Electrochemistry: An Old Field for A New Era

Yu Kawamata
The Scripps Research InstituteBasic Principle of Electrochemistry
Shono Oxidation

How fast = current (A)How strong = potential (V)How much = total charge (Q)Electrochemistry is a syringe pump of electron
M. Yan, Y. Kawamata, P. S. Baran, Synthetic Organic Electrochemical Methods Since
2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230-13319.

2

When to Use ElectrochemistryElectrochemistry is useful when:
Appropriate redox reagents are not easily accessible.

Jeffery Aube et al., Angew. Chem. Int. Ed. 2015, 54, 10555 –10558.

P. S. Baran et al., J. Am. Chem. Soc. 2017, 139, 7448−7451.

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When to Use ElectrochemistryElectrochemistry is useful when:
Appropriate redox reagents are not easily accessible.
Reactivity needs to be “dialed-in”.

P. S. Baran et al., J. Am. Chem. Soc. 2014, 136, 5571-5574.

4

When to Use ElectrochemistryElectrochemistry is useful when:
Appropriate redox reagents are not easily accessible.
Reactivity needs to be “dialed-in”.
Acceleration of redox steps in a complex catalytic cycle.

P. S. Baran et al., Angew. Chem. Int. Ed. 2017, 56, 13088 –13093.

5

When to Use Electrochemistry

6Electrochemistry is useful when:Appropriate redox reagents are not easily accessible.
Reactivity needs to be “dialed-in”.
Acceleration of redox steps in a complex catalytic cycle.

Product (M)Redox reactions with bad kinetics.

Time (h)P. S. Baran, D. G. Blackmond et al., Angew. Chem. Int. Ed. 2014, 53, 11868-11871.

Potential Application in Process Chemistry
Toxic and hazardous reagents could be removed entirely or replaced with more benign reagents.

P. S. Baran et al., Nature, 2016, 533, 77-81.

7Potential Application in Process Chemistry

8Toxic and hazardous reagents could be removed entirely or replaced with more benign reagents.

P. S. Baran et al., Nature, 2016, 533, 77-81.

Scalable

46 g scale
S. R. Waldvogel et al., Org. Process Res. Dev.
2015, 19, 1428−1433.

23g scale
P. S. Baran et al., Angew. Chem. Int. Ed. 2017, 56, 13088 –13093.

Recent Application of ElectrochemistryC-N bond formation

Review: P. S. Baran et al., Chem. Rev. 2017, 117, 13230-13319.

C-H amination

J. Yoshida et al, J. Am. Chem. Soc. 2013, 135, 5000-5003.

J. Yoshida et al, J. Am. Chem. Soc. 2015, 137, 9816-9819.

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Recent Application of ElectrochemistryC-N bond formation

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Review: P. S. Baran et al., Chem. Rev. 2017, 117, 13230-13319.

C-H amination

J. Yoshida et al, J. Am. Chem. Soc. 2013, 135, 5000-5003.

Diazidation

J. Yoshida et al, J. Am. Chem. Soc. 2015, 137, 9816-9819.

S. Lin et al, Science 2017, 357, 575-579.

Recent Application of ElectrochemistryC-C bond formation

11Review: P. S. Baran et al., Chem. Rev. 2017, 117, 13230-13319.

Cross electrophile coupling
E. C. Hansen et al.,Org. Lett. 2017, 19,3755-3758.

T. F. Jamison et al., Org.
Lett. 2018, 20, 1338-1341.

Recent Application of ElectrochemistryC-C bond formation

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Review: P. S. Baran et al., Chem. Rev. 2017, 117, 13230-13319.

Cross electrophile coupling
E. C. Hansen et al.,Org. Lett. 2017, 19,3755-3758.

T. F. Jamison et al., Org.
Lett. 2018, 20, 1338-1341.

Cross-metathesis

K. Chiba et al., Angew. Chem. Int. Ed. 2006, 45, 1461 –1463.

Electrochemical Parameters

Chemical reaction

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Electrochemical reaction• Substrate• Substrate• Redox reagent• Electricity• Solvent• Solvent• (Catalyst)• (Mediator)• Electrodes• Electrolyte• Constant current or constant potential• Flask• Divided or undivided cellDivided or Undivided?
Undivided cell

• Easy to set up• First choice

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Divided cell

• Higher resistance• Less convenient than undivided cell
• Useful when a product reacts at the opposite
electrode in undivided cell

Selection of Solvent

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AcOH
Water

DMF
DMSO
THFDCMMeCN-3-2-1

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Potential (V) vs SCE

alkyl ketones

2phenols

aromatic aldehyde/ketones
aryl halides
alkyl halides

3

aromatic hydrocarbons
Ar3N
anilines/alkyl amines

Oxidation: MeCN, acetone, MeNO2, acetic acid, DCM, MeOH
Reduction: DMF, DMA, THF, MeCN, DMSO
Impractical solvent: benzene, toluene, hexane
D. A. Nicewicz, Synlett 2016, 27, 714–723.

Selection of Electrodes

16AnodeAnode for reduction
Mg

AlFeNiSn

Anode for oxidation
PbCu

Hg

Sacrificial anode (Dissolve when used as anode)

AgAuPtCarbon-based material

Non-sacrificial anode

Carbon-based material: graphite, glassy carbon, RVC*, boron-doped diamond (BDD)*RVC (Reticulum Vitreous Carbon) is porous glassy carbon

Selection of Electrodes

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Anode
Anode for reduction
Mg

AlFe

Ni

Sn

Anode for oxidation
PbCu

Hg

AgAu

Pt

Sacrificial anode (Dissolve when used as anode)

Carbon-based material

Non-sacrificial anode

Carbon-based material: graphite, glassy carbon, RVC*, boron-doped diamond (BDD)*RVC (Reticulum Vitreous Carbon) is porous glassy carbon
CathodeCathode for reductionMgAlFeSn

PbHg

Cathode for oxidation
carbon-based material

Good for reduction of organic compounds

FeAuNiPt

When H2 evolution is neededOther Parameters

18Electrolyte• Ionic salt

Common electrolyte• Good solubility to organic solvents

Cation: Li+, R4N+

• Inert during a reaction• Concentration: 0.1-0.5 M

Anion: BF4, PF6 , ClO4 , triflate, halideOther Parameters

19Electrolyte• Ionic salt

Common electrolyte• Good solubility to organic solvents

Cation: Li+, R4N+

• Inert during a reaction• Concentration: 0.1-0.5 M

Anion: BF4, PF6 , ClO4 , triflate, halide

Reaction mode
Constant current

Constant potential• First choice• Lower conversion, but higher selectivity thanconstant current• Conversion is better than constant potential• Current value: 2-10 mA, 2-4 F/mol(0.1-0.3 mmol reaction)• Cyclic voltammetry helps to determine reaction
potential that needs to be applied.
• For an instruction of cyclic voltammetry, see
Go to Youtube → Search for ElectraSyn CV

Case Study 1: Finding the Right Conditions to Start
Conditions?

SelectionReason

AnodeRVC

Non-sacrificial anode

CathodeFe

Material with facile H2 evolution

Electrolyte

LiClO4Solvent

MeOH

Cell type

Undivided cell

Reaction mode

Constant current (5 mA)

Product is methanol adduct20

Optimization

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Initial conditions(+)RVC/(−)Fe
LiClO4
MeOH
Undivided cell
Constant current
5 mA

Was desired product obtained?
Yes

NoGood yield?
Yes
Optimization completed!

No(1) Change current withthe same F/mol(2) Change electrode(3) Change solvent(4) Change electrolyte

No reaction?
Yes
Increase current

No
Identify side reactions
and modify conditions toavoid them.

Case Study 2: Scaling

22E. C. Hansen et al., Org. Lett. 2017, 19, 3755-3758.

1.3 mmol

1.7 mmol65%

Case Study 2: Scaling

23
E. C. Hansen et al., Org. Lett. 2017, 19, 3755-3758.

0.33 mmol

0.43 mmol
Scale down

1.3 mmol

1.7 mmol

Constant current
1.3 mA, 2 F/mol

65%

Case Study 2: Scaling

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E. C. Hansen et al., Org. Lett. 2017, 19, 3755-3758.

0.33 mmol

0.43 mmol
Scale down

1.3 mmol

65%

1.7 mmol
Scale up

2.6 mmol

Constant current
1.3 mA, 2 F/mol

3.4 mmol

Constant current, 5 mA , 2 F/mol(To avoid high current density)

Case Study 2: Scaling

25E. C. Hansen et al., Org. Lett. 2017, 19, 3755-3758.

0.33 mmol

0.43 mmol
Scale down

1.3 mmol

2.6 mmol

65%

1.7 mmol
Scale up

3.4 mmolAmount of solvent& Vial size

Constant current
1.3 mA, 2 F/mol

Constant current, 5 mA , 2 F/mol(To avoid high current density)> 1.5 cm

Troubleshooting
ProblemVoltage is too high(> 20 V without reference)

Voltage is too low(<0.5 V without reference)

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Possible cause

Solution

Bad connection between an
electrode and a cap (corrosion,loose contact etc.)

Clean up and secure theconnection.

Electrode passivation

Wash or polish electrode.

Low concentration of electrolyte

Add more electrolyte.

Inappropriate solvent(low dielectric constant)

Change solvent or add more
electrolyte.

Short circuit

Make sure both electrodes arecompletely separated.

Electrode Maintenance and Cleaning

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Cleaning of Electrode1) Acetone wash to remove organicGood2) 1 M HCl wash, then water rinse

3) Acetone wash again

If the above method is not enough:Bad4) Sonication
5) Scrape off deposit

Color change/fauling

DepositComing Soon
6-Reaction Carousel

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ElectraSyn Extension

Microelectrodes

ElectraSyn App

1 -2 mL vials

Available from Testflight

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YOUR CHEMISTRY HAS POTENTIAL

Summary: Preferred Selections

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Oxidation

Reduction

Net redox neutral

Anode

Pt or carbon-based

Sacrificial anode (Mg,Zn, Al, Fe, Sn, etc. )Pt or carbon-based

CathodeVarious materials

Zn, Sn, Pb, carbonbased

Various materials

ElectrolyteSolvent

Various Li or tetraalkylammonium salts
MeCN, acetone, MeNO2,DCM, MeOH

DMF, DMA, THF, DMSOCell type

Undivided cell

Reaction mode

Constant current at 5 mA

MeCN, acetone, MeNO2,DCM, MeOH

Summary: Default Conditions

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Oxidation

Reduction

Net redox neutral

Anode

Graphite or RVC

Zn

Graphite or RVC

CathodeNi foamZn

Ni foam

Electrolyte
Solvent

LiClO4 or TBABF4
MeCN

DMF

Cell type

Undivided cell

Reaction mode

Constant current at 5 mA

MeCN