Spectroscopic, DFT, and XRD studies of hydrogen bonds in N-unsubstituted 2-aminobenzamides

Article abstract of DOI:10.3390/molecules22010083

The structures of the mono- and the dihalogenated N-unsubstituted 2-aminobenzamides were characterized by means of the spectroscopic (1H-NMR, UV-Vis, FT-IR, and FT-Raman) and X-ray crystallographic techniques complemented with a density functional theory (DFT) method. The hindered rotation of the C(O)-NH₂ single bond resulted in non-equivalence of the amide protons and therefore two distinct resonances of different chemical shift values in the ¹H-NMR spectra of these compounds were observed. 2-Amino-5-bromobenzamide (ABB) as a model confirmed the presence of strong intramolecular hydrogen bonds between oxygen and the amine hydrogen. However, intramolecular hydrogen bonding between the carbonyl oxygen and the amine protons was not observed in the solution phase due to a rapid exchange of these two protons with the solvent and fast rotation of the Ar-NH₂ single bond. XRD also revealed the ability of the amide unit of these compounds to function as a hydrogen bond donor and acceptor simultaneously to form strong intermolecular hydrogen bonding between oxygen of one molecule and the NH moiety of the amine or amide group of the other molecule and between the amine nitrogen and the amide hydrogen of different molecules. DFT calculations using the B3LYP/6-311++G(d,p) basis set revealed that the conformer (A) with oxygen and 2-amine on the same side predominates possibly due to the formation of a six-membered intramolecular ring, which is assisted by hydrogen bonding as observed in the single crystal XRD structure.

Full text of DOI:10.3390/molecules22010083

molecules
Article
Spectroscopic, DFT, and XRD Studies of Hydrogen
Bonds in N-Unsubstituted 2-Aminobenzamides
1
,
1
2
1
Malose Jack Mphahlele *, Marole Maria Maluleka , Lydia Rhyman , Ponnadurai Ramasami
and Richard Mokome Mampa 3
1
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa,
Private Bag X06, Florida 1710, South Africa; malulmm@unisa.ac.za (M.M.M.); p.ramasami@uom.ac.mu (P.R.)
Computational Chemistry Group, Department of Chemistry, Faculty of Science, University of Mauritius,
Reduit 80837, Mauritius; lyd.rhyman@gmail.com
Department of Chemistry, University of Limpopo, Private Bag X1106, Sovenga 0727, South Africa;
Richard.Mampa@ul.ac.za
2
3
*
Correspondence: mphahmj@unisa.ac.za; Tel.: +27-11-670-9301
Academic Editor: Steve Scheiner
Received: 18 November 2016; Accepted: 27 December 2016; Published: 4 January 2017
Abstract: The structures of the mono- and the dihalogenated N-unsubstituted 2-aminobenzamides
1
were characterized by means of the spectroscopic ( H-NMR, UV-Vis, FT-IR, and FT-Raman) and
X-ray crystallographic techniques complemented with a density functional theory (DFT) method.
The hindered rotation of the C(O)–NH single bond resulted in non-equivalence of the amide protons
2
1
and therefore two distinct resonances of different chemical shift values in the H-NMR spectra
of these compounds were observed. 2-Amino-5-bromobenzamide (ABB) as a model confirmed
the presence of strong intramolecular hydrogen bonds between oxygen and the amine hydrogen.
However, intramolecular hydrogen bonding between the carbonyl oxygen and the amine protons
was not observed in the solution phase due to a rapid exchange of these two protons with the solvent
and fast rotation of the Ar–NH single bond. XRD also revealed the ability of the amide unit of
2
these compounds to function as a hydrogen bond donor and acceptor simultaneously to form strong
intermolecular hydrogen bonding between oxygen of one molecule and the NH moiety of the amine
or amide group of the other molecule and between the amine nitrogen and the amide hydrogen of
different molecules. DFT calculations using the B3LYP/6-311++G(d,p) basis set revealed that the
conformer (A) with oxygen and 2-amine on the same side predominates possibly due to the formation
of a six-membered intramolecular ring, which is assisted by hydrogen bonding as observed in the
single crystal XRD structure.
1
Keywords: halogenated 2-aminobenzamides; H-NMR spectra; vibrational spectra; DFT; XRD
1
. Introduction
The amide moiety is abundant in biologically-relevant molecules and its propensity for hydrogen
bonding plays an important role in the spatial structure of proteins, nucleic acids and biological
membranes as well as in the interaction of bioactive compounds with receptors [ ]. From a structural
1,2
point of view, hydrogen bond formation causes changes in the distances between atoms and the
rearrangement of electron densities on the groups involved in the interaction and therefore chemical
reactivity (nucleophilicity or electrophilicity) especially if the reaction centres are directly involved
in the hydrogen bonding [
hydrogen bonded amide groups are often employed to study these interactions in solution and in
the solid state [ ]. Aminobenzamides, for example, are commonly used as hydrogen-bond donors to
form intramolecular hydrogen bonds with other O- or N-groups as hydrogen-bond acceptors [5,6]
1,3]. Small model systems with intramolecular and/or intermolecular
4
.
Molecules 2017, 22, 83; doi:10.3390/molecules22010083
www.mdpi.com/journal/molecules

Molecules 2017, 22, 83
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The amides also work as dual hydrogen-bond donors and acceptors to form intramolecular hydrogen
bonds between the adjacent amide-amide groups to construct linear sheets and helical conformations [ ].
7–9
The nature of the hydrogen-bonding network in the reagent, on the other hand, has been found to
dictate not only what chemical intermediates will form, but also which polymorph of the product
will be nucleated. 2-Acetamidobenzamide, for example, was found to undergo a series of thermal
solid-state rearrangements in which a polymorphic transformation and cyclodehydration occur to give
anhydrous 2-methylquinazolin-4-one [10].
2
-Aminobenzamide (anthranilamide) and its derivatives are efficient direct Factor Xa (FXa)
inhibitors, which plays a significant role in the blood coagulation cascade and catalyzes the conversion
of prothrombin to thrombine [11 12]. These compounds are extensively used as fluorescence labels for
,
the visualization of oligosaccharides after the cleavage from glycoprotein [13]. Oligomers derived from
anthranilamide, on the other hand, exhibit intrinsic dipole moments which make them suitable
candidates to serve as bioinspired molecular electrostatic analogues of magnets also known as
electrets [14]. A series of novel bioactive mixed ligand Cu(II) complexes [15] and Ni(II) complexes [16
]
have been prepared before from 2-aminobenzamide and some amino acids and then evaluated for
biological properties. 2-Aminobenzamide and its derivatives are envisaged to exist in four tautomeric
forms and two closed pharmacophore sites through the formation of six-membered intramolecular
rings assisted by hydrogen bonding, which are considered to be responsible for decreasing both
δ− δ+
δ+ δ−
antibacterial (C=O
–
HN) and antifungal activity (C-OH
– N=C) [17]. 2-Aminobenzamide,
on the other hand, is considered to lack intramolecular hydrogen bonds and this is attributed to a
rapid exchange of the two protons of amine hydrogens with the solvent [18]. However, intramolecular
hydrogen bonding has been observed for the corresponding N-aryl substituted anthranilamides in
solution and in the solid state [18]. Based on this observation, the authors then concluded that a
substituent on the nitrogen atom of the arylamine moiety plays an important role in promoting the
formation of intramolecular hydrogen bonds for these compounds.
Despite the enormous pharmacological [11
N-unsubstituted 2-aminobenzamides, to our knowledge, the presence of intramolecular hydrogen
bonding in these compounds has been less demonstrated in the literature [25 28]. This prompted us to
–13,15–17] and chemical [19–24] interest in the
–
study the structural properties of the known 5-bromo/iodo- and 3,5-dihalogenated 2-aminobezamides
by means of spectroscopic (NMR, UV-Vis, IR, Raman) methods and single X-ray crystallography in
combination with density functional theory methods.
2
. Results and Discussion
2
.1. Synthesis
2
-Amino-5-bromobenzamide (ABB) [19], 2-amino-5-iodobenzamide (AIB) [20], 2-amino-3,5-
dibromobenzamide (ABBB) [21 23], and 2-amino-5-bromo-3-iodobenzamide (ABIB) [24] were
previously prepared from the commercially available 2-aminobenzamide (AB) as depicted in Scheme 1.
–
Scheme 1. Halogenation of 2-aminobenzamide (AB). Reagents & conditions: (i) NBS, CH CN, RT, 0.5 h
3
(X = Br) or NIS, AcOH, RT, 1 h (X = I); (ii) NIS, AcOH, RT, 1 h; (iii) NBS (2 equiv.), AcOH, RT, 2 h.

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The structure of the four compounds under investigation (ABB
,
AIB
,
ABBB, and ABIB) was
1
evaluated in solution by means of H-NMR and UV-Vis spectroscopy and in the solid state using
vibrational (IR and Raman) spectroscopic methods. The structures were simulated in the gas and
solution phases using the B3LYP/6-311++G(d,p) basis set or the LanL2DZ ECP basis set in the case of
the iodine-containing derivatives. Single crystal X-ray diffraction (XRD), on the other hand, revealed
the presence of intramolecular and intermolecular hydrogen bonding.
1
2
.2. Solution Phase Studies Using H-NMR and UV-Vis Spectroscopy
1
The H-NMR spectra of the 2-amino-5-bromobenzamide ABB, 2-amino-5-iodobenzamide AIB
,
2-amino-3,5-dibromobenzamide ABBB and 2-amino-5-bromo-3-iodobenzamide ABIB acquired in
DMSO-d at 500 MHz are consistent with the expected structures (refer to Supplementary material, S1,
6
for full spectra). The spectra reveal the presence of the expected set of multiplets corresponding to
the aromatic protons and three broad singlets in the aromatic region ( H
singlet around 6.70 ppm in the spectra of ABB AIB, and ABIB, which is broader and less intense in
the case of ABBB integrate for two protons. The other two singlets of equal intensity each integrating
for a single proton resonate around 7.15 and 7.81 ppm for ABB and AIB and these singlets resonate
relatively down field at about 7.35 ppm and 8.00 ppm for the dihalogenated 2-aminobenzamides
δ 6.50–7.80 ppm). An intense
δ
,
δ
δ
δ
δ
ABBB and ABIB, respectively. Gorobets et al. previously observed a similar set of non-equivalent
1
proton signals in the H-NMR spectra of a series of N-aryl substituted benzamides in DMSO-d and
6
assigned them to the amide protons [3]. These authors attributed the non-equivalence of these protons
to be the consequence of the hindered rotation of the C(O)–NH single bond [
3]. The amide protons of
2
benzamide in DMSO-d solution, on the other hand, have also been found to be non-equivalent and
6
to resonate as the two well-resolved singlets of different chemical shifts [19]. In order to distinguish
between the hydrogens bonded to the amine and amide nitrogen atoms and to assign the three broad
singlets accordingly, we performed a 2D NOESY experiment on compound ABB (Figure 1). The 2D
NOESY experiment revealed that the set of non-equivalent broad singlets of reduced intensity interact
strongly (green circles) with a doublet (
e) at
δ
7.69 ppm for 6-H, whereas the intense broad singlet (
b)
around 6.70 ppm interacts strongly with a doublet (
δ
c
) at 6.65 ppm for 3-H. Based on the 2D NOESY
δ
experiment which provides 3D spatial hydrogen interaction, we assigned the set of non-equivalent
signals to the amide nitrogen. Their non-equivalence is attributed to some hindered rotation of the
C(O)–NH single bond in terms of NMR time scale in analogy with the literature precedents for the
2
N-aryl substituted benzamides [
as a singlet around 6.70 ppm due to a fast Ar–NH single bond rotation. The difference in line widths
and intensities of this signal for the four compounds is presumably due to H/D exchange with the
3] and benzamide [19]. The amine protons, on the other hand, resonate
δ
2
solvent molecule. We can thus conclude that a fast rotation around the Ar–NH single bond and a
2
rapid exchange of the two hydrogens with the solvent account for the lack of intramolecular hydrogen
bonding between oxygen and amine hydrogens in solution in analogy with the literature observation
for the 2-aminobenzamide [18].
The 2D NOESY experiment in our view further suggests the preponderance in solution of the
conformer (see structure insert in Figure 1) with H-6 and the amide nitrogen in alignment to result
in the observed strong interaction between H-6 and amide protons. Next, we performed geometry
optimization of the two possible conformers (
A and B) of 2-amino-5-bromobenzamide ABB in the gas
phase and also in solution (DMSO) by means of density functional theory methods as described below.

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c
e
d
b
a
2
a
1
a
H
H
N
e
c
Br
O
H
b
d
N
H
Figure 1. The 2D NOESY spectrum of ABB in DMSO-d at 400 MHz.
6
2
.3. DFT Studies
The density functional theory (DFT) computations were carried out using the B3LYP exchange-
correlation functional [29 30], together with the 6-311++G(d,p) [31] basis set for all atoms except for
iodine in which case the LanL2DZ ECP basis set was used [32 34]. All computations were performed
using the Gaussian 09 software suite [35] running on Gridchem [36 37]. The geometrical optimizations
were performed in the gas phase as well as in dimethyl sulfoxide (DMSO). The solvent effect was
taken into consideration based on the Polarizable Continuum Model (PCM) [38 39]. The tight criteria
,
–
,
,
was used for the optimization and the frequency calculation was carried out to confirm the nature
of the stationary points. In addition, the optimized structures in DMSO were used for computing
chemical shifts with the Gauge-Including Atomic Orbital (GIAO) method [40] using shieldings of TMS
computed at the same theoretical level and basis set. The TD-DFT [41
using the optimized structure in DMSO to obtain the electronic spectra. The DFT calculations using
the B3LYP/6-311++G(d,p) basis set revealed that conformer ( ) with oxygen and amine group in
alignment is more stable than conformer ( ) with amine and amide nitrogen aligned together by
5.8 kJ/mol and 9.4 kJ/mol in the gas phase and DMSO, respectively (Figure 2; Table 1). The free
–43] computation was conducted
A
B
1
energy data and calculated equilibrium constant indicate that the percentage of conformer (
A), which
is implicated in Figure 1, is above 99%.

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Table 1. Electronic energy of the conformers of the four studied compounds and their energy difference in the gas phase and in DMSO.
Gas Phase
DMSO
B3LYP
Electronic Energy (Hartree)
Electronic Energy (Hartree)
∆
E (kJ/mol)
∆E (kJ/mol)
Conformer (A)
Conformer (B)
Conformer (A)
Conformer (B)
ABB
AIB
ABBB
ABIB
−3030.994480
−467.228178
−5603.535596
−3040.768917
−3029.988460
−467.222193
−5603.529423
−3040.762660
15.81
15.72
16.21
16.43
−3030.006409
−467.240222
−5603.546023
−3040.779561
−3030.002821
−467.236665
−5603.541927
−3040.775398
9.42
9.34
10.75
10.93
Gibb Free Energy (Hartree)
∆G (kJ/mol)
Gibb Free Energy (Hartree)
∆G (kJ/mol)
ABB
AIB
ABBB
ABIB
−3029.897495
−467.132463
−5603.451831
−3040.686568
−3029.891223
16.47
16.50
16.96
17.61
−3029.909949
−467.144972
−5603.462814
−3040.697530
−3029.906365
9.41
9.51
10.71
10.38
−467.126178
−5603.445371
−3040.679861
−467.141348
−5603.458735
−3040.693577
B3LYP-D3
Electronic Energy (Hartree)
Electronic Energy (Hartree)
∆
E (kJ/mol)
∆E (kJ/mol)
Conformer (A)
Conformer (B)
Conformer (A)
Conformer (B)
ABB
AIB
ABBB
ABIB
−3030.010097
−467.244209
−5603.554266
−3040.788022
−3030.004505
−467.238646
−5603.548575
−3040.782271
14.68
14.61
14.94
15.10
−3030.022089
−467.256320
−5603.564784
−3040.798761
−3030.018918
−467.253167
−5603.561176
−3040.795110
8.32
8.28
9.47
9.58
Gibb Free Energy (Hartree)
∆G (kJ/mol)
Gibb Free Energy (Hartree)
∆G (kJ/mol)
ABB
AIB
ABBB
ABIB
−3029.912976
−467.148366
−5603.470457
−3040.705570
−3029.907178
−467.142508
−5603.464475
−3040.699515
15.22
15.38
15.71
15.90
−3029.925554
−467.160869
−5603.481694
−3040.716715
−3029.922248
−467.157580
−5603.477920
−3040.713097
8.68
8.64
9.91
9.50

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(
A)
(B)
Figure 2. Geometry optimized conformers (A) and (B) of ABB in the solution phase.
1
The computed GIAO H-NMR chemical shifts are collected in Table 2 (refer to Supplementary
material, S2, for computed NMR data). The peculiar down-field shift of one of the hydrogen of the
–
NH group in conformer (A) is presumably the consequence of its involvement in the formation
2
of six-membered intramolecular ring assisted by hydrogen bonding. Since protons attached to
nitrogen are solvent and environment dependent, it is not easy to compare the theoretical values
with the experimental ones. The computed chemical shift values are nevertheless in agreement with
assignments of the experimental NMR spectra.
1
Table 2. The computed GIAO H-NMR chemical shifts of conformers (
A
) and (
B) for ABB, numbering
as per Figure 2.
ABB
Conformer (A)
Conformer (B)
H7
H8
H9
H14
H15
H17
H18
7.02
7.46
7.73
5.17
5.76
4.30
7.45
7.11
7.51
8.05
5.49
6.30
4.06
4.18
2
.4. UV-VIS Spectroscopic Studies
The absorption spectra of the 2-aminobenzamides ABB
acquired in DMSO at room temperature and are characterized by two discernible absorption bands,
one around = 258 nm and the other around = 355 nm. The simulated absorption spectra of
, AIB, ABBB and ABIB (Figure 3) were
λ
λ
the 2-aminobenzamides in DMSO are illustrated in Figure 4 based on the TD-DFT computations.
The difference between the calculated and the experimental spectra is due to the high polarity of
DMSO which results in solvent-solute specific interactions. There is, however, a close similarity
between the experimental and the simulated spectra for these compounds.
A detailed analysis of the electronic transition of the 2-aminobenzamides in terms of frontier
orbital energies, wavelength and oscillator strength was done by employing the TD-DFT/B3LYP
calculations in both the gas phase and in DMSO solution (using IEF-PCM model) and the corresponding
values are collected in Table 3 The electronic transition occurred between the frontier molecular orbitals
from HOMO (highest occupied molecular orbitals) to LUMO (lowest unoccupied molecular orbitals)
and the energy gap is about 4.60 eV. The HOMO and LUMO surfaces of the most stable conformer (
A)
of ABB are illustrated in Figure 5. The HOMO-LUMO energy gaps of these compounds demonstrate

Molecules 2017, 22, 83
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that the charge transfer interaction is taking place within the molecule towards the amide group.
The strong charge transfer interaction through -conjugated system results in substantial ground
π
state Donor–Acceptor (DA) mixing and the appearance of a charge transfer band in the electron
absorption spectrum.
Figure 3. UV-Vis spectra of ABB, AIB, ABBB, and ABIB in DMSO (conc. = 1 × 10− mol/L).
6
30000
25000
20000
15000
10000
AIB
ABB
ABBB
ABIB
5000
0
2
00
220
240
260
280
300
320
340
360
380
400
Wavenumber, nm
Figure 4. Simulated UV-Vis spectra of ABB, AIB, ABBB, and ABIB in DMSO.
HOMO
LUMO
Figure 5. The HOMO and LUMO surfaces of ABB in DMSO.

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Table 3. Calculated electronic parameters of the two conformers of 2-aminobenzamides in DMSO.
λ (nm)
λ (eV)
Oscillator Strength
Conformer (A)
ABB (HOMO-LUMO gap = 4.38 eV)
Assignment
% Contribution
2
3
16.6
30.2
5.72
3.75
0.1174
0.0993
HOMO-3
HOMO→LUMO
→
LUMO
31.6
96.8
AIB (HOMO-LUMO gap = 4.36 eV)
2
3
13.6
33.0
5.80
3.72
0.2280
0.0840
HOMO-4
HOMO→LUMO
→
LUMO
21.0
93.8
2
3
34.9
34.7
5.28
3.70
44.7
96.7
ABIB (HOMO-LUMO gap = 4.35 eV)
2
3
43.1
34.9
5.10
3.70
0.3372
0.1186
HOMO
HOMO→LUMO
→
LUMO+2
65.7
89.4
2
3
17.9
11.0
5.69
3.99
35.2
95.2
AIB (HOMO-LUMO gap = 4.62 eV)
2
3
18.5
13.9
5.68
3.95
0.4237
0.0758
HOMO-4
HOMO→LUMO
→
LUMO
24.5
92.5
2
3
73.7
90.9
4.53
3.17
8.4
98.5
ABIB (HOMO-LUMO gap = 4.57 eV)
2
3
39.1
16.3
5.19
3.92
0.4646
0.0936
HOMO
HOMO→LUMO
→
LUMO+2
43.2
69.6
Amides have the ability to undergo self-association in less or non-polar mediums such as
chloroform and to form dimers in the solid state [44]. However, self-association has not been observed
in the strongly polar solvents such as DMSO-d due to intermolecular hydrogen bonding to the solvent
6
molecules [
3]. This led us to investigate the title compounds in the solid state by means of IR and
Raman spectroscopy as well as single crystal X-ray diffraction (XRD) technique.
2
.5. Solid State Studies Using IR and Raman Spectroscopy
The experimentally determined IR frequencies of compounds ABB, AIB, ABBB, and ABIB, which
−
ν 3157–3424 cm
1
are illustrated in Table 4 show characteristic peaks in the N-H stretching region
due to amino (NH ) and amido (NH CO) group vibrations. There is a good agreement between
2
2
the experimentally determined vibrational spectra of these compounds (solid state) and those
simulated using DFT method (refer to the Supplementary Materials for experimental IR spectra
(Supplementary 3), and Supplementary 5 for computed IR frequencies). The computed IR data are
uncorrected based on harmonic approximation. It is well known in the literature that on the basis
of this approximation, the computed wavenumbers will be larger than the experimentally observed
values because the experimental value is an anharmonic frequency whereas the calculated one is a
harmonic frequency. The literature scale factor to have the corrected wavenumbers for the method
used is 0.96. The proposed assignments are based on the experimental and the simulated IR spectral
−
1
data of ABB as a model. The band at
in benzene ring. The other three sets of bands corresponding to the N-H vibrations are assigned
ν 3161 cm corresponds to the stretching C-H vibration
−
−1
1
−1
−1
as follows: νas(NH ) = 3395 cm , νs(NH ) = 3355 cm , and
ν
(NH) = 3281 cm . The bands at
= 1672 cm are attributable to the azomethine ( C=N) and carbonyl ( C=O)
vibrations, respectively.
2
2
−
1
ν
= 1600 cm and
ν
ν
ν

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Table 4. The experimental IR frequencies for compounds ABB, AIB, ABBB, and ABIB.
Compound
IR Frequencies
5
3
08, 534, 581, 652, 694, 818, 857, 1068, 1162, 1257, 1366, 1476, 1538, 1600, 1672,
161, 3281, 3355, 3395
ABB
AIB
5
05, 537, 582, 657, 697, 798, 892, 1078, 1159, 1245, 1297, 1390, 1478, 1540, 1605,
1
673, 3157, 3287, 3347, 3395
13, 536, 584, 641, 800, 864, 1047, 1127, 1240, 1382, 1408, 1440, 1529, 1561, 1598,
638, 3186, 3317, 3369, 3412
13, 542, 644, 805, 873, 1054, 1130, 1240, 1276, 1386, 1414, 1451, 1536, 1567,
602, 1641, 3180, 3326, 3368, 3424
4
1
ABBB
ABIB
4
1
The calculated Raman frequencies for compounds ABB
,
AIB
,
ABBB, and ABIB (see
Supplementary Materials, S5) also compare favourably with the experimental ones (refer to
Supplementary 4, for the spectra). We have obtained single crystals of 2-amino-5-bromobenzamide
(ABB) suitable for X-ray crystallography by slow evaporation of toluene. This compound then
represented a model to study the solid state structure of these primary 2-aminobenzamides by X-ray
crystallography as described below.
2
.6. Solid State Studies of ABB Using X-ray Crystallography
Compound (ABB) crystallizes in the monoclinic space group C2/c (Figure 6; Table 5). Consideration
of the atomic sizes suggests that deviation from co-planarity should occur in these molecules due
to the presence of the heavy halogen atoms, which probably account for the high values for the
largest diff peak [45]. We observed the intramolecular hydrogen bonds intuitively between oxygen
of the amide moiety and NH of amine group (Figure 6). This X-ray crystal structure provides an
unambiguous proof of the existence of intramolecular hydrogen bonding between the amide oxygen
and the amine hydrogen for the N-unsubstituted 2-aminobenzamides in analogy with the literature
precedents for 2-aminobenzamide [25] or 2-amino-3-chloro-5-nitrobenzamide [26] and the co-crystals
involving 2-aminobenzamide [27,28]. XRD also revealed that the molecules are linked together by
intermolecular hydrogen bonding. The amide unit of these compounds functioned as a hydrogen
bond donor and an acceptor simultaneously to form an intermolecular hydrogen-bonded complex
(Figure 7). There is strong intermolecular hydrogen bonding between oxygen of one molecule and the
NH of the amine or amide group of the other molecule. Likewise, the amine nitrogen is involved in
hydrogen bonding with an amide proton. These results are in agreement with the previous observation
on the existence of intramolecular and intermolecular hydrogen bonding in 2-aminobenzamide [25
]
and 2-amino-3-chloro-5-nitrobenzamide [26].

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Table 5. The crystal data and structure refinement for ABB.
1511089
CDCC
Empirical formula
C H BrN O
7
7
2
Formula weight
Crystal system
Space group
215.06
Monoclinic
C2/c
◦
α = 90
a = 30.3359(6) Å
b = 6.50570(10) Å
c = 7.7930(2) Å
◦
Unit cell dimensions
β
= 91.4270(10)
◦
γ = 90
1537.52(6) Å3
8
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
3
1.858 Mg/m
−
1
5.285 mm
848
3
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 27.99
Absorption correction
0.44 × 0.19 × 0.06 mm
◦
1.34 to 27.99
1−1 47 04 2< h < 39, −8 < k < 8, −10 < l < 10
1865 [R(int) = 0.0970]
99.9%
Integration
◦
Max. and min. Transmission
Refinement method
0.7422 and 0.2045
Full-matrix least-squares on F
2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
1865/0/116
1.018
1
2
R = 0.0327, wR = 0.0854
1
2
R = 0.0408, wR = 0.0879
−
3
1.096 and −0.391 e.Å
Figure 6. The Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram of ABB showing crystallographic labelling.

Molecules 2017, 22, 83
11 of 14
Figure 7. The X-ray crystal structure of ABB showing intra- and intermolecular hydrogen bonding.
. Experimental
3
3
.1. Spectroscopic Analysis
1
The H-NMR spectra for these compounds were obtained as DMSO-d solutions using Agilent
6
5
00 MHz NMR spectrometer (Agilent Technologies, Oxford, UK) and the chemical shifts are quoted
relative to the TMS peak. The 2D NOESY experiment on compound ABB was performed on a Bruker
4
(
7
00 MHz NMR spectrometer (Bruker BioSpin GmhH, Karlsruhe, Germany) operating at 400 MHz
H). The FT-IR spectra were recorded at room temperature as powders using a Bruker VERTEX
0 FT-IR Spectrometer (Bruker Optics, Billerica, MA, USA) with a diamond ATR (attenuated total
1
reflectance) accessory by using the thin-film method. The Raman spectra were acquired on a Bruker
Multiram FT-Raman spectrometer (Bruker Optics, Billerica, MA, USA) using 100 mW laser power with
−
1
a resolution of about 4 cm and 64 scans.
3
.2. Single X-ray Data Collection and Processing
X-ray intensity data were determined on a Bruker Venture D8 Photon CMOS diffractometer
(
Bruker AXS, Madison, WI, USA) with graphite-monochromated MoK 1
α
(λ
= 71073 Å) radiation at
173 K using an Oxford Cryostream 600 cooler. Data reduction was carried out using the program
SAINT+, version 6.02 [46] and face-indexed [47] absorption corrections were made using the program
XPREP [47]. Space group assignments was made using XPREP [47]. The structure was solved in
the WinGX [47] suite of programs, using direct methods through using SHELXS-97 [48] and refined
2
using full-matrix least-squares/difference Fourier techniques on F using SHELXL-97 [48]. Thereafter,
the hydrogen atoms attached to the N atoms were located in the difference Fourier map and the
coordinates and isotropic parameter refined freely. All C-H hydrogen atoms were placed at idealized
positions and refined as riding atoms with isotropic parameters 1.2 times those of their parent atoms.
Diagrams and publication material were generated using ORTEP-3 [49] and PLATON [50].
4
. Conclusions
The non-equivalence of the amide protons in the solution phase is due to a hindered rotation
around the CO-NH single bond. Intramolecular hydrogen bonding between the carbonyl oxygen
2

Molecules 2017, 22, 83
12 of 14
and the amine proton was not observed in the solution phase due to a rapid exchange of the two
amine hydrogens with the solvent. The presence of strong intramolecular hydrogen bonds was,
however, verified by the crystal structure of ABB in the solid state, which also revealed the presence of
strong intermolecular hydrogen bonding between oxygen of one molecule and NH of the amine or
amide group of the other molecule. Such interactions also exist between the amine nitrogen and the
amide proton, and between the amine nitrogen and the amide hydrogen. Molecular orbital coefficient
analyses suggest that the electronic spectrum corresponds to the π→π* electronic transition. There is
a good agreement between experimentally determined structural parameters and the vibrational
frequencies of the compounds and those predicted theoretically using the DFT method. Our results
which incorporate X-ray data of the halogenated 2-aminobenzamides complement previously-reported
spectroscopic and computational data of N-substituted aminobenzamides and further confirm the
presence of intramolecular hydrogen bonding in the N-unsubstituted 2-aminobenzamides in the
solid state.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/22/
1
1
/83/s1. H-NMR, IR, and Raman spectra of compounds ABB
,
AIB
,
ABBB, and ABIB as well as their computed
IR and Raman spectral data have been included as Supplementary Information.
Acknowledgments: The authors are grateful for financial support on this project from the University of
South Africa (Unisa) and the National Research Foundation (SA). DFT calculations used the Extreme Science
and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant
number OCI-1053575. We also thank the Molecular Sciences Institute of University of the Witwatersrand for the
X-ray data.
Author Contributions: The experimental component was conducted by M.M.M. under the supervision of the
lead author (M.J.M.) who has conceptualized the project and designed this paper. R.M.M. acquired the 2D NOESY
spectrum and interpreted the corresponding data. L.R. and P.R. acquired the DFT data and also contributed in
some part in the interpretation of the corresponding data. All authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2017 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
(