Electrochemical behavior of N-oxyphthalimides: Cascades initiating self-sustaining catalytic reductive N―O bond cleavage

Article abstract of DOI:10.1002/poc.3744

N-oxyphthalimides are stable and easily accessible compounds that can produce oxygen radicals upon 1-electron reduction. We present a systematic study of electrochemical properties of N-oxyphthalimide derivatives (PI-ORs) in DMF by cyclic voltammetry. In all cases, electron transfer to the substrate leads to decomposition of the intermediate radical anion via the N―O bond cleavage. In the case of benzyloxyphthalimide or its derivatives containing electron-donating substituents, reductive electron transfer induces the chain decomposition of the substrate to phthalimide (PI) radical-anion and the corresponding carbonyl compound. The PI radical-anion product is a powerful reductant that can transfer an electron to the reactant PI-OR, thus establishing a catalytic cycle for reductive N―O scission. This self-catalytic process is reflected in a considerable decrease in the reduction current for the substrate (<1e^-/molecule). By contrast, reductive fragmentations of benzyl derivatives containing electron-withdrawing substituents in the aromatic ring or at the benzylic position, as well as tosyl and alkyl derivatives, occur via a 1-electron mechanism. A sequence of N―O and C―C scissions was engineered to support the intermediacy of O-centered radicals in these processes.

Full text of DOI:10.1002/poc.3744

Received: 24 April 2017
DOI: 10.1002/poc.3744
Revised: 29 June 2017
Accepted: 29 June 2017
S P E C I A L I S S U E A R T I C L E
Electrochemical behavior of N‐oxyphthalimides: Cascades
initiating self‐sustaining catalytic reductive N―O bond
cleavage
1
1
2
2
Mikhail A. Syroeshkin | Igor B. Krylov | Audrey M. Hughes | Igor V. Alabugin |
1
1
1
1
Darya V. Nasybullina | Mikhail Yu. Sharipov | Vadim P. Gultyai | Alexander O. Terent'ev
1
N. D. Zelinsky Institute of Organic
Abstract
Chemistry, Russian Academy of Sciences,
Moscow, Russian Federation
N‐oxyphthalimides are stable and easily accessible compounds that can pro-
duce oxygen radicals upon 1‐electron reduction. We present a systematic study
of electrochemical properties of N‐oxyphthalimide derivatives (PI‐ORs) in DMF
by cyclic voltammetry. In all cases, electron transfer to the substrate leads to
decomposition of the intermediate radical anion via the N―O bond cleavage.
In the case of benzyloxyphthalimide or its derivatives containing electron‐
donating substituents, reductive electron transfer induces the chain decomposi-
tion of the substrate to phthalimide (PI) radical‐anion and the corresponding
carbonyl compound. The PI radical‐anion product is a powerful reductant that
can transfer an electron to the reactant PI‐OR, thus establishing a catalytic cycle
for reductive N―O scission. This self‐catalytic process is reflected in a consider-
2
Department of Chemistry and
Biochemistry, Florida State University,
Tallahassee, FL, USA
Correspondence
Alexander O. Terent'ev, N. D. Zelinsky
Institute of Organic Chemistry, Russian
Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russian Federation.
Email: alterex@yandex.ru
Funding information
National Science Foundation, Grant/
Award Number: CHE‐1465142 and TG‐
CHE160006; Russian Science Foundation,
Grant/Award Number: 14‐50‐00126
‐
able decrease in the reduction current for the substrate (<1e /molecule). By
contrast, reductive fragmentations of benzyl derivatives containing electron‐
withdrawing substituents in the aromatic ring or at the benzylic position, as
well as tosyl and alkyl derivatives, occur via a 1‐electron mechanism. A
sequence of N―O and C―C scissions was engineered to support the intermedi-
acy of O‐centered radicals in these processes.
KEYWORDS
cyclic voltammetry, dissociative electron transfer, electrochemically induced cyclic reactions, N‐
hydroxyphthalimide derivatives, radical anions
1
| INTRODUCTION
in the selective liquid‐phase oxidation of organic sub-
[
1–3]
strates,
such as alkanes, alkylarenes, alkenes, alkynes,
N‐Hydroxyphthalimide (NHPI) and its О‐substituted
derivatives (PI‐ORs, Figure 1) play an increasingly
important role in organic synthesis and medicinal chemis-
alcohols, and ethers, as well as in oxidative cross‐coupling
reactions.
[
4–7]
Because the phthalic protecting group can easily be
removed, PI‐ORs are the main precursors of organic
O‐substituted hydroxylamines (Scheme 1, direction A),
valuable intermediates in the synthesis of biologically
[1–16]
try.
In particular, the highly reactive N‐oxyl radicals
generated from NHPI and its analogues are widely used
[
8–12]
active compounds.
In reactions with various reduc-
This paper is dedicated to Professor Waldemar Adam on the occasion of
th
his 80 birthday
ing agents, PI‐ORs can undergo a wide spectrum of
J Phys Org Chem. 2017;e3744.
wileyonlinelibrary.com/journal/poc
Copyright © 2017 John Wiley & Sons, Ltd.
1 of 15
https://doi.org/10.1002/poc.3744

2
of 15
SYROESHKIN ET AL.
number of O‐alkyl derivatives of NHPI with Bu SnH
3
[
14]
affords oxygen‐centered free radicals.
These findings
can be attributed to the specific coordination of the
[
31–33]
Sn‐radicals with the substrate.
On the other hand,
photochemical reductive fragmentation of NHPI deriva-
FIGURE 1 The structures of N‐hydroxyphthalimide (NHPI) and
its О‐substituted derivatives (PI‐OR)
tives did not reveal reactivity consistent with the
[25]
formation of free radicals.
Furthermore, yet another
mechanism is possible if the α‐C―H bond of the
transformations and participate in processes that lead to
N―O―CHR moiety is acidic (eg, in β‐keto deriva-
2
[
34]
the selective cleavage of either the CO pi‐bond (NaBH
tives ). In the latter case, the reaction can be induced
by bases (Scheme 1, direction G) produced in the
primary reactions of organic RAs. This mechanistic
diversity renders reductive fragmentation of NHPI
derivatives an interesting and challenging topic.
4
[17]
as the reducing agent, direction B),
the C―O bond
[
18]
(
H /Pd as the reducing agent, direction C),
or the
2
[
19]
N―O bond (TiCl3,
Bu SnH, or Ph SnH as the reduc-
3
3
[13–16]
ing agent, directions D‐E
). The reactions with
R SnH in the presence of the radical initiator AIBN are
In addition to organic synthesis, understanding the
processes of the formation and decomposition of PI‐OR
RAs gains increasing importance for medicinal chemistry.
In this field, there is a need for new structural units
capable of releasing active functional groups or generat-
3
believed to proceed via attack of R Sn• radical at the
3
carbonyl oxygen followed by a β‐scission to form an
oxygen‐centered free radical. The N―O bond cleavage
can occur in radical anions (RAs) of PI‐ORs that are
generated via 1‐electron reduction (direction F) under
ing reactive free radicals directly in living tissues, eg, via
[
20–25]
[35–37]
irradiation in the presence of a photosensitizer.
photoinduced electron transfer.
Compounds having
Recently, the photochemical versions of these reductive
fragmentations started to find an increasing number of
new applications.
such properties can be particularly useful for the develop-
ment of approaches to the therapy of hypoxic tumors,
which are difficult to treat with cytotoxic drugs with other
[26–30]
[
38–40]
Despite a large number of studies on the reductive
fragmentation of PI‐ORs accompanied by the N―O
bond cleavage, most of them include formation of PI‐
OR RAs as transient components of complex catalytic
cycles. Direct detection of these species and possible
intermediates of their further transformations remains
elusive. Because a variety of different PI‐ORs and reduc-
ing agents were used in the literature, the results of the
published studies are often difficult to analyze and to
compare systematically. For example, reduction of a
mechanisms of action.
The key feature of PI‐ORs
examined in the present work is the presence of the rela-
tively weak N―O bond, which is susceptible to cleavage
[
41–43]
via reductive 1‐electron transfer.
These compounds
provide an interesting counterpart to organic perox-
[
44–51]
ides,
a related class of biologically active antipara-
sitic and antitumor compounds containing a weak O―O
bond.
In order to obtain data on the mechanism of reductive
reactions of PI‐ORs, the present work applied
SCHEME 1 Transformations of N‐
hydroxyphthalimide derivatives (PI‐ORs)
in the presence of reducing agents and
bases

SYROESHKIN ET AL.
3 of 15
electroanalytical methods to investigate electrochemical
properties of these compounds. The electrochemical
behavior of NHPI derivatives has been scarcely studied.
Only a few of cyclic voltammetric peak potentials for the
electroreduction (ER) of selected O‐acyl derivatives of
TABLE 1 Voltammetric peak potentials (V) of the compounds at
4 4
a glassy carbon electrode in a 0.1 М Bu NClO solution in DMF
+
relative to Fc/Fc . The value of n is the number of electrons per
molecule; it was estimated with respect to the ferrocene oxidation
−
1
peak current (v = 0.05 V s ).
[20,21]
p
1
p
2
p
3
p
NHPI in acetonitrile
and the polarographic half‐
Compound
‐E
‐E
‐E
‐E
4
n
[52]
wave potentials in methanol
are known. One can also
PI
‐
1.941
‐
2.694
0.67
mention ER of benzyloxyphthalimide in aprotic medium
in the presence of chlorotrimethylsilane that led to
silylation of the substrate.
PI + AcOH
‐
‐
1.926
‐
‐
‐
2
PI + Bu
4
NOH
‐
2.649
[53]
1
1.765
1.940
2.288
2.290
2.464
2.457
2.448
2.431
2.272
2.701
< 0.4
< 0.4
< 0.4
< 0.4
In this work, we studied electrochemical behavior of
1
2
2
3
3
4
a
a
a
‐
‐
‐
1
5 PI‐ORs by cyclic voltammetry (CV) on a glassy carbon
working electrode in DMF in the presence of tetrabuty-
lammonium perchlorate as a supporting electrolyte. The
electrochemically induced N―O bond cleavage in PI‐
ORs was general, but the substrate structure had effect
on the reduction potentials and subsequent transforma-
tions. These results provide insights into the thermody-
namics of electron transfer reactions, stability of the
corresponding RAs, and the reductive cascades that
follow the N―O fragmentation.
1.768
1.945
2.693
‐
‐
‐
1.764
1.947
2.692
‐
‐
‐
1.749
1.920
2.656
a
4a
‐
‐
2.097
2.321
‐
a
a
a
a
PI +4a
‐
1.913
1.935
1.944
1.943
‐
2.283
2.742
2.650
2.645
2.670
2.652
‐
5
6
7
8
1.765
1.764
1.757
1.788
1.757
1.857
1.770
1.688
1.694
1.746
1.727
1.618
1.640
1.620
1.799
1.787
1.592
1.656
2.280
< 0.4
< 0.4
< 0.4
~1
2.348
2
| EXPERIMENTAL
2.350
‐
Cyclic voltammograms were recorded, and controlled
potential electrolysis were implemented with an IPC‐Pro
potentiostat (Econix) (the accuracy of the scan rate is
8 + AcOH
1.952
‐
‐
9
‐
2.679
‐
~1
~1
~1
1
.0%; the accuracy of the potential setting is 0.25 mV).
9
1
1
+ AcOH
1.967
‐
‐
Experiments were performed in a 10‐mL 5‐neck glass
conical‐shaped electrochemical cell with a water jacket
for thermal control. The glassy carbon disk electrode
0
2.276
2.635
‐
0 + AcOH
1.943
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
(
d = 1.7 mm) served as the working electrode; a platinum
11
2.633
‐
wire (insulated by a ceramic membrane in electrolysis), as
the auxiliary electrode. A graphite rod was utilized as a
cathode for the electrolysis. A saturated calomel electrode
1
1
1
1
1 + AcOH
1.966
1.963
‐
2
2.724
2.715
‐
~1
~1
3
(SCE) served as the reference electrode, which was linked
3 + AcOH
1.940
‐
to the solution under study by a bridge with a porous
ceramic diaphragm filled with the supporting electrolyte.
The potentials were corrected for the ferrocene oxidation
potentials under the same conditions (0.47 V vs SCE).
The solutions were kept under thermally controlled con-
ditions at 25 ± 0.5°С and then deaerated by bubbling
argon. Electrochemical experiments were performed
under an argon atmosphere. A typical experiment was
carried out using 5 mL of a substrate solution at a concen-
tration of 5 mmol/L. Listed peak potentials correspond to
the points of the maximum current on cyclic voltammo-
grams (Table 1).
14
2.714
‐
~1
1
1
1
4 + AcOH
1.937
1.952
‐
5
6
2.744
2.775
~2/3
~1
a
The voltammetric peak potentials for PI and 4a when they are simulta-
neously present in the solution are not equal to those for separately prepared
solutions of these compounds (see Figure 6).
Crystal 5000 instrument with flame ionization detector;
injector temperature was 250°С, column temperature
was raised from 70°С to 250°С at rate of 15°С/min,
helium was used as the carrier gas, flow rate was
2.19 mL/min; GC column phase: dimethylsiloxane; phase
thickness: 1.0 μm; column inner diameter: 0.32 mm;
Electrolysis of 1 was carried out at the potential of the
first step of the ER (−1.75 V). The solution was sampled
for GC after passing 0.20, 0.30 and 0.40 F of electricity.
Gas chromatography was performed on Chromatec‐

4
of 15
SYROESHKIN ET AL.
column length: 30 m. In the course of electrolysis, a grad-
ual decrease of intensity of N‐(benzyloxy)phthalimide 1
GC peak and simultaneous increase of GC peaks of benz-
aldehyde 1a and phthalimide PI were observed. Compo-
nents of the mixture were identified by the retention
times which were determined for individual compounds
7.70 (m, 2H, ArH), 7.68‐7.58 (m, 1H, ArH), 7.58‐7.42 (m,
13
3H, ArH), 4.44 (s, 2H, CH ); С NMR (75.47 MHz, CDCl ):
2
3
δ = 167.9 (COO), 162.0 (CON), 134.9, 134.0, 131.9,
129.03, 129.00, 128.96, 128.3, 128.1, 127.0, 126.2, 125.6,
124.1, 123.6, 35.7 (CH ); IR (KBr): ν
= 1816, 1785,
max
2
1737, 1373, 1355, 1189, 1137, 1067, 1043, 970, 877,
‐
1
1, 1a, and PI.
779, 694, 519 cm ; elemental analysis calcd. for
C H NO : C 72.50, H 3.96, N 4.23; found: C 72.51,
Compounds 1a‐4a, phthalimide (PI), DMF (“extra
2
0
13
4
dry”), Bu NClO , and 1.5 М Bu NOH aqueous solution
H 3.95, N 4.21.
4
4
4
were purchased from Acros Organics. Procedures for the
synthesis and purification and the establishment of the
[
4]
2.1 | Electrolysis of 1,3‐dioxoisoindolin‐2‐
yl 2‐(naphthalen‐1‐yl)acetate 16
structures of compounds 1‐11 were reported earlier.
Compounds 12, 13, and 15 were synthesized by the reac-
[
54]
[55]
tion of NHPI with benzoyl chloride,
and tosyl chloride,
acetyl chloride,
respectively. N‐Ethoxyphthalimide
4 was prepared by the reaction of NHPI with ethyl
At the potential −1800 mV, 48.8 mg (0.147 mmol) of 16
was electrolyzed. After consumption of 1.00 F, the
electrolysis was stopped, and the obtained dark‐orange
[
54]
1
[56]
bromide and sodium acetate
(Figure 2, Table 1).
solution was diluted with H O (10 mL) and extracted by
2
1,3‐dioxoisoindolin‐2‐yl 2‐(naphthalen‐1‐yl)acetate
petroleum ether (3 × 7 mL). The organic extracts were
16. EtOAc (5 mL) was added to a mixture of 2‐(naphthalen‐
combined and washed with H O (3 × 10 mL),
2
1
‐yl)acetic acid (372 mg, 2 mmol), N‐hydroxyphthalimide
concentrated in vacuum of the water aspirator. 1‐Methyl-
naphthalene 17 (7.0 mg, 0.049 mmol, 33%) was isolated
by TLC (20 × 15 cm plate, layer thickness 0.2 mm; silica
(
(
326 mg, 2 mmol), and N,N′‐dicyclohexylcarbodiimide
454 mg, 2.2 mmol). Resultant suspension was stirred for
2
72 hours at room temperature, then rotary‐evaporated to
gel 60 Å, specific surface [BET] ~ 500 m /g, particle size
dryness, suspended in CH Cl (5 mL), transferred to a
5–17 μm, with UV254 fluorescent indicator) using petro-
leum ether as eluent. The purity and identity of 1‐meth-
2
2
silica gel column (wet packed using CH Cl ) and eluted
2
2
[
57]
1
13
with CH Cl . The first fraction was rotary‐evaporated to
ylnaphthalene
H NMR (300.13 MHz, CDCl ): δ = 8.03‐7.97 (m, H),
were confirmed by H and С NMR.
2
2
1
give 1,3‐dioxoisoindolin‐2‐yl 2‐(naphthalen‐1‐yl)acetate 16
588 mg, 1.77 mmol, 89%) as a slightly yellow powder. M.
3
(
7.88‐7.81 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56‐7.44
1
13
p. = 138‐139°C; H NMR (300.13 MHz, CDCl ): δ = 8.03
(m, 2H), 7.42‐7.29 (m, 2H), 2.70 (s, 3H) С NMR
3
(d, J = 8.4 Hz, 1H, ArH), 7.93‐7.80 (m, 4H, ArH), 7.80‐
(75.47 MHz, CDCl ): δ = 134.4, 133.7, 132.8, 128.7,
3
FIGURE 2 Structures of the compounds discussed in this study

SYROESHKIN ET AL.
5 of 15
1
26.7, 126.5, 125.8, 125.70, 125.66, 124.2, 19.5. It should
voltammograms of these compounds measured under
the same conditions. Furthermore, the addition of phthal-
imide PI and benzaldehyde 1a to a solution of 1 leads to
an increase in the corresponding peaks. The formation
of phthalimide and benzaldehyde 1a in the ER of com-
pound 1 was additionally confirmed by GC analysis of
the electrolysis solution (see the experimental part).
It should be noted that the presence of both PI and
benzaldehyde 1a in the solution has virtually no effect
on both the reduction peak current for 1 and the peak cur-
rent on the reverse scan after the first reduction stage and,
consequently, has no effect on the decomposition rate.
This is evidence that the stages giving PI and 1a are appar-
ently not rate determining in the overall mechanism of
ER of 1.
be noted that the yield of 1‐methylnaphthalene was prob-
ably underestimated due to its volatility at reduced pres-
sure that was used for rotary evaporation of the solvent
before and after TLC.
3
3
| RESULTS AND DISCUSSION
.1 | Electrochemical behavior of 1, 1a,
and PI
The cyclic voltammograms of benzyloxyphthalimide 1 in
DMF (Figure 3) show a reduction peak at −1.765 V. The
peak is chemically irreversible at the scan rates of 0.025‐
.100 V s‐ but becomes partially reversible at the higher
1
0
scan rates. Therefore, RA is a short‐lived intermediate,
and the electron transfer to the substrate 1 is followed
by a fast chemical reaction.
The mechanism for ER of benzaldehyde 1a under
aprotic conditions involves dimerization of the benzalde-
[
58]
hyde RA. Due to the self‐protonation of PI RA, its peak
current (−1.940 V) corresponds to two‐third electrons, the
reduction peak of its anion being observed at more
Yet another distinguishing feature of the electrochem-
ical behavior of compound 1 under these conditions is a
substantial decrease in the cathodic peak current with
respect to the 1‐electron level. At the minimum potential
scan rate (v), a 3‐fold decrease with respect to the
ferrocene oxidation current at the same value of v was
observed. This decrease becomes smaller with increasing
scan rate, and a simultaneous increase in the chemical
reversibility of the peak is observed. Therefore, the forma-
tion of RA of 1 causes the progression of the subsequent
chemical chain reactions where the starting compound 1
is consumed in the near‐electrode region.
[
59,60]
cathodic potentials (−2.701 V).
Many electrochemically initiated reactions are base‐
catalyzed processes, in which electric current serves to
[
61]
generate a base at the cathode.
Such reactions can also
be initiated by addition of an external base and be sup-
[
62]
pressed by addition of acids (for example, see ). We
found that addition of acetic acid to a solution of 1 did
not decrease the reduction peak currents for the decom-
position products PI and benzaldehyde.
Because the decomposition of 1 in the presence of
acetic acid is not suppressed, the decomposition of 1 does
not involve base catalysis. Instead, it should be associated
with the formation of RA that triggers the chain reaction
(Scheme 2). It is most likely that the RA of PI rather than
RA of benzaldehyde serves as an electron carrier because
PI is reduced much earlier than benzaldehyde and,
At the expanded cathodic potential scan range, the
cyclic voltammogram of 1 (Figure 3, on the right) shows
the peaks corresponding to ER of phthalimide PI
(
−1.940 and −2.701 V) and benzaldehyde 1a (−2.288 V)
after the first reduction stage. Presence of these products
is evident from comparison of the cyclic
a
‐1
FIGURE 3 Cyclic voltammograms of solutions of compound 1 (5 mmol L ) obtained at different potential scan rates and normalized to the
‐1
square root of the scan rate (left) and at a scan rate of 0.100 V s compared with the voltammograms for PI and 1a (right) in DMF containing
.1 М Bu NClO
0
4
4

6
of 15
SYROESHKIN ET AL.
SCHEME 2 Mechanism of the electroreduction of 1 in a 0.1 M Bu
voltammograms are given relative to Fc/Fc )
4
NClO
4
solution in DMF (the peak potentials in the cyclic
+
consequently, has a higher electron affinity. This conclu-
According to the computational results, PI‐OR RAs
sion is consistent with the proposed mechanism of
adopt perpendicular geometry around the N―O bond
where the non‐bonding orbitals at the 2 heteroatoms
avoid interaction with each other and instead overlap
with the vicinal acceptor σ*‐orbitals (lone pair of N with
the σ*O―C bond, the p‐type lone pair of O with the
σ*N―C bonds). This perfect matching of the donor and
acceptor properties of the 2 “chameleonic” functional
[25]
photodegradation of 1
energy for the latter step according to DFT calculations
Scheme 2).
A priori, the N―O bond cleavage in the RAs can pro-
and with the −9 kcal/mol free
(
ceed via 2 alternative pathways: Path I where the extra
electron stays at the nitrogen or Path II where the nega-
tive charge goes to the oxygen (Scheme 3).
[
63]
groups
assures that the breaking N―O bond is
In the number of papers, the reductive decomposi-
constrained to orthogonality with the π‐system of the PI
moiety. As the result, electron reduction does not lead to
a significant N―O bond length increase whereas the
elongation of each of C¼O bonds is quite significant
(Figure 4, Table 3).
Interestingly, the driving force for the 2 fragmentation
paths strongly depends on substituent at oxygen. For
R = alkyl, the Path II fragmentation with the formation
of an alkoxy anion is so strongly disfavored (ΔG ~ +20‐
[13–16]
tion of alkoxyphthalimides
and acyloxyphthalimi-
[20–24]
des
is assumed to involve the formation of O‐
centered radicals. However, reductive N―O scission
benzyloxyphthalimide and its analogues under similar
[25]
conditions
did not provide alkoxy radicals trappable
by a fast intramolecular reaction (cyclization). In order
to differentiate between the 2 mechanisms, we used
result from DFT computations summarized in Table 2.
30 kcal/mol), that the only viable fragmentation mode is
the Path I that produces the phthalimide anion and an
alkoxy radical (ΔG ~ −20 kcal/mol). When R has a
carbonyl group directly attached to the oxygen, the
balance between the 2 pathways is much more delicately
poised. Both processes are exergonic, but the formation
of alkoxy radical (Path I in Scheme 3) is still slightly more
favorable.
In our opinion, the difficulties in the detection of
O‐centered radicals do not necessarily indicate their
SCHEME 3 Alternative pathways of N―O bond scission in the
PI‐OR radical anion

SYROESHKIN ET AL.
7 of 15
TABLE 2 DFT calculations of thermochemistry for the 2 possible paths of N―O bond cleavage in radical anions of PI‐ORs
b
a
a
a
Compound
Scission result
E
H
G
−
.
PI + RO
−4.2
39.2
−7.4
35.5
−21.5
21.1
1
2
8
R =
R =
R =
.
−
PI + RO
−
.
PI + RO
−2.1
41.2
−4.5
37.6
−17.7
24.1
.
−
PI + RO
−
.
PI + RO
−2.3
39.7
−5.2
36.2
−19.8
22.1
.
−
PI + RO
−
.
PI + RO
−4.1
32.8
−6.9
29.7
−20.4
15.0
c
.
−
1
1
0′ R =
PI + RO
−
.
PI + RO
1.7
6.7
−0.9
4.4
−13.5
−9.0
.
−
2 R =
PI + RO
−
.
PI + RO
1.5
11.3
−0.8
9.0
−13.7
−5.0
1
1
3 R =
4 R =
.
−
PI + RO
−
.
PI + RO
−2.5
45.4
−5.7
41.9
−17.9
29.0
.
−
PI + RO
a
UM06‐2X/6‐31 + G(d,p) in DMF, kcal/mol.
b
PI = phthalimide.
c
Compound 10′ has a shortened alkyl chain compared with the experimentally studied compound 10.
FIGURE 4 Calculated geometries (left) and distribution of spin density (right) in radical anion (RA) of PI‐OR 1
absence. It is known that the decomposition of organic
RAs often gives rise to radical ion pairs (ie, cage clus-
ters in the “sticky” dissociative electron transfer mech-
can be protonated by benzyloxy radical to form PI and
RA of benzaldehyde 1a (Scheme 4).
In order to provide in independent evaluation of the
above processes, we used DFT calculations with solvent
(DMF) corrections (see the SI part for computational
details). The calculated thermodynamics of proton
[64]
anism)
and the chemical properties of these ion
pairs can differ from those of the isolated particles
[65]
(
see, for example, ). The PI anion in the cage cluster

8
of 15
SYROESHKIN ET AL.
TABLE 3 Calculated geometry parameters of radical anion of PI‐OR 1
A
A
B
B
(
1 )
(Ra 1 )
(1 )
(Ra 1 )
a,b
b
C=O bond
1.208 / 1.208
1.358
1.249 / 1.249
1.363
1.209 / 1.207
1.358
1.250 / 1.246
1.365
N―O bond
a
∠CNOC
−96.0° / 94.0°
−89.3° / 89.1°
−83.7° / 103.7°
−72.2° / 102.8°
a
Formatted as proximal/distal as seen in Figure 4.
b
Reported in Å.
SCHEME 4 Possible mechanism of
benzyloxyphthalimide RA decomposition
transfer from the PhCH O radical to phthalimide anion
suggests that this process is highly favorable
reaction. The effect of the self‐protonation is even stron-
ger under electrolysis conditions, during which PI is accu-
mulated in the bulk of the solution. According to the
results of coulometry for 1, it is necessary to pass the
current of 0.4 F through the solution for the complete
consumption of the substrate, whereas the reduction peak
current for 1 with respect to the 1‐electron level at the
minimum scan rate in CV is 0.3 (see above).
2
(
ΔG ~ −20 kcal/mol). The high acidity of C―H bond adja-
cent to the radical center originates from the increased
stability provided to the product (radical‐anion of benzal-
dehyde) by a 2‐center/3‐electron bond between the radi-
cal and the anionic center.
Similar mechanism has been recently suggested for
the decomposition of 2‐nitro‐1‐phenylethanol RA, where
the nitromethane anion was protonated by α‐
[65]
hydroxybenzyl radical.
The location of the excess elec-
3.2 | Electrochemical behavior of 2‐2a, 3‐3a,
4‐4a, and 4‐7
tron on the nitrogen atom, which is less electronegative
than oxygen, can be explained in terms of the general
principle, according to which the formation of a more‐dif-
ficult‐to‐oxidize anion is thermodynamically more favor-
The electrochemical behavior of analogs of 1 containing
various substituents both at the benzylic position and in
the aromatic ring (Table 1) was studied under analogous
conditions.
The presence of a methyl group at the benzylic
position of substrate 2 slightly increases the life‐time of
RA, as evidenced by the partial chemical reversibility of
the first stage of ER at lower scan rates in comparison to
compound 1 (Figure 5).
At more cathodic potentials, the cyclic voltammogram
shows peaks (Figure 5) at potentials corresponding to
those of PI and acetophenone 2a (‐2.464 V). These peaks
grow after the addition of these compounds to the solu-
tion. As in the case with compound 1, the reaction is not
[66]
able.
PI anion in aprotic medium is oxidized in the
far region (>2 V relative to SCE in acetonitrile with
[66]
Bu NPF ),
whereas the benzyl alcohol anion is oxi-
4
6
dized much more easily (at −0.567 V relative to Fc/Fc
+
[67]
;
the oxidation potential of ferrocene in acetonitrile
[68]
with 0.1 М Bu NPF relative to SCE is 0.40 V ).
4
6
The difference between the reduction potentials of PI
and benzaldehyde 1a (>300 mV) indicates that benzalde-
hyde RA reduces PI with an equilibrium constant of an
6
order of 10 according to the equation:
nFΔE
lgK ¼ − 2
initiated by the addition of Bu NOH to the solution and
4
:303RT
not suppressed by acetic acid.
The self‐protonation of PI RA (protonation of PI RA
by PI) is a side process, which can terminate chain
We obtained similar results in the study of the
electrochemical behavior of compound 3 containing a p‐

SYROESHKIN ET AL.
9 of 15
‐1
FIGURE 5 Cyclic voltammograms of solutions of compound 2 (5 mmol L ) measured at different scan rates and normalized to the square
root of the scan rate (left) and at a scan rate of 0.100 V s‐ compared with the voltammograms for PI and 2a (right) in DMF containing 0.1 М
1
4 4
Bu NClO
methoxy group in the aromatic ring. Figure 6 (left)
illustrates the decomposition of 3 to PI and 4‐methox-
ybenzaldehyde 3a. The cyclic voltammogram of N‐(4‐
bromobenzyloxy)phthalimide 4 (Figure 6, right) is some-
what different from the voltammograms of the compounds
considered above. Thus, the peak current for ER of PI is
larger, and the peak current for its anion is small. In addi-
tion, the peak potential for the decomposition product is
decomposition with the formation of PI and the corre-
sponding carbonyl compounds 1a‐4a. All of the com-
pounds are reduced at rather similar potentials, and a
2.5‐3‐fold decrease in the peak current for ER with
respect to the 1‐electron level under the same condi-
tions is observed. These data are indicative of similar
rates of the rate‐limiting step in the decomposition of
different compounds. The constants for these reactions
0
1
‐1
not consistent with that for
a
solution of 4‐
vary within 10 ‐10 s .
bromobenzaldehyde 4a. However, the peaks in the volt-
ammogram for mixture of PI and 4a are in agreement with
the peaks for the products observed in the voltammogram
of 4. Therefore, the observed profile of the voltammogram
of 4 can be attributed to the specific electrochemical
behavior of PI and 4‐bromobenzaldehyde 4a in mixture.
The formation of PI and related aldehydes was
observed also in ER of 2‐methyl, 4‐methyl, and 4‐tert‐
butyl derivatives (structures 5‐7, Table 1). Therefore, in
aprotic medium, the electrochemical reduction of the
benzyloxyphthalimide derivatives containing electron‐
donating (compounds 1‐3, 5‐7) or weakly electron‐with-
drawing (compound 4) substituents leads to chain
3
.3 | Electrochemical behavior of 8‐11
The electrochemical behavior of derivatives 8‐11 contain-
ing π‐electron‐withdrawing substituents in the aromatic
ring or at the benzylic position substantially differs from
the behavior of the above‐considered compounds
(Figure 7). Thus, features indicative of the chain reaction
following the electron transfer, such as a substantial
decrease in the peak current for ER of the substrate with
respect to the 1‐electron level and the presence of the
reduction peak for PI at more cathodic potentials of cyclic
voltammograms, are lacking. All the above‐considered
‐1
FIGURE 6 Cyclic voltammograms of solutions (5 mmol L ) of compounds 3 (left) and 4 (right) compared with the voltammograms of PI
and 3a (4a) at a potential scan rate of 0.100 V s‐ in DMF containing 0.1 М Bu
1
4 4
NClO

10 of 15
SYROESHKIN ET AL.
‐1
FIGURE 7 Cyclic voltammograms of solutions (5 mmol L ) of compounds 8 (A), 9 (B), 10 (C), and 11 (D) in the absence and in the
‐1
presence of a molar equivalent of acetic acid compared with the voltammograms of PI at a potential scan rate of 0.100 V s in DMF
containing 0.1 М Bu NClO
4
4
(
Figure 7) cyclic voltammograms show reduction peaks at
benzyl‐, alkyl‐, and acyl‐substituted NHPI, we studied
the electrochemical behavior of compounds 12‐14. The
corresponding cyclic voltammograms are shown in
Figure 8 along with the voltammograms of tosyl deriva-
tive 15. Based on these results, the following conclusions
can be drawn.
potentials similar to the reduction potentials for the PI
anion (Table 1). The addition of acetic acid to the solution
causes the appearance of the reduction peak of PI (рК of
acetic acid in DMSO, the properties of which are similar
to those of DMF, is 12.05,
same conditions is 13.4
[
69]
whereas рК of PI under the
; consequently, the equilib-
[
70,71]
The reduction of derivatives 12‐14 occurs via a 1‐
electron mechanism, whereas the reduction peak for 15
rium favors the protonation of the PI anion).
−
It should be noted that the reductive fragmentation
cascade products, ie, the carbonyl compounds containing
strong electron‐withdrawing substituents, can undergo
ER at earlier potentials compared with PI or the substrate.
In this case, one would expect an increase in the current
peak for ER of the substrate and the disappearance of
the peaks for ER of PI, which is consumed in the proton-
ation of the reduction products of carbonyl compounds,
such as dianions formed by the dimerization of the corre-
sponding RAs.
is somewhat lower—~2/3 e . The process is chemically
irreversible at the applied scan rate range. The only
exception is the case of alkyl derivative 14, where
reduction becomes partially reversible with an increase
in the scan rate. As in all the cases considered previously,
the cyclic voltammograms of these compounds show
reduction peaks at potentials similar to the reduction
peak potentials for the PI anion. In addition, the voltam-
mograms of the benzoyl (12) and tosyl (15) derivatives
show strong peaks at potentials similar to the reduction
peak potentials for PI. On the other hand, the corre-
sponding peaks in the voltammograms of the acetyl (13)
and ethyl (14) derivatives are weak, but they sharply
increase after the addition of acetic acid.
3
.4 | Electrochemical behavior of
compounds 12‐15
In order to examine the question raised in the introduc-
tion about the difference in the reactions of RAs of
It can be concluded that the possible primary decom-
position products in the case with ethyl derivative 14, like

SYROESHKIN ET AL.
11 of 15
‐
1
FIGURE 8 Cyclic voltammograms of a solution of compound 12 (A), 13 (B), 14 (C), and 15 (D) (5 mmol L
,
black and gray lines) compared
‐1
4 4
with the voltammogram of PI (blue line) at a potential scan rate of 0.100 V s in DMF containing 0.1 М Bu NClO . Cyclic voltammograms of
1
3 (B) and 14 (C) in the presence of 1 molar equivalent of acetic acid (red line)
compared with the benzyl alcohol anion, the ethoxy anion
is oxidized at even earlier potentials (at −0.703 V relative
+[67]
to Fc/Fc
). The 1‐electron reduction of the substrate
indicates that ethoxy radical is not reduced and not
involved in a chain process (Schemes 3, 4, 4) under the
experimental conditions. Hydrogen abstraction from the
components of the medium is one of the possible alterna-
tive reactions for the ethoxy radical. The hydrogen
abstraction from the medium by a free radical that is
formed through dissociative electron transfer is described
[
72]
in the literature.
Due to the presence of more electron‐deficient substit-
uents, N‐acyloxy and N‐tosyloxy derivatives of PI (12, 13
and 15, respectively) are reduced at slightly less negative
FIGURE 9 Cyclic voltammograms of solution of compound 16
‐1
+
(
5 mmol L ) before and after 1.00 F at the potential −1800 mV
was passed through the solution at a potential scan rate of 0.100 V s
in DMF containing 0.1 М Bu NClO
potentials (from −1.64 to −1.59 V relative to Fc/Fc ).
‐1
Cyclic voltammograms of 12 and 15 contain the reduction
peaks corresponding to both PI and PI anion, whereas
cyclic voltammogram of acetyloxy derivative 13 contains
strong PI anion peak and almost no PI peak. PI formation
can be explained if one proposes that reductive ET
gives PI anion and O‐centered radical (PhCOO• or
Me‐p‐C H ‐SO •). The latter can abstract hydrogen
4
4
in the mechanism shown in Scheme 4, are the PI anion
that is detected in the cyclic voltammogram and the eth-
oxy radical. The location of the excess electron on the
nitrogen atom of the phthalimide moiety after the dissoci-
ation of RA of 14 should be facilitated by the fact that,
6
4
3
from the medium and form an acid (PhCOOH or Me‐
p‐C H ‐SO H) that protonates PI anion. An alternative
6
4
3

12 of 15
SYROESHKIN ET AL.
SCHEME 5 Plausible pathway of
electrochemical reduction of N‐((1‐
naphthyl)acetoxy)phthalimide 16
confirmed by isolation of the final product,
1‐methylnaphthalene 17
FIGURE 10 The reduction potentials of PI‐ORs in comparison to carbonyl compounds, anthraquinone, and oxygen
process where the O‐centered radical undergoes decar-
boxylation does not produce acid. If the latter scenario
dominates, no PI would be observed as we see in case
of compound 13. The experimental differences
discussed earlier may reflect the fact that rates of
acetoxyphthalimide 13. No starting compound was
detected electroanalytically after passage of 1 F of electric-
ity at potential of reduction of 16 (−1800 mV). Peaks of
phthalimide anion and small amounts of phthalimide
were observed on cyclic voltammogram.
decarboxylation in AlkCOO and ArCH COO radicals
are faster than in ArCOO radicals.
To confirm the reaction pathway (Scheme 5), prepara-
tive electrochemical reduction of 16 was conducted. 1‐
Methylnaphthalene, the product of double covalent bond
scission (N―O/C―C), was isolated instead of naphthyl
acetic acid (see the Experimental part for additional
details).
This result confirms that ET to the N‐((1‐naphthyl)
acetoxy)phthalimide 16 gives PI anion and acyloxy radical
A that undergoes decarboxylation giving the naphthy-
lmethyl radical B. The latter species abstracts hydrogen
2
[73]
3.5 | Electrochemical behavior of
compound 16—direct evidence for the
formation of O‐centered radicals in the
reductive fragmentations of PI‐ORs
Electrochemical behavior of N‐((1‐naphthyl)acetoxy)
phthalimide 16 (Figure 9) is similar to that of N‐

SYROESHKIN ET AL.
13 of 15
atom from the medium to form 1‐methylnaphthalene 17.
The isolation of C―C scission products such as 17 is a
characteristic sign of O‐centered radical formation in the
reaction. This additional fragmentation would be impossi-
ble if the primary N―O fragmentation would give an O‐
ACKNOWLEDGEMENTS
Electrochemical part of this study was financially sup-
ported by the Russian Science Foundation (Grant 14‐50‐
00126). The computational component of this project at
Florida State University was supported by the National
Science Foundation (Grant CHE‐1465142). We are also
grateful to NSF XSEDE (TG‐CHE160006) and RCC FSU
for computational resources.
[32]
centered anion.
4
| CONCLUSION
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exergonic and a catalytic cycle where electron serves as
[
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