Spectral characterization and crystal structures of two newly synthesized ligands of N-methyl o-substituted benzohydroxamic acids

Article abstract of DOI:10.1007/s10870-013-0469-z

Two new derivatives of hydroxamic acid having the general formula RC(O)N(RN)OH (R = alkyl/aryl; RN = alkyl/aryl or H), have been synthesized by the condensation method in an ice-bath. The compounds, N-methyl o-iodobenzohydroxamic acid and N-methyl o-bromo

Full text of DOI:10.1007/s10870-013-0469-z

J Chem Crystallogr (2013) 43:622–627
DOI 10.1007/s10870-013-0469-z
ORIGINAL PAPER
Spectral Characterization and Crystal Structures of Two Newly
Synthesized Ligands of N-Methyl O-Substituted Benzohydroxamic
Acids
•
Khan Naqeebullah Yang Farina Lo Kong Mun
•
•
•
Nor Fadilah Rajab Normah Awang
Received: 23 April 2013 / Accepted: 3 September 2013 / Published online: 2 October 2013
Ó Springer Science+Business Media New York 2013
Abstract Two new derivatives of hydroxamic acid hav-
ing the general formula RC(O)N(RN)OH (R = alkyl/aryl;
RN = alkyl/aryl or H), have been synthesized by the
condensation method in an ice-bath. The compounds, N-
methyl o-iodobenzohydroxamic acid and N-methyl o-bro-
mobenzohydroxamic acid have been isolated as crystalline
solids, stable in air and soluble in organic solvents and in
aqueous alcohol solution. A systematic investigation of the
derivatives were carried out both in solid and in solution.
They have been structurally characterized by elemental
analysis, and the results were in good agreement with the
values calculated for the proposed formula. These deriva-
tives were further investigated on the basis of FT-IR,
multinuclear 1H, 13C NMR spectroscopy, and Single
Crystal X-ray crystallographic studies, indicating that both
the compounds are structurally similar.
Keywords Hydroxamic acids ꢀ CHN ꢀ
NMR spectroscopy ꢀ X-ray diffraction
Introduction
Hydroxamic acids [1] RC(O)N(RN)OH (R = alkyl/aryl;
RN = alkyl/aryl or H), are among the some of the most
well studied compounds due to the fact that they demon-
strate a wide variety of biological activities and their sig-
nificance in so many different applications in modern
society. Much of their activity is due to their chelating
properties with metal ions, hence constituting a very
important class of chelating agents with versatile biological
activities [2]. These compounds are capable of inhibiting a
variety of enzymes, including ureases and matrix
metalloproteinases [3–5]. Hydroxamic acid moieties are
used as therapeutic targeting cancer, cardiovascular dis-
eases, HIV, Alzheimer’s, malaria, allergic diseases and
metal poisoning [6–12]. Moreover, the hydroxamic acids
have been used as insecticides [13] and antimicrobials [14].
They are also employed industrially as antioxidants [15], as
inhibitors of corrosion [16], and for the extraction of toxic
elements [17]. A number of synthetic routes are available
for the preparation of hydroxamic acids and have been
well-documented in the literature [18], but some of them
are tedious, time consuming and also expensive. The rea-
sonable way of producing hydroxamic acid derivative is
the reaction of hydroxylamine with acid chlorides or esters
[19]. Hydroxamic acids are weak acids with pKa values of
the N–OH proton in aqueous solvents of the order 8.5–9.4
[20]. Furthermore, studies have shown that in non-protic
solvents, such as dimethylsulfoxide (DMSO), some hy-
droxamic acids, including benzohydroxamic acid (1a:
RC = Ph, RN = H) act as N–H acids, rather than as N–OH
K. Naqeebullah (&) ꢀ Y. Farina (&)
Faculty of Science and Technology, School of Chemical
Sciences and Food Technology, Universiti Kebangsaan
Malaysia, 43600 Bangi, Selangor Darul Ehsan, Malaysia
e-mail: naqeebhmd2@gmail.com
Y. Farina
e-mail: farina@ukm.my
L. K. Mun
Department of Chemistry, Faculty of Science, University of
Malaya, 50603 Kuala Lumpur, Malaysia
N. F. Rajab
Biomedical Science, Faculty of Health Sciences, Universiti
Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz,
50300 Kuala Lumpur, Malaysia
N. Awang
Environmental Health Programme, Faculty of Allied Health
Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda
Abdul Aziz, 50300 Kuala Lumpur, Malaysia
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J Chem Crystallogr (2013) 43:622–627
623
acids [21, 22]. Primary hydroxamic acids (1) (R1 = H) can
go through two consecutive deprotonating proceedings,
loss of the first proton yields the hydroxamate anion (2),
and loss of the second proton yields the hydroximate di-
anion (3). The hydroxamic acid, hydroxamate and hy-
droximate groups can exhibit cis/trans or (Z, E) isomerism
(1a, 1b) resulting from the free rotation about the C–N
bond, keto (RCC(O)N(OH)R1)-enolic (RCC(OH)N(OH))
tautomerism (1b, 1c), as shown (Fig. 1), and have several
resonating structures [23–25].
potassium bromide discs using a Perkin-Elmer spectro-
1
photometer GX. The H and 13C nuclear magnetic reso-
nance spectra were recorded using the BRUKER FT-
NMR 600 MHz Cryo-Prob spectrometer, using d6-
DMSO as a solvent and tetramethylsilane as an internal
standard. Crystals structures determination were carried
out on a Bruker Smart APEX CCD area detector dif-
fractometer equipped with graphite mono-chromatised
˚
Mo-Ka (k = 0.71073 A) radiation in each case. All data
collection was carried out at 100 K. The program APEX2
[26] was used for collecting frames of data, indexing
of reflections and determination of lattice parameters,
SAINT [26] for absorption correction, and SHELX97
[27].
Keeping in view the structural and biological diversity
of hydroxamic acids, herein we report two new hydroxamic
acids.
Experimental
Synthesis of Ligand (1)
Materials and Methods
The titled compound N-methyl o-iodobenzohydroxamic
acid (C8H8INO2) was prepared by the dropwise addition of
o-iodobenzoyl chloride (2.66 g, 0.01 mol) to a stirred cold
solution of N-methylhydroxylamine (0.84 g, 0.01 mol)
containing sodium hydrogen carbonate (1.80 g, 0.02 mol),
for 30 min at 4 °C. The solution was filtered and reduced to
evaporate at low pressure which afforded a precipitate. The
precipitate was then dissolved in boiling ethyl acetate to
remove any undissolved substance and then the filtrate is
The chemicals were purchased from Aldrich and were used
as received. All the chemicals were of analytical grade.
The percentage compositions of the elements (CHN) for
the compounds were determined using an elemental ana-
lyzer CHNS-O Model Fison EA 1108. Solid state infrared
spectra of the compounds are recorded in the range
4,000–400 cm-1. The infrared spectra were recorded as
O
OH
C
N:
RC
R1
1a
O
R1
O
O
O
O
H+
H+
C
N:
C
N:
C
N:
RC
RC
RC
OH
OH
R1
1b
2
3
HO
C
N:
RC
1c
1a, 1b, 2 (R1 = H or R)
1c, 3 (R1 = H)
Fig. 1 Structures of hydroxamic acids (1), hydroxamates (2) and hydroximates (3), E$Z isomerism (1a, 1b), keto$enol tautomerism (1b, 1c)
123

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J Chem Crystallogr (2013) 43:622–627
O
C
O
C
OH
Cl
N
NaHCO3
CH3NHOH.HCl
2HCl
CH3OH/ 0oC
CH3
I
I
Fig. 2 Conversion of o-iodobenzoyl chloride to N-methyl o-iodobenzohydroxamic acid (1)
Fig. 3 Thermal ellipsoidal plot of C8 H8 I N O2. Displacement
ellipsoids are drawn at the 50 % probability level, and H atoms are
shown as spheres of arbitrary radii
Fig. 4 Thermal ellipsoidal plot of C8 H8 Br N O2. Displacement
ellipsoids are drawn at the 50 % probability level, and H atoms are
shown as spheres of arbitrary radii
placed at 4 °C overnight to afford single crystals (Fig. 2).
Yield: 84 %. Melting point: 134–135. Analysis: Calcd.
(%): C 34.67, H 2.89, N 5.06. Found (%): C 35.32, H 2.71,
4.93. Selected IR data (KBr pellets): 3,114(b, m O–H),
1,608 (s, m C = O), 1,494 (s, m C–N) and 915(s, m NO).
parameters are summarized in Table 1. Selected bond
lengths and angles are given in Tables 2 and 3.
Crystallographic data for the compounds (1) and (2)
have been deposited with the Cambridge Crystallographic
Data Centre, CCDC reference numbers (920,545 and
920,539). This information may be obtained free of charge
from: the Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (fax: ?44-1223-336033; e-mail:depo-
sit@ccdc.cam.ac.uk; website: http://www.ccdc.cam.ac.uk).
Synthesis of Ligand (2)
The titled compound N-methyl o-bromobenzohydroxamic
acid (C8H8BrNO2) was prepared in a similar method as for
(1), by using o-bromobenzoyl chloride (2.19 g,
0.01 mol).Yield: 87 %. Melting point: 127–128 Analysis:
Calcd. (%): C 41.76, H 3.48, N 6.10. Found (%): C 39.60,
H 2.98, 6.01. Selected IR data (KBr cm-1): 3,123(b, m O–
H), 1,600 (s, m C = O). 1,436 (s, m C–N) and 915(s, m NO).
Results and Discussion
The characteristic infrared frequencies for both compounds
have been observed in their specific range. The m(OH) band
is located within the range 3,123–3,114 cm-1 as broad
bands. The carbonyl, m(CO) stretching vibrations posi-
tioned within the range 1,608–1,600 cm-1 significantly,
below the typical ketonic m(CO) of 1,715–1,680 cm-1 [29–
37], reflecting the fact that the vibration is at an appreciably
lower frequency than the carbonyl absorption of normal
ketones, which may be caused by the resonance effect of
the ionic form. Moreover the significant shift of m(C = O)
to lower frequency together with the broad m(O–H) band is
X-ray Crystallography
The single crystals of N-methyl o-iodobenzohydroxamic
acid and N-methyl o-bromobenzohydroxamic acid (Figs. 3
and 4) of suitable quality were each mounted on a fine glass
capillary and aligned on the Bruker SMART APEX2 dif-
fractometer, equipped with graphite mono-chromated Mo-
˚
Ka radiation source (k = 0.71073 A). The range for data
collection was 2.67–25.50 for (1) and 2.78–25.98 for (2).
All calculations were performed using the SHELXTL-97
package [28]. The data collection and refinement
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J Chem Crystallogr (2013) 43:622–627
625
˚
Table 2 Selected bond lengths (A) for the ligands 1 and 2
Table 1 Crystal data and structure refinement for the ligands 1 and 2
(1)
(2)
Compound
(1)
(2)
I1 C2 2.103(4)
C1 C6 1.394(5) Br1 C2 1.897(3) C1 C6 1.390(4)
C1 C7 1.502(4)
N1 O2 1.396(4) C2 C3 1.391(5) O2 N1 1.390(3) C2 C3 1.381(4)
Gross formula
C8 H8 I N O2
277.05
C8 H8 Br N O2
230.06
N1 C7 1.320(5) C1 C7 1.499(5) O1 C7 1.239(3)
M
Crystal system, space
group
Orthorhombic,
Pbca
Orthorhombic,
Pbca
N1 C8 1.458(5) C3 C4 1.384(6) N1 C7 1.331(3)
O1 C7 1.249(5) C4 C5 1.383(6) N1 C8 1.444(3)
C1 C2 1.391(5) C5 C6 1.390(6) C1 C2 1.383(4)
C3 C4 1.383(4)
C4 C5 1.376(4)
C5 C6 1.388(4)
Crystal shape
Color
Block
Block
Colorless
8.3319(14)
13.945(2)
15.245(3)
90.00
Colorless
9.0280(17)
13.063(3)
14.634(3)
90.00
˚
a, A
˚
b, A
structure of the ligands, which were further supported by
1
X-ray diffraction studies. The H NMR spectrum of com-
˚
c, A
a, deg
b, deg
c, deg
pound 1 and 2 show broad signals at lower field 10.28 and
10.39 ppm, which are assigned to the OH protons thus
indicating the formation of the ketonic form even in solu-
tion. The aromatic protons appear as signals at
7.09–7.86 ppm and 7.22–7.64 ppm with an integration
equal to four protons corresponding to the protons attached
to the carbons. The methyl protons appeared as singlets at
3.244, in both compounds. The 13C NMR spectra for
compound 1 and 2 show downfield peaks at 169.02 ppm
and 168.28 were due to the carbonyl group C (7). The aryl
carbon C (1) attached to the carbonyl group appeared
downfield at 165.92 and 164.46 ppm. The aryl carbon C (2)
attached to the iodo and bromo group appeared upfield at
93.39 and 118.80 ppm respectively. The signals at
127.68–142.56 ppm and 127.88–138.18 ppm are assigned
to the aromatic carbons. The signals which appeared at
38.88 and 38.59 ppm are likely to arise from methyl C (8)
attached to the nitrogen atom.
90.00
90.00
90.00
90.00
3
˚
V, A
1,771.3(5)
8
1,725.8(6)
8
Z
dc (Mg/m3)
2.078
1.771
F(000)
l(mm-1
T, K
1,056
912
)
3.573
4.720
100(2)
100(2)
0.20, 0.15, 0.07
19,981
1,981
Crystal size, mm
0.40, 0.25, 0.10
21,271
2,174
Measured reflections
Independent reflections
Reflections with I [ 2 (I) 1,600
1,493
Rint
0.0632
28.198
2.678
0.0691
27.508
2.788
h
max
h
min
Completeness to theta
0.999
-11 11
-18 18
-20 20
0.0291
0.0597
1.029
2,174
111
1.00
h
-11 11
-16 16
-19 19
0.0313
0.0557
1.058
k
Crystal Structure Analysis
l
R[F2 [ 2 (F2)]
wR(F2)
The crystal structures of the ligand N-methyl o-io-
dobenzohydroxamic acid (1) and N-methyl o-bromobenzo-
hydroxamic acid (2) are depicted in Figs. 3 and 4 are
basically similar structures. The carbonyl oxygen and the
hydroxyl oxygen in both halogen substituted benzohydr-
oxamic acid are trans to each other, probably due to the
steric influence between the methyl substituent on the hy-
droxamate fragment with the halogen atom in both com-
pounds. As a result, there is absence of any intramolecular
hydrogen bonding between the hydroxyl group and the
carbonyl oxygen in the two structures. However, strong
intermolecular hydrogen bonds are found between the
hydroxyl group and the carbonyl oxygen atoms of adjacent
S
Reflections
Parameters
Restraints
1,981
111
0
0
-3
˚
maxe A
1.068
-0.875
0.776
-3
˚
mine A
-0.699
w = 1/[r2(Fo2) ? (0.0266P)2 ? 3.9774P] where P = (Fo2 ? 2F2c)/3
w = 1/[r2(Fo2) ? (0.1053P)2 ? 7.2069P] where P = (Fo2 ? 2F2c)/3
related with intramolecular hydrogen bonding for primary
hydroxamic acids [38] and intermolecular hydrogen
bonding for hydrated compounds [39]. In general, the m(C–
N) and m(N–O) bands occur as a sharp peak in the ranges
1,494–1,436 and 915 cm-1, respectively [40]. The free
hydroxamic acids have been shown to exist principally in
the keto form in solid state or in polar solvents [41, 42].
˚
molecules. (Fig. 5), (1): O1ꢀꢀꢀO2 2.598(4) A, symmetry
operator x - 0.5, 0.5 - y, 1 - z; (Fig. 6), (2): O1ꢀꢀꢀO2
2.641(3), symmetry operator x - 0.5, 0.5 - y, -z). The
plane occupied by the methyl substituted hydroxamic acid
fragment (excluding the hydrogen atoms) is evidently flat
in both compounds (1) and (2), with RMS deviation from
1
The H and 13C NMR spectra at room temperature have
˚
planarity of 0.0106 and 0.0336 A, respectively. These
been proven valuable in establishing the nature and
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J Chem Crystallogr (2013) 43:622–627
Table 3 Selected bond angles
(deg) for the ligands 1 and 2
(1)
(2)
C7 N1 O2 120.1(3)
C7 N1 C8 123.2(3)
O2 N1 C8 116.6(3)
C1 C2 I1 120.9(3)
C3 C2 I1 117.6(3)
O1 C7 N1 119.9(4)
O1 C7 C1 121.1(4)
N1 C7 C1 118.9(3)
C7 N1 O2 118.8(2)
C7 N1 C8 125.6(2)
O2 N1 C8 114.8(2)
C3 C2 Br1 118.4(2)
C1 C2 Br1 119.9(2)
O1 C7 N1 121.4(3)
O1 C7 C1 121.9(2)
N1 C7 C1 116.7(2)
Fig. 5 Polymeric chains of (1),
depicting the presence of
hydrogen bonding interaction
between the hydroxyl group
with the carbonyl oxygen of
adjacent molecules, symmetry
operator: -0.5 ? x, 0.5 - y,
1 - z
Fig. 6 Polymeric chains of (2),
depicting the presence of
hydrogen bonding interaction
between the hydroxyl group
with the carbonyl oxygen of
adjacent molecules, symmetry
operator: -0.5 ? x, 0.5 - y, -
z
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Both the ligands were prepared successfully and gave sharp
melting points, indicating that the compounds are pure. The
single crystal X-ray diffraction studies supported the
spectral characterization and further illustrated that both
the compounds are basically having the same structure.
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Acknowledgments This work was supported by Grant UKM-ST-
06-FRGS 112-2009, UKM-GUP-NBT-08-27-112 and GUP-2012-022
and we gratefully acknowledge the School of Chemical Sciences and
Food Technology, Universiti Kebangsaan Malaysia, for providing the
essential laboratory facilities. We would also like to thank the Faculty
Development Programme, University of Balochistan Quetta, Pakistan
for their financial support.
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