SYNTHESIS, CHARACTERIZATION, AND COMPUTATIONAL STUDIES OF N-[(9E)-8,10,17-TRIAZATETRACYCLO[8.7.0.02,7.011,16]HEPTADECA- 1(17),2,4,6,11(16),12,14-HEPTAEN-9-YLIDENE]BENZAMIDE

Article abstract of DOI:10.1134/S0022476620080016

Abstract: N-[(9E)-8,10,17-Triazatetracyclo[8.7.0.0^2,7.0^11,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (I) is synthesized and characterized by spectroscopy, microanalysis, and single crystal X-ray diffractometry. Compound I crystallizes in the monoclinic space group P2₁/c with a = 15.8980(7) ?, b = 4.8067(2) ?, c = 21.0455(10) ?, β = 101.153(2)°, and Z = 4. The experimental bond lengths and bond angles are contrasted with computed bond lengths and bond angles.

Full text of DOI:10.1134/S0022476620080016

ISSN 0022-4766, Journal of Structural Chemistry, 2020, Vol. 61, No. 8, pp. 1177-1185. © Pleiades Publishing, Ltd., 2020.
Text © The Author(s), 2020, published in Zhurnal Strukturnoi Khimii, 2020, Vol. 61, No. 8, pp. 1245-1253.
SYNTHESIS, CHARACTERIZATION, AND
COMPUTATIONAL STUDIES OF N-[(9E)-8,10,17-
2,7 11,16
TRIAZATETRACYCLO[8.7.0.0 .0 ]HEPTADECA-
1(17),2,4,6,11(16),12,14-HEPTAEN-9-YLIDENE]BENZAMIDE*
1,2
F. Odame **, E. C. Hosten , and Z. R. Tshentu
2
2
2,7 11,16
N-[(9E)-8,10,17-Triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]
benzamide (I) is synthesized and characterized by spectroscopy, microanalysis, and single crystal X-ray
diffractometry. Compound I crystallizes in the monoclinic space group P21/c with a = 15.8980(7) Å,
b = 4.8067(2) Å, c = 21.0455(10) Å, β = 101.153(2)°, and Z = 4. The experimental bond lengths and bond
angles are contrasted with computed bond lengths and bond angles.
DOI: 10.1134/S0022476620080016
Keywords: triazatetracyclic, benzoyl isothiocyanate, benzoyl chloride.
INTRODUCTION
Triazatetracyclics have been obtained by various methods [1-5]. Two protocols have been developed for the
synthesis of amino-functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-b]quinoxalines from o-
phenylene diamines and o-cyanobenzaldehydes [6]. An efficient tandem route to the synthesis of iodoisoquinoline-fused
benzimidazole derivatives, including an iodocylization strategy, has been developed. A variety of 2-ethynylbenzaldehydes
underwent the tandem reaction with benzenediamines and iodine to afford respective iodoisoquinoline-fused benzimidazoles
[7]. An efficient and facile Au(I)/Ag(I) cascade method has been developed for the one-pot synthesis of complex polycyclic
heterocycles of benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazzoline derivatives through treatment of substituted 2-(1H-
benzo[d]imidazole-2-yl)anilines with 4-pentynoic or 5-hexynoic acids [8]. Most HIV-1 protease inhibitors are designed to fit
the active site of the enzyme [9]. This allows the HIV-1 protease inhibitors to compete with the natural substrate. A class of
antimalarial pyrido[1,2-a]benzimidazoles has been synthesized and evaluated for the antiplasmodial activity and cytotoxicity
[10]. Imidazoyl-o-nitrobenzamides and isothiocyanates have been reacted in the presence of zinc and TiCl4 in THF, with an
in situ reduction of the nitro group occurring before cyclization [11]. Substituted methyl anthranilates have been reacted with
various iso(thio)cyanates in DMSO/H2O using microwave irradiation to generate diverse 2,4(1H,3H)-quinazolinediones or
2-thioxoquinazolinones [12].
1
Department of Basic Sciences, University of Health and Allied Sciences, Ho, P. R. Ghana; **felixessah15@gmail.com.
2
Department of Chemistry, Nelson Mandela University, Port Elizabeth, South African Republic. Original article submitted
December 16, 2019; revised January 31, 2020; accepted February 3, 2020.
* Supplementary materials are available for this article at doi 10.1134/S0022476620080016 and are accessible for
authorized users.
0022-4766/20/6108-1177 © 2020 by Pleiades Publishing, Ltd.
1177

2,7 11,16
In this work, N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-
ylidene]benzamide has been synthesized and characterized with IR, NMR, GC-MS, and elemental analysis. The single crystal
X-ray structure has been discussed; the experimental bond lengths and bond angles were compared to the computed ones.
The HOMO and LUMO energy levels were discussed, too.
EXPERIMENTAL
Materials and methods. Analytical grade reagents and solvents for the synthesis such as 2-(2′-aminophenyl)-1H-
benzimidazole and benzoyl chloride were obtained from Sigma Aldrich (USA) whilst acetone and ammonium thiocyanate
1
were obtained from Merck Chemicals (SA). The chemicals were used as received (i.e. without further purification). H and
13
1
C NMR spectra were recorded on a Bruker Avance AV 400 MHz spectrometer operating at 400 MHz for H and 100 MHz
13
for C using dimethyl sulfoxide as the solvent and tetramethylsilane as the internal standard. Chemical shifts are expressed
in ppm. FTIR spectra were recorded on a Bruker Platinum ATR Spectrophotometer Tensor 27. Elemental analyses were
performed using Vario Elementar Microcube ELIII. Melting points were obtained using a Stuart Lasec SMP30 and were
reported uncorrected whilst the masses were determined using an Agilent 7890A GC system connected to 5975C VL-MSC
with electron impact as the ionization mode and detection by a triple-axis detector. The GC system was fitted with
a 30 m×0.25 mm×0.25 μm DB-5 capillary column. Helium was used as carrier gas at a flow rate of 1.63 mL/min with
an average velocity of 30.16 cm/s and a pressure of 63.73 kPa.
2,7 11,16
N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]benzamide
(I). Ammonium thiocyanate (0.02 mol, 1.5224 g) was dissolved in 40 mL of acetone. The respective benzoyl chloride
derivative (0.02 mol) was added, followed by heating under reflux at 100-120 °C for 2 h. The benzoyl isothiocyanate
derivative (0.02 mol) obtained was filtered and 2-(2-aminophenyl)-1H-benzimidazole (0.02 mol, 4.185 g) was added to the
filtrate and refluxed at 100-120 °C for 6 h. The product obtained was filtered and recrystallized from DMSO:toluene (1:1) as
1
a yellow solid. Melting point = 205-206 °C. Yield = 78.27%. H NMR (ppm): 13.26 (br, 1H, N–H), 8.36 (m, 6H), 8.01 (d,
13
1H, J = 8.0 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.50 (t, 1H, J = 8.0 Hz), 7.35 (t, 1H, J = 7.2, 7.6 Hz). C NMR (ppm): 149.7 (C),
–1
129.8 (C–H), 126.4 (C–H), 124.0 (C–H), 123.6 (C–H), 121.9 (C–H). IR (νmax, cm ): 3056 (N–H), 1786 (C=O), 1633, 1593
+
(C=C), 1565 (C=C), 1547, 1479. LRMS (m/z, M ): Found for C21H14N4O 338.28; Expected mass 338.36; Anal. calcd for
C21H14N4O (%): C 74.54, H 4.17, N 16.56. Found for C21H14N4O (%): C 74.62, H 4.26, N 16.70.
X-ray crystallography. The X-ray diffraction analysis of I was performed at 200 K using a Bruker KAPPA
APEX II diffractometer with monochromated MoK radiation (λ = 0.71073 Å). APEX II [13] was used for the data
α
collection, the cell refinement, and the data reduction. The structures were solved by direct methods using SHELXS-2013
[13] and refined by least-squares procedures using SHELXL-2013 [14] with SHELXLE [13] as a graphical interface. All
non-hydrogen atoms were refined anisotropically. Carbon-bound H atoms were placed in calculated positions (C–H 0.95 Å
for aromatic carbon atoms and C–H 0.99 Å for methylene groups) and were included in the refinement in the riding model
approximation with Uiso (H) set to 1.2Ueq (C). The H atoms of methyl groups were allowed to rotate with a fixed angle around
the C–C bond to best fit the experimental electron density (HFIX 137 in the SHELX program suite [14]) with Uiso (H) set to
1.5Ueq (C). Nitrogen-bound H atoms were located on a difference Fourier map and refined freely. Data were corrected for
absorption effects, using the numerical method implemented in SADABS [15].
COMPUTATIONAL STUDIES
The calculations were carried out using the Gaussian 09 program [16]. Molecular geometries of the singlet ground
state of all the compounds were fully optimized in the gas phase at the density functional theory (DFT) level of theory using
hybrid B3LYP [17-19], B3PW91, and wB97XD functionals together with the 6-31G(d,p) basis set. For compound I
a frequency calculation was carried out to ensure that the optimized molecular structure corresponded to a minimum [20],
1178

thus only positive frequencies were expected. The HOMO and LUMO results as well as the information for bond lengths and
bond angles were obtained using the Avogadro method.
RESULTS AND DISCUSSION
2,7 11,16
Characterization of N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-
–1
9-ylidene]benzamide (Scheme 1). The IR spectrum showed a signal at 3056 cm for the N–H stretch. A signal was observed at
–1
1633 cm for the C=O stretch. The C–N stretch was observed near 1593 cm . The H NMR spectrum showed signals at
–1
1
13
14.38 ppm for the NH proton. Aromatic protons were observed between 8.36 ppm and 6.92 ppm. The C NMR spectra showed
signals between 144.4 ppm and 104.4 ppm for aromatic carbon atoms.
2,7 11,16
Scheme 1. Synthesis of N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0 ]hepta-
deca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene.
The triazatetracyclic acetyl derivative has been reported [21] to be synthesized by the reaction of acetyl chloride
with ammonium thiocyanate to give acetyl thiocyanate which was then refluxed with 2-(2-aminophenyl)-1H-benzimidazole
2,7 11,18
for 6 h to give N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2(7),3,5,11,13,15-heptaen-9-ylidene]
acetamide (methyl derivative). The reaction was reported to proceed as the attack of the thiocyanate carbon atom by the lone
pair from the nitrogen atom of the 2-aminophenyl group. A shift of the electron density on the carbonyl group onto the
oxygen atom was proposed to allow the cleavage of C=N bond, forming another C=N bond with the carbonyl group.
A subsequent attack by the lone pair of the nitrogen atom led to the formation of thiol and alcohol. A rearrangement was
reported to occur followed by the loss of hydrogen sulphide (which turns lead acetate paper black), leading to the formation
of the final product. The reaction for the phenyl derivative being reported here proceeds by the same mechanism as for the
triazatetracyclic acetyl derivative [21]. Two triazaspiro tetracycles have been synthesized by the reaction of 2-(2′-
aminophenyl)-1H-benzimidazole and 4-methylcyclohexanone or 3-methylcyclohexanone under reflux and solvent free
conditions [22]. In this reaction, the triazatetracyclic backbone was obtained by the attachment of cyclic ketone and the
subsequent loss of water whilst the formation the triazatetracyclic acetyl and phenyl derivatives proceeded through the
isothiocyanate intermediate with the formation of thione and the subsequent loss of hydrogen sulphide.
Crystal structure determination. The crystallographic data, selected experimental and computed bond lengths and
bond angles for compound I are provided in Tables 1 and 2. Compound I crystallized in the monoclinic space group P21/c
with a = 15.8980(7) Å, b = 4.8067(2) Å, c = 21.0455(10) Å, β = 101.153(2)°, and Z = 4. Compound I undergoes the
hydrogen bonding between N3---H3 and O1 and also between C13---H13 and N4. The triazaacetyl derivative crystallized in
the monoclinic space group P21/n with a = 17.5552(17) Å, b = 4.6163(4) Å, c = 17.7662(17) Å, β = 115.953(3)°, and Z = 4
[21], whilst the 4-methyl triazaspiro tetracycle derivative also crystalized in the monoclinic space group P21/n with
a = 12.9495(4) Å, b = 16.2186(4) Å, c = 15.6429(3) Å, β = 91.857(1)°, α = γ = 90°, Z = 8 [22]. The triazaacetyl and
triazabenzoyl derivatives are almost planar. The ORTEP diagram of compound I is presented in Fig. 1. The bond distance
O1–C3 = 1.245(1) Å in compound I is consistent with the carbonyl C=O bond, whilst the N1–C1 and N2–C1 bond distances
were 1301(2) Å and 1.406(2) Å respectively.
1179

TABLE 1. Crystallographic Data and Structure Refinement Summary for Compound I
Parameter
Compound I
Formula
CCDC number
Formula weight
Crystal system
Space group
a, b, c, Å
C21H14N4O
1448792
338.36
Monoclinic
P21/c
15.8980(7), 4.8067(2), 21.0455(10)
101.153(2)
1577.86(12)
4
β, deg
3
V, Å
Z
3
Dcalc, g/cm
1.424
0.092
μ(MoK ), mm
α
F(000)
Crystal size, mm
Temperature, K
Radiation, Å
704
0.05×0.32×0.59
200
0.71073
2.0-28.3
θmin–max, deg
Dataset
–21:21; –6:6; –27:28
21774, 3928, 0.022
3165
Tot., Uniq. Data, R(int)
Observed data (I > 2.0σ(I))
Nref / Npar
3928 / 239
0.0375 / 0.1047
1.03
R / wR2
S
Max. and Av. Shift / Error
Min. / Max. Resd. Dens., e/Å
0.00 / 0.00
–0.20 / 0.27
3
2,7 11,16
Fig. 1. ORTEP view of N-[(9E)-8,10,17-triazatetracyclo[8.7.0.0 .0
heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]benzamide
with 50% probability displacement ellipsoids and atom labeling.
]
(I)
1180

TABLE 2. Summary of Experimental and Theoretical Bond Lengths and Bond Angles for Compound I Obtained by B3LYP,
CAM-B3LYP, B3PW91, WB97XD, and M06 functionals and the 6-31G(d,p) Basis Set
Experimental
B3LYP CAM-B3LYP B3PW91 WB97XD M06 Min. deviation Max. deviation
Bond length, Å
O1–C3
1.245(1) 1.229
1.301(2) 1.303
1.406(1) 1.387
1.406(1) 1.422
1.378(1) 1.392
1.405(1) 1.408
1.345(2) 1.374
1.394(1) 1.391
1.317(1) 1.294
1.368(1) 1.383
1.222
1.293
1.387
1.411
1.386
1.405
1.367
1.390
1.288
1.378
1.227
1.301
1.383
1.415
1.388
1.402
1.370
1.386
1.292
1.379
1.221
1.295
1.388
1.408
1.387
1.402
1.368
1.391
1.288
1.381
1.222
1.297
1.383
1.414
1.387
1.404
1.370
1.388
1.287
1.380
0.016
0.002
0.019
0.002
0.008
0.001
0.022
0.003
0.023
0.01
0.024
0.006
0.023
0.016
0.014
0.003
0.029
0.006
0.03
N1–C1
N1–C11
N2–C1
N2–C2
N2–C12
N3–C2
N3–C22
N4–C2
N4–C3
0.015
Bond angle, deg
105.3
C1–N1–C11 104.8(1) 105.5
C1–N2–C2 124.1(1) 123.3
105.4
123.3
105.4
131.2
121.2
126.7
124.6
113.4
127.6
118.9
114.0
128.4
117.5
123.8
121.4
105.1
123.6
105.6
130.8
121.1
126.3
124.1
113.5
127.7
118.7
114.0
127.9
118.0
123.7
121.6
105.2
123.6
105.4
131.0
121.2
126.8
124.9
113.4
127.7
118.8
113.8
128.3
117.9
123.9
121.7
0.3
0.5
0.3
0.8
1.1
0.9
5.5
0.1
0.9
0.6
1.4
9.5
8.2
2.2
2.3
0.7
0.8
0.5
1.2
1.3
1.6
6.8
0.2
1.0
1.0
1.6
10.4
8.9
2.5
2.6
123.4
C1–N2–C12 105.9(1) 105.5
C2–N2–C12 130.0(1) 131.2
N3–C22–C23 120.0(1) 121.2
C2–N3–C22 125.4(1) 127.0
105.4
131.0
121.3
127.0
C2–N4–C3
N1–C1–N2
N1–C1–C21 128.6(1) 127.7
N2–C1–C21 118.1(1) 119.1
118.6(1) 125.4
125.2
113.3(1) 113.1
113.2
127.7
119.0
N2–C2–N3
N2–C2–N4
N3–C2–N4
O1–C3–N4
115.4(1) 113.8
118.4(1) 128.8
126.2(1) 117.3
126.2(1) 123.9
113.9
128.7
117.4
124.0
O1–C3–C31 119.1(1) 121.5
121.5
2
The N2–C2–N3 bond angle of 115.4(12)° confirms the sp hybridization of the C2 carbon atom, whilst the C1–N1–
C11 bond angle is 104.8(1)°. The C22–N3–C2–N4 torsion angle of 179.9(2)° confirms the planarity around C2. The C12–
N2–C2–N4 and C22–N3–C2–N2 torsion angles of 0.2(2)° and 0.4(2)° respestively also confirmed that C2 was planar
(Table S1). The bond lengths for the six-member ring C22–C21–C1–N2–C2–N3 ranged from 1.345 Å to 1.406 Å, confirming
that the bonds are neither distinctly single bonds (1.32 Å) nor distinctly double bonds (1.47 Å). This suggest that there is
electron delocalization over the entire ring to achieve the stability, and hence, the planarity of the ring. Fig. 1 gives the
ORTEP view of compound I with 50% probability displacement ellipsoids and atom labeling.
The O1–C3 bond length was experimentally determined as 1.245° whilst the computed bond length gave deviations
of 0.016 Å to 0.024 Å from the experimental values. For the N1–C1, N1–C11, N2–C1, and N2–C2 amide bonds the
experimental bond lengths obtained were 1.301(2) Å, 1.406(1) Å, 1.406(1) Å, and 1.378(1) Å, respectively; the computed
values deviated by 0.002 Å and 0.023 from the experimental values. The C1–N2–C2, C1–N2–C12, N1–C1–N2 bond angles
were experimentally determined as 124.1(1)°, 105.9(1)°, and 113.3(1)° whilst the computed values gave deviations between
0.2° and 0.8°, representing the lowest deviations from the computed values. The C2–N4–C3, N2–C2–N4, and N3–C2–N4
bond angles were obtained from the experiment as 118.6(1)°, 118.4(1)°, and 126.2(1)°, respectively, whilst the computed
values gave deviations between 6.8° and 10.4°. The large deviations that only occurred in these angles might be due to the
1181

fact that gas phase considerations in computations are different from the measurement obtained from the single crystal
structure. Fig. 2 shows the packing of the compounds in the unit cell of compound I. Four compounds are packed in the unit.
There is an intramolecular hydrogen bond between the carbonyl oxygen atom and the amide hydrogen atom.
Fig. 3 gives the intermolecular interactions that exists between the molecules of compound I. There are
intermolecular interactions between the hydroxyl group of one molecule and the electron density of nearest π-system of
a benzene ring of the adjacent molecule, inducing a dipole due to the polar character of the hydroxyl group. Van der Waals
interactions also occur between the electron clouds of the adjacent π-systems. A network of these interactions exists
throughout the compound and is responsible for the high melting point of compound I.
There exists a marked difference in the arrangement of molecules within the crystal lattice of the triazaacetyl
derivative compared to that in the triazobenzoyl derivative. The difference consists in that some molecules are stacked
together and held by Van der Waals forces. This is only possible because of the absence of a benzoyl moiety in the
triazaacetyl derivative molecules. Fig. 4 gives the stacking of the molecules within the crystal lattice of the triazaacetyl
derivative [21].
Fig. 2. Packing of the unit cell of compound I.
Fig. 3. Intermolecular interactions in compound I.
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Fig. 4. Stacking of molecules of the triazaacetyl derivative within the
crystal lattice [21].
Fig. 5 illustrates the intermolecular interactions in the triazaacetyl derivative. In addition to the stacking which
occurs between its molecules there is also a sideways interaction among the adjacent molecules, which involves the hydroxyl
moiety and the methyl group of one molecule and the π-system from the adjacent molecule.
Fig. 6 gives the packing in the unit cell of the 4-methyl triazaspiro tetracycle derivative. The unit cell contains 8
molecules in contrast to the 4 molecules found in the unit cells of both the triazaacetyl tetracyclic and triazabenzoyl
tetracyclic derivative.
Fig. 5. Intermolecular interactions in the triazaacetyl derivative [21].
Fig. 6. Packing in the unit cell of the 4-methyl triazaspiro
tetracycle derivative [22].
1183

Fig. 7. Intermolecular interactions in the methyl triazaspiro tetracycle derivative [22].
TABLE 3. HOMO–LUMO Energy Levels of N-[(Benzyloxy)Methanethioyl]Benzamide Compound I Calculated by B3LYP,
CAM-B3LYP, B3PW91, WB97XD, and M06 Functionals and the 6-31G(d,p) Basis Set
HOMO–LUMO
B3LYP
CAM-B3LYP
B3PW91
WB97XD
M06
LUMO+4
LUMO+3
0.00160
–0.00516
–0.02182
–0.05145
–0.06025
–0.21639
–0.23405
–0.23980
–0.24267
–0.24777
0.15614
0.05213
0.04569
0.02758
–0.00501
–0.01484
–0.26505
–028770
–0.29225
–0.30114
–0.30219
0.25021
–0.00171
–0.00833
–0.02546
–0.05512
–0.06389
–0.22081
–0.23803
–0.24432
–0.24677
–0.25253
0.15692
0.07092
0.06585
0.04670
0.01478
0.00561
–0.28666
–0.30982
–0.31404
–0.32378
–0.32515
0.29227
0.00637
0.00068
LUMO+2
–0.01649
–0.04485
–0.05440
–0.22805
–0.24740
–0.25251
–0.25774
–0.26013
0.17365
LUMO+1
LUMO
HOMO
HOMO–1
HOMO–2
HOMO–3
HOMO–4
HOMO–LUMO gap, eV
Fig. 7 illustrates intermolecular interactions in the 4-methyl triazaspiro tetracycle derivative. There are no
intramolecular interactions in a 4-methyl triazaspiro molecule, however, there exist intermolecular interactions between
a nitrogen atom and the 4-methyl cyclohexanyl moiety of the adjacent molecule or its nitrogen atom [22].
Table 3 gives the HOMO–LUMO energy levels of compounds I calculated by B3LYP, CAM-B3LYP, 3PW91,
WB97XD, and M06 functionals and the 6-31G(d,p) basis set. The HOMO and LUMO gave energy gaps are between
0.15614 eV and 0.29227 eV. The high energy gap is consistent with the high melting point of the compound and its low
solubility in most solvents.
CONCLUSIONS
2,7 11,16
N-[(9E)-8,10,17-Triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]benzamide
has been synthesized from the reaction of benzoyl isothiocyanate with 2(2-aminophenyl)-1H-benzimidazole. The compound
was characterized with spectroscopy, microanalysis, and GC-MS. The single crystal XRD molecular structure of N-[(9E)-
2,7 11,16
8,10,17-triazatetracyclo[8.7.0.0 .0 ]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide was discussed.
The experimental bond lengths and bond angles have been compared to the computed ones. The HOMO and LUMO energy
levels were also discussed.
ACKNOWLEDGMENTS
The authors would like to thank MRC for the financial support. F. Odame would like to thank NRF for the financial
support.
1184

CONFLICT OF INTERESTS
The authors declare that they have no conflict of interests.
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