Ole Hammerich, November 2010 Dias 1 Department of Chemistry, Organic Chmeistry Electrochemical Organic Synthesis Ole Hammerich Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 2 Department of Chemistry, Organic Chmeistry What is ’organic electrochemistry’ ? Organic electrochemistry is concerned with the exchange of electrons between a substrate and an electrode and the chemical reactions associated with such processes. Organic electrochemical processes are conceptually related to other organic reactions that include one or more electron transfer steps, such as oxidation by metal ions (e.g., Fe 3+ and Ce 4+ ) and reduction by metals (e.g. Na, K, Zn, Sn). At the borderline of organic chemistry, electron transfer processes play an important role in many reactions that involve organometallic compounds and in biological processes such as, e.g., photosynthesis. Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 3 Department of Chemistry, Organic Chmeistry Organic redox reactions vis-à-vis electrochemical reactions In the electrochemical process, the oxidation agent is replaced by the anode (+) and the reduction agent by the cathode (-) here illustrated by functional group conversion. Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 4 Department of Chemistry, Organic Chmeistry Organic electrochemical conversions Additions: R-CH=CH-R + 2Nu -  R-CHNu-CHNu-R + 2e - R-CH=CH-R + 2e - + 2H +  R-CH 2 -CH 2 -R Substitutions: R-CH 3 + Nu -  R-CH 2 Nu + 2e - + H + R-Cl + CO 2 + 2e -  R-COO - + Cl - Eliminations: R-CH 2 -CH 2 -R  R-CH=CH-R + 2e - + 2H + R-CHNu-CHNu-R + 2e -  R-CH=CH-R + 2Nu - Cleavages: RS-SR  2RS + + 2e -  further reaction of RS + RS-SR + 2e -  2RS - Couplings: 2R-H  R-R + 2e - + 2H + 2R-CH=CH-EWG + 2e - + 2H +  (Hydrodimerization) Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 5 Department of Chemistry, Organic Chmeistry Additions, examples Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 6 Department of Chemistry, Organic Chmeistry Substitutions, examples Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 7 Department of Chemistry, Organic Chmeistry Eliminations, examples Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 8 Department of Chemistry, Organic Chmeistry Cleavages, examples Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 9 Department of Chemistry, Organic Chmeistry Couplings, examples Kolbe-reaction Electrochemical Organic Synthesis, 2013 Hydrodimerization

Ole Hammerich, November 2010 Dias 10 Department of Chemistry, Organic Chmeistry Coupling/condensation reactions, example Dieckmann condensation Hydrodimerization Electrochemical Organic Synthesis, 2013 Fussing, I., Güllü, M., Hammerich, O., Hussain, A., Nielsen, M.F., Utley, J.H.P. J. Chem. Soc. Perkin Trans. II, 1996,

Ole Hammerich, November 2010 Dias 11 Department of Chemistry, Organic Chmeistry Electron transfer induced (catalyzed) chain reactions S RN 1 [2+2] cycloaddition Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 12 Department of Chemistry, Organic Chmeistry Organic chemistry is usually ’two-electron chemistry’ Most persistent organic compounds have an even number of electrons G.N. Lewis (1916): A covalent bond is the result of two atoms or groups sharing an electron-pair Most organic redox reactions are comprised of one or more ’two-electron conversions’ Examples of reductions: Ar-NO 2  Ar-NO  Ar-NHOH  Ar-NH 2 R-COOH  R-CHO  R-CH 2 OH  R-CH 3 R-SO 2 -R  R-SO-R  R-S-R R-CN  R-CH=NH  R-CH 2 NH 2 Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 13 Department of Chemistry, Organic Chmeistry Organic electrochemistry is usually ’one-electron chemistry’ and so are protons ! Thus, the electrochemical reduction of a –CH=CH- system R-CH=CH-R + 2e - + 2H +  R-CH 2 -CH 2 -R is a four-step process including the transfer of 2 electrons and 2 protons The order of the four steps depends on the substrate and the conditions Electrochemical Organic Synthesis, 2013 Electrochemistry is ’electron transfer chemistry’ and electrons are transferred one-by-one driven by the electrode potential

Ole Hammerich, November 2010 Dias 14 Department of Chemistry, Organic Chmeistry The mechanism of electrochemical hydrogenation Electrochemical Organic Synthesis, 2013 rds

Ole Hammerich, November 2010 Dias 15 Department of Chemistry, Organic Chmeistry Organic electrochemistry is usually ’one-electron chemistry’ For neutral π -systems the primary intermediates are radical cations and radical anions, that is, the intermediates are radicals and ions at the same time and it is not easy to predict whether the radical character or the ion character predominates for a given radical ion. For charged π -systems the primary intermediates are radicals that may dimerize. Electrochemistry is ’electron transfer chemistry’ and electrons are transferred one-by-one driven by the electrode potential. Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 16 Department of Chemistry, Organic Chmeistry Organic electrochemistry is usually ’one-electron chemistry’ For neutral σ -systems electron transfer is dissociative resulting in radicals and cations or anions For charged σ -systems dissociative electron transfer results in neutral fragments and radicals Electrochemical Organic Synthesis, 2013 Electrochemistry is ’electron transfer chemistry’ and electrons are transferred one-by-one driven by the electrode potential

Ole Hammerich, November 2010 Dias 17 Department of Chemistry 1.Electron transfer reactions Some organic solvents may be oxidized or reduced 2.Cleavage reactions Inherent - owing to bond weakening 3.Couplings Inherent - owing to the radical character 4.Reactions of radical cations with nucleophiles and of radical anions with electrophiles (electrochemical ‘umpolung’) Mostly non-inherent - owing to the ionic character Most organic solvents are nucleophiles and/or electrophiles Most organic solvents are bases and some are also Brønsted acids - the kinetics of proton transfer processes are solvent dependent 5.Atom (hydrogen) abstractions Inherent - owing to the radical character Some organic solvents are hydrogen-atom donors Radical ions and neutral radicals are reactive species

Ole Hammerich, November 2010 Dias 18 Department of Chemistry, Organic Chmeistry Important experimental parameters in electrochemistry The number of experimental parameters that may be manipulated in electrosynthesis is large including the a)electrode potential (driving force, rate of the ET process) b)current density (conversion speed) c)electrode material (overpotential - catalysis) d)solvent (often the reagent) and the supporting electrolyte (conductivity) e)mass transfer to/from the electrodes (stirring/pumping rate) f)cell design (electrode surface area, separation of anolyte and catholyte) in addition to, e.g., the temperature, the pressure etc etc Electrochemical Organic Synthesis, 2013 Any of these parameters may affect which products are formed and/or yields Take-home-message: Do as told in the recipe !

Ole Hammerich, November 2010 Dias 19 Department of Chemistry, Organic Chmeistry The electrode potential – the driving force The Nernst equation The standard potential, E o and the formal potential, E o ' n is the number of electrons (for organic compounds, typically, n = 1) R is the gas constant T is the absolute temperature F is the Faraday constant Parentheses, (), are used for activities and brackets, [], for concentrations f O and f R are the activity coefficients of O and R, respectively. Most organic compounds are oxidized or reduced in the potential range +3 to -3 V Electrochemical Organic Synthesis, 2013 The heterogenous electron transfer rate constants, k s red and k s ox k s red k s ox

Ole Hammerich, November 2010 Dias 20 Department of Chemistry, Organic Chmeistry The current – conversion speed The heterogenous electron transfer rate constants, k s k s red = k o exp[– α nF (E – E o ) /(RT)] k s ox = k o exp[(1 – α )nF (E – E o ) /(RT)] The Butler-Volmer equation i = nFA(k s red [O] x=0 – k s ox [R] x=0 ) = nFAk o {[O] x=0 exp[– α nF (E – E o ) /(RT)] – [R] x=0 exp[(1 – α )nF (E – E o ) /(RT)]} k o is the standard heterogeneous electron transfer rate constant α is the electrochemical transfer coefficient (corresponds in electrochemistry to the Brønsted coefficient in organic chemistry) A is the electrode area [O] x=0 and [R] x=0 are the surface concentrations of O and R, respectively (governed by the Nernst equation) Mass transport (stirring, pumping) is important Electrochemical Organic Synthesis, 2013 The current (the conversion speed) is potential dependent

Ole Hammerich, November 2010 Dias 21 Department of Chemistry - Organic Chemistry - Ole Hammerich Constant potential or constant current electrolysis ? The potential is essentially constant during constant current electrolysis; thus a reference electrode is not needed Constant current electrolysis is most simple and preferred whenever possible Requires a setup with a reference electrode

Ole Hammerich, November 2010 Dias 22 Department of Chemistry, Organic Chmeistry The current flow through the solution is caused by the transport of ions A high concentration of the supporting electrolyte is important (to lower the solution resistance) Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 23 Department of Chemistry, Organic Chmeistry The electrode material The potential limiting processes (in aqueous solution or water containing organic solvents) 2 H 2 O + 2e - → H OH - 2 H 2 O → O H + + 4e - Overpotential for hydrogen evolution Pd < Au < Fe < Pt < Ag < Ni < Cu < Cd < Sn < Pb < Zn < Hg Overpotential for oxygen evolution Ni < Fe < Pb < Ag < Cd < Pt < Au Special electrode materials Glassy carbon, carbon rods, boron-doped diamond (BDD), Dimensionally stable anodes (DSA, Ti covered with metal oxides) --- Cave: The electrode may dissolve during oxidations (M  M n+ ) Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 24 Department of Chemistry, Organic Chmeistry Solvent and supporting electrolyte The Solvent: In addition to the usual solvent properties: Applicable in the potential range +3V to -3V Medium to high dielectric constants The supporting electrolyte Applicable in the potential range +3V to -3V Well dissociated Both: Easy to remove during work-up Preferably non-toxic Aprotic Non-nucleophilic and/or non-electrophilic Recyclable Solvents for oxidation: MeCN, CH 2 Cl 2, MeOH (methoxylations) Solvents for reduction: MeCN, DMF, DMSO, THF Supporting electrolytes for aprotic conditions: R 4 NBF 4, R 4 NPF 6 typically Bu 4 NPF 6 Substitutions/additions: MNu or R 4 NNu Alkoxylations: KOH Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 25 Department of Chemistry, Organic Chmeistry Components of a simple, undivided cell for laboratory scale constant current electrolysis Electrochemical Organic Synthesis, cm Pt anode C cathode

Ole Hammerich, November 2010 Dias 26 Department of Chemistry, Organic Chmeistry Undivided ? Divided ? Two processes are going on in the electrochemical cell, always ! An oxidation at the anode A reduction at the cathode Potential problem: The product formed by oxidation at the anode may undergo reduction (e.g., back to the starting material) at the cathode In such a case a divided cell is needed Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 27 Department of Chemistry, Organic Chmeistry The classical, divided laboratory scale cell (H-cell) Electrochemical Organic Synthesis, 2013 cooling working electrode compartment counter electrode compartment

Ole Hammerich, November 2010 Dias 28 Department of Chemistry, Organic Chmeistry Small, large and very large (divided) flow cells Electrochemical Organic Synthesis, 2013 Electrochemical syntheses are easily scalable (expandable reaction vessels) Notice the small distance between the electrodes

Ole Hammerich, November 2010 Dias 29 Department of Chemistry, Organic Chmeistry Some commercial processes Monsanto (Solutia), BASF, Asahi Chemical Starting materialProductCompany ButanoneAcetoin (3-hydroxybutanone)BASF 1,4-ButynediolAcetylenedicarboxylic AcidBASF CyclohexanoneAdipoin Dimethyl AcetalBASF Acrylonitrile (hydrodimerization) Adiponitrile (nylon 66 synthesis) (> tons/year) Monsanto (Solutia), BASF, Asahi Chemical 4-Cyanopyridine4-AminomethylpyridineReilly Tar AnthraceneAnthraquinoneL. B. Holliday, ECRC NitrobenzeneAzobenzeneSeveral GlucoseCalcium GluconateSandoz, India L-CystineL-CysteineSeveral Diacetone-L-sorboseDiacetone-2-ketogulonic AcidHoffman-LaRoche Naphthalene1,4-DihydronaphthaleneHoechst Furan2,5-Dimethoxy-2,5-dihydrofuranBASF MonomethyladipateDimethylsebacateAsahi Chemical GlucoseGluconic AcidSandoz, India HexafluoropropyleneHexafluoropropyleneoxideHoechst m-Hydroxybenzoic Acidm-Hydroxybenzyl AlcoholOtsuka Galacturonic AcidMucic AcidEDF Alkyl substratesPerfluorinated hydrocarbons3M, Bayer, Hoechst p-Methoxytoluenep-MethoxybenzaldehydeBASF p-t-Butyltoluenep-t-ButylbenzaldehydeBASF, Givaudan o-Hydroxybenzoic AcidSalicylic AldehydeIndia Maleic AcidSuccinic AcidCERCI, India 3,4,5-Trimethoxytoluene3,4,5-TrimethoxybenzaldehydeOtsuka Chemical Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 30 Department of Chemistry, Organic Chmeistry Voltage difference vs. potential difference Two-electrode system for electrochemical synthesis in an undivided cell The voltage difference, V, between the two electrodes is NOT the same as the potential difference, E V = E + iR s R s : the solution resistance iR s : the ohmic drop (Ohm’s law) R s may amount to several hundred ohms if special precautions are not taken => practical implications Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 31 Department of Chemistry, Organic Chmeistry The power supply – constant current source Electrochemical Organic Synthesis, 2013 Max 100 VMax 1A If i=1A and R s =100Ω then ΔV = 100V + ΔE ≈ 100V (i)100V∙1A = 100 W (= heat, need for cooling) (ii)Waste of energy (= money) (ii) 100V may be dangerous

Ole Hammerich, November 2010 Dias 32 Department of Chemistry, Organic Chmeistry The undivided cell put together Electrochemical Organic Synthesis, 2013 cooling bath (ice/water)

Ole Hammerich, November 2010 Dias 33 The advantage of electrolysis in a boiling solvent – the electrochemical Pummerer reaction (substitution) RArYield (% by glc) Current yield (%) MePh98 Mep-Tol9791 Mep-Anisyl9889 EtPh9563 i-PrPh9527 PhCH 2 Ph9887 Department of Chemistry, Organic Chmeistry Almdal, K., Hammerich, O. Sulfur Lett. 1984, 2, 1-6.

Ole Hammerich, November 2010 Dias 34 Department of Chemistry, Organic Chmeistry Organic electrochemical synthesis in summary Pros 1.Replacement of inorganic redox reagents with electrode processes often reduces the number of steps in the overall reaction 2.Electrode reactions are often selective and present direct routes to products otherwise difficult to make (via electro- chemical ‘umpolung’) 3.Electrons are cheap and are easy to transport. Electricity can be made from many different natural resources 4.Green technology; no toxic wastes, no fire or explosion hazards, no storage and handling of aggressive reagents, mostly room temperature chemistry 5.Electrochemical synthesis is easily scalable to the industrial level Cons 1.Organic electrochemistry is (still) considered a specialists topic and is usually not a part of the chemistry curriculum. 2.Reaction mechanisms are often complex and require insight into radical ion (and radical) chemistry 3.Requires equipment (electrodes, cells, current sources and potentiostats) that is often not available in the traditional laboratory 4.Electron transfer is heterogeneous and for that reason electrochemical reactions take time. (1 Mole of e - = 1 F = C = A·s = 26.8 A·h) Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 35 Department of Chemistry, Organic Chmeistry Literature Lund/Hammerich eds.: Organic Electrochemistry, 4 th ed., Dekker, Shono: Electroorganic synthesis, Academic Press, Pletcher/Walsh: Industrial Electrochemistry, Chapman & Hall, Electrochemical Organic Synthesis, 2013 Recipe book

Ole Hammerich, November 2010 Dias 36 Department of Chemistry, Organic Chmeistry Recipe no 1 To a magnetically stirred solution of 1 g of KOH in 150 mL of methanol at ~0°C (ice-bath) is added 4.6 g (0.033 mol) of 1,4-dimethoxybenzene. The solution is electrolyzed at a constant current of 1 A for 2 h in an undivided cell using a Pt gauze anode and a C cathode. After oxidation, the solution is concentrated under reduced pressure. To the residue is added 100 mL of water that is extracted with three 50 mL portions of ether. After removal of solvent, the residue is recrystallized from light petroleum to give ~5 g of the product (m.p °C). Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 37 Department of Chemistry, Organic Chmeistry Recipe no 2 Into a cell equipped with a Pt anode and a C cathode is added a solution of furan (2 g) in a mixture of AcOH (120 mL) and MeCN (30 mL) containing AcONa (6 g). The mixture is cooled to 3 ~ 7°C during the oxidation. After 2.5 F (~1 A for 2h) of charge has passed, the reaction mixture is poured into water and extracted with CH 2 Cl 2. The extracts are dried with MgSO 4 and distilled to give the product. Electrochemical Organic Synthesis, 2013

Ole Hammerich, November 2010 Dias 38 Department of Chemistry, Organic Chmeistry Recipe no 3 A solution of tetrahydrofuran (7.4 mmol = 0.53 g) and Et 4 NOTs (2 mmol = 0.6 g) in a mixed solvent of acetic acid (10 mL) and methanol (120 mL) is put into an undivided cell equipped with a platinum anode and a graphite rod cathode. After 10 F (~1A for 4 h) of charge is passed, the product is obtained by distillation. Electrochemical Organic Synthesis, 2013