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