Electroactivated alkylation of amines with alcohols: Via both direct and indirect borrowing hydrogen mechanisms

Article abstract of DOI:10.1039/c9gc03747k

A green, efficient N-alkylation of amines with simple alcohols has been achieved in aqueous solution via an electrochemical version of the so-called "borrowing hydrogen methodology". Catalyzed by Ru on activated carbon cloth (Ru/ACC), the reaction works well with methanol, and with primary and secondary alcohols. Alkylation can be accomplished by either of two different electrocatalytic processes: (1) in an undivided cell, alcohol (present in excess) is oxidized at the Ru/ACC anode; the aldehyde or ketone product condenses with the amine; and the resulting imine is reduced at an ACC cathode, combining with protons released by the oxidation. This process consumes stoichiometric quantities of current. (2) In a membrane-divided cell, the current-activated Ru/ACC cathode effects direct C-H activation of the alcohol; the resulting carbonyl species, either free or still surface-adsorbed, condenses with amine to form imine and is reduced as in (1). These alcohol activation processes can alkylate primary and secondary aliphatic amines, as well as ammonia itself at 25-70 °C and ambient pressure.

Full text of DOI:10.1039/c9gc03747k

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DOI: 10.1039/C9GC03747K
Green Chemistry
ARTICLE
Electroactivated Alkylation of Amines with Alcohols via Both
Direct and Indirect Borrowing Hydrogen Mechanisms
Benjamin Appiagyei, Souful Bhatia, Gabriela L. Keeney, Troy Dolmetsch, and James E. Jackson*
Received 00th January 20xx,
Accepted 00th January 20xx
A
green, efficient N-alkylation of amines with simple alcohols has been achieved in aqueous solution via an
DOI: 10.1039/x0xx00000x
electrochemical version of the so-called “borrowing hydrogen methodology”. Catalyzed by Ru on activated carbon cloth
(Ru/ACC), the reaction works well with methanol, and with primary and secondary alcohols. Alkylation can be
accomplished by either of two different electrocatalytic processes: (1) In an undivided cell, alcohol (present in excess) is
oxidized at the Ru/ACC anode; the aldehyde or ketone product condenses with the amine; and the resulting imine is
reduced at an ACC cathode, combining with protons released by the oxidation. This process consumes stoichiometric
quantities of current. (2) In a membrane-divided cell, the current-activated Ru/ACC cathode effects direct C-H activation of
the alcohol; the resulting carbonyl species, either free or still surface-adsorbed, condenses with amine to form imine and is
reduced as in (1). These alcohol activation processes can alkylate primary and secondary aliphatic amines, as well as
www.rsc.org/
ammonia
itself
at
25-70
℃
and
ambient
pressure.
bulky ethylsulfate byproduct. Our net use of aqueous alcohol
as alkylating agent forms water as the only by-product, making
this process “green” and atom efficient.
Introduction
Amines play essential roles in industry, medicine, and the life
sciences;1–3 they are the building blocks of proteins, while
various cofactors, vitamins, neurotransmitters, and alkaloids,
not to mention the nucleic acids, bear alkylated amino
moieties. Amines are classically synthesized via amide or
nitrile reduction, by SN2 alkylation with alkyl halides or their
analogues, or via reductive alkylation with carbonyl species.4–7
However, these methods may suffer from various
disadvantages: (a) reducing agents such as LiAlH4 and
alkylating agents such as alkyl halides typically generate by-
product salts, raising material and disposal costs; and (b)
strong alkylating agents often over-alkylate to form quaternary
ammonium ions.
We describe here two modes of
heterogeneous electrocatalytic amine alkylation with low cost,
readily available alcohols: direct and indirect “borrowing
hydrogen” paths. In this reaction (Scheme 1a), an alcohol
undergoes temporary hydrogen removal to give an aldehyde
or ketone (I). Condensation with an amine forms an imine (II)
or iminium intermediate which is then reduced to the
alkylated amine product, replacing the hydrogen “borrowed”
in the alcohol oxidation. This path avoids the low
electrophilicity of alcohols and the poor atom economy of
classical alcohol activation methods, with their stoichiometric
waste
streams.
For
instance,
Hünig’s
base
(diisopropylethylamine) is made by reacting diisopropylamine
with diethyl sulfate, a toxic, alcohol-derived alkylating agent.8
The atom economy of the reaction is low (50%) due to the
Dept of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
E-mail: jackson@chemistry.msu.edu
†Electronic Supplementary Information (ESI) available: SEM of electrodes, and
structural and stereochemical product analyses. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Green Chemistry
Scheme 1. a) Mechanistic pathway of hydrogen auto-transfer catalyst of Yamaguchi et al. enabled reaction of 1° and 2°
(“borrowing hydrogen”) process with amines and alcohols. b) (i) alcohols such as n-hexanol and cyclohexanolVieinw Aratiqclue eOonluines
DOI: 10.1039/C9GC03747K
Stereoretentive C−H bond activation in the aqueous phase catalytic ammonia to yield trihexylamine (96%) and dicyclohexylamine
hydrogenation of amino acids to amino alcohols (ii) Stereoretentive (84%) respectively. The size of the alcohol controlled the
H/D exchange at sp3 sites bearing alcohols and amines.
selectivity of the reaction to the 2° or the 3° amines.19 Deutsch
et al. also reported
a
new homogeneous catalyst,
In previous work, we discovered stereoretentive H/D exchange
via chemical (2003)9 and electrochemical (2016)10 heteroge-
neous ruthenium activation at sp3 C-H sites bearing amine or
alcohol moieties. There we envisaged oxidative insertion of Ru
at the sp3 C-H geminal to the alcohol -OH, to form a surface-
[Ru(CO)ClH(PPh3)3], which enables mono-alkylation of NH3
with secondary alcohols in toluene.20 Overall, Ruthenium- and
Iridium-based homogeneous catalysts appear most effective in
N-alkylation of amines with alcohols.
bound sp2 intermediate which is then back reduced by surface- Heterogenous catalysis for alcohol amination has been known
bound deuterium formed from D2O (Scheme 1b). Building on since 1924, when Brown and Reid demonstrated the use of
these findings, in this manuscript, we exploit the silica gel as an effective catalyst for N-alkylation of aniline with
electrophilicity of the sp2 carbon intermediate to N-alkylate methyl, ethyl, n-propyl and n-butyl alcohols over
a
amines.
temperature range of 300-500 °C.21 In recent studies Shi and
Deng have used an iron oxide immobilized palladium catalyst
under base and solvent free conditions to achieve N-alkylation
of aniline with several primary alcohols to ca. 99% yield.22 Also,
Jaenicke et al. found Ag/Al2O3 promoted with Cs2CO3 or K3PO4
to be active and selective catalysts for N-alkylation or acylation
of amines with several primary alcohols at 120 C in xylene.23
Thus, with secondary amines, piperidine and pyrrolidine, the
hemiaminal intermediate underwent dehydrogenation as well
as dehydration/rehydrogenation to give amides and amines,
respectively. Mizuno et al. have developed heterogeneous
Ru24 and Cu25 catalysts for polyalkylation of aqueous ammonia
(or urea) by alcohols to form secondary and tertiary amines.
The same group have also used ruthenium hydroxide to
heterogeneously catalyze N-alkylation of various aromatic and
heteroaromatic amines, forming secondary amines in
moderate to excellent yields without need for co-catalysts or
promoters.26 Both homogeneous and heterogeneous catalysis
of hydrogen autotransfer processes have recently been
extensively reviewed.27–30
Ammonia alkylation by alcohols is thermodynamically favored,
largely due to the exothermicity of water loss. Scheme 2 shows
the uniformly favorable energetics for stepwise conversion of
ammonia and ethanol to triethylamine and water.
Energy Changes
Gas Phasea and
(aqueous phase)b
EtNH2
-13.8
(-18.3)
H2O
NH3
-11.0
+∆Ghyd (-15.3)
EtOH
-55.9
(-60.9)
+
+
+
+
(kcal/mol)
∆Hf
-57.6
(-63.9)
-4.5
(-6.0)
EtNH2
-13.8
+∆Ghyd (-18.3)
Et2NH
-23.9
(-28.0)
H2O
EtOH
-55.9
(-60.9)
∆Hf
-57.6
(-63.9)
-11.8
(-12.7)
Et2NH
∆Hf
-23.9
+∆Ghyd (-28.0)
Et3N
-34.2
(-37.4)
H2O
-57.6
(-63.9)
EtOH
-55.9
(-60.9)
+
+
-12.0
(-12.4)
Scheme 2. Energy changes for stepwise ammonia ethylation
a
b
to form triethylamine. Data from NIST Webbook11; Aqueous
12
phase energies = ∆Hf + ∆Ghyd
.
Most directly relevant to the work herein, electrocatalytic N-
alkylation of amines with alcohols was reported by Kagiya in
1986.31 Using Pt as electrodes and lithium nitrate as electrolyte
with Pt black powder stirring in neat alcohol, aromatic amines
and aniline were alkylated with methanol and ethanol with
65% current efficiency at ambient temperatures. Here, the
platinum black was the key to the high current efficiency in
reducing the Schiff base with the generated free hydrogen,
which was soluble in the alcohol electrolyte. (Scheme 3).
N-alkylation of amines with alcohols was first reported by J.U.
Nef in 1901. Achieved simply with sodium ethoxide at high
temperature, this work showed that a transition metal catalyst
was not necessary.13 Homogenous catalysis of such processes
was first reported in 1981 by Grigg et al.14 who used rhodium,
ruthenium and iridium catalysts to achieve selective mono N-
alkylation of pyrrolidine with primary and secondary alcohols,
and formed heterocyclic rings via inter- and intramolecular N-
alkylations. In similar work, Watanabe et al. used the
ruthenium complexes [RuCl2(PPh3)3] at 150-200 °C to N-
alkylate aminopyridines with primary alcohols.15 In 2009,
William et al. alkylated various amines regioselectively with 1°
and 2° alcohols using [Ru(p-cymene)Cl2]2 and the bidentate
phosphines dppf or DPEphos. In refluxing toluene for 24 h, this
approach converted primary to secondary and secondary to
tertiary amines. It was then used to synthesize Piribedil and
Tripelennamine, anti-Parkinsonism and antihistamine drugs.16
The team’s 2011 microwave-promoted solvent-free update
achieved similar N-alkylations of 1° and 2° amines with 1° and
2° alcohols.17 In 2016, Takacs et al. demonstrated
regioselective mono and sequential amination of diols with
several ruthenium (II) complexes via a bifunctional borrowing
hydrogen mechanism.18
Scheme 3. Electrolytic N-alkylation of amines with alcohol by
Kagiya et al.
Direct synthesis of alkyl amines from ammonia and alcohols is
also a growing field. The water-soluble [Cp*Ir(NH3)3][I2]2
2 | Green Chem., 2019, 00, 1-3
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ARTICLE
Though the methods above did achieve alcohol amination with pyrrolidine with methanol. Conversion of 20 mM of pyrrolidine
attractive yields, many used conditions of high temperature to 3° amine (1-methylpyrrolidine) would theoretVicieawllAyrtirceleqOunilirnee
DOI: 10.1039/C9GC03747K
and pressure, organic (non-green) solvents, or costly only 20 mM of methanol, but at this low alcohol
homogeneous catalysts requiring later separation. Here, we concentration, conversion was negligible at 33.3 mA/cm2 over
describe two different mechanisms for net electrocatalytic 6 hours.
alkylation of ammonia and other amines, in water at
temperatures below the boiling point over an easily prepared
Alcohol Concentration: Optimizing alcohol concentration to
achieve practical reaction times, we studied a range from 1%
and mechanically removable catalyst of ruthenium on
v/v (250 mM) to 30% v/v (7.25 M) methanol in 0.01 M
activated carbon cloth.
phosphate buffer at pH 7; rates rose with methanol
concentration up to a saturation point at 20% v/v (Figure 1a).
Catalyst Preparation
An electrodeposited Ru/ACC catalyst was developed and
optimized32 based on the activated carbon cloth (Zorflex® ACC
FM100) used in our earlier studies on electrocatalytic reduction by
Li et al.33 and H/D isotopic exchange by Bhatia et al.10 The ACC (3
cm x 1.5 cm) was initially washed in de-ionized (DI) water and then
allowed to dry in an oven overnight at 105 °C. It was then soaked in
a solution of Ru (NH3)6Cl3 (1.0089 g) dissolved in ammonium
hydroxide (1.98 mL) and water (13.02 mL). The damp ACC was dried
on the laboratory bench for 24 h, then under vacuum at room
temperature. The Ru-impregnated ACC was then electrochemically
reduced in an H-cell with 0.2 M HCl as electrolyte at a constant
current of 150 mA for 30 mins (about 3 times the quantity of charge
required). This catalyst showed similar reactivity to the H2 reduced
counterpart described by Li et al. and Bhatia et al. Figure 1 (I & II)
shows the SEM images of the Ru/ACC before and after
electrochemical reduction.
Current Density: Using 20% v/v alcohol, we then studied the
effect of varying current density on the rate of the reaction,
exploring values ranging from 0.4 mA/cm2 to 44.4 mA/cm2
(Figure 1b). Initially, we hypothesized that the reaction would
follow the borrowing hydrogen process at the cathode where
Ru/ACC would catalyze C-H activation of alcohol to form a
surface-bound aldehyde or ketone. This carbonyl species
would condense with amine to generate surface imine or
iminium species which would in turn undergo back reduction
to amine. The current in this scenario should only be that
needed for the electroactivation of Ru, ≥ 2.2 mA/cm2, as seen
in our earlier H/D exchange studies. But the alkylation rate
showed a direct relationship to current density, reaching a
maximum at 44.4 mA/cm2, indicative of
a
true
oxidation/reduction process. Further optimization studies used
currents of 33.3 mA/cm2.
Reaction Optimization
Temperature: As expected, increasing temperature accelerated
the reaction. However, at temperatures as low as 36 °C,
alkylation still proceeded at useful rates, demonstrating the
reaction’s mildness (Figure 1c).
The reaction was initially performed in a divided two-chamber
(2-C) electrochemical cell with Ru/ACC as cathode and Pt as
anode, separated by a Nafion®117 membrane. Preliminary
investigations examined methylation of the secondary amine
.
I
II
a)
MeOH (1% v/v)
MeOH (2% v/v)
MeOH (5% v/v)
MeOH (10% v/v)
MeOH (20% v/v)
MeOH(30% v/v)
100
80
60
40
20
0
0
2
4
6
8
10
t (h)
0.4 mA/cm²
1.1 mA/cm²
2.2 mA/cm²
6.6 mA/cm²
11.1 mA/cm²
22.2 mA/cm²
33.3 mA/cm²
100
80
60
40
20
0
b)
c)
100
80
60
40
20
0
36 ℃
50 ℃
70 ℃
0
2
4
6
8
10
0
2
4
6
8
10
t (h)
t (h)
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DOI: 10.1039/C9GC03747K
Figure 1. SEM images of (I) ACC and (II) electrochemically reduced Ru/ACC in a divided H-cell. The white coating represents the
reduced Ru as revealed by EDX in SI. (a) effect of alcohol concentration; (b) effect of current density and (c) effect of
temperature. Conditions: Pyrrolidine (20 mM in 20 mL) with alcohol added to the cathodic chamber. Standard conditions when
not
varied:
20%
v/v
methanol;
33.3
mA/cm2;
70
°C.
H+
-2H+
Mechanistic investigation and the role of the catalyst
H
H
N
To explore the importance of current density, an experiment
using Ru/ACC (cathode) and Pt (anode), was run with
pyrrolidine and methanol added to the cathodic chamber.
Though the Ru/ACC electrode was activated by passing
current prior to addition of the organics, no current was
passed afterward. No alkylated product was formed,
confirming the need for current to enable the reaction. Most
importantly, simple ACC without Ru as the cathode gave
alkylation results and rates similar to those with Ru/ACC. To
confirm that this finding did not arise via reductive deposition
of catalytic metal contaminants on the cathode, we conducted
two experiments: (a) the divided H-cell was rinsed with aqua
regia for 96 h, and (b) a brand-new H-cell was used to
eliminate the possibility of the presence of even minute
amounts of remaining Ru that could catalyze the reaction.
Both scenarios yielded alkylated product. Together with the
above current requirement, these results pointed to simple
anodic oxidation, imine formation, and reduction at the ACC
cathode. Even higher alkylation rates were seen if the
carbonyl species was supplied directly. Thus, with a Ru/ACC
cathode and a Pt anode at 33.3 mA/cm2, we found 92%
alkylation of pyrrolidine to 1-isopropyl pyrrolidine in the
presence of 20% v/v acetone over 4 h as compared to 62% in
the same period with isopropyl alcohol (figure 2).
H
OH
O
-2e-
2e-
H
NH
N
H
2H2O
H2O
+2H+
4H+ + O2 + 4e-
Pt Anode
Nafion membrane
ACC cathode
b)
100
80
60
40
20
0
Ru/ACC (CH₃OH), Pt
ACC (CH₃OH), Pt
ACC, Pt (CH₃OH)
0
120
240
360
t (min)
480
600
Figure 3. (a) Pyrrolidine methylation with methanol in the
anode chamber. (b) Alkylation with varied electrode (cathode,
anode) pairs with methanol. In the case of the (—blue line)
and (—red line) runs, methanol was added to the cathodic
side with pyrrolidine. In the last (—green line) example,
methanol was added to the Pt anode side. Conditions:
Pyrrolidine (20 mM in 20 mL) and 20% v/v methanol in a
divided cell with 33.3 mA/cm2 at 70 °C.
Figure 2. Comparison of reactions of pyrrolidine with isopropyl
alcohol vs acetone, confirming the corresponding carbonyl
species as an intermediate.
Substrate scope in divided 2-chamber (2-C) cell
The above findings implied that methanol had permeated
through the Nafion®117 membrane to the Pt anode, gotten
oxidized to formaldehyde, permeated back to the cathodic
chamber, condensed with pyrrolidine to form iminium, and
undergone reduction on the ACC. To test this hypothesis, a
cell with ACC (cathode) and Pt (anode) was charged with
Using ACC as cathode and Pt as anode at 33.3 mA/cm2 and 70
°C, we explored the reaction’s substrate scope by methylating
additional secondary amines to give 1,4-dimethylpiperazine,
1-methylmorpholine, 1-methyldicyclohexylamine, and 1-
methyl-piperidine-4-carboxylic acid. Except for morpholine,
these 8 h runs, with methanol in the cathode chamber, gave
relatively low yields but did demonstrate the ability of the 2-C
cell to effect alkylation with more diverse substrates (Figure
4).
amine (pyrrolidine) and methanol respectively in the cathodic
and anodic chambers. If methanol was indeed oxidized by the
Pt anode, amine methylation should be, and indeed was,
faster than the case with methanol on the cathode side
(Figure 3b, green line). Thus, Ru was unnecessary for the
alcohol activation in this case (Figure 3b, red line). This finding
also explained the observed 2 h induction periods seen in our
initial studies, which we had earlier attributed to
electroactivation of ruthenium.10
CH3
N
CH3
N
CH3
N
CH3
N
N
O
CH3
COOH
a)
(8 h, 58%)
(8 h, 99%)
(8 h, 34%)
(8 h, 45%)
4 | Green Chem., 2019, 00, 1-3
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DOI: 10.1039/C9GC03747K
Figure 4. Methylation products from alkylation with ACC/Pt in
2-C Cell. Conditions: Substrate (20 mM in 20 mL), 33.3
mA/cm2, 70 °C & CH3OH (20% v/v added to anodic chamber).
The undivided 1-chamber (1-C) cell
Noting that the above alkylations entailed alcohol oxidation at
the Pt anode rather than hydrogen auto-transfer at a Ru/ACC
cathode, the process was reoptimized in a 1-chamber (1-C)
cell with ACC cathode and Pt anode. This new context enabled
reaction at lower current density (2.2 mA/cm2), alcohol
concentration (5% v/v), and temperature (60 °C) values,
substantially improving over the 2-C conditions. Based on a
flow of 2e- per molecule to oxidize methanol to
formaldehyde, and to reduce the iminium species, the
optimized current efficiency (CE%, defined in equation 1) for
1-C pyrrolidine methylation was 22%, ignoring any losses due
to adsorption of organic substrates into the ACC cloth
electrode.
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DOI: 10.1039/C9GC03747K
100
ACC-Pt
ACC-ACC
ACC-Ru
Ru-Ru
퐶퐸% = (푀표푙 × 푛 × 퐹) × 100%
푝푟표푑
(1)
퐶푡표푡푎푙
80
60
where MolProd = moles of products formed, F = faraday’s
constant, 96,485 C mol−1, n = number of electrons per
reaction, and Ctotal = total charge passed in coulombs.
Ru-ACC
40
20
0
Several cathode-anode catalyst combinations (Figure 5) were
explored in the 1-C context, again using pyrrolidine
methylation as the test reaction. Use of ACC as cathode but
replacing Pt with Ru/ACC at the anode gave improved
conversion (98.3% vs. 83.3% in 6 h) and CE% (30% vs. 22%).
Use of Ru/ACC for both electrodes yielded similar results.
0
500
t (min)
Figure 5. Pyrrolidine methylation in 1-chamber cell (1-C, open
cell) with various cathode-anode electrode combinations.
Conditions: Pyrrolidine (20 mM in 20mL), 2.2 mA/cm2, 60 °C
and CH3OH (5% v/v).
Importantly, no reaction was observed when ACC was used as
both cathode and anode (Figure 5). As a check, the inability of
the ACC to activate alcohols was further explored via
experiments in D2O with ACC as both anode and cathode
electrodes; no C-H exchange was seen. Literature confirms the
inertness of carbon electrodes for alcohol oxidation. For
instance, glassy carbon (not competent) has been studied with
boron-doped diamond (BDD) (competent) for the oxidation of
methanol and benzyl alcohol.30 The inertness of common
carbon electrode materials makes them ideal as catalyst and
electrocatalyst supports. Examples include ultrathin Co3O4
supported on carbon paper and carbon cloth for ethanol
oxidation,31 platinum on graphite for benzyl alcohol
oxidation,32 and indium tin oxide (ITO) on reticulated vitreous
carbon34 electrodes for ethanol oxidation.
Table 1. Alkylation of pyrrolidine with 1° and 2° alcohols
Ru/ACC(anode)/ACC (cathode)
undivided cell
Phosphate buffer pH 8.5, 5% ROH
2.2 mA/cm2, 60 o
N
N
R
H
C
Entry
1
Conversion % Yield %
C.E %
Alcohol
product
N
42 (98)a
49 (99)a
CH3OH
HO
99 (100)
99 (100)
18
Most intriguing was the case with Ru/ACC as the cathode and
ACC as the anode, where methylation still occurred, albeit
slowly, even with an anode unable to oxidize alcohol. This
observation indicates that the electroactivated Ru/ACC
cathode is capable of alkylation via actual hydrogen auto-
transfer, the classic “borrowing hydrogen” mechanism.
N
N
2
3
18
16
39 (92)a
96 (98)
HO
For the two-electrode process, substrate scope was explored
with the ACC cathode and Ru/ACC anode combination in a 1-C
cell (Figure 5). Reaction of pyrrolidine in 5% methanol at 60 °C
gave a 98% yield of 1-methylpyrrolidine in 6 h at pH 7.5.
Though the ACC-Pt combination had given only modest yields
(≤ 30%) upon pyrrolidine alkylation with ethanol and 2-
propanol, at pH 8.5 these substrates, as well as cyclohexanol
and benzyl alcohol, now yielded 1-ethylpyrrolidine (99%), 1-
isopropylpyrrolidine (92%), 1-cyclohexylpyrrolidine (20%), and
1-benzylpyrrolidine (30%) respectively (Table 1). The slightly
alkaline pH increases the free amine concentration,
presumably accelerating imine formation. Pyrrolidine
alkylations with two alcohols incapable of oxidation to
carbonyl species, phenol and t-butanol, were also attempted,
but as expected, they yielded no alkylation products,
consistent with the borrowing hydrogen mechanism.
8 (20)b
4
5
55 (65)
90
4
N
N
HO
HO
30b
8
a
b
C.E % = current efficiency, yield at 6 hours, yield at 10 h.
Values in parentheses includes species in solution and
extracted from the electrodes using 5 mL t-BuOH. Conversion
values
are
based
on
pyrrolidine.
6 | Green Chem., 2019, 00, 1-3
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Attempting direct alkylation of ammonia with ethanol (Table
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3), a 9% yield of triethylamine was obtaDinOeId: 10in.101309/hCo9uGrCs0a37t4670K
°C. This low yield was attributed to loss of ammonia by
evaporation. We then studied the reaction at room
temperature (25 °C) and observed a decreased yield to 7% but
still suspected loss of ammonia by evaporation. Use of
ammonium acetate36 (to provide aqueous ammonia in situ) at
60 °C with a Teflon cap to partially seal the electrochemical
cell yielded 36% triethylamine. Reaction progress, monitored
by 1H NMR, showed the formation of ethylamine (b.p. = 16 °C)
and diethylamine (b.p. = 55 C) in small quantities, supporting
the expected stepwise formation of triethylamine. To explore
the possibility of intermediate disproportionation to mono
and triethylated products, diethylamine was subjected to the
Table 2. Alkylation of 2° amines with methanol and
ethanol
Ru/ACC(anode)/ACC (cathode)
divided cell
R1R2NH
R1R2R3N
Phosphate buffer pH 8.5, 20% R3OH
2.2 mA/cm2, 60 oC, 10 h
Entry
1
Alcohol
Conversion % Yield %
Product
N
R2NH
H
N
CH3OH
86
46
O
O
N
O
N
H
N
reaction with ethanol, yielding 92% triethylamine; ethylamine
91
59
2
3
4
OH
was not observed, indicating no disproportionation as
expected from the thermodynamic data in Scheme 2. Two
different paths to diethylbutylamine were explored: (1) a 1°
amine (n-butylamine) and 5% ethanol and (2) a 2° amine
(diethylamine) and 5% n-butanol, with yields of 32% to 52%
respectively. As expected, the reaction requiring two
sequential alkylations gave the lower yield. The low solubility
of n-butanol (8% v/v in H2O)37 compared to ethanol (fully
miscible with H2O) could also have contributed to its lower
O
H
N
CH3OH
71
67
55
47
H
N
N
N
OH
N
H
yield
.
O
O
With isopropyl alcohol, only diisopropylamine was formed,
regardless of reaction time. Consistent with the literature
report on cyclohexylation,19 this result is presumably due to
the bulky isopropyl groups hindering the formation of the final
imine intermediate. However, alkylation of diisopropylamine
with ethanol, a primary alcohol, did give a 28% yield of Hünigs
H
17
33
5
48
68
N
N
OH
HO
HO
H
N
N
CH3OH
6
COOH
COOH
N
H
N
CH3OH
7
58
34
Table 3. Synthesis of triethylamine and diisopropylamine
base (Table 3).
Ru/ACC(anode)/ACC (cathode)
undivided cell
Extending the amine substrate scope led to yields of 4-
methylmorpholine (46%) and 1-methylpiperidine (55%)
respectively after 10 h reactions with methanol at pH 7.5.
These efforts were extended to ethanol at pH 8.5, yielding 4-
ethylmorpholine (69%) and 1,6-diethylpiperazine (47%)
respectively (Table 3). Methylations worked best at pH 7.5
whereas the 1° and 2° alcohols gave excellent results at pH
8.5. Traces of hydrocarbon-range resonances in the H-NMR
are attributed to the possible formation of branched Guerbet
alcohols35 (See SI).
Substrate
Product
Phosphate buffer pH 8.5, 5% ROH
2.2 mA/cm2 10 h
Entry
1
Alcohol
substrate
product
Temp. °C
Yield %
NH3
60
9
OH
N
2
3
4
5
NH3
r.t
60
60
60
60
7
1
OH
OH
OH
OH
N
N
N
N
NH4OAc
36
39
26
20
As seen in Table 2, the system tolerated the carboxylic
functional groups in isonipeconic acid (4-carboxypiperazine)
and sarcosine (N-methylglycine). Though slow, methylation of
the strongly sterically hindered 2° amine dicyclohexylamine
gave (34%) 1-methyldicyclohexylamine. Turning to aniline as
the simplest aromatic amine, we attempted ethylation, but
even after substantial optimization efforts, lowering the pH to
3 to minimize aniline oxidation, we still only obtained small
amounts of the monosubstituted N-ethylaniline.
N
H
NH2
NH3
6
OH
OH
N
H
34
34
30
28
7a
N
N
N
N
H
8
9
OH
N
H
A
lkylation of Ammonia
H2N
32
52
70
69
OH
OH
N
10
This journal is © The Royal Society of Chemistry 2018
N
Green Chem., 2019, 00, 1-3 | 7
H
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Green Chemistry
Page 8 of 12
ARTICLE
Green Chemistry
expected alkylation did occur. The resulting 1:1 ratio of cis and
Single-electrode Alkylation
View Article Online
trans pyrrolidinyl cyclohexanes was essDeOntI:ia10ll.y10l3ik9/eC9thGaCt03s7e4e7nK
from classical sodium borohydride reduction (entry 5). As
expected with the ketone substrate, the nature of the anode
was unimportant (entries 6, 7). Significantly, with an
oxidation-competent Ru/ACC anode, reaction with the cis
isomer of the alcohol did yield the same 1:1 amination ratio,
consistent with formation of ketone at the anode (entry 8),
enabling the 2-electrode amination process.
Returning to the relatively slow amine alkylation achieved on
the cathode alone, a new mechanism must be considered.
Here no free carbonyl species is seen or expected. Our
previously reported finding of stereoretentive C-H activation
and H/D exchange in alcohols and amines on the Ru/ACC
cathode suggested that in the amine alkylation reactions, the
stereochemistry of the original alcohol might be carried over
to the resulting amine. We explored the stereochemical
outcome of the single-electrode alkylation with the cis/trans
A different pattern emerged with ACC anodes and Ru/ACC
cathodes. Here the amination must have occurred only at the
activated ruthenium cathode, as the ACC anode is not able to
oxidize the alcohol. With or without membrane present, this
one-electrode process effects amination of the ketone or
either of the 4-methylcyclohexanol isomers with a 2:1
cis:trans ratio of aminated cyclohexane. Disappointingly, no
direct reflection of the initial alcohol’s stereochemistry is seen
in the product ratio, but the Ru/ACC reduction does have a
different stereochemical selectivity than reduction by ACC
alone. Evidently the alcohol undergoes C-H activation at the
cathode (a process known to retain stereochemistry) but
undergoes release at some point in the process of forming the
imine intermediate and undergoing the final reduction. In
sum, the Ru/ACC cathode does activate and aminate alcohols
isomers
of
4-methylcyclohexanol
and
with
Using t-
4-
methylcyclohexanone reacting with pyrrolidine.
butanol as co-solvent to improve the solubility of the
cyclohexyl systems, reactions were conducted in a series of
membrane-separated and open electrochemical systems, with
1.18 ppm
0.83 ppm
0.77 ppm
a)
9.60 Hz
9.65 Hz
8.50 Hz
H
N
OH
O
H
Anode/Cathode
divided or undivided cell
CH3
H
N
H
CH3
H
or
H
H
H
Phosphate Buffer:t-BuOH (1:1)
pyrrolidine
H
H
3.37 Hz
3.38 Hz
4.1 Hz
1.21 ppm
0.79 ppm
0.73 ppm
pH 8.5, 60 °C, 24 h
20-30%
Either cis or trans
or a mixture of both
b)
c)
but is not able to retain
stereochemistry under the present reaction conditions.
a trace of their original
Relative Energies (kcal/mol)
Gas-phase
SMD
+1.6
+1.5
0.0
0.0
Table 4. Stereochemical outcome by electrode pairing in 1-C
and 2-C reactor configurations
Figure 6. (a) Reactions of pyrrolidine with cis-4-methylcyclo-
hexanol, trans-4-methylcyclohexanol, a mixture of cis/trans-
4-methylcyclohexanol or 4-methylcyclohexanone. (b)
Relative energies of the most stable conformers and coupling
constants of (left) cis-4-methylcyclohexylpyrrolidine and
(right) trans-4-methylcyclohexylpyrrolidine computed with
Gaussian16 at the b3lyp43/6-31G(d,p)44 level. For NMR
chemical shift and coupling constant calculations, the GIAO
method in Gaussian16 was used with the above geometries
at the mpw1pw9145/6-311+g(2d,p)46 level of theory, with
chemical shifts referenced against tetramethylsilane (TMS)
calculated at the same level of theory. Coupling constant
values shown are experimental (blue) and computed
“aqueous phase (SMD)” (red) and “gas phase” (black). (c)
Crystal structure of the picrate salt of trans-4-
methylcyclohexylpyrrolidine (m.p = 189-191 °C) obtained
from amination of 4-methylcyclohexanol. 38
Exp.
Cathode
Membrane
Anode
Alcohol
Product;
Cis/trans-
Selectivity
No
Reaction
No
1
2
ACC
ACC
Yes
No
ACC
ACC
Alcohola,b
(cis/trans)
Alcohola
(cis/trans)
Ketonec
Reaction
1:1
3
4
5
ACC
ACC
No
ACC
ACC
N/A
Yes
Ketoneb,c
Ketonec
1:1
1:1
NaBH4/TFE/ N/A
40 °C
6
7
8
ACC
ACC
ACC
Yes
No
No
Ru/ACC Ketoneb,c
Ru/ACC Ketonec
1:1
1:1
1:1
Ru/ACC Alcohola
(cis)
9
Ru/ACC
Ru/ACC
Ru/ACC
Ru/ACC
No
ACC
ACC
ACC
ACC
Alcohola
(cis)
2:1
2:1
2:1
2:1
10
11
12
Yes
Yes
Yes
Alcohola,b
(trans)
yields and product stereochemistry evaluated.
Alcohola,b
(cis/trans)
Ketoneb,c
Stereochemistry of One- and Two-electrode Alkylation
aAlcohol = 4-methylcyclohexanol; bSubstrate placed in cathode
compartment; cKetone = 4-methylcyclohexanone.
As seen in Table 4 (entries 1, 2), no alkylation product was
observed with ACC for the two electrodes, with or without a
membrane divider. This finding is consistent with the earlier
noted inability of ACC alone to oxidize alcohols to the
corresponding carbonyl compounds; as expected, no direct
reaction is seen between alcohol and pyrrolidine. On the other
hand, with cyclohexanone, regardless of membrane, the
Notably, no re-equilibration of the above cis/trans ratios was
observed after amination. Product mixtures with the 1:1 ratio
obtained from the ACC reductive amination reactions
remained the same when re-exposed to any of the electrode
8 | Green Chem., 2019, 00, 1-3
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Page 9 of 12
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ARTICLE
combinations. Products were identified by melting point,38
GC/MS and 2D-NMR, but most significantly confirmed by the
X-ray structure of the trans-N-(4-methylcyclohexyl)pyrrolidine,
which we obtained in the form of the picrate salt (Figure 6).
This isolated material enabled unambiguous assignments of
the NMR spectra, enabling easy analysis of product mixtures.
To estimate the energetics of the cis and trans aminated
isomers, we also ran b3lyp/6-31G(d,p) calculations in gas and
simulated aqueous39 phases on both neutral and protonated
forms of the 4-methylcyclohexyl pyrrolidine. For the latter,
which are expected to dominate at a pH of 8.5, the trans
isomer was calculated to be 1.5 kcal/mol lower in free energy
than the cis isomer, when solvation and vibrational analyses
are included. However, it was the cis product that dominated
in the Ru/ACC-reduced product mixtures. This apparent
deviation from the purely thermochemical ratio presumably
reflects imine adsorption on the catalyst surface and hydrogen
delivery to the less sterically hindered face of the cyclohexane
ring, opposite to the methyl substituent.
bond forming reactions observed in more conventional
View Article Online
catalytic settings.27–29
DOI: 10.1039/C9GC03747K
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors gratefully acknowledge financial support the US
Department of Energy (DOE) and National Corn Growers
Association for support. TD acknowledges support from the
National Science Foundation via the project entitled
“REU:Cross-Disciplinary Training in Sustainable Chemistry and
Chemical Processes”, CHE-1531238.
Notes and references
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methine hydrogens on the carbon bearing the nitrogen were
distinct in the experimental H-NMR with coupling constants
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(figure 6). Also, the 4-methyl protons were distinctly
separated in the experimental NMR. Computing the
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“hydrogen borrowing” pathways: an indirect, two-electrode
path in which the hydrogen “borrowed” at the anode is
returned via regeneration from H+ and e- at the cathode; and
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