Synthesis and structural insights of substituted 2-iodoacetanilides and 2-iodoanilines

Article abstract of DOI:10.1016/j.molstruc.2013.10.011

This study reports a simple and efficient method for the direct iodination of substituted anilines with molecular iodine and copper acetate in acetic acid producing 2-iodoacetanilies and 2-iodoanilines. Employing density functional theory (B3LYP) and MidiX basis set, computational study is performed to calculate equilibrium geometries, IR vibrational frequencies, and thermodynamic properties including change of energy, enthalpy and Gibbs free energies. The optimized geometries indicated longer C-I bond distance (2.133 ?) which makes iodine slightly positive. The partial atomic charge profile and electrostatic potential further confirmed that most of the iodinated products are capable of forming a distinct halogen bonding . The thermodynamic properties disclosed that all iodination reactions are endothermic. Understanding the substituents' effect, molecular frontier orbital (MO) calculations are conducted finding the HOMO, LUMO and HOMO-LUMO gaps for all compounds. The MO calculations revealed that two electron-withdrawing iodine groups have significant influence on lowering the HOMO-LUMO gap compared to one iodine group in the products.

Full text of DOI:10.1016/j.molstruc.2013.10.011

Journal of Molecular Structure 1054–1055 (2013) 367–374
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and structural insights of substituted 2-iodoacetanilides
and 2-iodoanilines
a
Mohammad Mazharol Hoque a, Mohammad A. Halim b, , Mohammad Mizanur Rahman ,
⇑
Mohammad Ismail Hossain a, Md. Wahab Khan a,
⇑
a Department of Chemistry, Bangladesh University of Engineering and Technology, Dhaka 1000, Bangladesh
b Department of Chemistry, The University of Western Ontario, London, Ontario N6H 4P5, Canada
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
A simple method is applied for the
direct iodination of substituted
anilines.
DFT study is conducted
understanding the structural features
of iodinated products.
Most of the iodinated products are
capable of forming a distinct
‘‘Halogen Bonding’’.
Noncovalent interaction between the
products may reduce the single
product yield.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 August 2013
Received in revised form 10 September 2013
Accepted 7 October 2013
Available online 15 October 2013
This study reports a simple and efficient method for the direct iodination of substituted anilines with
molecular iodine and copper acetate in acetic acid producing 2-iodoacetanilies and 2-iodoanilines.
Employing density functional theory (B3LYP) and MidiX basis set, computational study is performed to
calculate equilibrium geometries, IR vibrational frequencies, and thermodynamic properties including
change of energy, enthalpy and Gibbs free energies. The optimized geometries indicated longer C–I bond
distance (2.133 Å) which makes iodine slightly positive. The partial atomic charge profile and electro-
static potential further confirmed that most of the iodinated products are capable of forming a distinct
‘‘halogen bonding’’. The thermodynamic properties disclosed that all iodination reactions are endother-
mic. Understanding the substituents’ effect, molecular frontier orbital (MO) calculations are conducted
finding the HOMO, LUMO and HOMO–LUMO gaps for all compounds. The MO calculations revealed that
two electron-withdrawing iodine groups have significant influence on lowering the HOMO–LUMO gap
compared to one iodine group in the products.
Keywords:
Iodination
Density functional theory
Equilibrium geometry
Vibrational frequencies
Frontier molecular orbitals
Halogen bonding
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
straightforward access to a wide range of essential iodoarene inter-
mediates [3,4], and it was reported that iodine bonded at the ortho
In numerous transformations, aryl iodides are valuable synthetic
intermediate, particularly in metal-catalyzed cross-coupling reac-
tions [1,2]. Electrophilic iodination of anilines, phenols, provides
position to –NH2 or –NHCOCH3 makes the molecule a very conve-
nient synthon for further transformation [5,6]. In synthesis of
N-substituted-3-alkylisoindoline esters [7], isocoumarin [8] and
a-(aminocarbonyl)iminyl radicals [9], aryl iodides provided
evidence of their potential applications. Some iodo aromatic com-
pounds are employed in medicine as drugs or diagnostic aids. For in-
stance, a notable imaging agent (iodo-PK11195) and galanthamine
⇑
Corresponding authors. Tel.: +1 519 661 2111x86667 (M.A. Halim).
E-mail addresses: mhalim4@uwo.ca (M.A. Halim), mwkhan@chem.buet.ac.bd
(M.W. Khan).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.10.011

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M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
drug synthesized from iodo intermediate are frequently used for
treating Alzheimer patients [10,11]. The iodoarenes moiety is also
an important structural motif of various bioactive compound, such
as berkelic acid methyl ester [12]. The challenge of introducing io-
dine is particularly important since iodine is preferred over other
aromatic halides for some reactions.
Moreover, halogen (especially Br and I) atoms form halogen
bonding analogous to hydrogen bonding and these noncovalent
interactions play pivotal roles in biological and chemical systems.
In halogen bonding [13–15], X atom can act as an electron deficient
chloroform (3 Â 50 mL). The combined chloroform extracts were
washed with sodium hydrogen carbonate solution, sodium thiosul-
fate solution, distilled water and dried with anhydrous sodium sul-
fate. A crude semi-solid mass was obtained after removal of
solvent. The crude product was purified by column chromatogra-
phy on silica gel using n-hexane/ethyl acetate as eluant (4:1) and
compounds 7–24 were isolated.
In order to optimize the iodination reaction condition, 4-methyl
aniline 1 was considered as starting material and the reaction tem-
perature was varied from 25 °C to 120 °C (supplementary
Table S1). It was observed that in low concentration of substrate
in acetic acid and stirring the reaction mixture at higher tempera-
ture favored 2-iodo-4-methyl-N-ethanoylaniline 8 as a major
product. To find out the role of solvent, two solvents, acetic acid
or trifluro acetic acid, was used as reaction medium. No desired
iodo compound was obtained when the reaction was carried out
in trifluro acetic acid at the same condition. Therefore, acetic acid
was found to be the best solvent and entry 4 was found to be the
optimized condition to synthesize 2-iodo acetanilide.
The substitued-2-iodoacetanilides and 2-iodoanilineswere pre-
pared by a convenient procedure using iodine–copper(II) acetate in
acetic acid from their corresponding parent substituted anilines
(Scheme 1). Commercially available primary arylamines e.g. p-
methylaniline 1, p-chloroaniline 2, m-methylaniline 3, m-chloroan-
iline 4, p-nitroaniline 5 and m-aminophenol 6 were used to prepare
2-iodoacetanilide and 2-iodoaniline. The iodination reactions were
carried out by stirring the mixture of substituted arylamine 1–6
(10.0 mmol), granulated iodine (10.0 mmol) and copper acetate
(10.0 mmol) in glacial acetic acid (20 mL) at 120 °C for 12 h. After
usual workup, the crude product was purified by column chroma-
tography on silica gel using n-hexane/ethyl acetate (4:1) as eluant,
and products 7–24 were isolated as shown in the Table 1. Melting
points were determined in open capillary tubes in Gallenkamp
(England). IR spectra were recorded on a Shimadzu FTIR spectro-
photometer with 45 scan and range of 4000–400/cm. 1H NMR
and 13C NMR spectra were recorded on a Bruker DPX-400 spectro-
photometer (400 MHz) using tetramethylsilane as internal refer-
ence. Analytical thin layer chromatography (TLC) was performed
on precoated silica gel 60 F254 (E. Merck), and the spots were visu-
alized with UV light. Column chromatography was performed on
silica gel (60–120 mesh). Elemental analyses (C, H, N) were carried
out on Perkin–Elmer 240 C analyzer. All reagents were purchased
from E. Merck (Germany) and Fluka (Switzerland). IR and NMR
data related to all compounds are presented in the Supplementary
materials.
(electropositive crown or
r-hole) Lewis acid which in turn at-
tracted by electron rich Lewis bases (such as carbonyl oxygen,
amine nitrogen). The halogen bonding phenomena are also widely
available in the biological molecules such as proteins in which
some halogenated ligands form noncovalent halogen bonding with
carbonyl oxygen of amino acids [16]. It is also observed that install-
ing halogen atom in some drugs can significantly enhance the per-
formance since halogen atom can enter through the hydrophobic
regions of integral membrane proteins [17]. That’s why the versa-
tility of the C–I bond makes aryl iodides essential buildings block in
medicinal chemistry, supramolecular chemistry, and material
science.
Different methods, direct and in direct, are applied for iodoa-
rene synthesis [18–20]. In direct aromatic iodination, the iodonium
species directly forms cabon–iodine bond [21]. However, direct
halogenations suffer from some difficulties; firstly, the halogens
have incredibly dissimilar reactivity, with iodine generally requir-
ing some technique of activation, whereas others are reactive and
hazardous chemicals [22]. Secondly, there is a reducing effect of
hydrogen iodide produced in the system [23]. Iodination is carried
out under oxidative conditions, where iodide ions formed in reac-
tions are oxidized to molecular iodine. The oxidizing agents can de-
grade sensitive groups, for this reason it is not always feasible.
Several iodination methods have been reported using various re-
agents, such as-py, ICl, MeOH [24]; I2, NaNO2, H2O–MeOH [25];
I2/CAN [26]; KI or I2/polyvinylpyrrolodone supported H2O2/
H3PW12O40 in CH2Cl2 [27]; I2–HIO3 [28]; NaBO3Á4H2O/I2 in ionic
liquids [29]; NIS(N-Iodosuccinimide), [Rh(III)Cp * Cl2]2AgSbF6, Pi-
vOH in 1,2-DCE [30]; {[KÁ18-C-6]ICl2}n [31]. Moreover, Baird and
Surridge reported [32] that the iodination of aromatic compounds
with iodine and copper(II) halides gave the aryl iodides. It is also
indicated that the iodination of less reactive substrates with iodine
aluminum(III) and copper(II) chlorides [33] provided the corre-
sponding aryl halides. Although numerous methods related to
the iodination of aromatic compound for various transformations
are available, there is still a vast need finding of trouble-free,
non-hazardous, and cost-effective reagent for the introduction of
iodine into an aromatic ring.
3. Computational details
In this paper, we report the iodination of 2 or 3-substituted
anilines by copper(II) acetate in acetic acid employing one-pot syn-
thesis method. In addition, details quantum chemical investigations
have been performed exploring the equilibrium geometries, vibra-
tional frequencies, molecular orbitals of all synthesized compounds.
All calculations were performed with the Gaussian 09 software
package [34]. Equilibrium geometries of all compounds (1–24)
were first fully optimized and then vibrational frequencies were
calculated at density functional theory (B3LYP) using MidiX basis
set. Internal energies, enthalpy, free energies, entropy, Cv, and di-
pole moments of each compound were also investigated. The ab-
sence of imaginary frequencies confirmed that the stationary
points correspond to minima on the Potential Energy Surface.
The MidiX basis set is originally developed from the Huzinaga MIDI
basis and applied to H, C, F, S, Cl, Br, and I atoms [35]. The MidiX
basis set is comparatively smaller than the popular 6-31G(d); how-
ever, it can provide excellent geometries and charge balances with
reasonable computational time and accuracy [36]. Since all the
compounds of this study contains I atoms, and 6-31G(d) and other
related basis sets are not compatible with halogen atoms, MidiX is
the appropriate basis set option for these compounds. After com-
puting the optimized structures and vibrational frequencies,
2. Experimental methods
A typical procedure was followed for one-pot synthesis of
substituted 2-iodoaniline and 2-iodoacetanilide from substituted
aniline. A mixture of 5 g of substituted aniline 1–6 shown in
Table 1, granulated iodine (1 mol. equiv.) and copper(II) acetate
(1 mol. equiv.) were stirred in 50 mL of glacial acetic for 30 min.
The reaction mixture was refluxed for 12 h with constant stirring
at 120 °C. Then the reaction mixture was allowed to cool at room
temperature. The precipitate of copper(I) iodide was removed by
filtration and the filtrate was poured into water and extracted with

M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
369
Table 1
Iodination reactions of substituted primary aryl amines 1–6.
Entry
Aniline
Products
Yield%
a
b
c
a
(b)
c
1
30
(40)
12
2
35
(25)
20
3
4
35
30
(20)
(22)
16
12
5
6
38
25
(20)
(20)
15
30
molecular orbital calculations were conducted with all compounds
using B3LYP/MidiX level of theory for analysing the substitute’s
effect on the HOMO–LUMO gaps.
process experienced a prolong reaction time in compares to our
process. Kraszkiecs and co-workers revealed that iodination of
nitrobenzene by diiodine with various oxidants (activated MnO2,
KMnO4, CrO3, HIO3, NaIO3, or HIO4) dissolved in concentrated sul-
furic acid (90%), but p-nitro aniline 5, containing both a deactivat-
ing nitro group and activating amino group, is susceptible to such
iodination system as amino group is readily oxidized [38]. More-
over, we have to compensate the hazardous effects of concentrated
sulfuric acid. Our present iodination procedure, on the contrary,
does not encounter such difficulties as we employed acetic acid,
a mild solvent, easy to recover (to nearly pure form) from reaction
system under reduced pressure and is particularly not detrimental
in the form of vinegar. In addition, after proper treatment, the
byproduct, CuI can be utilized for different catalytic process [39].
A recent study [40] with 5 demonstrated that Ag2SO4–I2 in 1, 2-
ethandiol is a useful iodinated agent; however, silver salt is not
economical.
4. Results and discussion
All arylamines including 2,6-diiodoaniline (7, 13, 16, 19, 22), 2-
iodoacetanilide (8, 11, 14, 17, 20, 23), and 2-iodoaniline (9, 12, 15,
18, 21, 24) are produced in different yield percent. In most cases,
substituted-2, 6-diiodoanilines were obtained as a major product.
2, 4-diiodo-5-methylacetanilide and 2, 4, 6-triiodo-5-methylani-
line were obtained in trace amount from the iodination reaction
of m-toluidine 3. In case of m-chloroaniline 4, 2, 4-diiodoaniline
was obtained about 30%.
Shen et al. [37] studied iodination of m-chloro aniline 4 with the
aid of NIS (N-Iodosuccinimide) in acetic acid, unfortunately their

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M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
NH2
NH2
NH H
COC
NH2
3
I
I
I
I
u
( H
C
)
2
C
3COO C
H
H
3COO
+
+
120 oC 12
I2
h
,
,
X
X
X
X
-
1 6
7 10 13 16 19 22 8 11 14 17 20 23
,
,
,
,
,
,
,
,
,
,
9 12 15 18 21 24
,
,
,
,
,
= m-
= m-
=
-
N
O2
p
3 13 14 15 X
H
5 19 20 21 X
C
=
-
H
C
1 7 8 9 X
,
,
,
,
,
,
,
,
,
, ,
,
p
3
3
= -
p
2 10 11 12 X
4 16 17 18 X
, , , ,
Cl
Cl
= m-
6 22 23 24 X H
O
,
,
,
,
,
,
,
,
Scheme 1.
7
1
9
8
Fig. 1. Optimized structures of the compound 1, 7, 8, and 9 generated at B3LYP/MidiX level of theory.
4.1. Equilibrium geometries
compound 7 are 2.132 Å compared to C6–H and C4–H bond dis-
tances (1.090 Å) in compound 1 (see Fig. 1 for atom numbering).
Similar trend is observed for C6–I (2.130 Å) and C4–I (2.134 Å)
bond lengths in compound 8 and 9, respectively. The bond distance
of C4–C5 and C5–C6 are slightly increased in compound 7, 8 and 9
than compound 1. The I–C6–C5 bond angle in compound 7 and 8 is
120.1° and 120.6°, respectively whereas I–C4–C3 bond angle in
The bond distances (Å), bond angle (°) and dihedral angle (°) of
compounds 1, 7, 8, 9; and 2, 10, 11, 12 are presented in the supple-
mentary Tables S2–S9. Significant changes of bond distance are ap-
peared for iodination sites of the products compared to the
reactants. For instance, both C6–I and C4–I bond distances in the

M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
371
compound 9 is 118.7°. Large elongation of C5–I (2.128 Å) and C3–I
(2.128 Å) bonds in compound 10, I–C9 (2.126 Å) bond in com-
pound 11, and C3–I (2.127 Å) bond in compound 12 is observed
while iodination is performed in compound 2. The C1–Cl bond dis-
tance is nearly unchanged for the iodinated products.
The electrostatic potential of the iodinated products disclosed
that I in C–I bond is partially positive and making the carbon
slightly negative presented in Fig. 2. The positive hole (r-hole) in
the position of iodine also indicates that these compounds are
capable of forming halogen bonding [15]. The characteristic of C–
I bond is also confirmed by Mulliken charge calculation. For com-
pound 7, partial positive charge (0.113) is observed in iodine
whereas partial negative charge (À0.239) is appeared in carbon
shown in Fig. 3. Similar charge profile is also found in other iodin-
ated products.
the calculated frequencies (3451 and 3367 cmÀ1) without applying
any scaling factor. However, the calculated asymmetrical and sym-
metrical stretching frequencies with scaling of compound 7 are
quite lower compared to the experimental values. The experimen-
tal C–H (3037 cmÀ1) stretching frequencies are consistent with the
scaled computed frequencies (3099 cmÀ1). For compound 8, the
experimental N–H (asymmetrical and symmetrical) stretching
frequencies are significantly lower than the unscaled calculated
frequencies; however, they are agreed reasonably well with the
scaled computed frequencies. The scaled C–N stretching
(1291 cmÀ1) is also well matched with the experimental value
(1290 cmÀ1); nonetheless, the unscaled frequency (1332 cmÀ1) is
somewhat higher than the both frequencies.
A comparison of experimental and computed IR frequencies for
compound 10, 11 and 12 are shown in the supplementary
Table S10. The experimental asymmetrical and symmetrical N–H
stretching for compound 10 are 3408 and 3317 cmÀ1, respectively
similar to the unscaled computed frequencies (3463 and
3376 cmÀ1). For N–H stretching, nearly same feature is observed
for the compound 12. However, in case of compound 11, experi-
mental N–H stretching is close to the scaled computed frequencies.
The experimental C–H (sp2) stretching of 10 and 11 is remarkably
lower to both of the computed frequencies; however, it is very
close to the scaled frequencies in case of 12.
4.2. Vibrational frequencies
Experimental and computed vibrational frequencies (without
and with scaling) of the compounds 7 and 8 are presented in
Table 2. A scaling factor (0.9688) is applied to the for B3LYP vibra-
tional frequencies [41,42]. The experimental asymmetrical and
symmetrical N–H stretching of 7 is appeared in the region of
3406 and 3317 cmÀ1, respectively in very close agreement with
Fig. 2. Electrostatic potential surfaces of iodinated products 7, 9 and 11. Yellow circle in the blue region represent the partial positive electrostatic potential for iodine atom.
Molecular surfaces were plotted at an electron density of 0.003 eÀ/bohr 3 with electrostatic potentials from red (À0.06445 hartree) to blue (0.06579 hartree). (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
7
11
Fig. 3. Partial atomic charge (Mulliken) on compound 7 and 11 where red represent negative and blue represent positive charge. (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)

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M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
Table 2
Selected experimental and calculated (without and with scaling) vibrational frequencies (cmÀ1) of compound 7 and 8.
Experimental
Calculated without Scaling (intensity)
Calculated with scalinga
Assignmentb
Compound 7
3406
3317
3037
2898
3451(40.2817)
3367(11.4285)
3199(4.464)
3009(36.9285)
1661(85.8755)
1577(11.3629)
3343
3262
3099
2915
1609
1527
m
m
m
m
asym(NH2)
sym(NH2)
(sp2 CH)
sym(sp3 CH)
1566
1608, 1460
x(NH2)
m
ring + h(sp3 CH)
Compound 8
3265
3021
1655
1524
1290
1037
822
681
3410(35.1665)
3175(10.2054)
1777(379.892)
1546(149.982)
1332(361.296)
1264(51.8434)
872(28.8633)
518(34.3266)
3303
3076
1721
1496
1291
1225
844
m
m
m
asym(NH2)
sym(NH2)
(CO)
d(NH)
(CN)
d(CH)
m
p
p
(CH)
(NH)
502
a
Scaling factor of B3LYP is 0.9688.
b
m
stretching, d in-plane bending, p out-plane bending, x scissoring, h wagging.
Nevertheless, the change of thermodynamic energies of the reac-
tion with entry 6 is approximately 3–5 kcal/mol lower than the
reaction with entry 4 and 5. Overall, all iodination reactions found
to be endothermic.
Table 3
Thermodynamic properties (change of energy, enthalpy, and Gibbs free energy in
kcal/mol) of all iodination reactions.
Entry?
1
2
3
4
5
6
D
D
D
E
H
G
47.45
35.59
39.76
46.89
37.02
38.52
48.02
37.23
38.21
54.07
41.92
45.40
55.76
43.84
45.67
50.83
36.64
40.14
4.4. Frontier molecular orbitals
Molecular orbitals calculation is performed with the optimized
structure of all compounds using B3LYP/MidiX level of theory. The
energy profile of HOMO, LUMO and HOMO–LUMO gap of all com-
pound 1–24 are presented in Table 4. The pictorial view of the
HOMO and LUMO orbitals are depicted in Fig. 4. The HOMO and
LUMO energy of the entry 1 are 0.31 and À5.30 eV, respectively
with a HOMO–LUMO gap of 5.61 eV. In comparison with entry 1,
the two electron-withdrawing halide groups in product 7 signifi-
cantly decreased the LUMO energy to À1.17 eV whereas the HOMO
energy is slightly decreased to À5.41 eV. The overall gap of 7 is
4.24 eV which is 1.37 eV lower than the entry 1. One halide substi-
tuent in the product 9 has less effect on lowering the gap (4.81 eV)
compare to the two halide substitutes in 7. Moreover, incorporat-
ing –NHCOCH3 group and one electron withdrawing group in 8
slightly reduced the gap to 5.04 eV.
4.3. Thermodynamic properties of the reactions
Employing B3LYP/MidiX level of theory, the thermodynamic
properties of all reactions were calculated and the results are sum-
marized in Table 3. The reaction of entry 1 with iodine and acetic
acid produces three products (7, 8, and 9) along with hydrogen io-
dide and water. The change of electronic energy, enthalpy and
Gibbs free energy of this reaction is 47.45, 35.59 and 39.76 kcal/
mol. Nearly similar trends are observed with the reaction of entry
2 and 3 which yield the products (10, 11, and 12) and (13, 14, and
15), respectively. However, a moderate change of energy, enthalpy,
and free energy is observed for entry 4 and 5 compare to the other
reactions. The change of energy, enthalpy, and free energy of the
reaction with entry 4 and 5 is 7.18–7.74, 6.33–8.25, and 5.63–
7.46 kcal/mol higher than the reactions with entry 1, 2 and 3.
The frontier molecular orbitals of compound of 2 and 11 are
demonstrated in supplementary Fig. S1. Comparison with the
product 10, 11, and 12, the lowest HOMO–LUMO gap (4.28 eV) is
Table 4
Energies (eV) of HOMO and LUMO orbitals, HOMO–LUMO gaps are calculated at B3LYP/MidiX level of theory for all compounds 1–24.
Entry
Product
Entry
Product
Entry
Product
MO
1
7
8
9
2
10
11
12
3
13
14
15
LUMO+2
LUMO+1
LUMO
HOMO
HOMOÀ1
HOMOÀ2
GAP
2.20
0.65
0.31
À5.30
À6.65
À7.98
5.61
À0.33
À0.62
À1.17
À5.41
À6.30
À7.09
4.24
À0.39
À0.60
À1.00
À6.04
À6.66
À6.75
5.04
0.36
1.36
0.46
À0.73
À0.86
À1.71
À5.99
À6.74
À7.41
4.28
À0.90
À1.01
À1.39
À6.34
À6.97
À7.11
4.95
À0.14
À0.56
À1.09
À5.87
À6.81
À7.35
4.77
2.19
0.72
0.29
À5.40
À6.45
À8.08
5.69
À0.37
À0.40
À1.29
À5.74
À6.34
À7.11
4.45
À0.41
À0.58
À0.98
À6.09
À6.64
À6.72
5.11
0.40
À0.09
À0.70
À5.51
À6.42
À7.03
4.81
À0.10
À0.68
À5.60
À6.33
À7.02
4.92
À0.05
À5.35
À7.07
À7.84
5.30
MO
4
16
17
18
5
19
20
21
6
22
23
24
LUMO+2
LUMO+1
LUMO
HOMO
HOMOÀ1
HOMOÀ2
GAP
1.27
0.15
À0.75
À0.81
À1.58
À6.04
À6.59
À7.21
4.46
À0.89
À1.00
À1.31
À6.41
À6.96
À7.04
5.10
À0.12
À0.56
À1.01
À5.99
À6.71
À7.34
4.98
1.00
À0.94
À1.77
À1.80
À6.21
À6.88
À7.48
4.41
À1.24
À1.37
À2.47
À6.77
À7.06
À7.13
4.30
À0.63
À1.17
À1.61
À6.07
À6.98
À7.28
4.46
1.95
0.83
0.45
À5.38
À5.96
À7.88
5.83
À0.20
À0.28
À1.18
À5.69
À6.01
À6.97
4.50
À0.23
À0.53
À0.98
À5.96
À6.47
À6.72
4.98
0.60
0.10
À0.27
À1.37
À5.90
À7.05
À7.30
4.52
À0.21
À5.85
À6.83
À8.30
5.65
À0.44
À5.43
À6.03
À7.02
4.99

M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
373
Fig. 4. Frontier molecular orbitals (HOMO, HOMOÀ1, HOMOÀ2, LUMO, LUMO+1 and LUMO+2) of compound 1 and 8.
observed for 10 and the highest gap (4.95 eV) is calculated for 11.
Moreover, similar trends are observed for the products generated
from entry 3 and 4. The presence of NO2 group in entry 5 and its
products 19, 20, and 21 does not result any significant change in
HOMO and LUMO energies. Nevertheless, remarkable change is no-
ticed for the entry 6 and its related products. For example, the
LUMO and HOMO energies of the entry 6 are 0.45 and À5.38 eV,
respectively with a gap of 5.83 eV. Installing two iodide groups in
product 22 remarkably decreases the gap to 4.50 eV. The HOMO–
LUMO gap of one iodide based product 23 and 24 is also lowered
to 4.98 and 4.99 eV, respectively. Overall, the small HOMO–LUMO
gap indicates high chemical reactivity of products 7, 10, 13, 16 and
22 where two iodine groups are incorporated.
copper(I) iodide. The computational analysis revealed some inter-
esting features of these of compounds. The elongated C–I bond is
observed for all synthesized compounds indicates that these
compounds can be used as a starting reagents for medicinal and
supramolecular applications. Electrostatic and Mulliken charge
calculations confirmed that these iodinated compounds can easily
form halogen bond. Our preliminary quantum chemical calculation
also confirmed that there is a possibility of forming halogen bond-
ing (IÁ Á ÁN) between C–I of compound 8 and –NH2 of compound 7
(Fig. 5). The IÁ Á ÁN distance is 3.038 (Å) and the C–IÁ Á ÁN angle is
175.8° agreed with the distance and angle usually observed for hal-
ogen bonds. The calculated halogen bonding energy between 8 and
7 is À5.31 kcal/mol. This weak noncovalent interaction between
the products might have implication on reducing the single
product yield. Details computational calculations related to the
binding energy between different halogenated products are now
underway. The thermodynamic study also unveiled the endother-
mic nature of these reactions. In future, enhancing the synthetic
utility, this method will be applied to other aryl and hetero aryl
systems.
5. Conclusion
This study presents a facile and efficient one-pot iodination of
aryl amines synthesizing substituted 2-iodoacetanilides and
2-iodoanilineswith moderate to good yield. Easily recoverable mild
acetic acid is being used instead of concentrated sulfuric acid.
Another advantage of this procedure is the recycle of byproduct,
Acknowledgements
We gratefully acknowledge the financial assistance of Ministry
of National Science Information and Communication Technology
(NSICT) Bangladesh. We are thankful to Dr. Kazuaki Shimada,
Professor, Department of Chemical Engineering, Iwate University,
Japan, and BCSIR, Dhaka for taking NMR spectra. For allocating
computational resource and time, we are also thankful to Professor
Raymond Poirier, Department of Chemistry, Memorial University,
Canada, and the Atlantic Computational Excellence Network (ACE-
net) funded by the Canada Foundation for Innovation (CFI), the
Atlantic Canada Opportunities Agency (ACOA), and the provinces
of Newfoundland & Labrador, Nova Scotia, and New Brunswick.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.10.
011.
Fig. 5. Halogen bonding between compound 8 and 7 with a binding energy of
À5.31 kcal/mol.

374
M.M. Hoque et al. / Journal of Molecular Structure 1054–1055 (2013) 367–374
[25] Y.B. Kiran, T. Konakahara, N. Shakai, Synthesis (2008) 2327.
References
[26] B. Das, M. Krishnaiah, K. Venkateswarlu, V.S. Reddy, Tetrahedron Lett. 48
(2007) 81.
[27] A.R. Pourali, M. Ghanei, Chin. J. Chem. 24 (2006) 1077.
[28] S.B. Junne, A.Y. Vibhute, Y.B. Vibhute, V.M. Gurav, Int. J. Chem. Tech. Res. 1
(2009) 1005.
[29] S.V. Bhilare, A.R. Deorukhkar, N.B. Darvatkar, M.M. Salunkhe, Synth. Commun.
38 (2008) 2881.
[30] S. Nils, W.D. Joanna, G. Frank, J. Am. Chem. Soc. 134 (2012) 8298.
[31] W.M. Hannah, A.U. Olbelina, P.K. Daniel, D.I. Christopher, C.B. Shawn, Org.
Biomol. Chem. 9 (2011) 2987.
[32] C.W. Baird, J.H. Surridge, J. Org. Chem. 35 (1970) 3436.
[33] T. Sugita, M. Iddei, Y. Ishibashi, Y. Takegami, Chem. Lett. 9 (1982) 1481.
[34] Gaussian 09, Revision A.1, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria,
M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G.
Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A.
Montgomery, Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers,
K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A.
Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M.
Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E.
Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L.
Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg,
S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, and
D.J. Fox, Gaussian Inc., Wallingford CT, 2009.
[1] F. Diederich, P.J. Stang, Metal-Catalysed Cross-Coupling Reactions, Wiley-VCH,
New York, 1998.
[2] N. Kambe, T. Iwasaki, J. Terao, Chem. Soc. Rev. 40 (2011) 4937.
[3] S. Stavber, M. Jereb, M. Zupan, Synthesis (2008) 1487.
[4] J.R. Hanson, J. Chem. Res. (2006) 277.
[5] L.S. Hegedus, Angew. Chem. Int. Ed. Engl. 27 (1988) 1113.
[6] G.W. kabalka, L. Wang, R.M. Pagni, Tetrahedron 57 (2001) 8017.
[7] M.W. Khan, A.F.G. Masud R, Tetrahedron 61 (2005) 11204.
[8] V. Kavala, C.C. Wang, D.K. Barange, C.W. Kuo, P.M. Lei, C.F. Yao, J. Org. Chem. 77
(2012) 5022.
[9] G. Bencivenni, T. Lanza, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo, G.
Zanardi, J. Org. Chem. 73 (2008) 4721.
[10] A.A. Cant, B. Rajiv, S.L. Pimlott, A. Sutherland, Chem. Commun. 48 (2012) 3993.
[11] J.H. Chang, H.U. Kang, I.H. Jung, C.G. Cho, Org. Lett. 12 (2010) 2016.
[12] P. Buchgraber, T.N. Snaddon, C. Wirtz, R. Mynott, R. Goddard, A. Fürstner,
Angew. Chem. Int. Ed. 47 (2008) 8450.
[13] T.M. Beale, M.G. Chudzinski, M.G. Sarwar, M.S. Taylor, Chem. Soc. Rev. 42
(2013) 1667.
[14] R. Wilcken, M.O. Zimmermann, A. Lange, A.C. Joerger, F.M. Boeckler, J. Med.
Chem. 56 (2013) 1363.
[15] M.G. Sarwar, B. Dragisic, L.J. Salsberg, C. Gouliaras, M.S. Taylor, J. Am. Chem.
Soc. 132 (2010) 1646.
[16] M.R. Scholfield, C.M. Vander Zanden, M. Carter, P.S. Ho, Protein Sci. 22 (2013)
139.
[17] P. Metrangolo, G. Resnati, Science 321 (2008) 918.
[18] A. Roeding, in: Houben-Weyl, Methoden der organischen Chemie, Thieme:
Stuttgart 4 (1960) 517.
[19] J. March, Advanced Organic Chemistry, fourth ed., Reactions, Mechanisms and
Structure, Wiley, New York, 1992. pp. 501–507.
[20] J. March, Advanced Organic Chemistry, fourth ed., Reactions, Mechanisms and
Structure, Wiley, New York, 1992. pp. 533–534.
[21] E.B. Murkushev, Synthesis (1988) 923.
[22] A. Podgoršek, M. Zupan, J. Iskra, Angew. Chem. Int. Ed. 48 (2009) 8424.
[23] H. Firouzabadi, N. Iranpoor, M. Shiri, Tetrahedron Lett. 44 (2003) 8781.
[35] R.E. Easton, D.J. Giesen, A. Welch, C.J. Cramer, D.G. Truhlar, Theor. Chem. Acta
93 (1996) 281.
[36] J. Li, C.J. Cramer, D.G. TruhlarTheor, Chem. Acta 99 (1998) 192.
[37] H. Shen, K.P.C. Vollhard, Synlett (2012) 208.
[38] L. Kraszkiewicz, M. Sosnowski, L. Skulski, Tetrahedron 60 (2004) 9113.
[39] J. Zhao, Q. Zhang, L. Liu, Y. He, J. Li, J. Li, Q. Zhu, Org. Lett. 14 (2012) 5362.
[40] S.N. Joshi, S.M. Vyas, W. Huimin, M.W. Duffel, P. Sean, H.J. Lehmler,
Tetrahedron 67 (2011) 7461.
[41] J.P. Merrick, D. Moran, L. Radom, J. Phys. Chem. A 111 (2007) 11683.
[42] M.A. Halim, D.M. Shaw, R.A. Poirier, J. Mol. Struct. (Theochem) 960 (2010) 63.
9
[24] J.A. González Gomez, J. Green, K.P.C. Vollhardt, Synlett (2011) 805.