Ionic-Liquid Controlled Nitration of Double Bond: Highly Selective Synthesis of Nitrostyrenes and Benzonitriles

Article abstract of DOI:10.1002/ejoc.202001027

Unprecedented in literature, the conversion of aryl alkenes into β-nitrostyrenes (2) or benzonitriles (3) with sodium nitrite can be governed by an appropriate choice of ionic liquid (IL) medium. A general trend was found for the selectivity of these processes, which depends on the nature of IL, with imidazolium-based ILs, such as [Bmim]Cl, that favor the C–H nitration leading to β-nitrostyrenes, while tetraalkylammonium-based ILs, such as TBAA, privilege the C=C bond cleavage affording benzonitriles. Besides a substrate scope, mechanistic hypotheses were provided on the origin of the different selectivity in the two kinds of ILs, based on their own tunable properties such as polarity, viscosity, and solvent cage effects.

Full text of DOI:10.1002/ejoc.202001027

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Ionic-liquid controlled nitration of double bond: highly selective
synthesis of nitrostyrenes and benzonitriles
Authors: Michele Casiello, Daniela Caputo, Caterina Fusco, Pietro
Cotugno, Vito Rizzi, Michela M. Dell'Anna, Lucia D'Accolti,
and Angelo Nacci
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001027
Link to VoR: https://doi.org/10.1002/ejoc.202001027
01/2020

10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
Ionic-liquid controlled nitration of double bond: highly selective
synthesis of nitrostyrenes and benzonitriles
Michele Casiello,[a] Daniela Caputo,[a],[b] Caterina Fusco,[b] Pietro Cotugno,[c] Vito Rizzi,[a] Maria Michela
Dell’Anna,[d] Lucia D’Accolti,[a],[b] and Angelo Nacci*[a],[b]
[a]
Dr M. Casiello, Dr D. Caputo, Dr V. Rizzi, Prof. L. D’Accolti, Prof. A. Nacci
Department of Chemistry, University of Bari Aldo Moro,
Via Orabona 4, 70125, Bari, Italy; https://www.uniba.it/docenti/nacci-angelo
E-mail: angelo.nacci@uniba.it;
[b]
[c]
Dr C. Fusco;
ICCOM-CNR, SS Bari,
Via Orabona 4, 70125 Bari, Italy;
Dr P. Cotugno;
Department of Biology,
University of Bari Aldo Moro,
Via Orabona 4, 70125, Bari, Italy;
Prof. M.M. Dell’Anna
[d]
DICATECh, Politecnico di Bari,
Via E. Orabona 4, 70125 Bari, Italy.
Supporting information for this article is given via a link at the end of the document.
Abstract: Unprecedented the literature, the conversion of aryl
alkenes into β-nitrostyrenes (2) or benzonitriles (3) with sodium nitrite
can be governed by an appropriate choice of ionic liquid (IL) medium.
A general trend was found for the selectivity of these processes, which
depends on the nature of IL, with imidazolium-based ILs, such as
[Bmim]Cl, that favour the C-H nitration leading to -nitrostyrenes,
while tetraalkylammonium-based ILs, such as TBAA, privilege the
C=C bond cleavage affording benzonitriles. Besides a substrate
scope, mechanistic hypotheses were provided on the origin of the
different selectivity in the two kinds of ILs, based on their own tunable
properties such as polarity, viscosity, and solvent cage effects.
previous works
R1
C
N
NO2
NaNO2
NaNO2
AlCl3
R
R
R
R
R
R
TEMPO
K2S2O8
O
[ref. 8]
[ref. 16a]
NO2
NaNO2
Oxone
KI
C N
NaNO2
R
R
HCO2H, ACN
[ref.9a]
[ref. 16b]
this work
NO2
C
N
NaNO2
NaNO2
TBAA
R
R
R
[Bmim]Cl
Figure 1.
Introduction
on the direct nitration of olefin C–H bonds with different nitrating
agents, such as metal nitrates, nitric acid, NO and NO2.[14]
However, most of the above-mentioned ways of access to
nitrostyrenes and nitriles require toxic and/or expensive reagents,
such as for instance NBS/azides,[9c] iodonium salts,[9d] organic
nitrites,[10a] and silver salts,[15] and lead to the formation of
undesirable by-products (i.e. polyhalogenated compounds, etc.).
Recently, sodium nitrite has been found to function as a green
and cheap nitrogen source used to give the simple C-H nitration[16]
or the C-C bond cleavage,[8,9a] avoiding the use of highly toxic
cyanides and expensive metals. However, also these methods
require the assistance of oxidants, radical catalysts, Lewis or
Brønsted acids, toxic solvents or other additives (Figure 1).
To improve eco-sustainability of this strategy and
simultaneously govern the selectivity of these reactions, we
planned to exploit the peculiar properties of ionic liquids (ILs),[17]
the well-known alternative solvents where such nitrogenation
reactions proved to be totally unexplored.[18]
Nitriles are versatile synthetic intermediates that can be easily
transformed into a multitude of functional groups such as
carbonyls, carboxyls, amines, amides, and many nitrogen-
containing heterocycles.[1] Aryl nitriles are also a key tool for
introducing such functionalities on the aromatic rings.[2] In addition,
cyano group occurs in many natural compounds and several
industrially important products like dyes, pharmaceuticals,
herbicides and polymers.[3]
Many strategies have been developed for synthesizing aryl
nitriles such as Sandmeyer[4] and Rosenmund–von Braun[5]
reactions, dehydration of aldoximes and amides,[6] and transition
metal-catalyzed cyanations,2 which enable the use of safe
reagents and mild conditions.[7] More recently, a new strategy has
emerged based on the oxidative cleavage of single C-C,[8] double
C=C,[9] and triple C≡C[10] bonds, enabling the access to both
aliphatic and aromatic nitriles.[11]
Nitroolefins are another class of useful intermediates of
chemical industry,[12] that are widely used in synthetic organic
chemistry in many C-C bond forming reactions such as Michael
addition, Diels–Alder cycloaddition, and Morita–Baylis–Hillman
coupling. Nitroalkenes can be easily reduced to nitroalkanes,
During these investigations
we discovered that,
unprecedented in the literature, selectivity can be governed by
choosing appropriately the ionic liquid. Herein, we present the
nitrogenation of aromatic olefins with NaNO2 carried out in
[Bmim]Cl and TBAA affording, dependently on the ionic medium
adopted, to nitroalkenes and benzonitriles, respectively, without
requiring expensive and toxic catalysts or any other additive.
while NO2 group occurs in
a
multitude of materials,
pharmaceuticals, and fine chemicals.[10a,13]
The most common synthetic route to nitroalkenes is the Henry
reaction, a classic aldol-type condensation between carbonyl
compounds and nitroalkanes, but a simpler approach is based
1
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
100
80
60
40
20
0
Results and Discussion
2a
3a
Initially, the effect of the reaction medium was evaluated
performing nitration of aromatic olefins in a wide array of ionic
liquids (ILs) and molecular solvents (Table 1). Reaction conditions
were surveyed on styrene (1a) as a model substrate, which was
treated for 1 hour with 4 equivalents of sodium nitrite at 100 °C,
under inert atmosphere and without any other additive.[9a]
From the solvent scope in table 1 clearly emerged that ionic
liquids are better reaction media than the common molecular
solvents, since they could promote the nitration of the double
bond with conversions always higher than 90% (Table 1, runs 1-
14). At first sight, these reactions were devoid of selectivity,
leading to mixtures of nitrostyrene, benzonitrile and variable
amounts of oxidation by-products (see Fig. 3 in experimental
section).
However, in some cases nitrogenations occurred with
moderate to good selectivities (>70%), affording mainly the vinyl
C-H bond substitution product (namely -nitrostyrene 2a), or to
the C=C bond cleavage compound (namely benzonitrile 3a) (table
1, runs 3,6,10). A more careful analysis of results in Table 1 (re-
listed in Fig. 2) showed that predominance of these two products
was somehow dependent on the nature of ionic liquid.
IL
Figure 2. Trend of selectivities in the nitrogenation of styrene with
NaNO2 in ILs.
In particular, a trend of selectivities favourable to 2a was
observed in imidazolium-based ILs, while 3a was found to be the
major product in tetraalkylammonium-based ILs (Fig. 2). A clear
exception to this tendency was found in the case of
tetrabutylammonium iodide (TBAI), that privileged the formation
of -nitrostyrene 2a with a 77% of selectivity (Fig. 2 and Table 1,
run 6). As already reported, this can be due to I- anion that can
promote C-H substitution through a I+ species intermediate.[16b]
However, reaction in TBAI was complicated by the formation of
-
molecular iodine, by means of redox reaction involving NO2 anion
which destroyed the IL medium (2I- + NO2 + 2H+ → I2 + NO +
Table 1. Solvent scope in the reaction of styrene 1a with NaNO2.[a]
-
NO2
NaNO2 (4 equiv.)
+
H2O). Therefore, TBAI was excluded from any other investigation.
Disappointing results were also exhibited by ILs bearing
bromide anions, such as tetrabutylammonium bromide (TBAB)
and tetrabutylphosphonium bromide (TBPB). In these cases, high
percentages of by-products coming from bromination of styrene
were observed during nitrogenation (Table 1, runs 7,14).
Based on this preliminary screening, 1-butylimidazolim
chloride [Bmim]Cl and tetrabutylammonium acetate TBAA, that
had displayed (besides TBAI) the highest selectivities, were
selected for the successive process of conditions optimization
aimed at evaluating the influence of the other reaction parameters
(Table 2).
In [Bmim] Cl, where the C-H substitution was predominant,
selectivity towards 2a could be increased until a maximum of 80%,
by decreasing temperature at 80 °C and prolonging the reaction
time to 1.5 hours (Table 2, run 7). Furthermore, the amount of
reactant NaNO2 was found to be crucial, with the best value fixed
at 4 equiv. respect to the starting olefin (Table 2, runs 1-12).
In contrast, in TBAA selectivity inverted drastically affording
almost exclusively the C=C bond cleavage benzonitrile 3a (Table
2, run 13). From the optimization process, it clearly emerged that
the highest value of 95%, reached in 1 hour at 100 °C, could not
be improved neither using longer times, nor employing minor
amounts of NaNO2 or lower temperatures (Table 2, runs 14-17).
The properties of TBAA as a superior reaction medium for
promoting the C=C cleavage emerged also from nitrogenations
performed in toluene, a low polar solvent chosen as inert medium
for exploring other reactants and lower temperatures. Even in
these cases, where TBAA was used as an additive, reactions
afforded exclusively benzonitrile 3a, and the high selectivities
were maintained even at lower temperatures (including r.t.),
although with lower conversions and longer reaction times (Table
2, runs 18-22).
C
N
+
by-products
IL or solvent
100 °C, 1 h
1a
2a
3a
Selectivity (%)[c]
Run
IL or solvent
Conv. (%)[b]
2a
54
60
71
54
53
77
30
23
21
5
3a
2
by-prd[d]
1
[Bmim] Br
[Bmim] Ac
[Bmim] Cl
[Bdmim] Cl
[Bmpy] Cl
TBAI
>99
96
44
13
19
9
2
27
10
37
32
11
13
68
69
95
59
59
43
8
3
93
4
>99
95
5
6e)
15
12f)
57g)
9
88
7
TBAB
97
8
TBAC
>99
>99
>99
91
9
TBPA
10
-
10
11
12
11
14
15
16
17
18
19
20
21
22h)
23
24
TBAA
TBATf
TOAB
31
21
31
7
10
20
26
85
54
29
41
64
59
35
-
95
TBAOH
TBPB
>99
>99
78
Toluene
42
46
47
29
35
47
-
4
THF
iPrOH
51
25
12
7
74
EtOH
78
CH3OH
CH3CN
CH3CN
CH3CN
DMF
51
6
49
18
-
<1
>99
88
-
84
9
-
43
34
48
57
42
48
58
40
39
42
DMA
92
8
25
26
27
a)
DMSO
H2O
95
12
4
84
MEG
88
16
Reaction conditions: ionic liquid (0.3 g) or molecular solvent (0.5 mL),
styrene 1a (0.25 mmol), NaNO2 (1 mmol), heated under stirring and inert
b)
atmosphere for
1
hour at 100 °C.
Evaluated by GC-FID using p-
c)
methylanisole as an external standard. Percentages calculated based on
d)
GC-MS peaks areas.
Main by-products are carbonyl and nitrogenation
compounds 4-12 reported in Fig. 3 (experimental section). e) Reaction carried
out at 110 °C due to the higher melting point of IL. f) Molecular I2 was formed
due to the side-reaction between NaNO2 and I- ion of IL. High amounts of
g)
Interestingly, when TBAA was replaced by a different acetate
source (e.g. NaOAc), reaction lost selectivity, indicative that
tetraalkylammonium cation also exerts a role in directing reaction
h)
brominated styrenes were detected. Reaction carried out at 70 °C in the
presence of 0.5 mL of formic acid [ref. # 9a].
2
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
Table 3. Substrate scope in reaction of arylalkenes with NaNO2 in ILs.a)
Table 2. Conditions optimization for reaction of styrene 1a with NaNO2.a)
NO2
NaNO2
NaNO2
NO2
C
N
NaNO2
R
R
+
[Bmim] Cl
80 °C
TBAA
100 °C
C
3a
N
by-products
+
R
1a
additive,
solvent
2a
2a-p
1a-p
3a-p
Selectivity (%)
3a
by-prdd)
Products
IL or
solvent
NaNO2
eq.
Conv.
(%)b)
Run
Additive
T (°C) t (h)
Alkene
nitrile 3 (yield %)b)
(IL= TBAA)
-nitroalkene 2 (yield %)b)
2a
(IL= [Bmim Cl])
1
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
-
4
4
3
3
4
3
4
4
4
4
5
4
4
4
2
1
4
4
4
4
4
4
4
4
4
100
100
100
100
80
1
1
93
97
92
94
87
87
92
84
94
66
90
53
>99
>99
75
60
30
85
79
55
99
65
83
56
80
71
60
55
61
78
62
80
77
65
80
56
71
5
10
19
28
38
29
14
24
14
16
22
9
NO2
2a (80)
NO2
C N
3a (95)c
2
-
12
7
1a R= H
3
-
1
4
-
2
10
8
CH3
C N
1b: R= 4-CH3
1c R= 2-CH3
5
-
1
2b (70)
3b (85)
CH3
6
[Bmim] Cl
-
80
1.5
1.5
1.5
4
14
6
CH3
NO2
CH3
C N
3c (84)
[Bmim]
7
-
80
2c (82)
8
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
[Bmim] Cl
TBAA
-
70
7
NO2
9
tBu
Br
C N
3d (80)
-
70
13
11
8
1d: R=4-tBu
tBu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2d (81)
-
60
1.5
1.5
1.5
1
-
70
36
23
-
NO2
C
N
1e R= 4-Br
-
70
6
3e (95)
2e (76)
NO2
Br
F
-
100
100
100
100
90
95
89
70
65
70
10
75
92
93
90
25
46
32
F
C N
TBAA
-
4
6
5
1f: R= 4-F
3f (92)
2f (77)
TBAA
-
1
23
33
16
35
5
7
NO2
2g (55)
NO2
2h (68)
NO2
2i (56)
NO2
TBAA
-
1
2
CF3
C N
1g R= 4-CF3
TBAA
-
1
24
55
10
3
3g (61)
CF3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
100
100
50
4
CH3O
C N
3h (85)
1h: R=4-CH3O
1i R= 3,4-(OCH3)2
1j: R= 4-AcO
1k: 4-vinylpyridine
1l: 2-vinylnaphthalene
TBAA
TBAA
TBAA
TBAA
NaOAc
K2CO3
Bu3N
4
CH3O
CH3O
4
5
CH3O
50
15
15
4
5
2
CH3O
C N
CH3O
r.t.
5
5
3i (63)
100
100
100
35
29
47
58
25
21
HO
C N
4
2j (67)
3j (65)
AcO
N
4
NO2
a) Reaction conditions: ionic liquid (0.3 g) or molecular solvent (0.5 mL), styrene
1a (0.25 mmol), NaNO2 (1 mmol), heated under stirring at the proper
temperature and inert atmosphere.
methylanisole as an external standard. Based on GC-MS peaks areas of all
detectable products.
benzaldehyde, benzoic acid, and halogenated derivatives of styrene etc. (see
Fig. 3 in experimental section).
N
C N
2k (40)
NO2
3k (97)
b)
Evaluated by GC-FID using p-
c)
C
N
d)
Main by-products are: -nitroacetophenone,
2l (50)
CH3
3l (65)
noned)
NO2
1m: R= H, -CH3
1n: R= H, -CH3
1o: trans-stilbene
towards the C=C bond cleavage (Table 2, run 23). Similar poor
results were observed replacing TBAA with potassium carbonate
and tributylamine, suggesting that basic reagents have a
negligible effect on the reaction outcome (Table 2, runs 24-25).
With the optimized conditions in hand (boldfont runs in Table
2), a substrate scope was carried out to verify both application
range and limitations of this protocol (Table 3).
2m (51)
NO2
C N
CH3
2n (52)
3a (5)
C N
NO2
3a (traces)
2o (traces)
In the case of simple nitration of olefinic C-H bond, reactions
proceeded smoothly in [Bmim] Cl at 80 °C for several styrenic
substrates affording moderate to good yields of the corresponding
-nitrostyrenes (2a-n). Selectivity proved to be dependent on the
substitution on the aromatic ring in an unpredictable manner, with
moderate yields displayed, in some case, by both electron-rich
(2i) and electron-poor (2k,2l) substrates, indicative of a probable
radical mechanism (vide infra). Diphenyl substituted alkene (1o)
and 1-octene (1p) afforded only trace amounts of the
corresponding nitrostyrenes.
nC6H13
3p (traces)
C N
NO2
nC6H13
1p: 1-octene
2p (traces)
a) Reaction conditions: ionic liquid (0.3 g), alkene (0.25 mmol), NaNO2 (1 mmol),
heated under stirring for 1 hour at the proper temperature. b) Evaluated by GC-
FID using p-methylanisole as an external standard. c) Isolated yields 93%. d) No
nitrile product is expected. Expected product 3a. Small percentages of 3,4-
diphenyl-1,2,5-oxadiazol 12 were detected by GC-MS.
e)
Generally, better yields in the corresponding benzonitriles
(3a-p) were obtained in almost all cases, with excellent values
(above 90%) observed in the case of styrene, p-Br, p-F
substituted styrenes, and 4-vinylpyridine (products 3a, 3e, 3f and
3k, respectively).
The sharp change of selectivity towards the C=C bond
cleavage, observed in TBAA, was confirmed for all the styrenic
derivatives.
3
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
a) involvement of gaseous NO/NO2
Initially, proofs were searched on the involvement of both nitric
oxide (NO) and nitrogen dioxide (NO2). These gases are known
NO2
(blank)
[19]
3a (2%)
+
+
to be formed in the disproportion of NaNO2
and have been
2a (90%)
15 h
invoked as the true nitrogenating agents.9a A first evidence was
obtained by GLC detection of both NO and NO2 into the
headspace of glass reactor containing NaNO2 dissolved in
[Bmim]Cl and kept at the reaction temperature of 80 °C (see
section 3a into the supporting information). Further experiments
NO2
gaseous NO,NO2 [Bmim]Cl
3a (12%)
6h
1a
toluene, r.t., N2
2a (85%)
TBAA
2h
C
N
2a (5%)
+
3a (95%)
b) Proofs on radical pathway
[19]
were carried out by bubbling gaseous mixtures of NO and NO2
IL= [Bmim]Cl
BTH
2a (2%)
3a (5%)
into toluene solutions of 1a, under inert atmosphere and room
temperature, at the presence of [Bmim]Cl or TBAA as additives
(scheme 1a). Blank experiment (without ILs) showed the almost
complete conversion into β-nitrostyrene 2a in 15 hours. Similar
yields were obtained in the presence of [Bmimi]Cl in 6 hours,
demonstrating the activating effect of IL towards nitration. As
expected, in the presence of TBAA, selectivity inverted almost
completely towards benzonitrile 3a with a complete conversion in
only 2 hours. These results support the hypothesis that NO and
NO2 are the most probable nitrogenation agents.
IL= TBAA
BTH
standard conditions
IL= [Bmim]Cl
TEMPO
2a (1%)
1a
IL= TBAA
TEMPO
3a (traces)
IL= [Bmim]Cl
O2 (P= 2 bar)
2a (20%) + 8,9,10 (75%)
c) Role of -nitrostyrene 2a
Next, experimental evidences were collected on the
involvement of radical pathways (scheme 1b). At this end,
appropriate experiments were carried out involving the addition of
radical trapping agents such as TEMPO and BHT. Results
demonstrated that nitrations are noticeably affected by these
trapping species, resulting almost totally inhibited in both ILs
media [Bmim]Cl and TBAA (see supporting information for
details). A further evidence came from results of reaction
conducted under oxygen pressure in [Bmim]Cl. In this case,
besides a low yield of the expected product 2a, great amounts of
products 8-10 coming from trapping of benzyl radical with
dioxygen were detected (75% of overall yield).[20]
Ph
NO2
Ph
IL= TBAA
3a (<10%)
+
standard conditions
2a
Ph
Ph
4 (85%)
AcO
- AcO
Michael cascade
- 3 HNO2
AcO
Ph
Ph
AcO
Ph
Ph
AcO
Ph
2a
2a
Ph
NO2
NO2 NO2
NO2 NO2
NO2
d) Involvement of -ketonitrooxime 6
OH
N
Furthermore, β-nitrostyrene 2a was investigated as
a
standard
conditions
NO2
C
N
plausible intermediate of C=C bond cleavage (scheme 1c). For
this purpose, 2a was subjected to the standard nitrogenation
conditions in TBAA, thus revealing the formation of 1,3,5-
terphenylbenzene 4 as major product, with less than 10% of
expected benzonitrile 3a. This suggests that 2a is not an
intermediate of the C=C cleavage, while the formation of the main
product 4 can be readily explained with the occurrence of a
cascade Michael addition promoted, most probably, by acetate
anion of the ionic liquid.[21]
Finally, the role of -nitro-ketoxime 6, a compound detected
during reactions, was also examined as probable reaction
intermediate. After preparation with a known procedure,[22] 6 was
subjected to the standard nitration conditions leading to
benzonitrile 3a in 72% of yield (scheme 1d). This result suggests
that 6 is surely an intermediate on the way of C=C bond cleavage.
Based on these control experiments and on results of
substrate scope, we assumed a radical pathway for nitration of
styrenes in ionic liquids. Several literature evidences show ILs as
good reaction media for radical processes, due to their own
tunable properties such as polarity, viscosity and possible strong
solvent cage effects.[23,24] This may explain the better
performances displayed by these media compared with molecular
solvents listed in Table 1.
6
3a (72%)
[standard conditions= IL / NaNO2 / 80-100 °C / 1 h]
Scheme 1. Control studies to elucidate the mechanism.
Good performances were also achieved in the case of
substrates bearing methyl (3b,c) and tert-butyl (3d) groups on the
aromatic ring, with yields values above 80%. For benzonitrile
bearing trifluoromethyl (3g) and acetoxy groups (3j), lower yields
of 61% and 65% were obtained, respectively. In the latter case,
the expected hydrolysis of the acetoxy group occurred, so that p-
hydroxybenzonitrile 3j was solely observed. Unpredictably, while
a single methoxy group substituent afforded 85% of yield (product
3h), the double substitution gave a maximum of 63% (product 3i).
Structural variations of styrenic skeleton inhibited the process.
For instance, by introducing alkyl or aryl group on the double bond,
both to the alpha and beta position, led to little conversions, as
demonstrated by reactions on methylstyrenes (1m,1n), which
gave low yields of not identified products. Similarly, reaction on
the trans-stilbene afforded small percentages of 3,4-diphenyl-
1,2,5-oxadiazol (12) (see Fig. 3), most probably deriving from a
double addition of nitrite to the double bond. Finally, aliphatic
terminal olefin such as 1-octene (1p) was totally unreactive under
reaction conditions, as well as the phenylacetylene, the alkyne
analogous to styrene.
Strehmel et al. [23,25] have recently reviewed the interactions
between ionic liquids and radicals, emphasizing that stabilization
and diffusion of radical species into ILs are strictly dependent on
the structure of the ionic medium.
Then, attention was paid to gaining mechanistic insights. At
this end, a series of control experiments were carried out aimed
at identifying both intermediates and active species involved
(scheme 1).
Based on these studies, it can be inferred that
4
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
path c)
NO
path b)
N
OH
N
OH
NO2
IL
NaNO2

NaNO2
TBAA
NO2
N
OH
[in cage re-
combinnation]
5
[N2O3]
6
7
NO
Beckmann
rearrangement
NO,NO2
NO2
path d)
A
1a
solvent
cage
- NO
- H
C
N
NO2
3a
[Bmim]Cl
[faster out of
cage diffusion]
2a
path a)
Scheme 2. The plausible mechanism of nitration of styrenes in ionic liquids.
tetraalkylammonium-based ILs, due to the higher viscosity, tend
to favour the in-cage recombination of the trapped radicals. In
contrast, imidazolium-based ILs promote a faster diffusion of
radicals through the ionic liquid because of the lower viscosity and
by virtue of their higher polarity and aromatic structure, that
enable stabilization of radicals by means of ionic and hydrogen
bonding interactions.[26]
Inspired by these assumptions, the reaction mechanism
depicted in scheme 2 was proposed accounting for all the
experimental results. At first, the formation of the gaseous mixture
NO/NO2 was hypothesized coming from the disproportion of
sodium nitrite.[20,27] Next, the addition to styrene 1a would lead to
the -nitrobenzyl radical A and nitric oxide that would be trapped
in the solvent cage of IL.
of these processes.
Intriguing strategies have been recently developed based on
NaNO2, that require additional oxidants, radical catalysts, Lewis
or Brønsted acids, toxic solvents or other additives.[8,9a,16]
Exploiting the tunable properties of ILs, their ability to stabilize
radical species and a different solvent cage effect displayed by
imidazolium- and tetraalkylammonium-based ionic solvents,
nitration of styrenes with NaNO2 can proceed without additives in
the appropriate ionic medium, privileging either the C-H nitration
to -nitrostyrenes or the C=C oxidative cleavage to benzonitriles.
Mechanistic insights suggested a radical pathway and the
involvement of NO/NO2 gaseous mixture, generated thermally by
disproportion of NaNO2 that occurred rapidly in these ionic liquid
media.[27]
The evolution of this couple of radicals would depend on the
nature of IL medium and is crucial for determining the selectivity
Due to the simple procedure, the cheap reagents, and the
limited amounts of wastes, this protocol can favourably compete
of the whole process. In imidazolium-based ILs, such as [Bmim]Cl, with the analogous ones reported in the literature.
the stabilization effect of aromatic cation and the lower viscosity,
Experimental Section
would result in a faster diffusion of radical A out of cage, where it
would undergo a rapid elimination leading to -nitrostyrene 2a
(path a).[26] On the other hand, in tetraalkylammonium-based ILs,
such as TBAA, the in-cage reaction between benzylic radical A
and NO is favoured, due to the higher viscosity, affording the nitro
nitroso compound intermediate 5 (path b). This latter would
rapidly undergo tautomerization leading to the detected
intermediate α-nitro-ketoxime 6.[28]
The evolution of the ketoxime 6 to benzonitrile 3a would occur
as previously reported,[9a] with production of 1-phenylglyoxal
dioxime 7 (path c), which was detected as reaction intermediate
by GC-MS, that in turn should give the benzonitrile 3a most
probably through an abnormal Beckman rearrangement (path
d).[29]
It should be noted that, in competition with the coupling with
nitric oxide or with elimination, radical A could be trapped by
traces of dioxygen in the IL medium, leading to the carbonyl by-
products 8-10 (Fig. 3) observed in low selective reactions and in
the appropriate experiment conducted under oxygen pressure
(scheme 1b).[26] Further studies are in progress to confirm these
mechanistic hypotheses.
Materials
Chemicals, solvents, and ionic liquids were purchased from Aldrich or
Fluka (see supporting information for details). Ionic liquids employed are
listed below: [Bmim]Cl= 1-Butyl-3-methylimidazolium Chloride; [Bmim]Br=
1-Butyl-3-methylimidazolium
Bromide;
[Bmim]Ac=
1-Butyl-3-
methylimidazolium Acetate; [Bdmim]Cl= 1-Butyl-2,3-dimethylimidazolium
Chloride; [Bmpy]Cl= 1-Butyl-4-methylpridinium Chloride; TBAC=
Tetrabutylammonium Chloride; TBAB= Tetrabutylammonium Bromide;
TBAI= Tetrabutylammonium Iodide; TBAA= Tetrabutylammonium Acetate;
TBATf= Tetrabutylammonium Triflate; TBAOH= Tetrabutylammonium
Hydroxide;
TBPB=
Tetrabutylphosphonium
Bromide;
TBPA=
Tetrabutylphosphonium Acetate; TOAB= Tetraoctylammonium Bromide.
All the reaction products as well as intermediates and the main by-
products (Table 1) were identified by comparison of their MS spectral data
with the literature, or with the aid of authentic samples. Conversions of
styrenes and yields of nitration products were determined by GLC-FID
using p-methylanisole as an internal standard (details of analytic methods
are reported into the supporting information). The list of main by-products
and reaction intermediates detected is reported in Figure 3.
OH
OH
N
N
O
Ph
4
NO2
N OH
NO2
Ph
Ph
Conclusion
6
7
8
In summary, results of this work allowed to reach two main
synthetic advances: i) the development of a simple method for
converting aryl alkenes into β-nitrostyrenes and benzonitriles
using a cheap nitrogen source (NaNO2) and good solvents (ionic
liquids) and ii) the discovery, unprecedented the literature, of a
general trend in the nitration of styrenes in ionic liquids based on
structure of the latter, which open the way to govern the selectivity
O
N
N
O
N
O
O
N
H
OH
12
Figure 3. List of main by-products and intermediates detected.
9
10
11
5
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
Typical procedure for nitration of styrenes with NaNO2
[15] I. Jovel, S. Prateeptongkum, R. Jackstell, N. Vogl, C. Weckbecker, M.
Beller, Adv. Synth. Catal. 2008, 350, 2493-2497.
A 10 ml glass vial, equipped with a screw cap and a magnetic bar, was
charged with solvent or ionic liquid (0.5 mL or 300 mg, respectively), olefin
(0.25 mmol) and NaNO2 (69 mg, 1 mmol). Reaction mixture was stirred at
100 °C under nitrogen atmosphere for 1 hour. For conversions and yields
evaluation, a weighed aliquot of mixture is added with p-methylanisole as
an internal standard, then treated with HCl 5% and extracted with 0.5 mL
ethyl acetate. The organic phase is analysed by gas phase
chromatography.
For isolating the reaction products, after cooling to room temperature, the
whole reaction mixture was treated with HCl 5% (2 ml) and extracted twice
with 0.5 mL ethyl acetate. The solution was concentrated under vacuum
and purified on a short pad of silica gel (eluent: petroleum ether/ethyl
acetate) to obtain the desired products 2 (or 3).
[16] a) A. Zhao, Q. Jiang, J. Jia, B. Xu, Y. Liu, M. Zhang, Q. Liu, W. Luo, C.
Guo, Tetrahedron Lett. 2016, 57(1), 80-84; b) S. Hlekhlai, N.
Samakkanad, T. Sawangphon, M. Pohmakotr, V. Reutrakul, D.
Soorukram, T. Jaipetch, C. Kuhakarn, Eur. J. Org. Chem. 2014, 7433-
7442.
[17] a) V. Calò, A. Nacci, A. Monopoli, A. Damascelli, E. Ieva, N. Cioffi, J.
Organomet. Chem. 2007, 692(20), 4397-4401; b) C. G. Zambonin, C. D.
Calvano, L. D’Accolti, F. Palmisano, Rapid Commun. Mass Sp. 2006,
20(2), 325-327.
[18] M. Zarei, E. Noroozizadeh, A. R. Moosavi-Zare, M. A. Zolfigol, J. Org.
Chem. 2018, 83, 3645-3650.
[19] Mixture of NO and NO2 was generated by dropwise addition of a 2 M aq.
solution of H2SO4 to a saturated solution of NaNO2 in an outer balloon
connected to the reactor, see R. G. Aga, M. N. Hughes in Methods in
Enzymology: The Preparation and Purification of NO Gas and the Use of
NO Releasers: The Application of NO Donors and Other Agents of
Nitrosative Stress in Biological Systems, Volume 436, chapter 3, pp. 35-
48.
Acknowledgements
This work is partially supported by funds from European Union -
FESR “PON Ricerca e Innovazione 2014−2020. Progetto:
Energie per l’Ambiente TARANTO-Cod. ARS01_00637”.
[20] L. Grossi, P. C. Montevecchi, S. Strazzari, Eur. J. Org. Chem. 2001, 741-
748.
[21] B. Quiclet-Sire, S. Z. Zard, Synthesis 2005, 19, 3319-3326. It should be
noted that anions of tetraalkylammonium-based ILs behave as good
nucleophiles due to the low solvation by the hindered
tetraalkylammonium counterion.
Conflict of interest
[22] N. Chumnanvej, N. Samakkanad, M. Pohmakotr, V. Reutrakul, T.
Jaipetch, D. Soorukram, C. Kuhakarn, RSC Adv. 2014, 4, 59726-59732.
[23] V. Strehmel, S. Berdzinski, H. Rexhausen, J. Mol. Liquids 2014, 192,
153–170.
The authors declare no conflict of interest.
Keywords: Ionic liquids • double bond cleavage • Nitrostyrenes
[24] G. Yu, D. Zhao, L. Wen, S. Yang, X. Chen, AIChE Journal 2012, 58,
2885-2899.
• Nitriles • NaNO2
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[26] According to ref. [23], in the N-yloxyl radical of TEMPO, imidazolium ILs
may rather stabilize the electron density distribution described by the
ionic resonance structure (II), because of their ionic structure and their
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[2]
[3]
G. Yan, Y. Zhang, J. Wang, Adv. Synth. Catal. 2017, 359, 4068-4105.
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N(II)O
N (I)
O
On these bases NO should by better stabilized by imidazolium-based ILs
due to its ionic structures give the major contribute to the hybrid.
[27] Generation of gases NO/NO2 could be hypothesized based on
disproportion equation 3NaNO2 + H2O → 2NO + NaNO3 + 2NaOH,
favoured by the thermal conditions (80-100 °C) and the moisture of ILs
or the hygroscopic NaNO2 (see J.-M. Zen, A. S. Kumar, H.-F. Wang,
Analyst, 2000, 125, 2169–2172 and D. M. Stanbury, M. M. deMaine,
George Goodloe, J. Am. Chem. Soc. 1989, 111, 5496-5498).
To prove this assumption, two comparative nitration experiments were
carried out using, from one hand, dried [Bmim]Cl and NaNO2 (obtained
by heating overnight at 60 °C) and, from the other, by adding small
amounts of water to the reaction mixture. Really, in the first case
nitrogenation resulted inhibited (conv. < 10%), while in the second case
reaction proceeded completely but with the formation of high amounts of
by-products, indicative that the presence of water is mandatory but in
moderate amounts.
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Due to the formation of NaOH as by-product (confirmed also by the
increase of pH of the final reaction mixture), the fate of both ILs ([Bmim]Cl
and TBAA) was monitored by 1H-NMR confirming that these solvent
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6
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10.1002/ejoc.202001027
European Journal of Organic Chemistry
FULL PAPER
Ionic-liquid controlled nitration of double bond: highly selective synthesis of nitrostyrenes and benzonitriles
Unprecedented ionic-liquid controlled
nitration of double bond
IL=[Bmim]Cl
R
NO2
80 °C
2
Unprecedented the literature, conversion of
aryl alkenes into β-nitrostyrenes (2) or
benzonitriles (3) with NaNO2 can be governed
by an appropriate choice of ionic liquid
medium. A general trend was found for the
selectivity of these processes, which depends
on the nature of IL, with imidazolium-based
ILs, such as [Bmim] Cl, that favour the
formation of -nitrostyrenes, while
(yields 40-81%, 14 examples)
NaNO2
R
1
IL=TBAA
100 °C
C N
R
3
(yields 61-97%, 12 examples)
tetraalkylammonium-based ILs, such as TBAA,
that privilege the formation of benzonitriles.
7
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