Concentration-Dependent Thermal Isomerization of Nitrile N-Oxide

Article abstract of DOI:10.1002/ejoc.202000829

Kinetically stabilized nitrile N-oxides (NOs) have been regarded as viable tools for the postpolymerization functionalization of common polymers. However, thermal isomerization of NO to isocyanate restricts the applications of NO to industrial use. The re

Full text of DOI:10.1002/ejoc.202000829

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Concentration-Dependent Thermal Isomerization of Nitrile N-
Oxide
Authors: Shiho Bando, Yasuhito Koyama, and Toshikazu Takata
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
Concentration-Dependent Thermal Isomerization of Nitrile N-Oxide
[a]
[a]
[b]
Shiho Bando, Yasuhito Koyama* and Toshikazu Takata*
[
a]
S. Bando, Dr. Y. Koyama
Department of Pharmaceutical Engineering, Faculty of Engineering
Toyama Prefectural University
5180 Kurokawa, Imizu, Toyama 939-0398, Japan
E-mail: ykoyama@pu-toyama.ac.jp
Prof. T. Takata
https://www.pu-toyama.ac.jp/PH/koyama/
[
b]
School of Materials and Chemical Technology and RIPST (Research Institute of Polymer Science and Technology)
Tokyo Institute of Technology and JST-CREST
Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
E-mail: takata.t.ab@m.titech.ac.jp
http://www.op.titech.ac.jp/polymer/lab/takata/japanese/index-j.html
Abstract: Kinetically stabilized nitrile N-oxides (NOs) have been
regarded as viable tools for the postpolymerization functionalization
of common polymers. However, thermal isomerization of NO to
isocyanate restricts the applications of NO to industrial use. The
reaction mechanism for the thermal isomerization has not been
systematically evaluated. Herein, we report the concentration-
dependent isomerization of NOs for the first time. The time-course
plots suggest that the isomerization of NO would be driven by a very
small amount of polymeric intermediate generated in situ in a
substituent-dependent equilibrium. The substituent effects of NO on
the isomerization have been clarified with the kinetic parameters and
the reaction order. It is indicated that an electron-donating para-
substituent facilitates both the intermediate-forming reaction and the
rearrangement reaction.
As an experimental effort to clarify the mechanism, we herein report
the concentration-dependent thermal isomerization behaviors of NOs
and the substituent effects on the isomerization for the first time. As the
model compounds, we prepared four types of isolable NOs including
three aromatic NOs with different para-substituents and an aliphatic NO.
We investigated the thermal isomerization reactions of NOs in CDCl
3
or
in 1,2-dichlorobenzene-d as NMR solvents. The time-course plots of
4
isomerization reactions indicate that (i) the isomerization rate of NO
strongly depends on the concentration and (ii) the plots under diluted
conditions include an induction period (’) before the isomerization.
Such results rule out the possibility of Scheme 1A, which are also
supported by the analyses of reaction order. It turned out that an
electron-donating para-substituent tends to facilitate not only the
skeletal rearrangement but also the self-association reaction of NO to
give the intermediate. Considering all the results, we concluded that the
isomerization of NO would be driven by a very small amount of
intermediate generated in situ from plural NOs in a substituent-
dependent equilibrium.
Introduction
Nitrile N-oxide (NO) is a highly reactive 1,3-dipole, which reacts to
various unsaturated bonds via catalyst-free 1,3-dipolar cycloaddition
reaction.[1] Since NO is found to be highly reactive to alkenes and a
nitrile group in common polymers, NO-containing molecules could
have a potential usefulness for the postpolymerization functionalization
of elastomers and resins.[2] However, typical NOs are chemically
unstable, easily leading to dimerization and polymerization.[3]
On the other hand, NO bearing a steric barrier around the
functionality kinetically suppresses the self-degradations, enabling the
isolation of NO. According to the concept of kinetic stabilization, we
have developed stable NO-based ligation tools such as homoditopic
NOs to connect between unsaturated bonds,[4] ambident molecules to
connect an unsaturated bond with a nucleophile,[5] and NO-terminated
polymers as grafting agents.[6] Although these ligation tools provide a
viable mean for the catalyst-free postpolymerization functionalization,
Scheme 1. Proposed mechanisms for the thermal isomerization of NO to Isoc
via (A) monomeric, (B) dimeric, and (C) polymeric intermediates.
we have recently suffered from the unexpected side reaction of stable Results and Discussion
NOs during the practical use. It is indicated that the NOs thermally
rearrange to the corresponding isocyanates (Isocs) at high temperature,
while neither the oligomerization nor the polymerization were detected
due to the kinetic stability of NO.
As a result of literature survey, we found that the isomerization of
NO to Isoc has been reported, however, three types of reaction
mechanisms have been proposed to date, which has not been
systematically evaluated (Scheme 1). The first mechanism is a
unimolecular rearrangement via the intermediary formation of 1,2-
oxazirene skeleton (Scheme 1A).[7] The second is based on the skeletal
rearrangement of 1,4,2,5-dioxadiazine as a bimolecular intermediate
Scheme 2 shows the synthesis and structures of NOs. Considering
the structures of our previously developed NO-based ligation tools,4
,6
we determined the structures of NO-3 and NO-4 as the unit models in
order to make the discussion simplified. To know the electronic effects
on the isomerization, we also designed NO-1 and NO-2 with different
electron demands to that of NO-3. We used 3,5-dimethoxyaniline (1) as
the starting compound for NO-1 and NO-2. The acetylation of 1 was
followed by methylation to give amide 2. Rieche formylation of 2
proceeded regio-selectively to give 3.[10] Aldehyde 3 was converted to
oxime 4, which was further treated with N-chlorosuccinimide (NCS) to
give amide-substituted NO-1. We found that NO-1 was stable enough
for the purification using silica gel column chromatography. On the
[8]
(
1
Scheme 1B). The third is via the polymeric intermediate (Scheme
C).
[9]
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
other hand, the reduction of amide 2 with triethylsilane in the presence
of (C F ) B gave tert-amine 5. At the similar manner to the preparation
6 5 3
of NO-1, we synthesized tert-amine-containing NO-2 from 5. We also
prepared NO-3 without a para-substituent and aliphatic NO-4 according
to the reported procedures.[6a,11]
1
[12]
In the H NMR spectra of three aromatic NOs (Figure 1), the
chemical shifts of aromatic proton signals are 6.37 ppm for NO-1, 5.75
ppm for NO-2, and 6.53 ppm for NO-3, implying that the electron-
donating capacity of para-substituents to the aromatic ring is in the order
EtMeN- in NO-2 > AcMeN- in NO-1 > H- in NO-3.
Scheme 3. Thermal isomerization of NOs to Isocs.
Scheme 2. Synthesis and structures of stable NOs.
Figure 2. Time-course plots for the thermal isomerization of (A) NO-1, (B) NO-
, (C) NO-3, and (D) NO-4 (blue circle: 10 mM, red triangle: 30 mM, orange
square: 90 mM, and green rhombus: 270 mM).
2
1
Figure 1. H NMR spectra of NO-1, NO-2, and NO-3 (400 MHz, CDCl
3
, 298 K).
2
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European Journal of Organic Chemistry
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COMMUNICATION
Table 1. Dependences of concentration and substituent on the induction periods (’), half-lives (1/2), and kinetic constant (k) of thermal isomerization under the
conditions of Scheme 3.
1
0 mM
30 mM
0.46 h
90 mM
270 mM
’
1.6 h
150 h


a
a
a
a
NO-1
NO-2
NO-3
NO-4

1/2
108 h
90 h
40 h
ka
4.6 × 10-3 h-1

6.4 × 10-3 h-1

7.7 × 10-3 h-1
17 × 10-3 h-1
’

3.9 h

2.9 h

1/2
5.5 h
5.5 h
ka
126 × 10-3 h-1
42 h
126 × 10-3 h-1
11 h
178 × 10-3 h-1

239 × 10-3 h-1

’

1/2
506 h
437 h
249 h
135 h
ka
1.4 × 10-3 h-1

1.6 × 10-3 h-1

2.8 × 10-3 h-1

5.1 × 10-3 h-1

’

1/2
23 h
17 h
5.8 h
5.8 h
ka
30 × 10-3 h-1
41 × 10-3 h-1
120 × 10-3 h-1
120 × 10-3 h-1
aCalculated by the initial reaction rate.
Having four types of NOs in hand, we performed the thermal
isomerization of NOs at 60 C in CDCl
H
isomerization of NO-4 hardly occurred at 60 C in CDCl
3
and detected the reaction by
Because the thermal
, the reaction
of NO-4 was performed at 140 C in 1,2-dichlorobenzene-d (o-
Cl ). The thermal treatments of NOs were found to afford the
1
NMR spectroscopy (Scheme 3).[12]
3
4
C
6
D
4
2
corresponding Isocs with a small amount of 1,3-dialkyl urea caused by
the partial hydrolysis of Isoc, while the time scales of four
isomerization reactions were very different. We estimated the
1
conversions of NOs to Isocs by the integral ratio in the H NMR spectra.
In the time-course plots for the isomerization reactions (Figure 2), we
found that the higher concentration remarkably accelerates the thermal
isomerization of NOs. This is the first time to reveal the dependence
of concentration on the isomerization rate of NO. The results clearly
provide the experimental evidence for the existence of intermediate
generated by plural NOs on the isomerization of NO to Isoc. Therefore,
we ruled out the possibility of Scheme 1A as the unimolecular pathway
at this moment.
In addition, it is indicated that the isomerization reactions of NO-1
and NO-3 under diluted conditions hardly proceeded at the initial
reaction stages, suggesting that the isomerization reactions include
induction periods (’) for the initiation. On the other hand, we didn’t
1
observe any signals attributed to the intermediate in the H NMR
spectra, suggesting that the isomerization would be driven by a very
small amount of intermediate generated in situ.
From the slopes of plots on the initial reaction stages after ’, we
created approximate lines to estimate each kinetic constant (k) for the
initial reaction rate and the half-lives (1/2) of NOs based on the k values.
The kinetic parameters are summarized in Table 1. Through the
comparison of k and 1/2 values for aromatic NOs, we found that the
electron-donating group at the para-position facilitates the thermal
isomerization. It is well known that the electron-rich aromatics tend to
easily migrate on the skeletal rearrangements.[13,14] Our observations
are in a good agreement with the tendency of typical rearrangement
reactions. The higher activation energy for the isomerization of
aliphatic NO-4 could be dependent on the lower migration capacity of
the aliphatic framework than those of aromatics.
Figure 3. Logarithm of reaction velocity (lnv) as a function of the logarithm of
concentration (ln[NO]).
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
Then, we compared the ’ values of aromatic NOs. The time scale
of ’ could be regarded as the period to form the intermediate. Since
the order of ’ values is NO-2 < NO-1 < NO-3, we concluded that the
electron-donation of substituent would facilitate not only the skeletal
rearrangement but also the self-association to form the intermediate.
To know the reaction orders of each isomerization reaction, we
plotted the logarithm of reaction velocity (lnv) as a function of the
logarithm of NO concentration (ln[NO]) (Figure 3). From the slopes
of the approximate lines in the plots, we found that the reaction orders
are in a range from one to two (1.2-1.7), implying that the association
reactions of NOs would be a reversible reaction step, which could be
biased by the electronic character of substituent. The trend of reaction
orders indicates that the equilibrium between NO-3 and the
intermediate would be biased to the side of NO-3 compared with the
equilibrium of NO-2, because the higher reaction order should indicate
the large contribution of intermediate-forming rate on the total reaction
rate of isomerization.[14]
The reaction order itself has hardly suggested the association
number of NO in the intermediate structure. However, it has been
reported that several NOs easily form cyclic polymers with molecular
weight distributions.[15] 1,4,2,5-Dioxadiazine skeleton as the central
structure of dimeric intermediate can be regarded as a thermally stable
hetero-aromatics. The thermal degradation of 3,6-diphenyl-1,4,2,5-
dioxadiazine affords benzonitrile and nitrosocarbonylbenzene, which
never produces phenyl isocyanate nor benzonitrile N-oxide.[16]
Therefore, the polymeric structure described in Scheme 4 might be the
most plausible intermediate for the isomerization of NO.
appropriate to generalize the substituent effects of NO-isomerization
on the kinetic parameters in our system. Since we didn’t directly catch
the signals attributed to the intermediate in the H NMR spectra, the
theoretical study may unveil the intermediate structure. In our near
future, we will synthesize the isolable cyclic polymers according to the
literature[15] and investigate the thermal reaction of the cyclic polymers.
Such experiments can eventually evaluate the isomerization
mechanism and the possibility of thermal depolymerisation.
1
Conclusion
In conclusion, we found that the thermal isomerization of NO to
Isoc is strongly dependent on the concentration for the first time, which
suggests the existence of intermediate from plural NOs. The
substituent effects of NO on the isomerization have been clarified with
the kinetic parameters and the reaction order, in which it turned out that
an electron-donating substituent facilitates both the intermediate-
forming reaction and the rearrangement reaction. The trend of reaction
order indicates that the electron demand of para-substituent would
strongly relate to the dynamic formation of polymeric intermediate. On
the basis of the substituent effects on the isomerization of NO, the
creation of new ligation tool comprising NO with improved thermal
stability is currently underway.
Experimental Section
Materials: Acetic anhydride (Kanto Chemical Co., Inc., Tokyo, Japan),
3
,5-dimethoxyaniline (Tokyo Chemical Industry Co., Inc., Tokyo,
Japan), iodomethane (Fujifilm Wako Pure Chemicals Corp., Osaka,
Japan), sodium hydride (Fujifilm Wako Pure Chemicals Corp., Osaka,
Japan), anhydrous DMF (Fujifilm Wako Pure Chemicals Corp., Osaka,
2 2
Japan), anhydrous CH Cl (Kanto Chemical Co. Inc., Tokyo, Japan),
dichloromethyl methyl ether (Tokyo Chemical Industry Co., Inc.,
Tokyo, Japan), titanium chloride (Fujifilm Wako Pure Chemicals Corp.,
Osaka, Japan), hydroxylamine hydrochloride (Kanto Chemical Co.,
Inc., Tokyo, Japan), sodium acetate (Tokyo Chemical Industry Co., Inc.,
Tokyo, Japan), N-chlorosuccinimide (NCS, sigma-aldrich Co. LLC., St.
Louis, USA), triethylamine (Nacalai tesque Inc., Kyoto, Japan),
chloroform (Kanto Chemical Co., Inc., Tokyo, Japan), triethylsilane
(
Tokyo Chemical Industry Co., Inc., Tokyo, Japan),
tris(pentafluorophenyl)borane (Fujifilm Wako Pure Chemicals Corp.,
Osaka, Japan), and anhydrous dichloromethane (CH Cl , Kanto
Scheme 4. Plausible mechanism for the isomerization of NO to Isoc via cyclic
polymer formation.
2
2
Chemical Co., Inc., Tokyo, Japan) were used without further
purification. The other chemicals were used without purification.
Nitrile N-oxides (NO-3 and NO-4) were prepared according to the
literature.[6a,11]
Finally, we considered the correlations of kinetic parameters to
Hammett parameters. Hammett parameters are regarded as one of the
most widely used means for the study of organic reaction mechanisms.
According to the parameter list in the literature,[17] the Hammett
Measurements: H NMR (400 MHz) and 13C NMR (100 MHz) spectra
1
substituent constants for the para substituent (
and +0.26 for NMe(COMe) in NO-1. Although the 
for NO-2 is not included in the list, the numerical value for NMe
0.83) should be almost similar to that of NMeEt in NO-2. Based on
p
) are 0 for H in NO-3
were recorded on Bruker AVANCE II 400 spectrometers (Brucker,
p
value of NMeEt
Fällanden, Switzerland) using CDCl
3
,
DMSO-d
6
,
and 1,2-
2
dichlorobenzene-d (o-C Cl ) as the solvent, calibrated using an
4
6
D
4
2
(
internal standard and residual undeuterated solvent signals. FT-IR
spectra via an attenuated total reflection (ATR) method were measured
using an IRSpirit spectrometer (Shimadzu Co. Ltd., Kyoto, Japan).
MALDI-TOF MS spectra were recorded on a Shimadzu AXIMA-CFR
plus mass spectrometer (matrix: CHC).
the typical interpretation of Hammett parameters, the positive value for
NMe(COMe) in NO-1 suggests the electron-withdrawing capacity,
while the negative value for NMeEt in NO-2 indicates the electron-
p
donating capacity. We found that the  value for NMe(COMe) in NO-
1
is discrepant to our observed phenomena such as the upfield-shift of
1
aromatic proton signal in H NMR spectrum of NO-1 compared with
that of NO-3 (Figure 1) and the higher isomerization rate of NO-1 than
NO-3. The results indicate that Hammett parameters are not
Synthesis of 2.[18]
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
1
3
,5-Dimethoxyaniline (10.0 g, 65.3 mmol) was dissolved in Ac
mL, 78.3 mmol) and stirred for 1 h at room temperature. The mixture
was neutralized with sat. aq. NaHCO . The products were extracted
with CHCl . The combined organic layer was washed with water, dried
over MgSO
2
O (7.40
mmol) in 91% yield; mp 168.9-172.2 C; H NMR (400 MHz, CDCl
298 K)  6.37 (s, 2H), 3.88 (s, 6H), 3.27 (s, 3H), 1.98 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl , 298 K) d 169.9, 167.7, 148.2, 130.8, 128.7,
3
,
3
3
3
102.8, 56.3, 37.1 (CNO), 30.3, 28.8, 23.6, 22.3 ppm (Several signals
appear to be split due to the presence of amide rotamers.); IR (ATR) 
2303 (CNO) cm ; MALDI-TOF MS (matrix: CHC) calc’d for
12 15 2 4
C H N O [M+H ] 251.10, found 250.92.
4
, filtered, and concentrated in vacuo to give the
1
-1
corresponding acetylamide as white solids (11.8 g) in 93% yield; H
NMR (400 MHz, CDCl
+
+
3
, 298 K)  6.74 (d, J = 1.8 Hz, 2H), 6.23 (t, J
=
1.8 Hz, 1H), 2.16 (s, 6H), 1.56 (s, 3H) ppm.
Synthesis of 5.
The obtained amide (10.0 g, 51.2 mmol) was added to the suspension
of NaH (60%, 4.10 g, 102 mmol) in a mixed solvent of THF (76.5 mL)
and DMF (25.5 mL) at 0 C. Iodomethane (4.40 mL, 70.7 mmol) was
then added to the mixture. The mixture was warmed to room
temperature and stirred for 18 h. The reaction mixture was cooled to 0
2 2
To a solution of 2 (800 mg, 3.82 mmol) in CH Cl (38.2 mL) was
6 5 3
slowly added (C F ) B (196 mg, 0.382 mmol) and triethylsilane (3.03
mL, 19.1 mmol) at room temperature. The mixture was refluxed for 19
h, cooled to room temperature, and concentrated in vacuo. The crude
was purified by a silica gel column chromatography (eluent: hexane :

C and quenched by the addition of water. The products were extracted
with EtOAc. The combined organic layer was washed with sat. aq.
NaHCO , dried over MgSO , filtered, and concentrated in vacuo to give
EtOAc = 3:1) to give 5 as colorless solids (530 mg, 2.71 mmol) in 71%
1
yield; H NMR (400 MHz, CDCl
3
, 298 K) d 5.89 (m, 3H), 3.78 (s, 6H),
3.36 (q, J = 7.1 Hz, 2H), 2.89 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl , 298 K)  161.6, 150.9, 91.6, 88.1, 55.1, 46.9,
37.6, 11.3 ppm; IR (ATR)  2964 cm ; MALDI-TOF MS (matrix:
3
4
a crude material. The crude was purified by a silica gel column
chromatography (eluent: hexane : EtOAc = 1:2) to give 2 as yellow
solids (9.68 g, 46.3 mmol) in 90% yield; H NMR (400 MHz, CDCl
3
-1
1
+
+
3
,
2
CHC) calc’d for C11H18NO [M+H ] 196.13, found 196.13.
2
3
98 K)  6.43 (t, J = 2.2 Hz, 1H), 6.33 (d, J = 2.2 Hz, 2H), 3.80 (s, 6H),
.24 (s, 3H), 1.92 (s, 3H) ppm.
Synthesis of 6.
To the mixture of 5 (440 mg, 2.25 mmol) and MeOCHCl
2
(2.40 mL,
Synthesis of 3.[18]
27.0 mmol) in CH Cl (22.5 mL) was slowly added TiCl (980 L, 9.00
2
2
4
To the mixture of 2 (2.00 g, 9.56 mmol) and MeOCHCl
2 2 4
mmol) in CH Cl (95.6 mL) was slowly added TiCl (6.25 mL, 57.4
mmol) at 0 C. The mixture was warmed to room temperature, stirred
2
(5.12 mL, 57.4
mmol) at 0 C. The mixture was warmed to room temperature, stirred
for 20 h, and quenched by the addition of water. The aqueous layer was
neutralized by the addition of NaOH. The layers were separated and
for 5 h, and quenched by the addition of water. The layers were
the products were extracted with CHCl
3
. The combined organic layer
separated and the products were extracted with CHCl
3
. The combined
was washed with sat. aq. NaHCO , dried over MgSO
3
4
, filtered, and
organic layer was washed with sat. aq. NaHCO , dried over MgSO
3
4
,
concentrated in vacuo to give a crude material. The crude was purified
by a florisil column chromatography (eluent: hexane-EtOAc = 1:3) to
filtered, and concentrated in vacuo to give a crude material. The crude
was purified by a silica gel column chromatography (eluent: EtOAc) to
give 6 as gray solids (240 mg, 1.08 mmol) in 48% yield; mp 82.7-87.9
1
1
give 3 as white solids (640 mg, 2.70 mmol) in 28% yield; H NMR (400
C; H NMR (400 MHz, CDCl
3
, 298 K)  10.2 (s, 1H), 5.73 (s, 2H),
MHz, CDCl
3
, 298 K)  10.4 (s, 1H), 6.33 (s, 3H), 3.82 (s, 6H), 3.21 (s,
3.87 (s, &H), 3.47 (q, J = 7.1 Hz, 2H), 23.03 (s, 3H), 1.21 (t, J = 7.1
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl
, 298 K)  186.3, 164.2,
54.7, 104.9, 86.8, 55.5, 46.7, 37.6, 11.7 ppm; IR (ATR)  1647 (C=O)
3
H), 1.93 (s, 3H) ppm.
3
1
-1
+
Synthesis of 4.
cm ; MALDI-TOF MS (matrix: CHC) calc’d for C12
[M+H ] 224.13, found 224.10.
H
18NO
3
+
A mixture of hydroxylamine hydrochloride (164 mg, 2.50 mmol) and
sodium acetate (205 mg, 2.50 mmol) in water (2.6 mL) was added to
the mixture of 3 (500 mg, 2.11 mmol) in i-PrOH (8.4 mL) at room
temperature. The mixture was stirred for 2 h at the same temperature
and concentrated in vacuo. The mixture was repeatedly washed with
water and the residue was dried in vacuo to give 4 (429 mg) as white
solids in 80% yield. The obtained compound was used for next reaction
Synthesis of 7.
A mixture of hydroxylamine hydrochloride (832 mg, 1.29 mmol) and
sodium acetate (910 mg, 1.29 mmol) in water (1.1 mL) was added to
the mixture of 6 (240 mg, 1.08 mmol) in i-PrOH (4.3 mL) at room
temperature. The mixture was stirred for 1.5 h at the same temperature
and concentrated in vacuo. The mixture was repeatedly washed with
water and the residue was dried in vacuo to give 7. The obtained
1
without further purification; mp 242.4-248 C (decomp.); H NMR
(
400 MHz, CDCl
3
, 298 K)  8.52 (s, 1H), 6.42 (s, 2H), 3.88 (s, 6H),
, 298 K)
169.2, 158.7, 146.3, 142.1, 103.6, 56.2, 36.5, 22.4 ppm; IR (ATR) 
.28 (s, 3H), 2.00 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d
compound was used for next reaction without further purification; H
1
3

3
C
6
NMR (400 MHz, CDCl
6H), 3.43 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
, 298 K)  160.2, 151.1, 143.8, 98.4, 88.2,
5.5, 46.7, 37.5, 11.6 ppm; IR (ATR)  3193 (N-OH) cm ; MALDI-
3
, 298 K)  8.51 (s, 1H), 5.85 (s, 2H), 3.86 (s,
-1
245 (N-OH) cm ; MALDI-TOF MS (matrix: CHC) calc’d for
+
+
12
H
17
N O
2 4
[M+H ] 253.12, found 252.91.
3
-
1
5
+
+
Synthesis of NO-1.
19 2 3
TOF MS (matrix: CHC) calc’d for C12H N O [M+H ] 239.14,
To a mixture of 4 (200 mg, 0.792 mmol) and Et
3
N (165 L, 1.19 mmol)
found 239.09.
in CHCl (7.9 mL) was added NCS (158 mg, 1.19 mmol) at 0 C. The
3
mixture was warmed to room temperature and stirred for 1 h. The
Synthesis of NO-2.
reaction was quenched by the addition of water. The layers were
To a mixture of 7 (254 mg, 1.07 mmol) and Et
3
N (163 L, 1.17 mmol)
separated and the products were extracted with CHCl
3
. The combined
in CHCl (10.7 mL) was added NCS (157 mg, 1.17 mmol) at 0 C. The
3
organic layer was washed with sat. aq. NaHCO , dried over MgSO
3
4
,
mixture was warmed to room temperature and stirred for 1.5 h. The
reaction was quenched by the addition of water. The layers were
filtered, and concentrated in vacuo to give a crude material. The crude
was purified by a silica gel column chromatography (eluent: hexane :
EtOAc = 1:3 → EtOAc) to give NO-1 as yellow solids (179 mg, 0.715
separated and the products were extracted with CHCl
3
. The combined
organic layer was washed with water, dried over MgSO
4
, filtered, and
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
concentrated in vacuo to give NO-2 (242 mg) as yellow solid in 96%
Keywords: nitrile N-oxide • postpolymerization functionalization
1
yield; H NMR (400 MHz, CDCl
3
, 298 K)  5.75 (s, 2H), 3.83 (s, 6H),
•
thermal isomerization • isocyanate
3
.42 (q, J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl , 298 K)  163.4, 152.3, 98.6, 87.5, 55.6, 46.9, 37.7, 11.6
3
[
1]
a) L. I. Belen’kii, In Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis, 2nd ed., (Eds.: H. Feuer), Wiley-VCH, New York, 2008, pp. 1-128.
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the quadrupolar relaxation of the adjacent 14N nucleus.[19]); IR (ATR) 
b) C. Grundmann, P. Grünanger, The Nitrile Oxides, Springer-Verlag, Berlin,
1971.
-
1
+
2
[
245 cm ; MALDI-TOF MS (matrix: CHC) calc’d for C12
H N
17 2
O
3
+
[2]
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M+H ] 237.12, found 237.13.
Typical procedure for the thermal isomerization reaction of NO.
A solution of an arbitrary amount NO in CDCl (0.60 mL) was added
3
to an NMR tube, which was firmly sealed. The NMR spectrum was
measured to give the NMR proton signals for 0 h. The tube was directly
1
heated in an oil bath at 60 C. The signal change was detected by H
NMR spectroscopy after the defined time. Upon heating, the proton
signals of NO progressively decreased, while the signals of Isoc
increased. The system was kept heated for one week. The phenomena
clearly suggest the thermal isomerization of NO to Isoc. The
conversion of NO was determined by the integral ratio of proton signals
of methoxy groups.
[
3]
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[
4
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Isoc.
The conversion of NO was plotted as a function of heating time (Figure
[5]
2
). Since the conversion at the initial stage linearly correlates to the
[
6]
7]
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time, we drew an approximate straight line and calculated the apparent
half-life (1/2) of NO based on the initial reaction rate as a reference
value. From the intersection of the plots to x-axis, we estimated the
induction period (’) of isomerization reaction. On the assumption that
the reaction obeys the first-order kinetics, we also estimated the
apparent kinetic constant (k) based on the 1/2 value according to the
[
C. Grundmann, P. Kochs, Angew. Chem. 1970, 82, 637-638; Angew. Chem. Int.
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[8]
C. Grundmann, P. Koch, J. R. Boal, Justus Liebigs Ann. Chem. 1972, 761, 162-
181.
following equation: k = ln([NO] /[NO])/1/2 = ln2/1/2. To know the
0
[9]
G. A. Taylor, J. Chem. Soc. Perkin Trans. I. 1985, 1181-1184.
initial reaction velocity (v), we also plotted the concentration of NO as
a function of reaction time and drew the approximate straight line. The
slope of the approximate line indicates the v value. The logarithm of v
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(
(
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Figure 3).
3
555-3558.
[
12] See, supporting information.
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[
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Supporting Information
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Time-course plots of conversion at initial reaction stage, plots of
NO concentration as a function of reaction time, and H NMR 13
1
C
[16] W. R. Mitchell, R. M. Pato, J. Chem. Res. 1984, 58-59.
[
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NMR, IR, and MALDI-TOF MS spectra are provided in the
Supporting Information.
[
[19] Y. Koyama, Y.-G. Lee, S. Kuroki, T. Takata, Tetrahedron Lett. 2015, 56, 7038-
7
042.
Acknowledgements
This work was financially supported by JSPS KAKENHI (Grant
Number JP17H03070).
Conflict of Interest
The authors declare no conflict of interest.
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000829
COMMUNICATION
Entry for the Table of Contents
Nitrile N-Oxides
Thermal isomerization of nitrile N-oxide (NO) gives isocyanate. However, the reaction mechanism for the isomerization has not been
systematically evaluated. Herein, we report the concentration-dependent isomerization of NOs for the first time. The time-course plots
indicate that the isomerization of NO would be driven by a very small amount of polymeric intermediate generated in situ in a substituent-
dependent equilibrium.
7
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