Arene diazonium saccharin intermediates: A greener and cost-effective alternative method for the preparation of aryl iodide

Article abstract of DOI:10.3906/KIM-2002-26

In the current protocol, the arene diazonium saccharin derivatives were initially produced from various substituted aromatic amines; subsequently, these intermediates were treated with a greener organic iodide for the preparation of the aryl iodide. We tried to choose low-cost, commercially available, biodegradable, recoverable, ecofriendly, and safe reagents and solvents. The arene diazonium saccharin intermediates could be stored in the liquid phase into a refrigerator for a long time with no significant loss activity. The outstanding merits of the current protocol (a) included the partial recovering of saccharin and tetraethylammonium salt, (b) reduce the use of solvents and the reaction steps due to eliminating separation and purification of intermediates, (c) good yield of the sterically hindered substrates, and (d) avoid the generation of heavy metal or corrosive waste.

Full text of DOI:10.3906/KIM-2002-26

Turk J Chem
Turkish Journal of Chemistry
(2020) 44: 535 – 542
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-2002-26
Research Article
Arene diazonium saccharin intermediates: a greener and cost-effective alternative
method for the preparation of aryl iodide
Lia ZAHARANI, Nader GHAFFARI KHALIGH∗, Zohreh SHAHNAVAZ,
Mohd RAFIE JOHAN
Nanotechnology & Catalysis Research Centre, Institute of Postgraduate Studies,
University of Malaya, Kuala Lumpur, Malaysia
Received: 08.02.2020
•
Accepted/Published Online: 28.02.2020
•
Final Version: 01.04.2020
Abstract: In the current protocol, the arene diazonium saccharin derivatives were initially produced from various
substituted aromatic amines; subsequently, these intermediates were treated with a greener organic iodide for the
preparation of the aryl iodide. We tried to choose low-cost, commercially available, biodegradable, recoverable, eco-
friendly, and safe reagents and solvents. The arene diazonium saccharin intermediates could be stored in the liquid phase
into a refrigerator for a long time with no significant loss activity. The outstanding merits of the current protocol (a)
included the partial recovering of saccharin and tetraethylammonium salt, (b) reduce the use of solvents and the reaction
steps due to eliminating separation and purification of intermediates, (c) good yield of the sterically hindered substrates,
and (d) avoid the generation of heavy metal or corrosive waste.
Key words: Aromatic iodide, one-pot diazotization-iodination, saccharin, waste prevention
1. Introduction
In the course of our research regarding the synthesis of aromatic iodides through the Sandmeyer reaction
or its alternatives, we required an efficient, low cost, and sustainable method for accessing relative stable
arene diazonium salts. The most arene diazonium salts are often prepared in situ due to their instability and
explosive risk [1]. It is clear that the anion nature can influence in situ the generation of the arene diazonium
salts [2], and facilitated the preparation of aryl iodides. The preparation of relative stable benzenediazonium
tetrafluoroborates was reported in ethanol using HBF4 and isoamyl nitrite [3]. Most of the reported chemicals
and reagents are expensive, toxic, nonbiodegradable, unrecoverable, and metal-containing, so we looked for a
cheap, nontoxic, recoverable, biodegradable, and biocompatible reagent that show high efficiency under mild
conditions.
In continuation of our previous work [4] and application of saccharin [5–7], we encouraged to investigate
the potential of saccharin for the synthesis of the aryl iodides through in situ formation the arene diazonium
saccharin salts which to the best of our knowledge has not been presented to date. According to the current
strategy, aryl iodides are formed from diazotization of in situ generated arene diazonium salts which are in turn
formed from aniline derivatives and tert-butyl nitrite (TBN) in the presence of saccharin. The intermediates
are not isolated and purified in the current protocol which lead to minimizing the solvent waste, and energy
efficiency is enhanced by the reaction performance at room temperature and shorter reaction times.
∗Correspondence: ngkhaligh@gmail.com
535
This work is licensed under a Creative Commons Attribution 4.0 International License.

ZAHARANI et al./Turk J Chem
2. Results and discussion
TBN and tetraethylammonium iodide (TEAI) were preferred as a nitrating agent and iodide precursors due to
their unique properties like safe handling, metal-free, inexpensive, and commercial availability [8,9].
Based on our previous works [4,5], the glacial acetic acid and TBN together with Sac–H were slowly
stirred in ethanol at low temperatures (an ice bath). After 5 min, aniline 1a was slowly added at the same
temperature. After completion of the first step (monitored by a colour test of azo coupling with 2-naphthol),
the generated t-BuOH and unreacted TBN were removed under vacuum by a rotary evaporator. Then, the
TEAI solution was added into the stirring intermediate 2a at one time and final product 3a was purified by
the flash chromatography (Scheme 1).
Schema 1. Preparation of aryl iodides using TBN= saccharine, and TEAI.
The scope and generality of current methodology was evaluated through transformation of a variety of
aniline derivatives into the corresponding iodides using the current protocol. The aryl iodides bearing electron-
donating and electron-withdrawing groups were obtained from the corresponding anilines in good to excellent
yields (Table 1). However, the steric hindered anilines viz. 2,6-dimethylaniline, 2,6-diethylaniline, and 2,6-
diisopropylaniline 3(d-f) were isolated in 67%, 40%, 42% yields, respectively as expected (Table 1, entry 4–6)
[6]. All known products showed an identical melting point and NMR spectra to those in the literature (See
Supplementary Material) [4].
a
Table 1. Synthesis of aryl iodides through in situ formation of the arene diazonium saccharin intermediates.
b
Entry Ar-NH2 1(a-l)
Product 3(a-l) Yield (%)
Melting point (°C)
Found
Reported [4]
1
2
3
4
5
6
7
8
C6H5-
4-CH3O-C6H4-
4-CH3-C6H4-
2,6-(CH3)2-C6H3-
2,6-(CH3CH2)2-C6H3-
2,6-[(CH3)2CH]2-C6H3-
4-Cl-C6H4-
2-Cl-C6H4-
4-Br-C6H4-
4-NO2-C6H4-
2-NO2-C6H4-
A
B
C
D
e
80
72
78
67
40
42
79
77
80
82
78
70
Oil
50–51
Oil
Oil
Oil
Oil
54–55
Oil
Oil
52–54
Oil
Oil
Oil
Oil
55–56
Oil
f
g
h
i
j
k
l
9
88–90
87-88
10
11
12
168–169 170–172
51–52 51–53
158–159 159–161
4-morpholinoaniline
aReaction conditions: TBN (0.30 mL, ~2.3 mmol), aniline derivatives 1(a-l) (2.0 mmol), glacial acetic acid (0.12 mL, 2.1 mmol),
Sac-H (0.37 g, 2.0 mmol), TEAI (0.52 g, 2.0 mmol), solvent (H2O/EtOH 1:1 v/v, 5 mL); total reaction time (2 h).
bIsolated yield.
536

ZAHARANI et al./Turk J Chem
Complete or partial recovering of the catalyst and reagents are very important in the industrial processes
due to minimizing the waste, as well as lower raw material, energy, and waste disposal costs. According to
the reported procedure in the literature [6], the saccharin and tetraethylammonium chloride (TEAC) could be
recovered in the range of 77%–72% and 68%–64% yield, respectively.
The possible reaction of aniline and saccharin was investigated by a control experiment under optimal
conditions. No 3-amino-1, 2-benzisothiazole-1, 1-dioxide were detected by LC-MS analysis.
Another experiment was performed to study the stability of the arene diazonium intermediate. After the
first step, the intermediate 2a can be isolated by removing the excess TBN and t-BuOH under vacuum and
stored in a refrigerator (4°C). After four days, the stored arene diazonium 2a was treated with a TEAI solution
which afforded iodobenzene (3a) in a 74% yield.
A proposed mechanism is illustrated in Scheme 2 [6]. Saccharin and tert-butyl nitrite generate the nitroso
+
+
( N=O ↔ N≡O ) in the first step, which can act as a mild electrophile. The reaction of nitroso and arylamine
+
will form arene diazonium saccharinate [ArN2 ] [Sac]− or arenediazosaccharine adduct Ar–N=N–Sac. High
stability of intermediate assigned to the inductive and resonance effects of the carbonyl and sulfonyl groups
+
on saccharin moiety. In the second step, [ArN2 ] [Sac]− salt or Ar–N=N–Sac adduct will participate in an
electrophilic substitution reaction with TEAI, which finally affords the corresponding aryl iodides. Our group
is working to investigate the detailed processes of reaction mechanism based on 2 routes A and B.
A large scale of the current protocol was also conducted for 1.9 g of 1a under optimal conditions, which
afforded 3.12 g of 3a (ca.75%).
Table 2 showed some of the reported methods and their conditions for the preparation of 2-nitro-1-
iodobenzene 2k. The previously reported methods have their own merits and limitations, for example, the use
of metal-containing nitrites and iodides (Table 2, entries 1, 3–11), low yield and slow rate (Table 2, entries 5,12),
2 steps performance (Table, entries 2,5), use of expensive reagent or strong acids (Table 2, entries 1, 9–11),
generation of waste for the preparation of the nitrating reagent (Table 2, entries 5,11), tedious workup (Table 2,
entry 12), the formation of toxic and hazard by-products, and incomplete conversions (Table 2, entries 5,7,11).
ao-BDSI: o−benzenedisulfonimide, CSA: cellulose sulphuric acid, NMP: N-methyl-2-pyrrolidone, P4-VP:
poly(4-vinylpyridine), IPN: i-pentyl nitrite, Sac–H: Saccharin, p- SSA: silica sulphuric acid, TBAI: tetrabutyl
ammonium iodide, TsOH: p-toluenesulfonic acid, TFSI–H: bis(trifluoromethylsulfonyl) imide.
3. Conclusion
In summary, a telescopic reaction developed for the synthesis of aryl iodides in the presence of TBN, Sac–H,
glacial acetic acid, and TEAI. The arene diazonium intermediates could be stored for relatively long periods
with little reduce of activity. The current methodology is safe, cost-effective, broad substrate scope, and metal-
free. All used reagents are commercially available and inert to moisture and air. Also, the saccharine and
tetraethylammonium cation were easily isolated from the reaction mixture which reduces the cost and waste of
the current protocol.
4. Experimental Section
4.1. General
The analytical grade chemicals were provided from Merck and Sigma Aldrich Chemical Companies. The
chemicals were used without further purification. Products were characterized by their physical constants
537

ZAHARANI et al./Turk J Chem
Route A:
Route B:
Schema 2. Two proposed mechanisms for the preparation of aryl iodides using TBN and saccharine.
1
such as melting point and H NMR. The purity determination of the substrates and reaction monitoring were
accompanied by TLC using silica gel SIL G/UV 254 plates or colour test of azo coupling with 2-naphthol. The
1
H NMR spectra and melting points were recorded with Bruker Avance 400 MHz instrument and Büchi B-545
apparatus in open capillary tubes, respectively.
4.2. Typical procedure for the synthesis of aryl iodide
To a stirring mixture of glacial acetic acid (0.12 mL, 2.1 mmol) and TBN (0.30 mL, ~
2.3mmol)inethanol(10mL), Sac − −H(0.37g, 2.0mmol)wasslowlyaddedatlow
538

ZAHARANI et al./Turk J Chem
a
Table 2. Some reported reagents and methods for the diazotization-iodination of 2-nitro aniline 1k.
Entry mmol of
aryl amine
Nitrating agent
Reagents
conditions
Time (min) Yield (%) Ref.
1
2
TBN (2.3 mmol)
TFSI–H (2 mmol)
HOAc (2.1 mmol)
TEAI (2.0 mmol)
EtOH:H2O(1:1)/0-5 °C
110
82
4
2
10
IPN (11 mmol)
o−BDSI (12 mmol)
glacial AcOH (60 mL)
TBAI (10 mmol)
Two steps:
45
92
10
Step 1: 0–5 °C;
Step 2: CH3CN/r.t. °C
3
4
5
2
NaNO2 (5 mmol)
NaNO2 (4 mmol)
p-TsOH (6 mmol)
Water-paste form
H2O/r.t.
20–30
90
72
71
34
11
12
13
KI (5 mmol)
2
sulfonated-resin (5 g)
KI (5 mmol)
5.25
resin-NO2(5.25 mmol) p-TsOH (5.25 mmol)
glacial AcOH (8 mL)
Two steps:
Step 1: H2O/r.t.;
Step 2: H2O/r.t.
30
KI (13.125 mmol)
6
2
Resin-NO2 (6 mmol)
p-TsOH (6 mmol)
KI (5 mmol)
H2O/r.t.
90
91
14
7
8
5
3
KNO2 (20 mmol)
NaNO2 (6 mmol)
HI (20 mmol)
p-TsOH (9 mmol)
KI (7.5 mmol)
DMSO/35 °C
MeCN/10–20 °C
15
50
89
81
15
16
9
1
2
1
NaNO2 (2.5 mmol)
NaNO2(4 mmol)
[H-NMP]HSO4 (4 mmol) Solvent-free/r.t.
20–30
12
85
82
74
17
18
19
NaI (2.5 mmol)
10
11
Wet CSA (1.5 g)
KI (5 mmol)
H2SO4 (2 mmol)
KI (2.5 mmol)
Solvent-free/r.t.
[P4-VP]NO2 (0.54 g)
Two steps:
Step 1: 0–5 °C;
100
Step 2: r.t. or 60 °C
12
13
10
2
IPN (30 mmol)
TBN (2.3 mmol)
diiodomethane (10 mL)
80 °C
240
65
78
20
Sac–H (2 mmol)
HOAc (2.1 mmol)
TEAI (2.0 mmol)
EtOH:H2O(1:1)/0-r.t. °C 120
This work
temperature (an ice bath). After 5 min, aniline derivative 1(a-l) (2.0 mmol) was added dropwise over 5 minutes
into the mixture. The solvent, t-BuOH, and residue TBN were removed under reduced pressure after consuming
of aniline derivatives (monitored by a color test of azo coupling with 2-naphthol). Then, 5 mL of 0.4 M TEAI
solution was added into stirring as-obtained intermediate 2(a-l) in one portion at low temperature. After
confirmation of substrate consumption by a negative test of azo coupling with 2-naphthol, the boiling water
was added to the reaction mixture (15 mL) and the aqueous layer was separated. The organic layer was washed
with aq. 10% sodium sulphite (3 ×5 mL), then dried over Na2 SO4 , filtered, and dried under reduced pressure
in a rotary evaporator. The purification was conducted by flash chromatography with n-hexane-EtOAc (9:1,
v/v) as eluent.
The recovery of reagents was conducted by adding the concentrated hydrochloric acid into the aqueous
layer, and the water evaporated under reduced pressure. Then, the residue was extracted 5times with EtOAc (5
mL), and the collected extracts were dried over anhydrous Na2 SO4 and filtrated. The evaporation of solvent
afforded Sac–H in 72% yield. The tetraethylammonium chloride (TEAC) was isolated in a yield of 0.25 g from
the residue of the above procedure (68%). The melting points and FTIR spectra of recovered saccharin and
TEAC were identical to the authentic compound (Sigma Aldrich ≥ 98%).
1
Physical and H NMR data of 4-methoxybenzenediazonium saccharinate (2b):1 H NMR (400 MHz,
DMSO-d6)δ 8.41-8.48 (m, 1H), 8.32-8.39 (m, 2H, ArH), 7.87-7.94 (m, 1H, ArH), 7.29 (d, J = 8.8 Hz, 2H,
539

ZAHARANI et al./Turk J Chem
ArH), 7.03 (d, J = 8.8 Hz, 2H, ArH), 3.80 (s, 3H, OCH3) ppm [6].
Spectra data of the aryl iodides 3a-3l [6]
1
Iodobenzene (3a): H NMR (400 MHz, CDCl3)δ 7.75 (d, J = 8.2 Hz, 2H, ArH), 7.34 (t, J = 7.2 Hz,
13
1H, ArH), 7.13 (t, J = 7.2 Hz, 2H, ArH) ppm; C NMR (100 MHz, CDCl3)δ 137.7, 130.4, 127.8, 95.0 ppm;
+
EI-MS: M m/z 204.
1
1-Iodo-4-methoxybenzene (3b): H NMR (400 MHz, CDCl3)δ 7.56 (d, J = 8.2 Hz, 2H, ArH), 6.65 (d,
13
J = 8.2 Hz, 2H, ArH), 3.76 (s, 3H, OCH3) ppm; C NMR (100 MHz, CDCl3)δ 159.6, 138.4, 116.5, 82.8, 55.5
ppm; EI-MS: M+ m/z 234.
1
1-Iodo-4-methylbenzene (3c): H NMR (400 MHz, CDCl3)δ 7.59 (d, J = 8.2 Hz, 2H, ArH), 6.94 (d,
13
J = 8.2 Hz, 2H, ArH), 2.32 (s, 3H, CH3) ppm; C NMR (100 MHz, CDCl3)δ 136.9, 136.5, 131.4, 91.2, 21.1
ppm; EI-MS: M+ m/z 218.
1
1,3-Dimethyl-2-iodobenzene (3d): H NMR (400 MHz, CDCl3): δ 7.20-6.92 (m, 3H, ArH) , 2.42 (s, 6H,
13
+
2 ×CH3) ppm; C NMR (100 MHz, CDCl3): δ 141.7, 126.4, 126.2, 123.3, 21.8 ppm; MS (EI) m/z M 232.
1
1,3-Diethyl-2-iodobenzene (3e): H NMR (400 MHz, CDCl3): δ 7.21 (t, J = 8.0 Hz, 1H, ArH), 7.06
13
(d, J = 8.0 Hz, 2H, ArH), 2.81 (q, J = 7.0 Hz, 4H, 2 ×CH2), 1.23 (t, J = 7.0 Hz, 6H, 2 ×CH3) ppm;
NMR (100 MHz, CDCl3): δ 147.3, 128.1, 125.9, 107.2, 35.5, 14.7 ppm; MS (EI) m/z M 260.
C
+
1
1,3-diisopropyl-2-iodobenzene (3f): H NMR (400 MHz, CDCl3)δ 7.23 (t, J = 8.0 Hz, 1H, ArH), 7.05
13
(d, J = 8.0 Hz, 2H, ArH), 3.39 (sept, J = 7.0 Hz, 2H, 2 ×CH), 1.23 (d, J = 7.0 Hz, 12H, 4 ×CH3) ppm;
NMR (100 MHz, CDCl3)δ 151.0, 128.3, 123.8, 109.2, 39.4, 23.4 ppm; MS (EI) m/z M 288.
C
+
1
1-Chloro-4-iodobenzene (3g): H NMR (400 MHz, CDCl3)δ 7.59 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d,
13
+
J = 8.2 Hz, 2H, ArH) ppm; C NMR (100 MHz, CDCl3)δ 138.0, 133.8, 130.4, 91.2 ppm; EI-MS: M m/z
238.0.
1
1-Chloro-2-iodobenzene (3h): H NMR (400 MHz, CDCl3)δ 7.82 (d, J = 7.8 Hz, 1H, ArH), 7.44 (d,
13
J = 7.8 Hz, 1H, ArH), 7.28 (t, J = 7.2 Hz, 1H, ArH), 6.97 (t, J = 7.8 Hz, 1H, ArH) ppm; C NMR (100
MHz, CDCl3)δ 141.1, 138.8, 129.6, 128.6, 128.0, 98.6 ppm; EI-MS: M m/z 238.0.
+
1
1-Bromo-4-iodobenzene (3i): H NMR (400 MHz, CDCl3)δ 7.53 (d, J = 8.2 Hz, 2H, ArH), 7.20 (d, J =
13
+
8.2 Hz, 2H, ArH) ppm; C NMR (100 MHz, CDCl3)δ 139.1, 133.4, 122.0, 92.2 ppm; EI-MS: M m/z 238.0.
1
1-Iodo-4-nitrobenzene (3j): H NMR (400 MHz, CDCl3)δ 7.97 (d, J = 8.2, 2H, ArH), 7.89 (d, J = 8.2
13
+
Hz, 2H, ArH) ppm; C NMR (100 MHz, CDCl3)δ 147.6, 138.8, 125.2, 102.8 ppm; EI-MS: M m/z 249.
1
1-Iodo-2-nitrobenzene (3k): H NMR (400 MHz, CDCl3)δ 7.91 (d, J = 7.8 Hz, 1H, ArH), 7.84 (d, J =
13
8.2 Hz, 1H, ArH), 7.49 (t, J = 7.8 Hz, 1H, ArH), 7.30 (t, J = 8.2 Hz, 1H, ArH) ppm; C NMR (100 MHz,
+
CDCl3)δ 153.1, 142.0, 133.5, 129.2, 125.5, 86.3 ppm; EI-MS: M m/z 249.
1
4-(4-iodophenyl)morpholine (3l): H NMR (400 MHz, CDCl3)δ 7.56 (d, J = 9.0 Hz, 2H, ArH), 6.70 (d,
13
J = 9.0 Hz, 2H, ArH), 3.88-3.83 (m, 4H, 2 ×CH2(eq)), 3.13-3.09 (m, 4H, 2 ×CH2(ax)) ppm; C NMR (100
+
MHz, CDCl3)δ 151.0, 138.0, 117.8, 81.9, 66.9, 50.2 ppm; EI-MS: M m/z 289.
Caution! The arene diazonium salts are known potentially explosive in the dry state, thus, they must be
cautiously stored and handled in the laboratories. Avoid unnecessary heating and mechanical impact, especially
when working on a large scale.
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ZAHARANI et al./Turk J Chem
Acknowledgement
This work was supported by NANOCAT RU001-2008 Grant for Scientific Research from University of Malaya,
Malaysia. The authors are grateful to staff members in the Nanotechnology & Catalysis Research Centre of
Malaya University for the partial support.
Supplementary material
1
H NMR spectra copies of the aryl iodides 3a-3l can be found at Supplementary Material.
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542

Supplementary material
Caution! The arene diazonium salts are known potentially explosive in the dry state.
Thus, they must be cautiously stored and handled in the laboratories. Avoid
unnecessary heating and mechanical impact, especially when working on a large scale.
1H NMR spectra copies of the aryl iodides (400 MHz, CDCl3)
Iodobenzene (3a)
1

1-Iodo-4-methoxybenzene (3b)
1-Iodo-4-methylbenzene (3c)
2

1,3-Dimethyl-2-iodobenzene (3d)
1,3-Diethyl-2-iodobenzene (3e)
3

1,3-diisopropyl-2-iodobenzene (3f)
1-Chloro-4-iodobenzene (3g)
4

1-Chloro-2-iodobenzene (3h)
1-Bromo-4-iodobenzene (3i)
5

1-Iodo-4-nitrobenzene (3j)
1-Iodo-2-nitrobenzene (3k)
6

4-(4-iodophenyl)morpholine (3l)
7