Electrochemical reduction of 2-chloro-N-phenylacetamides at carbon and silver cathodes in dimethylformamide

Article abstract of DOI:10.1016/j.electacta.2014.01.133

Cyclic voltammetry and controlled-potential (bulk) electrolysis have been employed to investigate the direct electrochemical reduction of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at carbon and silver cathodes, as well as the catalytic reduction of these compounds by electrogenerated nickel(I) salen, in dimethylformamide (DMF) containing 0.050 M tetramethylammonium tetrafluoroborate (TMABF₄). Cyclic voltammograms for reduction of 1a and 1b show a single irreversible cathodic peak for cleavage of the carbon-chlorine bond, but two irreversible cathodic peaks are observed in cyclic voltammograms for reduction of 1c. Controlled-potential reduction of 1a and 1b gives mixtures of dechlorinated amide and N-alkyl-N-phenylaniline, whereas bulk electrolyses of 1c afford N-phenylacetamide in almost quantitative yield. In addition, bulk electrolyses of 1a and 1b result in the formation of very small amounts of dimeric species that arise from coupling of the radical intermediate formed by one-electron cleavage of the carbon-chlorine bond. On the basis of the coulometric n values and product distributions, together with computations based on density functional theory, we propose mechanistic pictures for the reduction of 1a and 1b that involve radical intermediates, whereas reduction of 1c involves carbanion intermediates.

Full text of DOI:10.1016/j.electacta.2014.01.133

Electrochimica Acta 127 (2014) 159–166
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Electrochemical reduction of 2-chloro-N-phenylacetamides at carbon
and silver cathodes in dimethylformamide
Erick M. Pasciaka, Arkajyoti Senguptaa, Mohammad S. Mubarakb,
Krishnan Raghavacharia, Dennis G. Petersa,∗
a Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
b Department of Chemistry, The University of Jordan, Amman 11942, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic voltammetry and controlled-potential (bulk) electrolysis have been employed to investigate the
direct electrochemical reduction of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-
phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at carbon and silver cathodes, as well as
the catalytic reduction of these compounds by electrogenerated nickel(I) salen, in dimethylformamide
(DMF) containing 0.050 M tetramethylammonium tetrafluoroborate (TMABF4). Cyclic voltammograms
for reduction of 1a and 1b show a single irreversible cathodic peak for cleavage of the carbon–chlorine
bond, but two irreversible cathodic peaks are observed in cyclic voltammograms for reduction of 1c.
Controlled-potential reduction of 1a and 1b gives mixtures of dechlorinated amide and N-alkyl-N-
phenylaniline, whereas bulk electrolyses of 1c afford N-phenylacetamide in almost quantitative yield.
In addition, bulk electrolyses of 1a and 1b result in the formation of very small amounts of dimeric
species that arise from coupling of the radical intermediate formed by one-electron cleavage of the
carbon–chlorine bond. On the basis of the coulometric n values and product distributions, together with
computations based on density functional theory, we propose mechanistic pictures for the reduction of
1a and 1b that involve radical intermediates, whereas reduction of 1c involves carbanion intermediates.
© 2014 Elsevier Ltd. All rights reserved.
Received 7 November 2013
Received in revised form 24 January 2014
Accepted 24 January 2014
Available online 10 February 2014
Keywords:
2-Chloro-N-phenylacetamides
Carbon cathodes
Silver cathodes
Carbon–chlorine bond cleavage
Density functional theory
1. Introduction
Buchwald [15] have studied the palladium acetate-catalyzed reac-
tion of 2-chloroacetamides as a synthetic route to the formation of
Numerous reports [1–14] dealing with the electrochemical
reduction of 2-haloacetamides have been published. These inves-
tigations have revealed a surprisingly complex set of reaction
pathways that depend on the structure of the compound and on the
conditions employed for the electrochemical experiments. In the
simplest of situations, a 2-haloacetamide undergoes a two-electron
reductive cleavage of the carbon–halogen bond at a mercury
or carbon cathode to afford a carbanion that, upon protonation
(perhaps by the parent compound itself), yields the dehalo-
genated acetamide [1,2,4,5,7–9]. Electrochemical reduction of
2-haloacetamides has been utilized for the synthesis of ␤-lactams
[3,6,12–14] as well as for the preparation of oxazolidine-2,4-diones
[10]. Furthermore, cyclic dimers (e.g., piperazine-2,5-diones)
have been detected [8] as products of the reduction of 2-
haloacetamides, along with species that arise from cyclocoupling
of the conjugate base of the 2-haloacetamide with the solvent
(dimethylformamide or dimethylacetamide) [4]. Hennessy and
oxindoles.
Acetyl groups are often used as protecting groups for amines,
such as aniline, due to the mild conditions required to attach
the acetyl moiety. However, harsh hydrolysis may be needed to
achieve deprotection. In attempting to use electrochemical meth-
ods for such deprotection, Kopilov and Evans [16] probed the
electrochemical reduction of mono-, di-, and trihaloacetanilide at
a mercury cathode in solutions of 0.10 M tetraethylammonium
chloride in ethanol and 0.10 M tetraethylammonium perchlorate
in acetonitrile to determine whether ␣-haloacetanilides would
undergo C–N bond cleavage to afford aniline; however, only
the dehalogenated acetanilide remained upon completion of the
electrolysis.
In the present investigation, we have employed cyclic voltam-
metry and controlled-potential (bulk) electrolysis to examine the
direct electrochemical reduction of the carbon–chlorine bond of
2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-
phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at
carbon and silver cathodes in dimethylformamide (DMF) contain-
ing 0.050 M tetramethylammonium tetrafluoroborate (TMABF4). In
addition, a study has been conducted of the catalytic reduction of
∗
Corresponding author. Tel.: +1 812 855 9671; fax: +1 812 855 8300.
E-mail address: peters@indiana.edu (D.G. Peters).
0013-4686/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.electacta.2014.01.133

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E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
the carbon–chlorine bonds of 1a–1c by nickel(I) salen electrogen-
erated at reticulated vitreous carbon electrodes.
Electrolysis products have been separated, identified, and
quantitated with the aid of gas chromatography (GC) and gas
chromatography–mass spectrometry (GC–MS). Surprisingly, the
behavior of the methyl- and ethyl-substituted compounds (1a and
1b, respectively) is not the same as that of 1c with respect to cyclic
voltammetry, coulometric n value, and electrolysis products. Thus,
the mechanistic picture for the reduction of 1a and 1b appears to
differ from that for the reduction of 1c, a conclusion corroborated
with the aid of calculations based on density functional theory.
Fig. 1. Cyclic voltammograms recorded at 100 mV s−1 for reduction of 2.0 mM
solutions of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-
phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at a glassy carbon
cathode (solid curves, scanned from ca. 0 to –2.1 to 0 V) and at a silver cathode
(dash–dot curves, scanned from ca. 0 to –1.6 to 0 V) in DMF containing 0.050 M
TMABF4.
2. Experimental
Figs. 1–3], in contact with DMF saturated with both cadmium
chloride and sodium chloride [18–20]; this electrode has a poten-
tial of –0.76 V versus an aqueous saturated calomel electrode
(SCE) at 25 ◦C. Cyclic voltammetric experiments were performed
as described in a previous paper [21].
Information about the cell, instrumentation, and procedures
used for controlled-potential (bulk) electrolysis is provided else-
where [21,22]. We constructed carbon working cathodes by cutting
disks to have approximately a 2.4-cm diameter, a 0.4-cm thick-
ness, and a 200-cm2 surface area from reticulated vitreous carbon
logs (RVC 2X1–100S, ERG Aerospace Corporation, Oakland, CA);
preparing, cleaning, and storing of these electrodes are described
in a previous publication [23]. Silver gauze working electrodes
(approximate surface area of 20 cm2) were constructed from com-
mercially available material (Alfa Aesar, 99.9%, 20 mesh woven
from 0.356-mm diameter wire). For all experiments, the aforemen-
tioned cadmium-saturated mercury amalgam reference electrode
2.1. Reagents
Each of the following chemicals was employed, as received,
without further purification: anhydrous diethyl ether (abso-
lute, EMD Chemicals), n-hexadecane (99%, Sigma), chloroacetyl
chloride (98%, Aldrich), chloroform-d (99.8%, Aldrich), acetyl
chloride (98%, EMD Chemicals), succinyl chloride (95%, Aldrich),
[[2,2ꢀ-[1,2-ethanediylbis(nitrilomethylidyne)]bis[phenolato]]-
(N,NꢀO,Oꢀ)]nickel(II) (nickel(II) salen, 98%, Aldrich), potassium
hydroxide (97%, Alfa Aesar), deuterium oxide (D2O, 99.9 atom%,
Aldrich), tetramethylammonium hydroxide (TMAOH, 97%, Sigma),
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 99 + %, Alfa Aesar).
Vacuum distillation was used to purify the following com-
pounds: aniline (99%, Alfa Aesar), N-methylaniline (99%, Aldrich),
and N-ethylaniline (97%, Alfa Aesar). Dimethylformamide (DMF,
99.9%, EMD Chemicals) was utilized without further purification
as the solvent for all electrochemical experiments. Tetramethyl-
ammonium tetrafluoroborate (TMABF4, >99%, GFS Chemicals),
which served as the supporting electrolyte, was recrystallized from
water–methanol and stored in a vacuum oven at 70–80 ◦C prior to
use. All deaeration procedures were accomplished with zero-grade
argon (Air Products).
2.2. Cells, electrodes, procedures, and instrumentation
A description and photograph of the cell used for cyclic voltam-
metry appear in a previous publication [17]. We constructed planar,
circular glassy carbon and silver cathodes (each with a geomet-
ric area of 0.071 cm2) by press-fitting a short piece of either a
glassy carbon rod (Grade GC-20, 3.0-mm-diameter, Tokai Electrode
Manufacturing Company, Tokyo, Japan) or a silver rod (3.0-mm-
diameter, 99.9% purity, Alfa Aesar) into the end of a machined
Teflon tube. Electrical connections to these working electrodes
were made via a 3.0-mm-diameter stainless-steel pole that con-
tacted the cathode material and extended upward through the
tube. A coil of platinum wire served as the auxiliary (counter) elec-
trode for cyclic voltammetry. Prior to each scan, the glassy carbon
and silver working electrodes were cleaned with an aqueous sus-
pension of 0.05-␮m alumina on a polishing pad, followed by a
rinse with distilled water in an ultrasonic bath. All potentials are
reported with respect to a reference electrode that consisted of a
cadmium-saturated mercury amalgam [denoted as Cd(Hg) for
Fig. 2. Cyclic voltammograms recorded at 100 mV s−1 and scanned from ca. 0 to
–2.0 to 0 V for reduction of 3.0 mM solutions of 2-chloro-N-phenylacetamide (1c)
at a glassy carbon cathode in DMF containing 0.050 M TMABF4: (A) no added HFIP
or TMAOH (solid curve), (B) 30 mM HFIP added (dashed curve), (C) 10 mM TMAOH
added (dotted curve).

E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
161
bath. Each reaction mixture was stirred for 1 h at 0 ◦C and then
transferred to a separatory funnel; the organic layer was separated,
washed twice with brine, dried over anhydrous sodium sulfate,
and concentrated with the aid of rotary evaporation. Products 1a
and 1c were purified by recrystallization of each resulting solid,
respectively, from ethanol and water, whereas 1b was obtained
as a yellow oil via vacuum distillation. Melting points for the two
solids were found to be as follows: 1a (Mp 66–67 ◦C); 1c (Mp
133–134 ◦C). High-resolution mass spectral data for these three
compounds are as follows: (a) for 1a, HRMS (ESI) m/z: calculated for
C9H10ClNO [M]+ 183.0445, found 183.0449; (b) for 1b, HRMS (ESI)
m/z: calculated for C10H12ClNO [M]+ 197.0602, found 197.0597;
(c) for 1c, HRMS (ESI) m/z: calculated for C8H8ClNO [M]+ 169.0289,
found 169.0288.
2.5. General procedure for synthesis of products (3a–3c)
We prepared N-methyl-N-phenylacetamide (3a), N-ethyl-N-
phenylacetamide (3b), and N-phenylacetamide (3c) according to
the protocol described in the preceding section by substituting
acetyl chloride for chloroacetyl chloride. Compounds 3a and 3c
were obtained as colorless crystals, and 3b was isolated as a yellow
oil by means of vacuum distillation. High-resolution mass spectral
data for these three compounds are as follows: (a) for 3a, HRMS
(ESI) m/z: calculated for C9H11NO [M]+ 149.0835, found 149.0834;
(b) for 3b, HRMS (ESI) m/z: calculated for C10H13NO [M]+ 163.0992,
found 163.0991; (c) for 3c, HRMS (ESI) m/z: calculated for C8H9NO
[M]+ 135.0679, found 135.0681.
Fig. 3. Cyclic voltammograms recorded at 100 mV s−1 for reduction of 1.0 mM
nickel(II) salen in the absence (solid curve) and in the presence of 2.0 mM 2-chloro-
N-methyl-N-phenylacetamide (1a, dashed curve) at a glassy carbon cathode scanned
from ca. –0.05 to –1.25 to –0.05 V in DMF containing 0.050 M TMABF4.
was utilized, and the auxiliary anode was a graphite rod immersed
in a DMF–0.050 M TMABF4 solution separated from the cath-
ode compartment by a sintered-glass disk backed by a methyl
cellulose–DMF–0.050 M TMABF4 plug.
2.6. Syntheses of N,Nꢀ-dimethyl-N,Nꢀ-diphenylsuccinamide (5a)
and N,Nꢀ-diethyl-N,Nꢀ-diphenylsuccinamide (5b)
2.3. Separation, identification, and quantitation of electrolysis
products
At the end of each controlled-potential (bulk) electrolysis, the
catholyte was partitioned three times between diethyl ether and
brine. Then the ether phase was dried over anhydrous sodium
sulfate and concentrated with the aid of rotary evaporation.
Products were separated and identified by means of gas chro-
matography (GC) and gas chromatography–mass spectrometry
(GC–MS). Each chromatograph (Agilent 7890A) was equipped with
a 30 m × 0.25 mm capillary column (J & W Scientific) with a DB-
5 stationary phase; the GC system utilized a flame-ionization
detector, whereas the GC–MS system contained an inert mass-
selective detector operating in electron ionization mode (70 eV).
Gas chromatographic retention times and mass spectral data for the
electrolysis products were compared with those for commercially
available or chemically synthesized authentic samples.
Procedures used for the quantitation of electrolysis products
have been described in an earlier paper [24]. Peak areas for the
different products were determined with respect to an internal
standard (n-hexadecane) added in known amount to the electrol-
ysis cell prior to the start of a controlled-potential reduction.
Identities of the several starting materials and products, syn-
thesized as described below, were confirmed by means of both
1H and 13C NMR spectrometry (400 MHz, Varian Inova) and high-
resolution GC–MS (Thermo Electron Corporation) coupled to a
MAT-95XP magnetic-sector mass spectrometer.
We prepared the title compounds according to the follow-
ing general procedure based, with some modification, on that
employed for the synthesis of compounds 1a–1c. Freshly dis-
tilled N-methylaniline or N-ethylaniline (18.5 mmol) was added
to 40 mL of cold ethyl acetate (in an ice bath). To this mixture
was added sodium hydroxide (4 g, 100 mmol) dissolved in 20 mL
of water, and the solution was allowed to cool to near 0 ◦C. Suc-
cinyl chloride (1.5 mL, 13.6 mmol) was slowly added, with stirring,
to the reaction mixture and stirring was continued for 1 h. After
the organic layer was separated, it was washed twice with brine,
and dried over anhydrous sodium sulfate. Solvent was removed
under reduced pressure, and the solid product was recrystallized
from ethanol–water. A melting point and spectroscopic data were
acquired for each compound: (a) for 5a, Mp 155–156 ◦C; 1H NMR
(CDCl3): ␦ 2.33 (s, 4H), 3.23 (s, 6H), 7.23–7.42 (m, 10H); 13C NMR
(CDCl3): ␦ 29.5, 37.2, 127.4, 128.5, 129.7, 143.9, 172.8; HRMS
(ESI) m/z: calculated for C18H20N2NaO2 [M + Na]+ 319.1422; found
319.1412; (b) for 5b, Mp 104–105 ◦C; 1H NMR (CDCl3): ␦ 1.05 (t,
J = 7.2 Hz, 6H), 2.26 (s, 4H), 3.72 (q, J = 7.2 Hz, 4H), 7.19–7.42 (m,
10H); 13C NMR (CDCl3): ␦ 13.1, 29.9, 44.0, 127.8, 128.6, 129.7, 142.3,
171.4; HRMS (ESI) m/z: calculated for C20H24N2NaO2 [M + Na]+
347.1735; found 347.1728.
2.7. Computational methods
2.4. General procedure for synthesis of chloroacetamides (1a–1c)
Computational studies involving density functional theory were
performed to understand the mechanistic origin of the different
products observed for electrochemical reduction of the three 2-
chloro-N-phenylacetamides (1a–1c). All calculations were carried
out with the Gaussian suite of electronic structure programs [25].
Geometry optimizations were done with the popular B3LYP den-
sity functional [26,27] that uses a standard 6-31 + G(d,p) basis set
[28,29]. At this level of theory, the nature of the stationary points
(minima or transition states) as well as zero-point vibrational
We
synthesized
(1a),
and
purified
2-chloro-N-methyl-N-
phenylacetamide
2-chloro-N-ethyl-N-phenylacetamide
(1b), and 2-chloro-N-phenylacetamide (1c) according to the
procedure outlined by Hennessy and Buchwald [15], which entails
the reaction of 1 equivalent of N-alkylaniline or aniline with 1.5
equivalents of chloroacetyl chloride in a 2:1 ethyl acetate–water
mixture and in the presence of 3 equivalents of KOH in an ice–water

162
E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
effects and thermal corrections were determined. Single-point
calculations were then carried out with a larger 6-311 + +G(3df,2p)
basis set [30,31] [triple zeta + diffuse functions (sp functions on
C, O, and Cl, s functions on H) + multiple polarization functions
(3d,1f on C, O, and Cl, 2p on H)] to obtain more reliable rela-
tive energies. Solvent effects arising from DMF (␧ = 37) were then
incorporated into these larger basis set calculations by use of the
continuum solvation model with the SCRF–SMD framework as for-
mulated by Marenich and co-workers [32]. Final Gibbs free energies
of solutes in the solvent continuum are reported at the B3LYP/6-
311 + +G(3df,2p) level by addition of thermal and entropic terms,
obtained through the gas-phase calculations, to the single-point
energies in the condensed-phase calculations. All transition states
were characterized as possessing one and only one imaginary fre-
quency characteristic of a true first-order saddle point. Identities of
these transition states were further confirmed as representing the
desired reaction coordinate by use of intrinsic reaction coordinate
(IRC) analysis [33,34].
Remarkably, only the first cathodic peak is seen when HFIP is added,
whereas only the second cathodic peak is observed when TMAOH is
added. As discussed more extensively later, it appears that the first
cathodic peak is due to reduction of the parent compound (1c),
whereas the second cathodic peak can be attributed to reduction
of the (2-chloroacetyl)(phenyl)amide anion (1c−,which arises from
deprotonation of 1c).
3.3. Cyclic voltammetric behavior of nickel(II) salen at glassy
carbon in the presence of 2-chloro-N-phenylacetamides (1a–1c)
In a separate series of experiments, we examined the cyclic
voltammetric behavior of nickel(II) salen at a glassy carbon
electrode in DMF–0.050 M TMABF4 to establish experimental con-
ditions required to carry out the bulk catalytic reduction of each
of the three 2-chloro-N-phenylacetamides (1a–1c) by electrogen-
erated nickel(I) salen. Shown in Fig. 3 are cyclic voltammograms
recorded at 100 mV s−1 for the reduction of 1.0 mM nickel(II)
salen at a glassy carbon electrode in DMF–0.050 M TMABF4 in the
absence (solid curve) and in the presence (dashed curve) of 2.0 mM
2-chloro-N-methyl-N-phenylacetamide (1a). We found that the
electrochemical response of nickel(II) salen in the absence and
presence of 1a (as well as the other two substrates) is similar to
that depicted in a recent paper [41] from our laboratory. However,
in the present research, we observed no cyclic voltammetric peak
for reduction of a nickel(II) salen species with an imino (C=N) bond
modified by a fragment derived from a substrate molecule [42].
3. Results and discussion
3.1. Cyclic voltammetric behavior of
2-chloro-N-methyl-N-phenylacetamide (1a) and
2-chloro-N-ethyl-N-phenylacetamide (1b) at glassy carbon and
silver cathodes
Displayed in Fig. 1 are cyclic voltammograms recorded at
100 mV s−1 for reduction of 2.0 mM solutions of 1a and 1b at
either a glassy carbon electrode (solid curves) or a silver cathode
(dash–dot curves) in DMF containing 0.050 M TMABF4. For reduc-
tions of 1a and 1b at a glassy carbon electrode, a single irreversible
cathodic peak is seen with a peak potential (Epc) of –1.36 and
–1.46 V, respectively, which we attribute to reductive cleavage of
the carbon–chlorine bond. Reduction of 1a at a silver cathode shows
a definite pre-peak (Epc = –0.35 V), followed by a main cathodic peak
(Epc = –0.87 V); although the main peak is clearly associated with
reductive cleavage of the carbon–chlorine bond (as discussed later
in this paper), the process associated with the pre-peak is not yet
known. Reduction of 1b at silver gives rise to two merged peaks,
with the more negative peak at –0.84 V. In addition, electrochemi-
cal cleavage of the carbon–chlorine bond of 1a and 1b is decidedly
more facile at silver than at glassy carbon, with corresponding peak
potentials differing by 500–600 mV; this trend is common to the
reduction of halogenated organic compounds studied in our labo-
ratory [21,35–37] and by other groups [38–40].
3.4. Controlled–potential (bulk) electrolyses of
2-chloro-N-phenylacetamides (1a–1c)
A series of controlled-potential (bulk) electrolyses of 5.0 mM
solutions of the three 2-chloro-N-phenylacetamides at reticulated
vitreous carbon and at silver gauze cathodes in DMF containing
0.050 M TMABF4 was conducted. In addition, bulk electrolyses of
nickel(II) salen at reticulated vitreous carbon cathodes in the pres-
ence of each of the 2-chloro-N-phenylacetamides were carried out.
Compiled in Table 1 are coulometric data and product distributions
for all of these experiments. Each entry corresponds to the average
of at least two separate experiments. Product yields, which were
reproducible to 5% absolute, represent the amount of 2-chloro-
N-phenylacetamide incorporated into each species.
Electrolyses of either 1a or 1b at both carbon and silver cathodes
at potentials corresponding to those listed in Table 1 led to coulo-
metric n values close to 1.0, whereas the nickel(I) salen-catalyzed
reductions of 1a or 1b showed n values ranging from 0.9 to 1.2. On
the other hand, because reduction of 1c gives rise to two irreversible
cyclic voltammetric peaks, bulk electrolyses were carried out at two
different potentials for both carbon and silver electrodes; at less
negative potentials, the coulometric n values tended to be close to
1, whereas the n values approached 2 for electrolyses performed at
more negative potentials (including those accomplished with elec-
trogenerated nickel(I) salen). These n values suggest that radical
intermediates are involved in the electroreduction of 1a and 1b.
However, because reduction of 1c is a more intricate process, no
conclusions can be reached solely on the basis of the n values.
Table 1 reveals that (a) direct reduction of 1a at reticu-
lated vitreous carbon and silver gauze cathodes or (b) nickel(I)
salen-catalyzed reduction of 1a leads to the formation of N-
methyl-N-phenylacetamide (3a) and N-methylaniline (4a), along
with a small amount (if any) of a dimeric species (5a). Simi-
larly, reduction of 1b under the same experimental conditions
afforded N-ethyl-N-phenylacetamide (3b) as the major product,
N-ethylaniline (4b) in substantial yield, and a trace of a dimer
(5b). On the other hand, direct electroreduction of 1c at either car-
bon or silver and at potentials corresponding to the first cathodic
3.2. Cyclic voltammetric behavior of 2-chloro-N-phenylacetamide
(1c) at glassy carbon and silver cathodes
As depicted in Fig. 1, when cyclic voltammograms for reduction
of 1c at carbon and silver electrodes are recorded, two well sepa-
rated peaks are seen; values for Epc are –1.22 and –1.76 V at glassy
carbon and –0.65 and –1.20 V at silver. In contrast to the behavior of
1a and 1b, reduction of 1c exhibits two discrete steps at both glassy
carbon and silver cathodes. As described above, electrochemical
cleavage of the carbon–chlorine bond of 1c is decidedly more facile
at silver than at glassy carbon; note that both of the cathodic peaks
are shifted to less negative potentials for silver cathodes.
We have examined the cyclic voltammetric behavior of 1c in
the presence of an added proton donor (HFIP) or an added base
(TMAOH). Fig. 2 compares a cyclic voltammogram recorded with a
glassy carbon electrode at 100 mV s−1 for the reduction of 3.0 mM
1c in DMF–0.050 M TMABF4 containing no added acid or base
(solid curve) with those for which 1c was reduced in the presence
of 30 mM HFIP (dashed curve) or 10 mM TMAOH (dotted curve).

E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
163
Table 1
Coulometric n values and product distributions for electrochemical reduction of 5.0 mM solutions of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-N-
phenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at reticulated vitreous carbon and silver gauze cathodes in DMF containing 0.050 M TMABF4.
Product distribution (%)a
Starting material
Cathode
E, V
n
1
3
4
5
Total
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1c
C
–1.56
–1.07
–1.13
–1.47
–0.87
–1.13
–1.46
–1.84
–0.74
–1.30
–1.13
1.0
1.0
1.2
1.0
1.1
0.9
1.2
1.8
1.1
1.5
1.9
NDc
ND
ND
ND
ND
ND
30
ND
32
5
48
61
48
52
73
28
78
107
51
84
30
36
37
21
16
40
ND
ND
ND
ND
ND
2
ND
2
2
ND
1
ND
ND
ND
ND
ND
80
97
86
75
89
Ag
Cb
C
Ag
Cb
C
69
108
107
83
89
101
C
Ag
Ag
Cb
ND
101
1 = starting material; 3 = phenylacetamide (3a, 3b, 3c); 4 = aniline (4a, 4b); 5 = dimer (5a, 5b).
a
Yield expressed as the percentage of starting material incorporated into each species.
For these experiments, 2.0 mM nickel(I) salen, electrogenerated at carbon (RVC), served as a catalyst.
ND = species not detected.
b
c
peak gave N-phenylacetamide (3c) as the main product, along
3.6. Mechanistic features of the reduction of
with unreduced starting material. Electrolyses of 1c at poten-
tials corresponding to the second cathodic peak at both cathodes
afforded N-phenylacetamide (3c) as the only product, and very lit-
tle (if any) of the starting material remained. Indirect (mediated)
reduction of 1c by electrogenerated nickel(I) salen led only to N-
phenylacetamide (3c).
2-chloro-N-methyl-N-phenylacetamide (1a) and
2-chloro-N-ethyl-N-phenylacetamide (1b) at glassy carbon and
silver cathodes
On the basis of coulometric n values, product distributions, and
theoretical calculations, a plausible set of pathways for the forma-
tion of each product is proposed in Scheme 1 for the reduction of
1a and 1b in DMF. Thus, 2-chloro-N-alkyl-N-phenylacetamide (1a
or 1b) initially undergoes one-electron reductive cleavage of the
carbon–chlorine bond to give radical 2a or 2b, a step in accord with
the coulometric n value of 1 (Table 1). Abstraction of a hydrogen
atom from the solvent affords the major product (3a or 3b). To
explain the formation of the substituted aniline (4a or 4b) during
an electrolysis, we suggest that radical 2a or 2b eliminates ketene
to yield a N-substituted aniline radical which abstracts a hydrogen
atom from the solvent to form the observed product. Optimized
structures for the radical species (2a and 2b) as well as for the tran-
sition states for ketene elimination (TS1a and TS1b) are given in
Fig. 5. Stretching of the N–C distance from 1.4 A in 2 to 2.0 A in
TS1 (for both the methyl and ethyl derivatives) clearly shows the
process of bond breaking to form the ketene; the calculated Gibbs
free energy of the transition states (TS1a and TS1b) for ketene
elimination are very similar, 21 and 22 kcal mol−1, respectively,
with respect to the corresponding radical 2. This finding is consis-
tent with the observed experimental results where the amines (4a
and 4b) are formed as significant products via the electrochemi-
cal reduction of 1a and 1b, respectively. However, experimental
attempts to verify directly the formation of the ketene by means
Because cyclic voltammograms for reduction of 1c exhibit two
cathodic peaks at both glassy carbon and silver electrodes (Fig. 1),
we sought specific evidence for the generation of carbanionic
intermediates at potentials corresponding to either or both of
the cathodic peaks for reduction of this compound. Accordingly,
controlled-potential (bulk) electrolyses of 1c at both reticulated
vitreous carbon and silver gauze cathodes were undertaken in the
presence of both HFIP and D2O. First, electrolyses of 5.0 mM solu-
tions of 1c in DMF–0.050 M TMABF4 containing 50 mM HFIP were
carried out at a potential corresponding to the first stage of reduc-
tion (Ecarbon = –1.46 V and Esilver = –0.74 V). Reduction of 1c afforded
N-phenylacetamide (3c) as the only product in essentially quanti-
tative yield (102–106%); coulometric n values were 2.7 for carbon
and 2.2 for silver, and the unusually large n value obtained for car-
bon appears to be due to co-reduction of some HFIP. Second, bulk
electrolyses of 5.0 mM solutions of 1c in DMF–0.050 M TMABF4 con-
taining 50 mM D2O were, once again, performed at both cathodes
and at a potential corresponding to the first stage of reduction. For
these experiments, the coulometric n values were 1.2 for carbon
and 1.1 for silver; interestingly, and in accord with appropriate
entries in Table 1, the product distribution consisted of unreduced
starting material (1c) and N-phenylacetamide (3c), the latter being
singly deuterated.
˚
˚
3.5. Conformations of 2-chloro-N-phenylacetamides (1a–1c)
Initial theoretical calculations were performed to identify the
most stable conformations of the 2-chloro-N-phenylacetamides.
We found that the lowest energy conformer (CF1) possesses a
trans orientation, as shown in Fig. 4a; this conformer is approxi-
mately 6 kcal mol−1 more stable than the conformer (CF2) with a cis
orientation (Fig. 4b). This finding is in agreement with previous con-
formational studies of amides [43–45]. With the more stable trans
orientation as a starting point, mechanistic studies were carried out
for the three derivatives (1a–1c) to understand our experimental
findings. As discussed in the following sections, these calculations
clearly reveal why the electrochemical behavior of 1a and 1b is
different from that of 1c.
Fig. 4. Optimized geometries of lowest energy conformers (a) CF1 and (b) CF2
corresponding to the two different orientations, trans and cis, respectively. Given
in parentheses for each conformer is the relative Gibbs free energy (kcal mol−1
calculated at the B3LYP/6-31 + G(d,p) level.
)

164
E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
Fig. 5. Optimized geometries for reactive species (radicals and carbanions) generated by electrochemical reduction and for the transition states involved in various mechanistic
steps.
of trapping with tert-butyl alcohol were unsuccessful [46]. Finally,
formation of the dimer (5a or 5b) as a minor product arises from
combination of two radical species (2a or 2b).
pathway wherein 6c undergoes a proton migration from nitrogen
to the carbanion site via TS3c, as depicted in Fig. 5 and Scheme 2.
Interestingly, the resulting anion (8c), pictured in Scheme 2, is
substantially more stable than carbanion 6c by 14.8 kcal mol−1
(Table 2); therefore, the anion will readily convert from 6c to
8c. What follows is protonation of 8c by the medium to form
the observed product (N-phenylacetamide, 3c). In addition, as
shown at the bottom of Scheme 2, it is conceivable that 3c
could arise via proton transfer between 1c and 6c, leaving a (2-
chloroacetyl)(phenyl)amide anion (1c−) that is reducible to 3c at
potentials corresponding to the second cathodic peak seen in Fig. 1
for reduction of 1c. A calculation, based on density functional the-
ory, indicated that reductive cleavage of the carbon–chlorine bond
of 1c should be 0.38 V easier than that of 1c−. This result, which
does not take into account any interaction between 1c−and the
supporting–electrolyte cation (TMA+), is consistent with the differ-
ence (0.54–0.55 V) in the cathodic peak potentials shown in Fig. 1
for the two-step reduction of 1c at both glassy carbon and silver.
Table 2 compares the relative energies of the different station-
ary points for the one- and two-electron reduction of the three
2-chloro-N-phenylacetamides (1a–1c). Observed differences in the
products arising from electrochemical reduction of these com-
pounds can be attributed to the formation of the stable amide
anion (8c). Because the migration of methyl and ethyl groups is
unlikely, the amide anions (8a and 8b) will not form. Without
this additional stabilizing effect, reductions of 1a and 1b do not
go through the anionic pathway, but follow the radical pathway
considered earlier (Scheme 1). Moreover, even for 1c, the forma-
tion of 8c precludes elimination of ketene or dimerization reactions
3.7. Mechanistic features of the reduction of
2-chloro-N-phenylacetamide (1c) at glassy carbon and silver
cathodes
Theoretical calculations reveal that the electrochemical reduc-
tion of 1c must take place via a mechanism different from what has
just been described for the electrochemistry of 1a and 1b. Shown
in Scheme 2 is our proposed set of mechanistic pathways for the
reduction of 1c. Experimentally, the coulometric measurements (n
∼ 2) clearly suggest that 1c undergoes a two-electron reduction to
form a resonance-stabilized carbanion (6c) which, in the simplest
mechanism, can extract a proton, most likely from residual water
present in the solvent, to give the dehalogenated acetamide (3c).
However, such a process does not explain why 1c behaves very
differently from 1a and 1b.
Our calculations suggest that proton migration in the carbanion
is principally responsible for the differences seen in the behav-
ior of 1c in comparison with 1a and 1b. By first considering the
involvement of a resonance form of carbanion 6c, namely eno-
late 6cꢀ in Scheme 2, we examined the migration of the proton
from the N atom to the O atom via transition state TS2c (shown
in Fig. 5 and Scheme 2), which leads to an anionic intermediate
(7c). However, our calculations show that 7c is less stable than 6c
by 10.9 kcal mol−1 (Table 2), so that 7c is not likely to play a role
in the reaction. This revelation led us to consider an alternative

E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
165
Table 2
Relative energies of key stationary points involved in formation of the feasible products after one- and two-electron reduction of 2-chloro-N-phenylacetamides (1a–1c).
Geometries were optimized at the B3LYP/6-31 + G(d,p) level of theory.
Coulometric n value
Starting compound
Stationary points
B3LYP/
6-311 + +G(3df,2p)
SMD(DMF): B3LYP/
6-311 + +G(3df,2p)
ꢀG
ꢀGsol
1
1a
1b
1c
1c
2a
TS1a
2b
TS1b
2c
TS1c
6c
0.0
20.5
0.0
20.9
0.0
0.0
21.0
0.0
21.9
0.0
27.1
0.0
28.7
0.0
2
TS2c
7c
TS3c
8c
26.8
7.5
33.7
–17.0
31.0
10.9
37.7
–14.8
involving the anion. Thus, our calculations are in agree-
ment with the observed experimental results for the electro-
chemical reduction of all three 2-chloro-N-phenylacetamides
(1a–1c).
Finally, we considered the possibility of a radical pathway for
reduction of 1c. Experimental results for reduction of 1c compiled
in Table 1 do suggest that a radical pathway (n = 1) is operative,
along with the anionic pathway (n = 2). Accordingly, reactions sim-
ilar to those proposed for 1a and 1b are also conceivable for 1c.
To explore this point further, we obtained a transition state (TS1c,
Fig. 5) for the elimination of ketene from 2c (analogous to 2a and
2b in Scheme 1) that would lead to aniline as the product (not
observed experimentally). As can be seen from Table 2, the free-
energy barrier (∼29 kcal mol−1) of the transition state TS1c for
ketene elimination from 2c, that would be formed by one-electron
reduction of 1c, is significantly higher than the corresponding val-
ues for transition states TS1a and TS1b that arise, respectively, from
reduction of 1a and 1b. This result suggests that ketene elimination
from 2c is not feasible at room temperature, unlike the situation
for 2a and 2b. In addition, this conclusion is consistent with the
observed experimental results where the alkyl-substituted aniline
products (4a and 4b) are formed via ketene elimination upon reduc-
tion of 1a and 1b, respectively. In the case of 2c, hydrogen atom
abstraction from the solvent then leads to the observed product
(3c).
Scheme 1. Proposed mechanistic scheme for electrochemical reductions of 1a and
1b at reticulated vitreous carbon and silver gauze cathodes in DMF–0.050 M TMABF4.
Scheme 2. Proposed mechanistic scheme for electrochemical reduction of 1c at
reticulated vitreous carbon and silver gauze cathodes in DMF–0.050 M TMABF4.

166
E.M. Pasciak et al. / Electrochimica Acta 127 (2014) 159–166
in dimethylformamide, Journal of The Electrochemical Society 160 (2013)
Acknowledgments
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This work was supported in part by Department of Energy Grant
No. DE-FG02-07ER15889 to K. R.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.electacta.
2014.01.133.
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