internally to 1,3- dimethyl-2-fluorobenzene (* -122.6) or 4-fluorotoluene (* -118.85). 7Li and 6Li spectra were referenced externally to 0.3 M LiCl/MeOH standard (* 0.00 ppm). Probe temperatures were measured internally with the 13C chemical 13 [S1a] shift thermometer: 10% C enriched (Me3Si)3CH.
S-4 S2. Synthesis
O O O
OH OH NMe 1) s-BuLi, TMEDA, -90 °C 1) (COCl)2, CH2Cl2 2 O 2) Me2NH HCl, Et3N, CH2Cl2 2) , THF -78 C D D D3C OD ° F F F N,N-Dimethyl 2-Deutero-3-fluorobenzamide. s-BuLi (33.6 mL, 47.1 mmol, 1.4M in cyclohexane) was added dropwise to a solution of 3-fluorobenzoic acid (3.0 g, 21.4 mmol) and TMEDA (7.3 mL, 49.2 mmol) in THF (100 mL) at -90 °C.[S2] After stirring for 1.5 h the reaction was warmed to -78 °C for 30 min before being quenched with acetic acid-d4. After stirring for 15 min the reaction was warmed to room temperature and aqueous NH4Cl was added. The aqueous layer was extracted with 1:1 Et2O:Hexanes (3 x 50 mL). The combined organic layers were washed with brine, dried (MgSO4), and the solvent removed under reduced pressure. The resulting off-white solid was dissolved in CH2Cl2 (100 mL) and cooled to 0 °C. Five drops of DMF was added followed by dropwise addition of oxalyl chloride (2.7 mL, 32.1 mmol) and the reaction warmed to room temperature. After gas evolution ceased (~1 h) the reaction was cooled to 0 °C and dimethylamine hydrochloride (5.23 g, 64.2 mmol) and triethylamine (15 mL, 107 mmol) were added. The reaction was stirred for 16 hours before being quenched with
NH4Cl. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine , dried (MgSO4), and the solvent removed under reduced pressure. The product was purified by column chromatography (7:3 EtOAc:Hexane) to give the product as a colorless oil (2.4 g, 14.3 mmol) The compound was 1 98% deuterated at C-2. H NMR (CDCl3,300 MHz ) * 7.38 (ddd, J = 8.3, 7.7, 5.6 Hz, 1H), 7.19 (dd, J = 7.6, 1.0 13 Hz, 1H),7.11 (td, J = 8.6, 1.0 Hz, 1H), 2.98 (s, 3H), 3.11 (s, 3H) C NMR (101 MHz, CDCl3) * 170.28 (d, J = 2.5 Hz), 162.58 (d, J = 247.8 Hz), 138.44 (d, J = 6.8 Hz), 130.33 (d, J = 8.0 Hz), 122.88 (d, J = 3.2 Hz), 116.72 (d, J = 19 21.0 Hz), 114.25 (dd, J = 48.5, 23.5 Hz), 39.64 , 35.53. F NMR (377 MHz, CDCl3) d -114.2 (dd, J = 9.0, 5.3 Hz). HRMS (EI) (m/z): calcd. for C9H9DFNO (M+)169.0869; found 169.0874. O OH
1. F MgBr
THF 0 °C F F 2. NH4Cl F 1-(3-Fluorophenyl)-1-(4-fluorophenyl)ethan-1-ol. Under nitrogen, 3-fluoroacetophenone (5,1 g, 7.2 mmol) was added to a round bottom flask containing THF (20 mL) and cooled to 0 °C. 4-Fluorophenylmagnesium bromide (8.6 mL, 8.6 mmol, 1.0 M in THF) was added and allowed to react for 30 min and then warmed to room temperature for 30 min. The reaction was quenched with aqueous NH4Cl. The mixture was extracted with diethyl ether twice. The organic layer was washed with water and brine, dried with MgSO4 and the solvent removed in 1 vacuo. The product was purified via flash chromatography (30% Et2O in hexanes) with 87% isolated yield. H NMR (CDCl3, 300 MHz) * 1.93 (s, 3H), 6.94 (tdd, J = 8.2, 2.9, 0.9 Hz, 1H), 7.00 (t, J = 8.25 Hz, 2H), 7.14 (d, J = 13 7.6 Hz, 2H), 7.27 (m, 1H), 7.37 (dd, J = 9.0, 5.5 Hz). C NMR (CDCl3, 75 MHz) * 31.15 (CH3),75.77 (C), 2 113.21 (d, J13C-19F = 22.3 Hz, CH), 114.13 (d, J = 21.2 Hz, CH), 115.25 (d, J = 21.2 Hz, CH), 121.60 (d, J = 2.2 4 Hz, CH), 127.80 (d, J = 8.3 Hz, CH), 129.94 (d, J = 8.3 Hz, CH), 143.41 (d, J = 3.3 Hz, C), 150.75 (d, J=6.7 Hz, 19 C), 162.10 (d, J = 245.4 Hz, C), 162.99 (d, J = 245.4 Hz, C). F NMR (CDCl3, 282 MHz) * -114.37 (tt J = 8.6, 5.5 A+ Hz), -117.23 (ddd, J = 10.8, 8.5, 6.1Hz). HRMS (EI) (m/z):calcd for C14H12F2O (M ) = 234.0851; found 234.0854. General Tertiary Alcohol Synthesis. To a solution of ethyl 3-fluorobenzoate (1, 0.15 mL, 1 mmol) in THF (3.3 mL) at -78 °C was added the organolithium reagent (2.2 equiv) dropwise. After stirring for 1 h the reaction was quenched with aqueous NH4Cl. The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine, dried (MgSO4), and the solvent removed under reduced pressure. The product was purified by column chromatography. General Ketone Synthesis. To a solution of N-methoxy-N-methyl 3-fluorobenzamide (0.12 mL, 1 mmol) in 3.3 mL of THF at -78 °C was added the organolithium reagent (1.0 equiv) dropwise. After stirring for 1 h the reaction
S-5 was quenched with aqueous NH4Cl. The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine, dried (MgSO4), and the solvent removed under reduced pressure. The product was purified by column chromatography. 1-(3-Fluorophenyl)pentan-1-one. Synthesized from N-methoxy-N-methyl 3-fluorobenzamide and n-BuLi. 1H
NMR (400 MHz, CDCl3) * 7.74 (dt, J = 7.8, 1.2 Hz, 1H), 7.64 (ddd, J = 9.5, 2.6, 1.5 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz, 1H), 7.25 (tdd, J = 8.2, 2.7, 1.0 Hz, 1H), 2.95 (t, J = 7.4 Hz, 2H), 1.82 – 1.63 (m, 2H), 1.49 – 1.34 (m, 2H), 13 0.96 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) * 199.22 (d, J = 2.1 Hz), 163.07 (d, J = 247.6 Hz), 139.20 (d, J = 6.1 Hz), 130.21 (d, J = 7.6 Hz), 123.79 (d, J = 3.0 Hz), 119.87 (d, J = 21.5 Hz), 114.79 (d, J = 22.2 Hz), 19 38.49, 26.33, 22.44, 13.93. F NMR (377 MHz, CDCl3) d -113.90 (ddd, J = 9.4, 8.2, 5.6 Hz). HRMS (EI) (m/z): calcd. for C11H13FO (M+)180.0945; found 180.0944. 5-(3-Fluorophenyl)nonan-5-ol. Synthesized from ethyl 3-fluorobenzoate (1) and n-BuLi. 1H NMR (400 MHz,
CDCl3) * 7.20 (td, J = 7.9, 5.9 Hz, 1H), 7.09 – 6.97 (m, 2H), 6.83 (td, J = 8.5, 2.1 Hz, 1H), 1.85 – 1.66 (m, 4H), 1.65 (d, J = 2.2 Hz, 1H), 1.25 – 1.08 (m, 6H), 1.00 – 0.86 (m, 2H), 0.76 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz,
CDCl3) * 161.90 (d, J = 244.6 Hz), 148.50 (d, J = 6.4 Hz), 128.37 (d, J = 8.1 Hz), 119.83 (d, J = 2.8 Hz), 111.76 19 (dd, J = 38.8, 21.8 Hz), 41.74, 24.51, 22.01, 12.97. F NMR (377 MHz, CDCl3) * -115.6 (ddd, J = 11.0, 8.7, 6.2 Hz). HRMS (EI) (m/z): calcd. for C15H23FO (M+) 238.1728; found 238.1718. 1-(3-Fluorophenyl)ethanone (5). Commercially available from Sigma Aldrich. 2-(3-Fluorophenyl)propan-2-ol. Synthesized from ethyl 3-fluorobenzoate (1) and MeLi. 1H NMR (400 MHz, 13 CDCl3) * 7.36-7.14 (m, 3H), 7.01 – 6.87 (m, 1H),1.58 (s, 6H). C NMR (101 MHz, CDCl3) * d 162.88 (d, J = 245.1 Hz), 151.94 (d, J = 6.6 Hz), 129.71 (d, J = 8.1 Hz), 128.35, 120.01 (d, J = 2.9 Hz), 113.47 (d, J = 21.2 Hz), 19 111.75 (d, J = 22.4 Hz), 72.36, 31.74. F NMR (377 MHz, CDCl3) * -115.1 (ddd, J = 10.4, 8.5, 5.8 Hz). HRMS (EI) (m/z): calcd. for C9H11FO (M+)154.0789; found 174.0781. (3-Fluorophenyl)(phenyl)methanone. Known.[S3] (3-Fluorophenyl)diphenylmethanol. Known. [S4] (3-Fluorophenyl)(4-fluorophenyl)methanone (7). Synthesized by reaction of N-methoxy-N-methyl 3- fluorobenzamide with 4-fluorophenyllithium (prepared from (4-fluoropheny)trimethyltin and n-BuLi). 1H NMR
(400 MHz, CDCl3) * 7.85 (dd, J = 8.8, 5.4 Hz, 2H), 7.54 (dt, J = 7.8, 1.3 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.30 (tdd, 13 J = 8.3, 2.6, 1.1 Hz, 1H), 7.18 (t, J = 8.6 Hz, 2H). C NMR (101 MHz, CDCl3) * 194.02, 165.79 (d, J = 255.0 Hz), 162.71 (d, J = 248.7 Hz), 139.75 (d, J = 6.4 Hz), 133.46 (d, J = 3.3 Hz), 132.88 (d, J = 9.2 Hz), 130.28 (d, J = 7.7 Hz), 125.83 (d, J = 3.2 Hz), 119.70 (d, J = 21.4 Hz), 116.83 (d, J = 22.6 Hz), 115.86 (d, J = 21.9 Hz).19F NMR
(377 MHz, CDCl3) * -107.02 (tt, J = 8.4, 5.4 Hz), -113.57 (ddd, J = 8.9, 8.5, 5.4 Hz). HRMS (EI) (m/z): calcd. for C13H8F2O (M+) 218.0538; found 218.0530. (3-Fluorophenyl)bis(4-fluorophenyl)methanol (8). Synthesized from ethyl 3-fluorobenzoate and 1 4-fluorophenyllithium prepared from (4-fluoropheny)trimethyltin and n-BuLi). H NMR (400 MHz, CDCl3) * 13 7.34 – 7.18 (m, 6H), 7.04 – 6.97 (m, 6H), 2.75 (s, 1H). C NMR (101 MHz, CDCl3) * 162.61 (d, J = 246.3 Hz), 162.12 (d, J = 247.3 Hz), 149.12 (d, J = 6.3 Hz), 142.02 (d, J = 3.2 Hz), 129.61 (d, J = 7.9, Hz), 123.41 (d, J = 3.0, Hz), 115.01 (d, J = 21.4, Hz), 114.92 (d, J = 22.4, Hz), 114.48 (d, J = 21.1, Hz), 81.00. 19F NMR (377 MHz,
CDCl3) * -113.6 (ddd, J = 10.7, 8.4, 5.9 Hz), -115.91 (tt, J = 8.4, 5.3 Hz). HRMS (EI) (m/z): calcd. for C19H13F3O (M+) 314.0913; found 314.0923. 1-(3-Fluorophenyl)-3-(4-fluorophenyl)prop-2-yn-1-one. Synthesized from N-methoxy-N-methyl 3- fluorobenzamide and ((4-fluorophenyl)ethynyl)lithium (prepared from 4-fluorophenylacetylene and n-BuLi). 1H
NMR (400 MHz, CDCl3) * 8.01 (dt, J = 7.7, 1.3 Hz, 1H), 7.86 (dt, J = 9.2, 2.0 Hz, 1H), 7.70 (dd, J = 8.6, 5.5 Hz, 2H), 7.51 (td, J = 8.0, 5.4 Hz, 1H), 7.34 (td, J = 8.3, 2.6 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H). 13C NMR (101 MHz,
CDCl3) * 176.48 (d, J = 2.8 Hz), 164.19 (d, J = 254.3 Hz), 162.77 (d, J = 248.4 Hz), 138.85 (d, J = 6.7 Hz), 135.51 (d, J = 8.9 Hz), 130.39 (d, J = 7.7 Hz), 125.41 (d, J = 3.0 Hz), 121.24 (d, J = 21.6 Hz), 116.36 (d, J = 22.4 19 Hz), 115.96 (d, J = 22.8 Hz), 115.96 (d, J = 3.6 Hz), 92.62, 86.54. F NMR (377 MHz, CDCl3) * -107.36 (tt, J = 8.3, 5.3 Hz), -113.44 (ddd, J = 9.0, 8.1, 5.4 Hz). HRMS (EI) (m/z): calcd. for C15H8F2O (M+) 242.0538; found 242.0539.
S-6 3-(3-Fluorophenyl)-1,5-bis(4-fluorophenyl)penta-1,4-diyn-3-ol. Synthesized from ethyl 3-fluorobenzoate (1) and (4-fluorophenyl)ethynyllithium (prepared from 4-fluorophenylethyne and n-BuLi) 1H NMR (400 MHz,
CDCl3) * 7.69 (dt, J = 7.9, 1.3 Hz, 1H), 7.61 (dt, J = 10.0, 2.1 Hz, 1H), 7.47 (dd, J = 8.7, 5.4 Hz, 4H), 7.39 (td, J = 13 8.0, 6.0 Hz, 1H), 7.06 (td, J = 8.3, 2.2 Hz, 1H) 7.01 (t, J = 8.7 Hz, 4H), 3.39 (s, 1H). C NMR (101 MHz, CDCl3) * 162.97 (d, J = 250.7 Hz), 162.76 (d, J = 246.4 Hz), 144.42 (d, J = 7.0 Hz), 133.92 (d, J = 8.5 Hz), 130.15 (d, J = 8.1 Hz), 121.60 (d, J = 3.0 Hz), 117.81 (d, J = 3.6 Hz), 115.74 (d, J = 22.0 Hz), 113.30 (d, J = 23.6 Hz), 88.30 (d, J 19 = 1.6 Hz), 84.44, 65.35 (d, J = 2.2 Hz). F NMR (377 MHz, CDCl3) * -111.81 (tt, J = 8.5, 5.4 Hz), -114.40 (ddd, J = 9.7, 8.5, 5.9 Hz). HRMS (EI) (m/z): calcd. for C23H13F3O (M+) 362.0913; found 362.0913.
S-7 S3. NMR Data and Spectra for Competition Experiments O O O O HO R
OMe RLi R NMe2 R R + + + D THF, -78 °C D F F F F F 2-d 1 AB C k(amide) ln(1.0-(A/(A+2-d)) = k(ester) ln(1.0-(B+C)/(1+B+C)) Competition Experiments of R-Li with ester 1 and Amide 2. To a solution of amide 2-d (50 mg, 0.3 mmol) and ester 1 (50 mg, 0.3 mmol) in 3 mL of THF at -78 /C (0 °C for 4-fluorophenylethynyllithium) was added the organolithium reagent (0.15 mmol) dropwise. After 30 min the reaction was quenched with 1M propionic acid in ether (0.15 mL, 0.15 mmol) and the reaction warmed to room temperature. 4-Fluoroacetophenone (0.012 mL, 0.1 mmol) was added as a internal standard and an aliquot was removed for 19F NMR analysis. No work up was performed, as this tended to result in some loss of 2. The relative rates were calculated using the standard competition experiment equation shown. The results are shown in Figures S-1 to S-5.
O O O HO Bu O n-BuLi Bu Bu NMe2 + Bu + OEt + THF, -78 °C D D F F F F F 1 2-d O O O
Bu NMe2 OEt HO Bu 19F NMR D D Bu O F F F
Bu F
F
-113.8 -114.0 -114.2 -114.4 -114.6 -114.8 -115.0 -115.2 -115.4 -115.6 ppm Ester H-Ketone H-alcohol D-Amide D-Ketone D-alcohol k(amide)/k(ester) Trial 1 7.86 1 0.73 3.96 2.73 0 2.64 Trial 2 9.17 1 0.89 6.41 3.18 0 2.15 Trial 3 8.72 1 0.48 4.17 1.99 0 2.49 BuLi average 2.42
Figure S-1. n-BuLi competition experiment (THF, -78 °C). The numbers are scaled relative to a peak area of 1 for the H-ketone.
S-8 O O O O HO Me MeLi OEt NMe Me Me Me + 2 + + THF, -78 °C D D F F F F F 1 2-d O O
NMe2 OEt O D HO Me O Me F F Me Me D F F F 19F NMR
-113.4 -113.6 -113.8 -114.0 -114.2 -114.4 -114.6 -114.8 -115.0 -115.2 ppm Ester H-Ketone H-alcohol D-Amide D-Ketone D-alcohol k(amide)/k(ester) Trial 1 16.35 1 0.25 13.32 4.13 0 3.67 Trial 2 12.56 1 0.31 8.68 3.46 0 3.38 Trial 3 11.38 1 0.27 7.03 3.35 0 3.68 MeLi average 3.58
Figure S-2. Methyllithium competition experiment (THF, -78 °C). The numbers are scaled relative to a peak area of 1 for the H-ketone.
O O O O HO Ph
OEt NMe PhLi Ph Ph + 2 + Ph + THF, -78 °C D D F F F F F 1 2-d O O O NMe2 OEt Ph D O F
Ph F HO Ph F D Ph F
19F NMR F
-113.6 -113.8 -114.0 -114.2 -114.4 -114.6 -114.8 -115.0 -115.2 -115.4 ppm
Ester H-Ketone H-alcohol D-Amide D-Ketone D-alcohol k(amide)/k(ester) Trial 1 2.21 1 0.04 2.33 0.28 0 0.29 Trial 2 2.36 1 0 2.56 0.31 0 0.32 Trial 3 2.63 1 0.08 2.89 0.34 0 0.32 PhLi average 0.31
Figure S-3. Phenyllithium competition experiment (THF, -78 °C). The numbers are scaled relative to a peak area of 1 for the H-ketone.
S-9 O O O O HO Ar F Li Ar Ar OEt NMe + Ar + 2 + THF, -78 °C D D F F F F F 1 2-d O O Ar = OEt NMe2 F O D Ar O F F HO Ar Ar Ar F D F F 19F
-113.4 -113.6 -113.8 -114.0 -114.2 -114.4 -114.6 -114.8 -115.0 -115.2 ppm
Ester H-Ketone H-alcohol D-Amide D-Ketone D-alcohol k(amide)/k(ester) Trial 1 5.18 1 0.03 5.8 0.26 0 0.24 Trial 2 4.44 1 0.02 4.81 0.23 0 0.23 4-F-PhLi Average 0.23
Figure S-4. 4-Fluorophenyllithium competition experiment (THF, -78 °C). The numbers are scaled relative to a peak area of 1 for the H-ketone.
S-10 O O O F F Li OEt NMe2 + OH D + THF, 0 °C D F F F F 1 2-d F F O O
NMe OEt + 2 + 19 F NMR R D F F O
F alcohol F H
F F
-111.7 -112.0 -112.3 -112.6 -112.9 -113.2 -113.5 -113.8 -114.1 -114.4 ppm
Ester H-Ketone H-alcohol D-Amide D-Ketone D-alcohol k(amide)/k(ester) Trial 1 6.69 0 1 6.81 0.09 0 0.09 Trial 2 7.08 0 1 6.98 0.11 0 0.12 LiAcetylide Avrg 0.11
Figure S-5. 4-Fluorophenylethynyllithium competition experiment (THF, 0 °C). The numbers are scaled relative to a peak area of 1 for the H-alcohol.
S-11 S4. 4-Fluorophenyllithium Synthesis of 4-Fluorophenyllithium (9) by Lithium/Tin Exchange (KNP3021). A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added to the NMR tube and cooled in a dry ice/acetone bath and Me2O (-3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). The 13C chemical shift thermometer (10% 13C labeled tris(trimethylsilyl)methane, 2 µL), an internal standard for concentrations (4-fluorotoluene, 1 µL), 0.114 mL of (4- fluorophenyl)trimethyltin (0.6 mmol) and n-BuLi (0.24 mL, 0.6 mmol, 2.5 M/hexane) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C (1536 scans), 19F, and 1H NMR were obtained at -119 °C.
-119 °C, 0.14 M 179.96 162.2 3:1 Me2O:THF Li F F 9D 9D Li 19F 9M 7 144.9 111.5 Li 9M 187.89 9D 163.9 -120 -122 -124 -126 Li F 2.5 2.0 1.5 1.0 0.5
142.9 110.7 9M 9D 1:2:3:4:3:2:1 septet
Unresolved 1:1:1:1 quartet JCLi=19.5 Hz
JCLi = ca 35 Hz
9M
190 188 186 184 182 180 178 9D 9D
9D 9M
13 9D 9M C 9M 9M
190 180 170 160 150 140 130 120 110
Figure S-6. 19F, 7Li, and 13C NMR spectroscopy of 9M and 9D prepared by lithium/tin exchange at -119 °C in 3:1
Me2O/THF.
S-12 Variable Temperature NMR Experiment of 4-Fluorophenyllithium: 9D and 9M Interconversion. (KNP3175) A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled
THF (1 mL) was added to the NMR tube and cooled in a dry ice/acetone bath and Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). The 13C chemical shift thermometer (10% 13C labeled tris(trimethylsilyl)methane, 2 µL),[S1] an internal standard for concentrations (4-fluorotoluene, 1 µL), 0.063 mL of 4-fluorophenyltrimethyltin (0.33 mmol) and n-BuLi (0.018 mL, 0.33 mmol) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C, 19F and 1H NMR were obtained at -123, -117, -110, -104, -97, -92, -75 and -72 °C until coalescence of the fluorine signals was observed (Figure S-7). A linear least squares fit to the rates obtained by simulation of 19F NMR with [S5] ‡ ‡ WINDNMR yields enthalpy and entropy of activation values of )H = 6.4 kcal/mol and )S = -7.0 eu for kDM ‡ ‡ and )H = 6.4 kcal/mol and )S = -3.3 eu for kMD (Table S-1). 19 F 3:1 Me2O/THF Li F F Li -72 °C 9D
3:1 Me2O/THF -75 °C
Li F
-92 °C 9M
8.2 k 8.0 9D DM 9M -97 °C 7.8 ΔH = 6.4 kcal/mol ΔS = -7.0 eu 7.6
7.4 -104°C 7.2 (kcal/mol)
G 7.0 k Δ 9M MD 9D -110 °C 6.8 6.6 ΔH = 6.4 kcal/mol ΔS = -3.3 eu 6.4 9D -117 °C 9M -120 -110 -100 -90 -80 -70 -60 -50 Temperature (°C)
-121 -122 -123 -124 -125 -126 ppm
19 Figure S-7. (KNP3175) Variable Temperature F NMR experiment of 9M and 9D in 3:1 Me2O/THF. Rates were determined by simulation with WINDNMR using the 2-spin simulation.[S5] Black spectra are measured, red dashed are simulated and blue are the difference spectra.
S-13 Table S-1. Numeric data for the line shape simulation of Figure S-7 (D = dimer, M = monomer).
Temperature / °C -117 -110 -104 -97 -92 -75 -72
WD /Hz23191919191919 WM /Hz28282828282828 Fraction Dimer 0.81 0.81 0.81 0.81 0.81 0.81 0.81 -1 kDM /sec 38.1 140.9 276.2 642.3 1107 6073 7612 ‡ )G DM /kcal/mol 7.61 7.53 7.57 7.63 7.69 7.71 7.80 -1 kMD /sec 8.9 33.1 64.8 151 260 1424 1785 ‡ )G MD /kcal/mol 7.02 6.92 6.94 6.97 6.99 6.97 7.04 S-14 PMDTA Titration of 4-Fluorophenyllithium (9). (KNP3192) A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added, the tube was cooled in a dry ice/acetone bath and Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). The 13C chemical shift thermometer (10% 13C labeled tris(trimethylsilyl)methane, 0.002 mL),[S1] an internal standard for concentrations (4-fluorotoluene, 0.002 mL), 0.050 mL of (4- fluorophenyl)trimethyltin (0.3 mmol) and n-BuLi (0.12 mL, 0.3 mmol, 2.5 M in hexanes) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C, 19F and 1H NMR spectra were obtained at -115 °C with 0, 0.33, 0.66, and 1.0 equivalents PMDTA (neat) (Figure S-8). F N Li N N Li N 187.3 (JCLi = 34 Hz) Li Li + NN 142.7 109.9 PMDTA 160.3 F F 9M 9M-P F 3:1 Me2O/THF 9D -115 °C 13 13 equiv 19F 7Li C 13C C PMDTA C-2 C-3 1.0 C-1 & C-4 0.66 9M-P 9M-P 9M-P 9M-P 9M-P 9M-P 0.33 C-Li C-F 9D 9D 9D 9D 9D 9M 9M 9M 9M 9D 9M 0 180 160 3 2 1 145 140 112 110 108 -122 -124 -126 ppm 19 7 13 Figure S-8 F, Li and C NMR spectra of a PMDTA titration of 9 in 3:1 Me2O/THF at -115 °C. S-15 13C NMR of 9M-P with Excess PMDTA. (KNP3262) A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added to the NMR tube and cooled in a dry ice/acetone bath and Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). An internal standard for concentrations (4-fluorotoluene, 2 µL), (4- fluorophenyl)trimethyltin (50 µL, 0.3 mmol) and n-BuLi (0.12 mL, 0.3 mmol, 2.5 M in hexanes) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C, 19F and 1H NMR spectra were obtained at -115 °C with 0, 0.44, 0.66 and 0.88 equivalents PMDTA and at -125 °C with 1.0, 1.1 and 1.5 equivalents PMDTA (Figure S-9). 3:1 Me O/THF, -125 °C 2 Free PMDTA N 19F NMR 13C N N 9M-P Li 9M-P N + NN PMDTA F 9M-P -122-124-126-128 62 60 58 56 54 52 50 48 46 44 42 40 ppm ppm 19 13 Figure S-9. F and C NMR spectra of 9M-P and free PMDTA in 3:1 Me2O/THF at -125 °C when 1.5 equivalents of PMDTA was added to 4-fluorophenyllithium (9). At low temperatures PMDTA complexed to lithium reagents shows all nine carbons non-equivalent, as seen here for 9M-P. The four signals of free PMDTA are also marked. Neopentyllithium[S6] and phenyllithium[S7] show similar desymmetrized signals for PMDTA complexes. S-16 Association Constant of PMDTA with 4-Fluorophenyllithium (Keq of 9M + PMDTA » 9M-P). (KNP3266) A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added to the NMR tube and cooled in a dry ice/acetone bath and Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). An internal standard for concentrations (4-fluorotoluene, 2 µL), (4-fluorophenyl)trimethyltin (50 µL, 0.3 mmol) and n-BuLi (0.12 mL, 0.3 mmol, 2.5 M in hexanes) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C, 19F and 1H NMR spectra were obtained at -150 °C with 0, 0.9 and 1.0 equivalents PMDTA (Figure S-10). 13C NMR subtraction spectra were used to calculate the quantity of free PMDTA with 1.0 equivalents . The association constant was calculated as 2.1 x 103 M-1 (9M + PMDTA » 9M-P). N Li N N 3:1 Me2O/THF Li N -150 °C + NN PMDTA F F 9M 13C NMR 9M-P free PMDTA 1.0 equiv. PMDTA Difference: C-A 9D 9M-P 9M C C signals for 9M-P 0.9 equiv. PMDTA Difference: B-A B 0 equiv. PMDTA A 190 180 170 160 150 140 130 120 110 ppm 55 50 45 40 At equilibrium [9M][9M-PMDTA] [PMDTA] Keq 1.25 mM 42.85 mM 16.28 mM 2.1 mM-1 19 13 Figure S-10. F and C NMR spectra of 9 with 0, 0.9 and 1.0 equivalents PMDTA in 3:1 Me2O/THF at -150 °C. Red spectra are the result of the original spectra (0 equiv. PMDTA) subtracted from those with PMDTA (0.9 or 1.0 equiv.). S-17 Variable Temperature NMR Experiment of 9D, 9M and 9M-P. (KNP3197) A 10 mm NMR tube was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added to the NMR tube and cooled in a dry ice/acetone bath and Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). An internal standard for concentrations (4- fluorotoluene, 2 µL), (4-fluorophenyl)trimethyltin (50 µL, 0.3 mmol), n-BuLi (0.12 mL, 0.3 mmol, 2.5 M in hexanes) and PMDTA (0.5 eq. 30 uL) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. 7Li, 13C, 19F and 1H NMR spectra were obtained at -110, -95, -80, -70 and -60 °C (temperatures are estimated) (Figure S-11). 19 F NMR 3:1 Me2O/THF -60 °C F N N -70 °C N N N N Li + Li Li Li -80 °C F F -95 °C F 9M P 9D 9D 9M-P 9M pF-Tol 9M -110 °C -120 -125 ppm 19 Figure S-11. Variable temperature F NMR experiment of 9D, 9M and 9M-P in 3:1 Me2O/THF. S-18 S5. Rapid Injection NMR Experiments General Preparation of RINMR Samples. A 10 mm NMR tube cut to a length of <18 cm was sealed with a septum, grease, and parafilm, and purged with argon. Solvent, 1 mL of freshly distilled THF and 3 mL of Me2O freshly distilled from n-BuLi, a 13C chemical shift thermometer (10% 13C labeled tris(trimethylsilyl)methane, 0.004 mL),[S1] and substrate were measured out. 4-Fluorotoluene (0.005 mL) was added as a 19F NMR standard. The NMR tube was cooled in a dry ice/acetone bath while back-filling with argon, and the final additions to the sample were made. The material to be injected was weighed into a separate, septum-sealed, argon purged flask and dissolved in Et2O at a concentration appropriate for a standard 0.15 mL injection. The NMR sample (still sealed with a septum) was inserted into the NMR probe, which has been equilibrated to the appropriate temperature, and preliminary spectra were collected to adjust spectrometer tuning, check the quality and concentration of the sample and measure the temperature of the sample using 13C NMR.[S1] The sample was raised, the septum removed, and the open NMR tube was expeditiously lowered into the spectrometer and the apparatus was assembled. 19F RINMR experiments were performed as follows (a more detailed description of the sequence and apparatus has been given[S8*9]). The pulse program was started, which includes10 pre-injection scans set to last about 20 to 30 s. Approximately 10 s prior to the injection the spectrometer temperature setting was raised ca 2 ºC for every 0.1 mL injected to correct for the warming caused by sample injection.[S8*9] After the pre-injection scans, the automated pulse program lowers the apparatus, starts the stirrer and injects the sample, continues stirring for 0.6 s, stops the stirrer, raises the apparatus and continues collecting spectra. Depending on the length of the experiment, spectra were typically taken at 2 to 3 s intervals (T1 for 4-fluorophenyl signals was ca 0.3 s at -125 ºC) for a few min after which a longer time interval between scans (10-30 s) was selected for the remainder of the experiment (up to 3 h). During the course of an experiment the mass balance (reactants + product) was checked using the internal 19F NMR standard as well and agreement was found to be within ±5%. At the completion of the experiment, the temperature of the sample was again checked, and post-kinetics analyses of the sample were performed. Post-kinetic analysis included acquisition and analysis of the resulting product(s) NMR spectra and the determination of NMR yields which agreed within 5% to the theoretical yield. S-19 7Li RINMR of n-BuLi with Ethyl Formate. (ACJ3010) A RINMR sample was prepared containing n-BuLi (0.05 mL, 2.5 M/hexane, 0.125 mmol) in 1 mL of THF and 3 mL of Me2O. A separate flask was prepared containing ethyl formate (1.28 M in Et2O, 0.25 mmol). A 0.2 mL injection was done (Figure S-12). 7Li NMR O Time(sec) H OEt Bu OLi n-BuLi 11,700 1:3 THF/Me O H OEt 2 n -130.5 °C 9,740 12 Diappearance of BuLi dimer 5,940 10 3,170 8 -1 ] (mM) kobs = 0.65 sec 2 6 460 4 -BuLi) n [( 98 2 0 35 0 1 2 3 4 5 6 7 Time (sec) 3.0 3 Dissappearance of BuLi tetramer 2.0 -4 -1 kobs = 1.9 x 10 sec 2 1.0 ] (mM) 4 0.75 -BuLi) n 1 [( 0.5 (n-BuLi)4 (n-BuLi)2 0 0 0 2000 4000 6000 8000 10000 3 2 1 0 Time (sec) ppm Figure S-12. Injection of ethyl formate into a solution of n-BuLi (0.03 M total BuLi) in 1:3 THF/Me2O at -130 °C. The graphs shows the decay of (n-BuLi)2 and (n-BuLi)4 as a function of time. The lines are first order decays with the rate constant shown. S-20 Products from RINMR of n-BuLi with Ethyl Formate. A RINMR sample was prepared containing n-BuLi (2.5 M in hexanes, 0.12 mL, 0.3 mmol). Ethyl formate (0.024 mL, 0.3 mmol) in 0.175 mL of THF was injected at -135 /C. After 30 seconds all of the dimer had reacted and the reaction was quenched with propionic acid (0.029 mL, 0.39 mmol 1.3 equiv) at -135 °C. 7Li spectrum showed no n-BuLi left. The sample was warmed to 25 °C to 1 13 let the Me2O evaporate. Acetone-d6 (0.10 mL to provide an NMR lock signal) was added, and H and C NMR spectra were run on on a 500 MHz Bruker spectrometer equipped with a DCH cryoprobe (Figure S-13). Only signals corresponding to the aldehyde could be seen. Integration vs the ethyl formate signals in the 1H spectrum gave a 40% yield of the aldehyde, essentially 100% based in reaction of only (n-BuLi)2 during the 30 sec time period (see Figure S-9). The presence of any secondary alcohol, from double addition of n-BuLi was ruled out based on the lack of a significant signal at 72 ppm in the 13C NMR spectrum. O Bu OLi O O H EtCO2H Li H OEt n H 3:1 Me2O : THF -135 °C 13C ethyl formate 85 80 75 70 aldehyde x ppm 200 190 180 170 160 150 140 130 120 110 100 90 80 70 ppm 1H ethyl formate aldehyde 10 9 8 7 6 5 4 3 2 1 0 ppm 1 13 Figure S-13. H and C spectra of the reaction of (n-BuLi)2 with ethyl formate after propionic acid quench. No significant signal for the secondary alcohol from double addition (nonan-5-ol) at 72 ppm was detected in the 13C NMR spectrum. S-21 7Li RINMR of n-BuLi with Acetone (ACJ4184). A RINMR sample was prepared containing n-BuLi (0.1 mL, 2.5 M/hexane, 0.25 mmol) in 1 mL of THF and 3 mL of Me2O. A separate flask was prepared containing acetone (0.40 mL, 5.5 mmol) and 1.2 mL each of THF and ether for a 2.3 M solution. A 0.24 mL injection (0.55 mmol) was done (Figure S-14). 7 O Li NMR (n-BuLi)4 Time (sec) LiO Bu (n-BuLi)2 5,050 1:3 THF/Me2O -130.5 °C 2,020 804 14 12 134 k = 0.24 sec-1 10 obs 24.1 ] (mM) 2 8 (n-BuLi)2 -BuLi) 6 n [( 8.0 4 2 5.1 0 0 5 10 15 20 25 30 35 40 45 50 Time (sec) 2.2 0.73 (n-BuLi)4 (n-BuLi)2 0 3 2 1 0 ppm Figure S-14. Injection of acetone into a solution of n-BuLi (0.07 M) in 1:3 THF/Me2O at -135 °C. Several intermediate product 7Li signals were present, presumably various mixed aggregates between n-BuLi and the alkoxide product, but these were not identified. The graph shows the decay of (n-BuLi)2 as a function of time. The line is first order decay with the rate constant shown. S-22 7Li RINMR of n-BuLi with 3-Methoxyacetophenone (ACJ7188). A RINMR sample was prepared containing n-BuLi (0.05 mL, 2.5 M/hexane, 0.125 mmol) in 1 mL of THF and 3 mL of Me2O with PhSiMe3 (0.037 g, 0.23 mmol). A separate flask was prepared containing 3-methoxyacetophenone (0.13 mL, 0.95 mmol) and 435 :L each of THF and ether for a 0.95 M solution. A 0.2 mL injection (0.19 mmol) was done (Figure S-15). 7Li NMR Time(sec) Higher aggregates? O MeO 82 LiO Bu n-BuLi Ar Me 1:3 THF/Me2O n -129 °C 51 Mixed dimer intermediate? 30.5 T = -129.4 °C 20.2 8 9.9 6 obs -1 k D = 0.16 s (mM) 2 4.7 4 -BuLi) n ( 2.7 2 1.6 0 0 10 20 30 40 50 Time (sec) 0.6 (n-BuLi)4 (BuLi)3(BuOLi) (n-BuLi)2 0 3 2 1 0 ppm Figure S-15. Injection of 3-methoxyacetophenone into a solution of n-BuLi (0.03 M) in 1:3 THF/Me2O at -135 °C. If the transient peak at * 1.3 is correctly identified as the mixed dimer (n-BuLi)(ROLi), as seems likely, then it is slightly less reactive towards the ketone than (n-BuLi)2. It is interesting that the signal for (BuLi)3(BuOLi) at * 1.2 was unchanged in this time period. Thus (n-BuLi)2 is substantially more reactive towards the ketone than the mixed alkoxide tetramer. The graph shows the decay of (n-BuLi)2 as a function of time. The line is first order decay with the rate constant shown. Note that significant deviations from first order behavior are seen. S-23 7Li RINMR of n-BuLi with N,N-Dimethyl 3-Methoxybenzamide. (ACJ6049) A RINMR sample was prepared with n-BuLi (0.05 mL, 2.4 M/hexane, 0.12 mol) in 1 mL of THF and 3 mL of Me2O with (Me3Si)3CH (10 :L). A separate flask was prepared with N,N-dimethyl 3-methoxybenzamide (ca 200 :L liquid) (0.24 g, 1.33 mmol) and 0.4 mL each of THF and ether for a 1.3 M solution. A 0.2 ml injection was done with AQ = 0.5 s for 500spectra with a delay of 0 s (See Figure S-16). Propionic acid quench and workup gave 3-methoxyphenyl butyl ketone as product. 7Li NMR t / s O MeO NMe2 18.5 NMe n-BuLi LiO 2 1:3 THF/Me2O Ar Bu 12.9 -129.2 °C 10.6 8 6.2 [MeO-Amide] = 0.08 M 6 T = -129.2 °C 4.5 0.02 mL Injection Warming expected. (mM) BuLi Dimer 3.4 2 4 (c) -BuLi) n [( kobs = 0.2 s-1 2.2 D 2 1.1 0 0 5 10 15 20 0.6 Time (sec) 0 3 2 1 0 ppm Figure S-16. Injection of N,N-dimethyl 3-methoxybenzamide into a solution of n-BuLi (0.03 M) in 1:3 THF/Me2O at -129 °C. The graph shows the decay of (n-BuLi)2 as a function of time. The line is first order decay with the rate constant shown. S-24 7Li RINMR of n-BuLi with Methyl Benzoate. (ACJ5031) A RINMR sample was prepared with n-BuLi (0.08 13 mL, 2.58 M/hexane, 0.26 mol) in 1 mL of THF and 3 mL of Me2O with unlabeled (Me3Si)3CH ( C shift thermometer,[S1a] 0.010 mL). A separate flask was prepared with methyl benzoate (0.6 mL, 4.8 mmol) and 0.7 mL each of THF and ether for a 2.4 M solution. A 0.21 mL injection was done (Figure S-17). A propionic acid quench at the end of the experiment showed methyl benzoate and valerophenone. 7Li NMR O Time(sec) Ph OMe LiO OMe 9,290 n-BuLi Ph Bu 1:3 THF/Me2O n -130.5 °C 5,650 2,380 1,330 15.0 245 90 12.0 64 k = 0.02 sec-1 9.0 obs (mM) 28 2 6.0 -BuLi) n ( 7.2 3.0 2.1 0.0 0.52 0 60 120 180 240 300 360 (n-BuLi)2 (n-BuLi)4 t (sec) 0 3 2 1 0 ppm Figure S-17. Selected spectra from injection of methyl benzoate into a solution of n-BuLi (0.06 M) in 1:3 THF/Me2O at -130 °C. The graph shows the decay of (n-BuLi)2 as a function of time. The line is first order decay with the rate constant shown. S-25 19F RINMR of 4-Fluorophenyllithium (9) with Ester 1 at -110 ºC. (KNP3039) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Ester 1 (0.2 mL, 1.5 M in THF) was injected into the NMR sample containing 9. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at -110 ºC. Spectra and concentration traces are shown in Figure S-18. Additional characterization of the intermediates 3AArLi and (3)2 is shown in Figures S-19. The reaction was quenched with 0.15 mL of propionic acid (3.0 M in THF) using the RINMR apparatus at -110 ºC. 19F, 7Li, 13C and 1H NMR spectra were taken of the final solution. Outside the spectrometer, the reaction was quenched with aqueous NH4Cl. The mixture was extracted with 1:1 ether/hexanes twice. The organic layer was washed with water and brine, dried with MgSO4 and the solvent removed in vacuo, giving 99 % conversion of 9 to ketone 7. F O F2 F2 F OEt Li 3 1.75 equiv. F 1 OEt + F 70 mM OEt Li 1 Li H + Li Li O F1 OO O Li Li 3:1 Me2O:THF EtO F3 F -110 °C F3 2 9M 3 ArLi (3)2 F 7 F F 1 9D 19 3 40 mM F F F2 time (s) 3620 60 394 [1] (3)2 40 185 3 ArLi [(3) ] Concentration (mM) 2 20 62 3 2 1 [3 ArLi] F F F 0 0 1000 2000 3000 10.3 time (sec) 2.1 9D PhF TolF 9M 0 -115 -120 -125 ppm Figure S-18. 19F RINMR experiment of the injection of 1.75 equivalents of ester 1 into a solution of 4- fluorophenyllithium (9) in 3:1 Me2O/THF at -110 °C. S-26 F -110 °C, 3:1 Me2O/THF 180.9 19 150.2 F Li 102.7 O F OEt Li 147.5 158.0 -115 -120 -125 F 3 ArLi ppm 1:2:3:4:3:2:1 septet JCLi=19.5 Hz 13 C C-F 184 182 190 180 170 160 150 140 130 120 110 100 -105 °C, 3:1 Me2O/THF F F 19F 149.5 EtO Li O O 102.8 ester 1 Li OEt 157.2 (3) F 2 F -110 -115 -120 -125 ppm also contains ester 1, 4-fluorobenzene and benzene tetrahedral C 13C aryl quaternary C C-F 190 180 170 160 150 140 130 120 110 100 ppm Figure S-19. 13C and 19F NMR spectroscopic characterization of intermediates in the reaction of 1 with 4- fluorophenyllithium (9). S-27 19F RINMR of 4-Fluorophenyllithium (9) with Ester 1 at -97 ºC. (KNP3271, 3273) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Ester 1 (1.25 equiv., 44.5 mg in 0.16 mL of THF; 8 equiv., 0.22 g) was injected into the NMR sample containing 9. The reaction was monitored by 19F NMR with AQ = 1 s for 1000 spectra with a delay of 1 s, and 490 spectra with a delay of 180 s at -97 ºC. Sample spectra are shown in Figure S-20, kinetic traces in Figure S-21. O 2 F F2 OEt Li 3 F F3 OEt OEt 1 Li F 1 1.25 equiv Li OO O F1 Li O k Li k EtO ArLi MD F3 kTD F F3 3:1 Me2O:THF (3) 2 F2 9 -97 °C 3 ArLi 2 F 7 (3)2 7 3 2 3 2 F F F F time (s) 19 (LiOEt)n time (s) 1 F 37651 3 ArLi 581 time (s) F3 F2 F1 28548 214 9.2 19445 6.1 153 1 92 8521 3.1 3 ArLi (3)2 9D PhF TolF 4880 0 9M 30.6 -115 -120 -125 ppm -115 -120 -110 -115 -120 Figure S-20. 19F RINMR of the injection of 1.25 equivalents of ester 1 into a solution of 4-fluorophenyllithium (9) in 4 mL of 3:1 Me2O/THF at -97 ºC. S-28 25 25 [1] = 51 mM, [9] = 40 mM [3 ArLi] = 20 mM k = 0.35 s -1 M-1 20 20 MD [9D] [3 ArLi] [1] = 31 mM 15 15 -1 [3 ArLi] kArLi = 0.3 s 10 10 [3 ArLi] conc (mM) conc conc (mM) conc [9M] 5 5 [1] = 300 mM 0 0 0 5 10 15 0 20 40 60 80 100 time (s) time (s) (a) First phase (complete in ca 15 s): reaction of (b) Second phase (complete in several min): ArLi 9 with ester 1 to form 3AArLi. The red line is a reaction of 3AArLi with two different first order rate simulation of the increase in [3AArLi] concentrations of ester ( [1] = 31 mM and [1] = -1 with k = 0.3 s . The rates are too fast and there are 300 mM) to form (3)2. The red lines are second not enough data points to determine order in ester, order rate simulations with k = 0.35 s-1 M-1. The but qualitatively higher ester concentration leads to reaction follows approximate second order faster formation of 3AArLi. kinetics. 30 25 [1] = 11 mM, [(3)2] = `0 mM [1] = 281 mM, [(3)2] = 10 mM 25 -5 -1 k = 5.6 x 10-5 s -1 kTD = 5.6 x 10 s 20 TD 20 [7] 15 [7] 15 10 conc (mM) conc 10 (mM) conc [(3) ] [(3)2] 5 2 5 0 0 0 15000 30000 0 15000 30000 time (s) time (s) (c) Third phase (complete in ca 20 hours): decomposition of dimeric tetrahedral intermediate (3)2 to ketone 7 with either 10 mM or 280 mM excess ester 1 present. The red lines correspond to first order decay or increase with k = 5.6 × 10-5 s-1. Thus decomposition of the tetrahedral intermediate is unimolecular and is not affected by the concentration of ester. Figure S-21. Concentration plots from RINMR of the injection of 1.25 (See Figure S-20) and 8 equivalents of ester 1 into a solution of 9 in 4 mL of 3:1 Me2O/THF at -97 ºC. Time vs. concentration plots are shown for each reaction separately. The red lines are first (parts a and c) and second (part b) order decay or appearance curves with the rate constants shown. The reaction of 3AArLi with 1 is first order in ester. The decomposition of (3)2 to ketone 7 is unaffected by ester concentration. S-29 Diffusion Ordered NMR Spectroscopy (DOSY). DOSY experiments were performed on a Bruker AVANCE DMX-360 equipped with a GRASP II z-axis gradient amplifier and a 5mm BBO probe with z-axis gradients (10mm tubes, and therefore RINMR experiments, were not possible due to the lack of gradients on the 10mm probe). Maximum gradient strength was 40 G/cm. Pulse sequence (DSTE-BP-CC) included stimulated echoes, bipolar sine- shaped gradients, longitudinal eddy current delays and convection compensation. 19 F DOSY of Tetrahedral Intermediate 3AArLi and (3)2. (KNP3253) A 5 mm NMR tube was sealed with a septum and parafilm, purged with argon and cooled in a dry ice/acetone bath. Me2O (0.7 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). 4-Fluorotoluene (2 µL), (4-fluorophenyl)trimethyltin (15 µL, 0.09 mmol) and n-BuLi (0.03 mL, 0.07 mmol, 2.5 M in hexanes) were added to the NMR tube at -78 °C. The sample was inserted into a precooled NMR spectrometer (-115 °C) and allowed to equilibrate. Optimization of the shims based on the FID of C-3 of THF was performed. The RINMR apparatus was not available on this spectrometer, so the sample was ejected and frozen with liquid N2. Under liquid N2, Et2O (0.05 mL) and ester 1 (7 mg in 0.05 mL Et2O) were layered on the sample and immediately frozen. The septa was removed and the sample inserted into a NMR spectrometer precooled to -150 °C manually with low lift air to minimize warming and glass rod to facilitate mixing. The sample was allowed to warm to -115 °C over 1 hour. 19F DOSY spectra were recorded with varying gradient strength (ns = 64, ds = 4, aq = 2, rg = 300, d1 = 8, d20 = 0.1 s, p30 = 3ms, d16 = 0.1 s). Individual rows of the diffusion sets were phased and baseline corrected.. The integrations were plotted vs. gradient strength (Stejskal-Tanner plot, Figure S-22a), and the slope of this line was taken as an estimation of diffusion. A log-log plot of diffusion as a function of formula weight was used to estimate the formula weight of the tetrahedral intermediate 3 and is shown in Figure S-22b. In DOSY, the diffusion coefficients of molecules in solution are measured by fitting peak areas to the Stejskal-Tanner equation for the pulse sequence (Equation S-1)[S-9] and can provide their relative particle size. The Stokes-Einstein equation (Equation S-2) theoretically correlates diffusion coefficients and molecular radii. Williard has shown through examination of solid-state X-ray crystal structures that the densities of organolithium aggregates are very simliar (about 1.0 g/cm3) and are relatively spherical.[S-10] Therefore, it is assumed that the volume of the aggregate is proportional to the formula weight. The diffusion coefficient obtained from a DOSY experiment can be related to formula weight (FW) by Equation S-3. Taking the logarithm of both sides yields a linear correlation between measured diffusion coefficients and the formula weight of the aggregates (Equation S- 4). A calibration curve can be established from the use of molecules with known formula weight in solution. Extrapolation of the curve allows empirical formula weights of molecules of unknown aggregation state like tetrahedral intermediate (3)n to be calculated. 2 2 2 ln(I /I0) = -G ( * [D + 4*/3 + 3J/2]D Equation S-1 where I = intensity of a given peak, I0 = intensity at a very small gradient value, G = gradient strength, ( = gyromagnetic ratio, * = length of the bipolar gradient pulse, D = time between pulses, J = gradient ringdown delay and D = diffusion coefficient D = kT/6B0r Equation S-2 where D = diffusion coeffiecient, k = the Boltzman constant, T = temperature in Kelvin, 0 = the viscosity of the solution and r = the radius of the molecular sphere D . FWa Equation S-3 log(D) = a log(FW) + b Equation S-4 While DOSY experiments have been applied to organolithium species with nuclei such as 1H, 6Li, 7Li, 13C, 31P, and 29Si nuclei,[S-11] 19F diffusion analysis is more rare[S-12] but similar to 1H DOSY pulse sequences due to their similar high natural abundance and gyromagnetic ratio. Previously published DOSY experiments were performed at temperatures at or above -85 °C. However, our studies of reactive intermediates mixed dimer 3AArLi and the tetrahedral intermediate 3 must be performed at temperatures below -100 °C to avoid alkoxide elimination to form benzophenone. At these low temperatures, the higher viscosity of the solvent restricts diffusion and convection currents associated with temperature gradients form. To avoid these complications, an ethereal solvent mixture that is largely composed of non-viscous Me2O (no THF, approx. 1.0:0.1 Me2O/Et2O) and a convection compensated pulse program (DSTE-BP-CC) was used.[S-9] The 19F NMR signals of fluorobenzene, 4-fluorotoluene, (4-fluorophenyl)trimethyltin), mixed dimer 3AArLi, S-30 and tetrahedral intermediate 3 are well separated. In a series of experiments, the gradient field was incremented with the DSTE-BP-CC 19F pulse program. The peak areas by integration were determined and decay curves (area vs. gradient strength squared) were generated. The decay curves were linearized (Figure S-22a), but the absolute diffusion coefficients were not calculated. Instead, the slopes of the decay curves were used as a relative estimation of diffusion (“D”) and plotted as a function of formula weight, as defined by Equation S-4 (Figure S- 22b). The correlation between log FW and log “D” of the linear least-squares fit to the molecules of known molecular weight is high (R2 = 0.9955). Formula weights were estimated with minimal solvation using the most polar solvent available to the lithium, Me2O. Extrapolation of the measured diffusion values to the known line confirms the mixed dimer structure for 3AArLi (FW = 464.28 for bis-Me2O solvate, measured: 512.6) and dimer structures for (3)2 (FW = 632.5 for bis-Me2O solvate, measured: 559.3). (a) 0 Legend PhF y = -0.00154 x - 0.0137 -1 TolF y = -0.00138 x - 0.0624 ) -2 Sn y = -0.000529 x - 0.0105 0 3 ArLi y = -0.000480 x - 0.112 ln (I/I -3 y = -0.000530 x - 0.0274 -4 y = -0.000817 x - 0.0485 -5 (3)2 y = -0.000526 x - 0.0272 0 1000 2000 3000 4000 5000 6000 y = -0.000513 x - 0.0205 Squared Gradient Strength (a.u.) (b) -2.5 F F SnMe3 -2.6 FW = 96.1 EtO FW = 258.9 Li OO -2.7 Li F OEt CH 3 F -2.8 ) F F -2.9 "D" (3)2 (+ 2 Me2O) F FW = 632.5 log ( FW = 110.1 -3.0 (Observed: 559.3) F -3.1 F F -3.2 EtO Li Li O O -3.3 O F OEt R Li OEt Li O Li Li F -3.4 F O OEt 3 ArLi (+ 2 Me2O) F FW = 464.28 (Observed: 512.6) -3.5 F F 1.5 2.0 2.5 3.0 3.5 log (FW) (3)4 (+ 4 Me2O) FW = 1265.1 19 Figure S-22. (KNP3254) Results of F DSTE-BP-CC DOSY experiment in 1.0:0.1 Me2O/Et2O at -115 °C on 3AArLi, (3)n and reference compounds fluorobenzene (PhF), 4-fluorotoluene (TolF), (4-fluorophenyl)trimethyltin (Sn). (a) Stejskal-Tanner plot of experimental peaks and their best fit lines. Three lines and points are shown for 3AArLi, and two for 3 for the behavior of each individual 19F signal. The nearly identical diffusion rates for the multiple fluorines of each product shows that the signals are in the same molecule. (b) Log-log plot of diffusion as a function of formula weight. The diffusion points for 3 are also plotted with molecular weights corresponding to both dimer (3)2 and tetramer (3)4 . S-31 19F RINMR of 4-Fluorophenyllithium (9) with Amide 2 at -110 ºC. (KNP3036) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. A solution of amide 2 (0.2 mL, 1.5 M in THF) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 600 spectra with a delay of 10 s at -110 ºC. Data is shown in Figure S-23. The build-up of PhF during the reaction, the greater loss in [9] than of [2], as well as the complexity of the products suggest that some competing metalation of 2 and/or 10 was occurring during the reaction, but such products were not characterized. Analysis of the final solution after protic quenching showed 60% conversion of 9 to ketone 7. (10)n F O F NMe2 19 Li F LiO NMe2 time (sec) 2 75 mM F + Li Li 3620 3:1 Me2O:THF F 10 ArLi? F -111 °C n (10) 9M n F 9D ca 65 mM 390 185 60 62 [2] 40 10.3 [(10) ] n 2 20 Concentration (mM) [9] 2.06 (M + D) 9D 0 PhF TolF x 9M 0 500 1000 1500 2000 2500 3000 3500 0 time (sec) -115 -120 -125 ppm Figure S-23. 19F RINMR experiment of the injection of amide 2 into a solution of 4-fluorophenyllithium (9) in 3:1 Me2O/THF at -110 ºC. The concentrations of 9 and 10 are given in monomer units (normality). There are several tetrahedral intermediates at the end of the experiment, presumably the major two peaks correspond to the dimer [S12] (10)2, as also found for (3)2, and for the crystal structure of a bis-THF-solvate of the bisphenyl analog of 10. Three minor peaks may be the mixed dimer 10AArLi. S-32 19F RINMR Competition Experiments between Amide 2 and Ester 1. (KNP3061, 3063, 3069, 3071) 4- Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. A pre-mixed solution of amide 2 or 2-d (0.67 g, 0.4 mmol) and ester 1 or 1-d (0.67 g, 0.4 mmol) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at -110 ºC. The sample was quenched with of 0.15 mL of propionic acid (3.0 M in THF) at -110 ºC. 19F, 7Li, 13C and 1H NMR spectra were taken of the final solution. Results are shown in Table S-2 and Figure S-24. Outside the spectrometer, the reaction was quenched with aqueous NH4Cl. The mixture was extracted with 1:1 ether/hexanes twice. The organic layer was washed with water and brine, dried with MgSO4 and the solvent removed in vacuo. The relative ratios of products and remaining starting 19 1 materials were determined by F{ H} NMR integration with CDCl3 as a solvent. Conversion was calculated by dividing the sum of the products by the sum of the products and starting materials. Table S-2. Results of Competition Experiments of Ester 1 And Amide 2 in Reaction with 4-Fluorophenyllithium Ester 1-d Ketone 7-d Alcohol 8-d Amide 2 Ketone 7 k(amide)/k(ester) KNP3063 271.94 180.00 0.00 100.00 16.67 0.30 KNP3061 171.75 139.75 0.00 88.94 19.46 0.33 Ester 1 Ketone 7 Alcohol 8 Amide 2-d Ketone 7-d k(amide)/k(ester) KNP3069 20.45 13.94 0.00 20.05 1.97 0.18 KNP3071 4.81 6.14 0.00 8.65 1.00 0.13 Average 0.21 D O F D O O F kamide / kester = 1/4.8 F F OEt Li NMe2 + F 7-d F + Li Li 2-d 1 + O HO F 3:1 Me2O:THF F F 9M -110 °C + F F F 9D 7 8 0.5 equiv. Figure S-24. RINMR competition reaction between amide 2-d and ester 1 with 0.5 equivalents of 4- 19 fluorophenyllithium (9) in 3:1 Me2O/THF at -110 °C. The numbers are arbitrary peak areas in F NMR spectra. S-33 19F RINMR of Excess 4-Fluorophenyllithium (9) with Ester 1 at -120 ºC. (KNP3097) 4- Fluorophenyllithium (9) (0.6 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Ester 1 (0.025 mmol, 0.05 mL, 0.5 M in THF) was injected into the NMR sample. The concentrations reported in Figure S-25 are those measured in the actual sample using an internal standard. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at - 120 ºC. An equal second portion of ester 1 was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at -120 ºC. F O F OEt Li 10 mM F 1 Li + Li Li O F OEt Li 3:1 Me2O:THF F -120 °C 3 ArLi 9M F F 9D 25 25 Second injection of 1: [ArLi] = 90 mM First injection of 1: [ArLi] = 114 mM 20 20 3 ArLi 15 15 k = 0.065 s-1 3 ArLi 10 10 k = 0.065 s-1 1 Concentration (mM) Concentration (mM) 5 5 1 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 time (s) time (s) Figure S-25. Time vs. concentration plots for the reaction of 4-fluorophenyllithium (9) with two portions of ester 1 in 3:1 Me2O/THF at -120 ºC to form 3AArLi. Both rates are identical within experimental error. The Blue and red lines correspond to first-order increase/decrease with k = 0.065 s-1. Thus the mixed aggregate products do not catalyze or inhibit the reaction between 9 and 1. S-34 19F RINMR of Excess Mixed Dimer 3AArLi with Ester 1 at -120 ºC. (KNP3097) Continuing with sample from above experiment, several portions ester 1 were injected into the NMR sample containing 4- fluorophenyllithium (9) at -120 ºC until conversion to mixed dimer 3AArLi was complete. Solution concentration of 3AArLi was measured at 62 mM, and this solution was used for two kinetic experiments to determine the reactivity of the mixed dimer. One portion of ester 1 (0.025 mmol, 0.05 mL, 0.025 M in THF) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 390 spectra with a delay of 10 s at -120 ºC. A second equal portion of ester 1 was injected into the NMR sample and the reaction was similarly monitored. Concentrations were measured by comparison of 19F integrations with the internal standard 4-fluorotoluene. Results are reported in Figure S-26. F O F F OEt 6 mM EtO Li Li O F F 1 OO Li Li OEt OEt 3:1 Me2O:THF 3 ArLi -120 °C (3) F F 2 F 10 10 First injection of 1: [3 ArLi] = 62 mM Second injection of 1: [3 ArLi] = 56 mM 8 8 6 6 4 11-1 ] (mM) ] (mM) 4 1 -1 k = 0.0008 s [ 1 k = 0.0008 s [ 2 2 0 0 0 1000 2000 3000 4000 5000 0 1000 2000 3000 4000 5000 time (s) time (s) Figure S-26. Time vs. concentration plots for the reaction of preformed mixed dimer 3AArLi with ester 1 in 3:1 Me2O/THF at -120 ºC. Two consecutive injections of ester gave the same rate constant within experimental error, so no obvious acceleration or inhibition by the product (3)2. S-35 19F RINMR of Excess 4-Fluorophenyllithium (9) with Amide 2 at -120 ºC. (KNP3100) 4- Fluorophenyllithium (9) (0.6 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. The concentration of 9 was measured at 124 mM. A solution of amide 2 (0.025 mmol, 0.05 mL, 0.5 M in THF) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at -120 ºC. A second equal portion of amide 2 was injected into the NMR sample and the reaction was similarly monitored. Concentrations were measured by comparison of 19F integrations with the internal standard 4-fluorotoluene. Results are reported in Figure S-27. F O F NMe2 Li F 2 10 mM OLi + Li Li NMe2 3:1 Me2O:THF F -120 °C 9M n F F 9D (10)n 6 Second injection of 2: [ArLi] = 95 mM 5 First injection of 2: [ArLi] = 124 mM 5 4 [2] 4 [2] k = 0.0003 s-1 3 k = 0.0004 s-1 3 ] (mM) ] (mM) 2 2 [ [ 2 2 1 1 0 0 0 1000 2000 3000 4000 5000 6000 7000 8000 0 2000 4000 6000 8000 10000 time (s) time (s) Figure S-27. Time vs. concentration plots for the reaction of 4-fluorophenyllithium (9) with two portions of amide 2 in 3:1 Me2O/THF at -120 ºC. The red lines are first-order traces with the rate constants shown. No significant inhibition or catalysis of the addition to amide 2 was detected. S-36 19F RINMR of Excess Mixed Dimer 3AArLi with Amide 2 at -120 ºC. (KNP3102) A solution of 4- fluorophenyllithium (9) ( ca 0.7 mM) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Ester 1 was injected in 0.1 mmol increments at -120 ºC and the reaction was monitored by 19F NMR until conversion of ArLi to mixed dimer 3AArLi was complete (34 mM, as measured by NMR integration). A solution of amide 2 (0.025 mmol, 0.05 mL, 0.5 M in THF) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 100 spectra with a delay of 1 s, and 390 spectra with a delay of 10 s at -120 ºC. A second equal portion of 2 was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 100 spectra with a delay of 1 s, and 390 spectra with a delay of 10 s at -120 ºC. Results are reported in Figure S-28. A summary of the kinetic experiments with 3AArLi is shown in Figure S-29. O F F F NMe2 F 2 7 mM OEt Li OLi OLi O F Li 3:1 Me2O:THF NMe2 OEt F -120 °C F F 3 ArLi n n 10 10 9 First injection of 2: [3 ArLi] = 34 mM 9 Second injection of 2: [3 ArLii] = 26 mM 8 8 7 k = 0.0002 s-1 7 k = 0.0004 s-1 6 6 2 5 5 ] (mM) ] (mM) 4 2 4 [ 2 [ 3 3 2 2 1 1 0 0 0 1000 2000 3000 4000 5000 6000 0 2000 4000 6000 8000 time (s) time (s) Figure S-28. Time vs. concentration plots for the reaction of mixed dimer 3AArLi with two portions of amide 2 in 3:1 Me2O/THF at -120 ºC. The red lines are first-order traces with the rate constants shown. The rate difference in the two injections may be outside experimental error. S-37 F F F Li O O OEt OEt B EtO + A OEt Li + Li O F -1 OO -1 kobs = 0.0008 s Li kobs = 0.065 s Li OEt F F F 3 ArLi 1 9 1 (3)2 + F F F O NMe2 2 F -1 B kobs = 0.0004 s Li O F NMe2 A + -1 OLi kobs=0.0004 s F F NMe2 F n 9 2 (10)n Figure S-29. Scheme detailing reactions occurring in competition experiments between ester 1 and amide 2. In the initial additions (reactions A: 9 + 1 / 2) the ester is about 160 times as fast (Figure S-25 and S-27), so when both 1 and 2 are present, more than 99% of the reaction should form 3AArLi. In the second phase (reactions B in the scheme: 3AArLi + 1 / 2 ) the ester is only twice as fast as the amide (Figures S-26 and S-28). Observed rate 19 constants are from F RINMR injections of electrophile into lithium reagent at -120 °C in 3:1 Me2O/THF. S-38 19F RINMR of PMDTA Complex 9M-P with Ester 1. (KNP3209) A solution of PMDTA monomer of 4-fluorophenyllithium (9M-P, 0.03 M in 4 mL of 3:1 Me2O/THF) was prepared using the typical RINMR sample preparation procedure. Ester 1 (50 mg in 0.2 mL of THF, 0.3 mmol) was injected into the NMR sample containing 9. The reaction was monitored with AQ = 1 s for 150 spectra with a delay of 1 s, and 340 spectra with a delay of 10 s at -110 ºC. 19F, 7Li, 13C and 1H NMR spectra were taken of the final solution (94% conversion). Results are reported in Figure S-30. (10% excess PMDTA) O N F F N F OEt N N N N Li Li OEt O 2.5 equiv. Li EtO F 1 + O F + Li OEt Li OO Li OEt 3:1 Me2O:THF F F -110 °C F F 9M-P 3 PMDTA 3 ArLi F (3)2 F (3)2 19F 1 time (s) (3)2 3 PMDTA 7949.4 144.2 3 ArLi 40 3537.4 1 (3)2 3 PMDTA 20.6 1331.4 3 ArLi 9M-P PhF TolF 9M-P 0 779.9 -110 -115 ppm -120 -125 -110 -115 -120 -125 Figure S-30. 19F RINMR of PMDTA monomer 9M-P with excess ester 1 in the presence of 1.1 equivalents PMDTA in 3:1 Me2O/THF at -110 °C. With a small excess of PMDTA the dissociation of 9M-P to form THF- solvated 9 is competitive with the reaction of 9M-P with the ester 1, leading to a mixture of 3APMDTA, 3AArLi, and (3)2. Eventually almost all of the PMDTA is expelled to give (3)2. S-39 19F RINMR of PMDTA Complex 9M-P with Ester 1 with excess PMDTA. (KNP3196) A sample of 4- fluorophenyllithium (9) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. PMDTA (0.180 mL, 0.9 mmol) was added, the concentration of 9APMDTA was measured as 31 mM. A solution of ester 1 (50 mg in 0.2 mL THF, 0.3 mmol) was injected into the NMR sample. The reaction was monitored by 19F NMR with AQ = 1 s for 150 spectra with a delay of 1 s, and 340 spectra with a delay of 10 s at - 110 ºC. Sample spectra and concentration plots are shown in Figure S-31. O N F F N F OEt N N N N Li Li EtO EtO O Li 1 2.4 equiv. F + OO Li 3:1 Me O:THF OEt 2 F F -110 °C F F 3 PMDTA (3) 9M-P 2 19 1 F (3)2 time (s) 3 PMDTA time (s) 144 7612 30 -1 kobs= 0.0023 s t1/2 = 290 s [9M P] 4410 30.9 20 [3 PMDTA] [(3)2] (3)2 Conc (mM) 10 2.1 1997 3 PMDTA 0 9M P 0 1000 2000 3000 4000 time (s) PhF TolF 0 791 -115 -120 -125 -115 -120 -125 ppm ppm Figure S-31. (KNP3196) 19F RINMR of PMDTA monomer 9M-P with ester 1 in the presence of ca 6 equivalents -1 of PMDTA in 3:1 Me2O/THF at -110 °C. The red line represents first order decay of 9MAP with k = 0.0023 s . S-40 Long Term Observation of the Reaction of 9M-P with Ester 1. (KNP3226) A solution of 4-fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. PMDTA (0.18 mL, 0.9 mmol) was added. A solution of ester 1 (50 mg in 0.2 mL THF, 0.3 mmol was injected into the NMR sample. The reaction was monitored by 19F NMR with AQ = 1 s for 20 spectra with a delay of 1 s, and 470 spectra with a delay of 180 s at -110 ºC. Results are reported in Figure S-32. O F F F F F N OEt N N N Li OEt EtO 1 2.4 equiv. Li Li N O O O O Li F OEt 3:1 Me2O:THF F N F F F -110 °C 9M-P (3) 3 PMDTA 2 7 19 F NMR (3) time (s) 2 time (s) 18247 7 66129 12785 58300 7324 49197 3 PMDTA 1862 41915 3 PMDTA 2.06 29171 (3)2 9M-P 0 23709 PhF TolF -110 -115 -120 -125 -105 -110 -115 -120 ppm Figure S-32 19F RINMR (long term observation) of monomeric PMDTA complex 9M-P with ester 1 in 3:1 Me2O/THF at -110 °C in the presence of 200% excess PMDTA. No significant amount of 3AArLi was formed. Ketone formation began before equilibrium between 3APMDTA and (3)2 was reached. S-41 19F RINMR of 4-Fluorophenyllithium (9) with Ethyl Formate. (KNP3278a) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Ethyl formate (40 mg in 0.2 mL THF, 0.5 mmol) was injected into the NMR sample containing 9. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 0.3 s, and 290 spectra with a delay of 10 s at -137 ºC. Results are reported in Figure S-33. F O F Li H OEt + Li Li 2 equiv. Li O F 3:1 Me O:THF F + several other products 2 H OEt Li -137 °C 9M F 9D 11 ArLi 19F time (s) time (s) 6.8 2430 other products 4.1 122 11 ArLi? 2.7 54 1.4 27 9D 9M TolF PhF 0 13.6 -115 -120 -125 -115 -120 -125 Figure S-33. 19F RINMR of the injection of two equivalents of ethyl formate into a solution of 4- fluorophenyllithium (9) in 3:1 Me2O/THF at -137 °C (the rate at -137 °C is similar to rate of addition to 1 at -110 °C. The rate of addition of 9 to ethyl formate is, as expected, faster than addition to ester 1, but slower than reaction with ketone 5 (Figures S-40 and S-42 below). However, the addition of 9 is slower than interconversion of 9M and 9D, so no direct information about which aggregate reacts can be obtained (Curtin-Hammett). The marked peaks were assigned to the mixed dimer 11AArLi, which was not further characterized. As was seen with the mixed dimer 3AArLi, the proposed 11AArLi is also less reactive than is 9. Several other unidentified intermediates were also formed. S-42 19F RINMR of 4-Fluorophenyllithium (9) with Methyl Trifluoroacetate. (KNP3294, 3185 higher temperature) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. Methyl trifluoroacetate (45 mg in 0.2 mL 1:1 Et2O/THF) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 0.3 s, and 200 spectra with a delay of 10 s at -130 ºC (Figure S-33a). The sample was warmed to -78 ºC and 19F, 6Li, and 13C NMR spectra were taken. The main product was a 1:1 mixture of two tetrahedral intermediates, as shown by the doubling of most peaks in the 19F and 13C NMR spectra (Figure S-34b). The sample was quenched with aqueous NH4Cl, extracted with ether, dried over MgSO4, filtered and rotary evaporated, yielding trifluoromethyl 4- fluorophenyl ketone (95%). Results are reported in Figure S-34. F OMe O F C Ar = F Li 3 Ar F C OMe 3 O Li OMe + Li F3C Ar 5 equiv. Li Li F3C Ar F O 3:1 Me2O:THF OLi -130 °C (a) 9M n F 9D (12) 19F NMR F n 12 ArLi time (s) 2553 1280.8 40.8 CF3 products Possible 12 ArLi slow rotation around C-CF bond 27.2 3 O 4.08 F3C OMe 9D 9M PhF 0 TolF -80 -90 -100 -110 -120 -130 (b) 13 C NMR CF m-F 3 3:1 Me2O:THF o-F -130 °C quat C aryl C-F tet. C 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 19 Figure S-34. (a) F RINMR of the injection of 5 equivalents of CF3CO2Me into 4-fluorophenyllithium (9) in 3:1 Me2O/THF at -130 °C. The CF3 fluorines in the tetrahedral intermediates are non-equivalent due to slow rotation of the CF3 group. This is not a special property of the lithium species due to Li-F bonding, since rotation is also slow in the related lithium alkoxide Q13-Li (Figure S-35), the alcohol Q13-H and the methyl ether Q13-Me (Figure S-36). (b) 13C NMR of the reaction solution before the final quench. S-43 Lithium alkoxide of 2,2,2-Trifluoro-1,1-bis(4-fluorophenyl)ethan-1-ol (13-Li). A solution of 13-Li was prepared by addition of 13-H (0.05 g, 0.17 mmol) to a 10 mm NMR tube that was sealed with a septum, and parafilm, and purged with argon. Freshly distilled THF (1 mL) was added and the tube was cooled in a dry ice/acetone bath. Me2O (3 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). The 13C chemical shift thermometer (10% 13C labeled tris(trimethylsilyl)methane, 0.002 mL),[S1a] an internal standard for concentrations (2,6-dimethyl-1- fluorobenzene, 0.005 mL), and n-BuLi (0.08 mL, 0.2 mmol, 2.5 M/hexane) were added to the NMR tube at -78 /C. 2,2,2-Trifluoro-1,1-bis(4-fluorophenyl)-1-methoxy-ethane (13-Me). NaH (60% dispersion in mineral oil, 180 mg, 4.6 mmol) was added portionwise to a solution of 2,2,2-trifluoro-1,1-bis(4-fluorophenyl)ethan-1-ol (1.2g, 4.16 mmol) in DMF (8 mL) at 0 °C. The solution was warmed to room temperature and stirred for 20 min. Methyl iodide (0.29 mL, 4.6 mmol) was added dropwise and the mixture stirred for 2 h. The mixture was poured into a mixture of Et2O and H2O (30 mL each) and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure to give 13-Me as a colorless oil (1.26 g, 4.16 mmol, 100%) that was used without any further purification. MeO CF3 LiO CF HO CF3 3 F Ar Ar NaH, MeI n-BuLi F F F F F F F F O ? Li 13-Me 13-H 13-Li 14 Restricted Rotation of Trifluoromethyl Group. A variable temperature NMR study of 13-Li is shown in Figure S-35. The appearance of a 1:2 ratio of doublet and triplet below -100 °C indicates slow rotation around the F3C-C bond. Below -120 °C the upfield signal begins to split into two signals, most reasonably interpreted in terms of a desymmetrization of the otherwise symmetric structure, perhaps by Li-F interactions with one of the fluorines, as in structure 14. The upfield signal appears broader, perhaps due to Li-F J-coupling, although no coupling could be resolved at accessible temperatures. Although other explanations are also possible, the relatively sharp Ar-F signal at * -188 argues against an explanation involving slow exchange between multiple aggregates. A Li-F interaction is not the principal reason for the slow rotation of the CF3 group in Q13-Li, since the alcohol Q13-H also shows decoalescence of the fluorine signals at a similar temperature. A F-H hydrogen bond is not the principal reason for this slow rotation, since the methyl ether Q13-Me also shows slow rotation (Figure S- 36). S-44 F LiO CF3 Ar-F 19F CF 3 F F 29 °C 13-Li -34 °C -56 °C -67 °C -74 °C -84 °C -95 °C 2.01 1.00 -108 °C -122 °C -129 °C -135 °C -65 -70 -75 -80 -85 ppm -117 -118 -119 -120 -121 -122 -123 -124 ppm 19 Figure S-35. Variable temperature F NMR study of 13-Li in 3:1 Me2O:THF. S-45 HO CF3 Ar-F F F 13-H -73 °C CF3 -96 °C 2.03 1.00 -120 °C -128 °C -68 -70 -72 -74 -76 -78 -80 -114 -116 -118 -120 -122 -124 ppm ppm MeO CF3 -120 °C F F 13-Me 1.78 1.00 -65 -70 -75 -80 -85 -116 -118 -120 -122 -124 ppm ppm 19 Figure S-36. Low temperature F NMR spectra of Q13-H and Q13-Me in 3:1 Me2O:THF. S-46 19F RINMR of 4-Fluorophenyllithium (9) with S-iso-Propyl 3-Fluorobenzothioate. (KNP3298) 4- Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. S-iso-Propyl 3-fluorobenzothioate (45 mg in 0.2 mL THF, 0.45 mmol) was injected into the NMR sample containing 9. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 0.3 s, and 290 spectra with a delay of 10 s -130 ºC. The sample was stored overnight at -78 ºC and 19F NMR spectra were taken. The sample was quenched with aqueous NH4Cl, extracted with ether, dried over MgSO4, filtered and rotary evaporated, yielding the tertiary alcohol (95%). Spectra are shown in Figure S-37. F O F Ar Ar Li S F Ar F Ar O + Li Li 2.5 equiv. O Li Li + Li Li (15)n F 3:1 Me2O:THF O 9M -130 °C F Ar F 9D Ar F 19 Ar = F F 15 ArLi (15)2 PhF TolF time (s) after warming 54 to -78 °C (15)2 (15)2 15 ArLi time (s) 16.3 2430 thioester 5.4 122 9D 12 ArLi? PhF 9M TolF 0 82 -115 -120 -125 ppm -115 -120 -125 Figure S-37. 19F RINMR of the injection of 1.5 equivalents of S-iso-propyl 3-fluorobenzothioate into a solution of 9 in 4 mL of 3:1 Me2O/THF at -130 °C. The two intermediates where identified as the mixed dimer 15AArLi 19 (1:2:1 ratio of F peaks) and the homodimer (15)2 (1:2 ratio of signals) of the tertiary alkoxide 15 formed by double addition of ArLi to the thioester. No tetrahedral intermediates were detected. These assignments were supported by an experiment in which two of the same intermediates ( 15AArLi and (15)2) were formed by addition of 9 to 3,4'-difluorobenzophenone (7) (Figure S-38). Both intermediates are metastable, since they disappeared on warming to -78 °C, being replaced by a complex set of resonances. S-47 19F RINMR of 4-Fluorophenyllithium (9) with 3,4'-Difluorobenzophenone (7). (KNP3300) 4- Fluorophenyllithium (9) (0.15 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. 3, 4'-Difluorobenzophenone (31 mg in 0.2 mL 1:1 Et2O/THF, 0.15 mmol) was injected into the NMR sample. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s at -124 ºC. Results are reported in Figure S-38. Injection of LiS-i-Pr into the end solution at -124 °C formed no new fluorine-containing species, although additional species were formed when the sample was warmed above -90 °C. O Ar F Ar Ar F Ar = F Li Ar F F Ar O 7 O F Ar Li Li Li Li OLi O 3:1 Me2O:THF F -124 °C Ar F (15)1 9 Ar F (15) (15) 1 15 ArLi 2 (15)2 time (s) (15)2 7 time (s) 41.2 3910 15 ArLi 1497 10.3 (15) 1 (15)1 391 2.1 7 15 ArLi PhF 9D 9M TolF 185 0 -105 -110 -115 -120 -125 ppm -105 -110 -115 -120 -125 19 Figure S-38. F RINMR of the injection of 3,4'-difluorobenzophenone (7) into a solution of 9 in 3:1 Me2O/THF at -124 °C. The kinetic product is the alkoxide monomer (15)1 (thus 9M is probably the reactive ArLi species), which then forms both mixed dimer 15AArLi and the homodimer (15)2. S-48 19F RINMR of 4-Fluorophenyllithium (9) with Excess 3-Fluoroacetophenone (5) at -115 °C. (KNP3188) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. 3-Fluoroacetophenone (0.40 g in 0.2 mL THF, 0.6 mmol) was injected into the NMR sample at -115 °C. The reaction was monitored with AQ = 1 s for 100 spectra with a delay of 1 s, and 390 spectra with a delay of 30 s at -115 ºC. 19F, 7Li, 13C and 1H NMR spectra were taken of the final solution. Spectra are shown in Figure S-39. F O F F F F Me Li Me Me Li Li + Li Li O F 5 2.0 equiv. + F OO Li + Li OLi Me Me F 3:1 Me2O:THF -115 °C 9M F F F F (6) F 9D (6)1 6 ArLi 2 (6)2 75 mM (6)2 19F time (s) 5 time (s) 4.1 103 6 ArLi 5 (6)1 18.5 2.1 9M 6 ArLi 9D PhF PhF TolF TolF 0 12.3 -110 -115 -120 -125 -110 -115 -120 -125 ppm Figure S-39. (KNP3188) 19F RINMR of 4-fluorophenyllithium (9) with 2 equivalents of 3-fluoroacetophenone (5) in 3:1 Me2O/THF at -115 °C. The ArLi is has fully reacted when the first spectrum was measured at 2.1 seconds. The intermediates visible at this point were the mixed dimer 6AArLi , and two aggregates of the alkoxide 6, very likely the monomer and dimer. Thus here also, the mixed dimer 6AArLi is substantially less reactive than the ArLi 9 towards 5. After several minutes only (6)2 remained. S-49 19F RINMR of 4-Fluorophenyllithium (9) with 3-Fluoroacetophenone (5) at -135 °C (under Curtin Hammett conditions). (KNP3258) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. 3-Fluoroacetophenone (10 mg in 0.1 mL THF, 0.15 mmol) was injected into the NMR sample at -135 °C. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 0.3 s, and 290 spectra with a delay of 10 s at -135 ºC. Results are reported in Figure S- 40. F O F F Me Li Li Me O + Li Li F 5 0.5 equiv. + F Me Li OLi F 3:1 Me2O:THF -135 °C 9M F F F 9D (6)1 6 ArLi 0.75 M 19F 6 ArLi (6) 1 time (s) time (s) (6)2 890 7.8 9D 9M 6 ArLi 3.1 257 (6)1 (6)1 1.6 94 9D 9M PhF (6) PhF 2 TolF TolF 0 46.8 -115 ppm -120 -125 -115 -120 -125 Figure S-4019F RINMR spectra of the reaction of 4-fluorophenyllithium (9) with 0.5 equivalent of 3- fluoroacetophenone 5 in 3:1 Me2O/THF at -135 °C. In this experiment, carried out at 20 °C lower temperature than that of Figure S-39 and with excess lithium reagent, the monomeric alkoxide (6)1 is the sole kinetic product. (6)1 then cross dimerizes with 9 to form 6AArLi with a half life of ca 7 seconds. Only traces of the homodimer (6)2 is formed at this temperature during this 15-minute experiment. The cross-dimerization to form 6AArLi is thus substantially faster than the homodimerization of (6)1. S-50 19F RINMR of the Reaction of 4-Fluorophenyllithium (9) with 3-Fluoroacetophenone (5) at -140 °C. (KNP3258) 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. 3-Fluoroacetophenone 5 (25 mg in 0.2 mL of THF, 0.75 mmol) was injected into the NMR sample at -140 °C. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 0.3 s, and 290 spectra with a delay of 10 s at -135 ºC. Spectra are shown in Figure S-41. O PhF F F (6)1 Me 19F Li 14 time (s) F + Li Li 5 2.5 equiv. Me 4.1 OLi F 3:1 Me2O:THF -140 °C 9M F 15 9D F 75 mM (6)1 2.7 F (6)1 Me 5 Me Me 9D Monomer 9M Sn is almost gone Li+ ArLi CH3 1.4 Sn CH3 CH 3 PhF F 14 15 16 9M TolF 9D F 17 0 -110 -115 -120 -125 ppm Figure S-41. 19F RINMR of 4-fluorophenyllithium (9) with 2.5 equivalents of 3-fluoroacetophenone (5) in 3:1 19 Me2O/THF at -140 °C. The almost complete disappearance of the F signal for 9M unambiguously shows that 9M is more reactive towards ketone 5 than is 9D. No mixed dimer 6AArLi is formed in this experiment because the rate of addition of 9M to ketone is much faster than either the hetero or homo-dimerization of (6)1. There is a trace of 9M detectable at 1.4 and 2.7 seconds, indicating that the rate of 9D going to 9M is almost competitive with the rate of reaction of 9M with the ketone. The peak at -122.7 is due to a small amount of tin ate complex 17[S13] formed a result of a stoichiometry error (ratio of n-BuLi/16 was < 1.0). There is a possibility that the lithium counterion of the ate complex could participate in the process as an Lewis acid catalyst for ketone addition. We are operating so close to the practical limits of temperature, ketone solubility, solvent freezing, and time in this experiment that only two out of a total of 5 experiments gave a comparable result, but these appear to be sound. The others showed clear signs of inadequate mixing, probably due to crystallization or gelling of ketone and/or solvent. Even this experiment showed less excess ketone than was injected, presumably some has solidified during the injection and was not visible in the NMR spectrum. S-51 19F RINMR of the Reaction of Alcohol 6-OH with 4-Fluorophenyllithium (9). 4-Fluorophenyllithium (9) (0.3 mmol) was prepared in 4 mL of 3:1 Me2O/THF using the typical RINMR sample preparation procedure. 1-(3'-Fluorophenyl)-1-(4'-fluorophenyl) ethan-1-ol 6-OH (0.07 g in 0.3 mL THF, 0.3 mmol) was injected into the NMR sample at -110 °C. The reaction was monitored with AQ = 1 s for 200 spectra with a delay of 1 s, and 290 spectra with a delay of 10 s. Results are reported in Figure S-42. F F F F F Li OH Me Me + Li Li F Li Li 6-OH 0.5 equiv. O + OO F Li Me Li Me F 3:1 Me2O:THF -110 °C 9M F F (6) F 9D F 6 ArLi 2 0.13 M 19F NMR Thermodynamic Products after warming to -70 °C for 25 min. (6)2 F 6 ArLi Kinetic Products (10 s after alcohol 6-OH injection) 9D Aryllithium 9 F Pre-injection 9M -110 -115 -120 -125 ppm Figure S-42. 19F NMR of kinetic product mixture from injection of 0.5 equivalent of alcohol into a solution of 4- fluorophenyllithium (9) in 3:1 Me2O/THF at -110 °C. No alkoxide monomer (6)1 is formed at this temperature, nor at -135 °C, where dimerization of (6)1 is known to be slow (see Figure S-40). Our rationalization of this observation is that either the hydrogen bonded dimer 18 which might be present at these low temperatures is deprotonated to directly form 19, which is deprotonated a second time to form (6)2 without ever forming (6)1, or, perhaps more likely, (6)1 forms a strong hydrogen bonded dimer 19 with alcohol more rapidly than the deprotonation process, and deprotonation by 9M then leads directly to (6)2. R H R ArLi R H R R H ArLi R Li O O O O O O or O O R Li R Li H Li (6)2 18 19 very fast R H O R H ArLi R Li O O (6)1 S-52 19F RINMR of 2,5-Difluorophenyllithium with Ester 1 at -115 ºC. 1,3-Dimethyl-2-fluorobenzene (0.005 mL,0.01M, internal standard) was added to 4 mL of a freshly prepared 3:1 Me2O/Et2O solution of 2,5-difluorophenyllithium (prepared from 1,4-difluorobenzene and n-BuLi) in a dried thin-walled 10 mm NMR tube. 13C, 19F and 7Li spectra were acquired at -115 ºC to check concentration and sample integrity. Following the general RI-NMR procedure, ester 1 (0.06 mL, 0.4 mmol) was injected at -115 ºC. Spectra were obtained every 2 sec for 200 spectra followed by every 20 sec for 300 spectra. The concentrations of the reagents were determined from the first scan after injection to be 0.07 M for 2,5-difluorophenyllithium and 0.11 M for the ester. Results are reported in Figure S-43. O OEt F F Li F 1 1 3:1 THF:Me O -115 °C 2 F F F Li F Li F F F 7612 sec 4612 sec 1612 sec 288 sec 82 sec 2 sec -85 -86 -87 -88 -114 -116 -118 -120 -122 -124 -126 -128 ppm ppm Figure S-43. 19F RINMR experiment of the injection of 1.6 equivalents of ester 1 into a solution of 2,5- difluorophenyllithium in 4 mL of 3:1 Me2O/THF at -115 °C. The half life for the disappearance of the lithium reagent is ca 860 sec, thus almost 100 times slower than for 4-fluorophenyllithium (9). Thus E,Z-isomerization of the starting ester cannot be the rate-determining step for both 9 and 2,5-difluorophenyllithium. This does not rule out rate determining isomerization for reaction of 1 with 9, but does argue against it. S-53 Lithium Iodide Titration of Amide 2 and Ester 1. (KNP3051) Four 5 mm NMR tubes were sealed with a septa and parafilm, and purged with nitrogen. THF (0.2 mL), methyllithium (0, 0.02 mL, 0.04 mL and 0.14 mL of a 1.4 M solution in ether) and methyl iodide (0, 0.002, 0.004, 0.012 mL, respectively) were added to the NMR tubes at room temperature and cooled in a dry ice/acetone bath to form solutions of anhydrous LiI. Me2O (-0.7 mL) was distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). 4-Fluorotoluene (0.001 mL) as internal chemical shift standard, 0.06 mL of a 1.5 M solution of amide 2, and 15 :L of ester 1 was added and 19F NMR was taken at -80 ºC. Spectra are shown in Figure S-44. HMPA Titration of Amide 2 and Ester 1 with 2.0 Equivalents LiI (KNP3051) A 5 mm NMR tube was sealed with a septa and parafilm, and purged with nitrogen. THF (0.2 mL), methyllithium (0.14 mL of a 1.4 M solution in ether) and methyl iodide (0.012 mL) was added to each NMR tube at room temperature and cooled in a dry ice/acetone bath. Me2O (-0.7 mL) is distilled via cannula into the NMR tube from a graduated conical cylinder containing n-BuLi (for drying). 4-Fluorotoluene (0.001 mL) as internal chemical shift standard, 0.06 mL of a 1.5 M solution of amide 2, and 15 :L of ester 1 was added. 19F NMR was taken at -80 ºC with 0.5 (0.017 mL), 1.0 (0.034 m:L), 2.0 (0.068 m:L) equivalents of HMPA and are shown in Figure S-44. O O OEt NMe2 + I. LiI titration 1 2 II. HMPA titration F F 19F 3:1 Me2O/THF -80 °C 2.0 equiv. LiI with 3.0 equiv. HMPA 2.0 equiv. LiI with 2.0 equiv. HMPA 2.0 equiv. LiI with 1.0 equiv. HMPA 2.0 equiv. LiI 0.67 equiv. LiI 0.33 equiv. LiI F 1 2 1 equiv. 1 to 1 equiv. 2 -113 -114 -115 -116 -117 -118 -119 ppm Figure S-44. LiI titration of amide 2 and ester 1, followed by an HMPA titration to show reversibility. 4- Fluorotoluene was used as an internal chemical shift standard and the dotted lines indicate initial chemical shifts. The amide 2 appears to complex with the LiI. The ester 1 shows no significant effects of added LiI, it is presumably less basic than solvent THF. S-54 S6. NMR Data and Spectra 7.41 7.39 7.39 7.37 7.37 7.36 7.35 7.28 7.20 7.18 7.13 7.11 7.08 3.11 2.98 O NMe2 D F 2-d 1 ( H, CDCl3, 400 MHz) 7.5 7.4 7.3 7.2 7.1 7.0 ppm 1H 0.83 6.26 Hz 1.00 80 60 40 20 0 0.97 9 8 7 6 5 4 3 2 1 0 ppm S-55 39.5 35.4 170.1 163.7 161.2 138.3 138.3 130.2 130.1 130.1 122.8 122.7 116.7 116.5 114.5 114.2 114.0 113.8 O NMe2 D F 2-d 13 ( C, CDCl3, 101 MHz) 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-56 O -114.20 -114.21 -114.23 NMe2 D F 2-d 19 ( F, CDCl3, 377 MHz) -114.1 -114.2 -114.3 -114.4 ppm Hz 80 60 40 20 0 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-57 HO F F 6-OH 1 ( H, CDCl3, 300 MHz) 7.4 7.3 7.2 7.1 7.0 6.9 ppm 2.94 2.90 Hz 1.84 1.90 80 60 40 20 0 1.07 8 7 6 5 4 3 2 1 0 ppm S-58 75.8 31.2 164.6 163.7 161.3 160.5 150.8 150.7 143.4 143.4 130.0 129.9 127.8 127.7 121.6 121.6 115.4 115.1 114.3 114.0 113.4 113.0 HO F F 6-OH 13 ( C, CDCl3, 75 MHz) 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-59 HO -114.4 -114.4 -114.4 -114.4 -114.4 -114.4 -114.4 -114.4 -114.4 -117.2 -117.2 -117.2 -117.3 -117.3 -117.3 -117.3 -117.3 -117.3 F F 6-OH 19 ( F, CDCl3, 282 MHz) -114.3 -114.4 -114.5 ppm -117.2 -117.4 ppm Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-60 1.38 0.98 0.96 0.94 7.75 7.73 7.65 7.65 7.63 7.62 7.47 7.45 7.45 7.43 7.43 7.41 7.27 7.27 7.25 7.25 7.23 7.23 2.97 2.95 2.93 1.76 1.74 1.72 1.70 1.68 1.44 1.42 1.40 O Bu F 1.8 1.7 1.5 1.4 1.3 0.95 1 3.0 2.9 ppm ( H, CDCl3, 400 MHz) ppm ppm ppm Hz 2.85 80 60 40 20 0 1.84 1.90 1.86 1H 0.94 0.98 0.94 0.89 7.7 7.6 7.5 7.4 7.3 7.2 ppm 9 8 7 6 5 4 3 2 1 0 ppm S-61 38.5 26.3 22.5 14.0 199.2 199.2 164.1 161.7 139.2 139.2 130.3 130.2 123.8 123.8 120.0 119.8 114.9 114.7 O Bu F 13 ( C, CDCl3, 101 MHz) 13C 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-62 -113.88 -113.90 -113.90 -113.91 -113.92 -113.92 -113.93 -113.94 O Bu F 19 ( F, CDCl3, 377 MHz) -113.9 -114.0 ppm Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-63 7.23 7.21 7.19 7.19 7.18 7.17 7.05 7.05 7.03 7.02 6.85 6.85 6.84 6.83 6.82 6.81 6.81 6.80 1.75 1.73 1.72 1.71 1.70 1.70 1.69 1.68 1.68 1.67 1.65 1.22 1.21 1.18 1.16 1.14 1.12 0.97 0.96 0.95 0.94 0.93 0.92 0.90 0.78 0.76 0.74 HO Bu Bu 6.68 0.80 0.75 0.70 6.53 ppm F 5.42 1 ( H, CDCl3, 400 MHz) 1.8 1.7 1.6 1.2 1.1 0.9 ppm ppm ppm Hz 80 60 40 20 0 2.01 1.72 1H 1.28 0.89 7.3 7.2 7.1 7.0 6.9 6.8 ppm 9 8 7 6 5 4 3 2 1 0 ppm S-64 38.5 26.3 22.5 14.0 114.9 114.7 199.2 199.2 164.1 161.7 139.2 139.2 130.3 130.2 123.8 123.8 120.0 119.8 HO Bu Bu F 13 ( C, CDCl3, 101 MHz) 13C 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-65 HO Bu -115.58 -115.60 -115.60 -115.61 -115.62 -115.63 -115.63 -115.65 Bu F 19 ( F, CDCl3, 377 MHz) -115.5 -115.6 -115.7 ppm Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-66 7.83 7.83 7.55 7.53 7.50 7.49 7.49 7.48 7.46 7.45 7.32 7.32 7.30 7.30 7.28 7.20 7.18 7.16 7.87 7.86 7.85 7.84 O F F 7 1 ( H, CDCl3, 400 MHz) 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 ppm 1 Hz H 80 60 40 20 0 2.00 1.84 1.98 1.03 0.85 9 8 7 6 5 4 3 2 1 0 S-67 194.0 167.1 164.5 163.9 161.5 139.8 139.7 133.5 133.4 132.9 132.8 130.3 130.2 125.8 125.8 119.8 119.6 116.9 116.7 116.0 115.8 O F F 7 13 ( C, CDCl3, 101 MHz) 13C 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 S-68 -107.0 -107.1 -107.1 -107.1 -107.1 -107.1 -107.1 -107.1 -107.1 -113.6 -113.6 -113.6 -113.6 -113.6 -113.7 O F F 7 19 ( F, CDCl3, 377 MHz) -107.1 -113.6 -113.7 ppm ppm Hz 80 60 40 20 0 -102 -104 -106 -108 -110 -112 -114 -116 -118 -120 S-69 7.29 7.28 7.27 7.26 7.25 7.25 7.24 7.23 7.22 7.22 7.22 7.21 7.20 7.03 7.02 7.02 7.02 7.00 6.99 6.98 2.75 F HO F 8 F 1 ( H, CDCl3, 400 MHz) 6.40 1H 2.29 1.00 9 8 7 6 5 4 3 2 1 0 ppm S-70 81.0 163.9 163.4 161.4 160.9 149.2 149.1 142.1 142.0 129.7 129.6 129.6 129.6 123.4 123.4 115.1 115.1 114.9 114.8 114.6 114.4 F HO F F 8 13 ( C, CDCl3, 101 MHz) 13C 200 180 160 140 120 100 80 60 40 20 0 ppm S-71 -113.57 -113.59 -113.60 -113.60 -113.61 -113.62 -113.62 -113.64 -115.90 -115.91 -115.92 -115.92 -115.93 -115.94 -115.95 -115.95 -115.97 F HO F 8 F 19 ( F, CDCl3, 377 MHz) -113.55 -113.60 -113.65 -113.70 ppm 2.05 -115.85 -115.90 -115.95 -116.00 -116.05 ppm 0.98 Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-72 8.02 8.00 7.87 7.85 7.72 7.70 7.70 7.68 7.54 7.52 7.52 7.51 7.50 7.49 7.36 7.36 7.34 7.34 7.32 7.32 7.26 7.16 7.14 7.12 O F F 1 ( H, CDCl3, 400 MHz) 2.19 2.14 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 ppm 1.09 1 H 1.14 Hz 1.04 80 60 40 20 0 1.00 8 7 6 5 4 3 2 1 0 ppm S-73 92.6 86.6 176.5 176.5 165.5 164.0 162.9 161.6 138.9 138.8 135.6 135.5 130.4 130.4 125.4 125.4 121.4 121.2 116.5 116.3 116.1 116.0 116.0 115.9 O F F 13 ( C, CDCl3, 101 MHz) 13C 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-74 -107.38 -107.39 -107.40 -107.40 -107.41 -107.42 -107.43 -107.43 -107.45 -113.46 -113.47 -113.48 -113.49 -113.50 -113.52 O F F 19 ( F, CDCl3, 377 MHz) -107.4 -107.5 -113.4 -113.5 ppm ppm Hz 80 60 40 20 0 -102 -104 -106 -108 -110 -112 -114 -116 -118 -120 ppm S-75 7.70 7.68 7.62 7.60 7.50 7.48 7.48 7.46 7.42 7.40 7.39 7.37 7.10 7.09 7.07 7.07 7.04 7.02 7.00 3.16 F HO F F 1 ( H, CDCl3, 400 MHz) 4.98 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 ppm 3.99 Hz 80 60 40 20 0 1.00 0.89 1.01 0.79 9 8 7 6 5 4 3 2 1 0 ppm S-76 88.2 88.2 84.5 65.4 65.4 164.2 164.0 161.8 161.6 144.4 144.3 134.0 133.9 130.2 130.1 121.6 121.6 117.8 117.8 115.9 115.7 115.7 113.4 113.2 F HO F F 13 ( C, CDCl3, 101 MHz) 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm S-77 -111.79 -111.80 -111.81 -111.81 -111.82 -111.83 -111.84 -111.84 -111.86 -114.39 -114.40 -114.41 -114.41 -114.42 -114.43 -114.43 -114.45 F HO F F 19 ( F, CDCl3, 377 MHz) -111.8 -111.9 -114.4 -114.5 ppm ppm Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-78 7.36 7.31 7.29 7.27 7.26 7.25 7.23 7.20 6.95 6.95 6.93 6.91 1.72 1.58 HO F 1 ( H, CDCl3, 400 MHz) 7.30 7.25 7.20 7.15 7.10 7.05 7.00 6.95 6.90 5.74 ppm 1H 3.26 Hz 80 60 40 20 0 0.99 0.78 9 8 7 6 5 4 3 2 1 0 ppm S-79 72.5 72.5 31.9 164.3 161.8 152.2 152.1 129.9 129.8 120.2 120.2 113.8 113.5 112.0 111.8 HO F 13 ( C, CDCl3, 101 MHz) 13C 170 160 150 140 ppm 200 180 160 140 120 100 80 60 40 20 0 ppm S-80 HO -115.18 -115.20 -115.20 -115.21 -115.22 -115.22 -115.23 -115.25 F 19 ( F, CDCl3, 377 MHz) -115.15 -115.20 -115.25 -115.30 -115.35 ppm Hz 80 60 40 20 0 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 ppm S-81 S5. References [S1] a) “Tris(trimethylsilyl)methane as an internal C-13 NMR chemical shift thermometer.” Sikorski, W. H.; Sanders, A. W.; Reich, H. J. Magn. Reson. Chem. 1998, 36, S118-S124. b) “Multinuclear NMR Study of the Solution Structure and Reactivity of Tris(trimethylsilyl)methyllithium and its Iodine Ate Complex.” Reich, H. J.; Sikorski, W. H.; Sanders, A. W.; Jones, A. C.; Plessel, K. N. J. Org. Chem. 2009, 74, 719–729. [S2] "Regiospecific Synthesis of Mixed 2,3-Dihalobenzoic Acids and Related Acetophenones via Ortho-Metalation Reactions" Moyroud, J.; Guesnet, J. L.; Bennetau, B.; Mortier, J. Tetrahedron Lett, 1995, 36, 881-884. [S3] “Selective Electrochemical Aromatic Fluorination of Acetophenone and Benzophenone.” Shainyan, B. A.; Danilevich, Y. S.; Grigor’eva, A. A.; Chuvashev, Y, A. Russian. J. Org. Chem. 2003, 39, 1581-1586. [S4] “The Reduction of Fluorine-containing Triarylmethanols by Formic Acid” Andrews, A.F.; Mackie, R. K.; Walton, J. C. J. Chem. Soc. Perk T 2, 1980, 96-102. [S5] 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) [S6] “Structure and Dynamic Behavior of Solvated Neopentyllithium Monomers, Dimers, and Tetramers: 1H, 13C, and 6Li NMR.” Fraenkel, G.; Chow, A.; Winchester, W. R. J. Am. Chem. Soc. 1990, 112, 6190-6198. [S7] “Aggregation and Reactivity of Phenyllithium Solutions.” Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. S.; Gudmundsson, B. Ö.; Dykstra, R. R.; Phillips, N. H. J. Am. Chem. Soc. 1998, 120, 7201-7210. [S8] “Reactivity of Individual Organolithium Aggregates: A RINMR Study of n-Butyllithium and 2-Methoxy- 6-(methoxymethyl)phenyllihtium.” Jones, A. C.; Sanders, A. W.; Bevan, M. J.; Reich, H. J. J. Am. Chem. Soc. 2007, 129, 3492-3493. [S9] a) “Suppression of Convection Artifacts in Stimulated-Echo Diffusion Experiments. Double- Stimulated- Echo Experiments” Jerschow, A.; Muller, N. J. Magn. Reson. 1997, 125, 372-375. b) “Stereogenic Lithium Centers in a Complex Between n-Butyllithium and a Dilithiated Chiral Amine: Solution Studies by 6Li, 1H-HOESY, 6Li,6Li-COSY, and 6Li, 6Li-EXSY NMR.” Hilmersson, G.; Davidsson, O. Organometallics, 1995, 14, 912-918. [S10] “Characterization of Reactive Intermediates by Multinuclear Diffusion-Ordered NMR Spectroscopy.” Li, D.; Keresztes, I.; Hopson, R.; Williard, P. G. Acc. Chem. Res. 2009, 42, 270-280. [S11] a) “Diffusion-Ordered NMR Spectroscopy (DOSY) of THF Solvated n-Butyllithium Aggregates.” Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 10228–10229. b) “On the Mechanism of THF Catalyzed Vinylic Lithiation of Allylamine Derivatives: Structural Studies Using 2-D and Diffusion-Ordered NMR Spectroscopy.” Jacobson, M. A.; Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2005, 127, 4965–4975. c) “Synthesis and Structural Characterization of the Bis(diisopropylamino)boron Enolate of tert-Butyl Methyl Ketone.” Ma, L.; Hopson, R.; Li, D.; Zhang, Y.; Williard, P. G. Organometallics, 2007, 26, 5834–5839. d) “13C INEPT Diffusion-Ordered NMR Spectroscopy (DOSY) with Internal References.” Li, D.; Hopson, R.; Li, W.; Liu, J.; Williard, P. G. Org. Lett. 2008, 10, 909–911. e) “Aggregation Studies of Complexes Containing a Chiral Lithium Amide and Butyllithium.” Li, D.; Sun, C.; Liu, J.; Hopson, R.; Li, W.; Williard, P. G. J. Org. Chem. 2008, 73, 2373–2381. f) “Analysis of an Asymmetric Addition with a 2:1 Mixed Lithium Amide/n-butyllithium Agregate.” Liu, J.; Li, D.; Sun, C.; Williard, P. G. J. Org. Chem. 2008, 73, 4045–4052. S-82 [S12] “19F Diffusion NMR Analysis of Enzyme-Inhibitor Binding.” Derrick, T.S.; Lucas, L.H.; Dimicoli, J.L.; Larive, C.K. Magn. Reson. Chem. 2002, 40, S98-S105. [S12] “[(Ph)2(NMe2)C(OLi) ' THF]2: Crystal Structure of the Tetrahedral Intermediate Formed in the Reaction of N,N-Dimethylbenzamide and Phenyllithium.” Adler M.; Marsch, M.; Nudelman, N. S.; Boche, G. Angew. Chem. 1999; 111, 1345–1347; Angew. Chem., Int. Ed. 1999, 38, 1261–1263. [S13] “Lithium-Metalloid Exchange Reactions. Observations of Lithium Pentaalkyl(aryl) Tin Ate Complexes” Reich, H. J.; Phillips, N. H. J. Am. Chem. Soc. 1986, 108, 2102-2103. S-83