Brandon Rosen Electroorganic Chemistry Electrochemistry is the study of chemical reactions which take place at the interface of an electrode, usually a solid metal or a semiconductor, and an ionic conductor, the electrolyte. These reactions involve electric charges moving between the electrodes and the electrolyte (or ionic species in a solution). In short, electrochemistry is redox chemistry. Refer to Electrochemistry in Organic Synthesis group meeting (2005) for experimental setup/equipment basics. Undivided cell vs. divided cell (H-cell): 8 November 2014 Reference electrodes have stable and well-known electrode potentials. Standard Hydrogen Electrode (SHE) Saturated Calomel Electrode (SCE) Cu/CuSO 4 electrode (CSE) Ag/AgCl electrode E = 0.000 V E = 0.241 V E = 0.314 V E = 0.197 V Cyclic voltammetry shows current response to changes in the working electrode's potential; useful to study redox behavior of a substrate, including whether oxidation/reduction is reversible, irreversible, or quasi-reversible. Fe Fe E° = +0.45 V CV of ferrocene in 0.1 M Bu 4NPF 6 /MeCN; Pt working electrode, Pt-wire counter electrode, aqueous Ag/AgCl reference, scan rate = 0.10 V/s. Undivided cells are more straightforward to set up (can be shot glass, beaker, roundbottom flask, etc.); both oxidation and reduction take place within the same compartment. Divided cells require more specialized setup; advantage is that no substrate/reagent moves between compartments; substrate to be oxidized is placed in anodic compartment, while substrate to be reduced is placed in cathodic compartment. Anode is typically graphite, platinum, etc. Cathode is typically graphite, mercury, lead, etc. Reaction parameters for an electrochemical reaction closely mirror those of a "normal" chemical reaction with two notable differences: the necessary electrolyte and constant current/potential experiment. Electrolyte can be LiClO 4, AcOH, H 2SO 4, Brawndo TM, R 4NClO 4, R 4NBF 4, other tetraalkyl ammonium salts. Constant potential experiments allow for selective oxidation/reduction; as reactive species is consumed, current drops, so reaction time can be much longer; requires reference electrode. Constant current experiments allow simplified reaction setup; rate of reaction can be carefully controlled (i.e. slow addition of electrons). Industrial electrosynthesis is widespread for production of both inorganic and organic chemicals. Chemical Aluminum Chlorine/NaOH Fluorine Ozone Equation 2 Al2O3 + 3 C --> 4 Al + 3 CO2 2 NaCl + 2 H 2O --> Cl2 + H 2 + 2 NaOH 2 F - --> F 2 + 2 eO2 + H 2O --> O3 + 2 H + + 2 e- Electrodes Carbon (A), Aluminum (C) Ti(A), steel or Hg (C) Carbon (A), steel (C) Vitreous carbon (A) Aluminum and chloroalkali industries together account for > 90% of electricity used in electrolytic processes, with aluminum the largest in terms of energy usage and chloroalkali the largest in terms of tonnage. O HO 2C OH acetoin (BASF) NH 2 CO2H acetylenedicarboxylic acid (BASF) Me Me HO OH Me Me pinacol (BASF) OH N 2-aminomethylpyridine (Reilly Tar) OHC OH OH OH arabinose (Electrosynthesis Co.) O tol I R ditolyliodonium salts (Eastman Chemical) Me OMe anisaldehyde (BASF) 1 Electroorganic Chemistry Brandon Rosen Kolbe Oxidation Electrochemical transformations have featured prominently in total synthesis. anodic oxidation O R OH RR - 2 CO2 TBS Me Me TBSO Me Me OH CO2H Me Kolbe [O] Pt electrodes O O OH Me MeOH, NaOMe, 50 °C 29% HO Me Me OH O 20% MeOH/CH 2Cl2 2.1 F/mol; TsOH, 88% O O Me Me Me Me Me HO O O S H N +RY Nuc O RY Nuc O N cathodic reduction 74-97% CH2OAc CO2H CO2H O S H N O O H 2N N CO2H Shono Oxidation N O R Nuc N H O R Me Me Me N Nuc TBDPSO Markó-Lam Reduction Me O O Me Me TBDPSO O H cathodic reduction Me R O S N Me OTBS O 130 °C Trauner, Org. Lett. 2005, 3425. R H Markó, Chem. Commun. 2009, 95. Tafel Rearrangement O S en route to Guanacastepene O Me RVC anode carbon cathode LiClO 4, 2,6-lut OTBS 20% MeOH/CH 2Cl2 2.4 F/mol; OTBS HCl, 60% O Shono, Tetrahedron 1984, 811. Me H N N CO2H Ceftibuten OPRD 2002, 178. [2.84 kg scale] anodic oxidation OH O CO2H CO2H - 2 CO2 O O Moeller, JACS 2004, 9106. Y = N, O, etc. R Me (–)-alliacol A Non-Kolbe Oxidation anodic oxidation RVC anode carbon cathode LiClO 4, 2,6-lut Me α-onocerin Stork, JACS 1959, 5516. O O O HO Me Me RY 8 November 2014 OMe MeO MeO MeO NMe anodic oxidation O OEt cathodic reduction mechanism? OMe OMe Me Stenzl, HCA 1934, 669. NMe MeO O O-methylflavinantine Miller, JACS 1972, 2651. 2 Electroorganic Chemistry Brandon Rosen 8 November 2014 Direct C(sp2)–H Functionalization Indirect oxidation: Strategy I: Oxidation of arene. anodic oxidation Nuc Nuc OMe OH anodic oxidation Me anodic oxidation OMe OMe OMe OMe OMe OMe E° = 1.54 V OMe E° = 1.38 V E° = 1.10 V 21% 49% 20% OMe Me Me OMe ab: bb > 100:1 MeOH, KOH OMe Et 3NMeO 3SOMe 50 °C HFIP/MeOH Me OMe OH anodic oxidation BDD anode OMe OMe ROH - e-, - H + RO• OMe O Ar OH Ar H Me 6% pdt Walvogel, JACS 2012 3571. Strategy II: Oxidation of Meisenheimer complex. Fritz, Electrochim Acta 1976, 1099. Overoxidation of pdt common problem; one solution is to prepare an electrooxidatively inert intermediate: Ms N OMe Bz N Me O N anodic oxidation; piperidine, ∆ OEt NO 2 EWG OMe Bz N Me anodic oxidation pyridine; NO 2 N N Yoshida, JACS 2014, 4496. O OEt NO 2 H 2N MeO MeO N anodic oxidation; piperidine, ∆ N MeO Nuc EWG CN NO 2 Et 4NCN, DMF; Gallardo, Chem Eur J 2001, 1759. CF 3 BuNH 2, KOtBu; NHBu NO 2 anodic oxidation 40% N Gallardo, Chem Eur J 2002, 251. Cl NO 2 Lund, Acta Chem Scand 1957, 1323. Yoshida, JACS 2013, 5000. Benzylic functionalization often takes place alongside (or in preference to) arene functionalization; innate reactivity of substrate dictates pdt: Ms N Me anodic oxidation EWG anodic oxidation 35% CF 3 piperidine, ∆ MeO H Nuc Nuc N Yoshida, JACS 2014, 4496. N Cl O Me O Me KOtBu; anodic oxidation 57% Me Me NO 2 N Gallardo, Chem Eur J 2002, 261. Cl For a review on nucleophilic functionalization of arenes by electrochemical methods, see: Petrosyan, Russian Chemical Reviews 2013, 747. 3 Electroorganic Chemistry Brandon Rosen Direct C(sp 3)–H Functionalization Me Me Miller, JACS 1973, 8631. NHAc - e- OTFA - e- Cl Me Me TFA, CH2Cl2 91% Me H H Me Me Me H 7 AcOH, CH2Cl2 15% (40:1:2) H 7.6% 16.8% Me Me Me Me Me anodic oxidation O O Me AcO OAc Me O N OH N OH Me anodic oxidation Schäfer, ACIE 1985, 1055. anodic oxidation OMe 24% Additional ring rearrangement pdt isolated. anodic oxidation anodic oxidation OH H 2O/MeCN Me AcOH O MeO 2C 0% Me 14.7% OMe Me 15.3% Me pyr, MeCN 83% O MeO 2C CO2Me N N OH anodic oxidation steps N MeOH O O AcO O CO2Me O anodic oxidation MeO 2C Me 17% OAc Me CO2Me N NHAc OAc Me Me Oxidation adjacent to heteroatoms MeCN/H 2O anodic oxidation pyr, MeCN 13% Me Me O 14% anodic oxidation Masui, Chem Pharm Bull 1983, 4209. Masui, Chem Pharm Bull 1985, 4798. MeOH 55% Me O O pyr, MeCN 44% Allylic systems - direct oxidation AcOH Me 67% Utley, J Chem Soc 1987, 41. O OAc Me Me Me O LiBr, NaOAc HOAc, 77% Me OAc anodic oxidation OAc Me 9.0% Shono, JACS 1972, 7892. O 6 Me pdts Me H OAc Me 3.1% Allylic systems - indirect oxidation Me Me Me H Me ring opening Me Me anodic oxidation Me Me AcOH 4% Fritz, JCS Perkin Trans I, 1976, 610. Me 12 Me OAc Me Me anodic oxidation Me OAc OAc AcOH Me Me CH 3CN, H 2O 90% Me Me OAc anodic oxidation Fully saturated systems anodic oxidation 8 November 2014 O O OH Moeller, JACS 1993, 11434. Masui, Chem Pharm Bull 1983, 4209. For a review on reactions of alkenes induced by electrochemical oxidation, see: Ogibin, Russian Chemical Reviews 2001, 543. 4 Electroorganic Chemistry Brandon Rosen Direct C(sp 3)–H Functionalization Uniquely active allylic alcohols Carbonyl oxidation Me O cathodic reduction OTFA Me Me Me TFA 70% Me n-Bu OH O anodic oxidation Me Me 8 November 2014 71% Me Me OH Me n-Bu Me H Me O Me OH H O Me R vs. H H Me Me O H R H O Pletcher, Electrochim Acta 1978, 923. O Misc. oxidation Me anodic oxidation NHTs NHTs OMe Me KBr, NaOMe MeOH, -10 °C 82% TsHN Me OH cathodic reduction Me Me OH Me OH R Me Me Me Me Me OH H H O R vs. H O O H H Addition to heterocycles R Me KBr, KOH, H 2O cyclohexane, ∆ 92% H Shono, JOC 1994, 274. NHTs Ts N Me n-Bu Ts N OMe anodic oxidation NHTs n-Bu mechanism? 70% KBr, NaOMe MeOH, -10 °C 79% Me Me OMe anodic oxidation NHTs Me cathodic reduction N Me 41-62% R N H OH Me O Shono, Tet Lett 1986, 6083. Shono, JACS 1990, 2368. • Intermolecular requires large excess of ketone Schäfer, ACIE 1995, 2007. Carbonyl Reductive Couplings cathodic reduction O R HO Me cathodic reduction R 35-66% R = Me, Et, i-Pr, etc. 64% O OH Shono, JACS 1971, 5284. 1-decene cathodic reduction O Me 63% Me Me Me OH octyl H General for terminal olefins H of substitution pattern: R H Me Me O Me Me Me OH cathodic reduction 80% Me Me Me Shono, JACS 1989, 6001. 5 Electroorganic Chemistry Brandon Rosen 8 November 2014 Cation Pool Method Low-temperature electorolysis technique allows for the generation and accumulation of highly reactive species. R' R R' R R' anodic oxidation N CO2Me R MeOH or CN- R' anodic oxidation N CO2Me R -72 °C R' in situ trapping R N CO2Me R' Nuc N CO2Me N OMe (CN) CO2Me R -72 °C - r.t. N Nuc CO2Me stable at -72 °C R' R' R N CO2Me CO2Me R 2e- N R'' CO2Me R''MgX CO2Me OTMS R' R O R N R'' CO2Me R'' R' R'' R' R N MeO 2C N CO2Me R'' TMS R'' R'' R'' R N CO2Me R' R'' R' R R' R O R'' N O O R'' N O R'' R'' Yoshida, Chem Rev 2008, 2265. 6
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