Investigation of nicotinamide and isonicotinamide derivatives: A quantitative and qualitative structural analysis

Article abstract of DOI:10.1016/j.molstruc.2019.07.033

An anhydrous nature of benzylidene derivatives of nicotin and isonicotinamides crystal structures is determined and studied for their weak intermolecular interactions. The molecular structure is non-planar in general with the pyridine ring twisted with re

Full text of DOI:10.1016/j.molstruc.2019.07.033

Accepted Manuscript
Investigation of nicotinamide and isonicotinamide derivatives: A quantitative and
qualitative structural analysis
Gayathri Purushothaman, Deekshi Angira, Vijay Thiruvenkatam
PII:
S0022-2860(19)30867-1
DOI:
https://doi.org/10.1016/j.molstruc.2019.07.033
MOLSTR 26786
Reference:
To appear in: Journal of Molecular Structure
Received Date: 7 May 2019
Revised Date: 3 July 2019
Accepted Date: 6 July 2019
Please cite this article as: G. Purushothaman, D. Angira, V. Thiruvenkatam, Investigation of nicotinamide
and isonicotinamide derivatives: A quantitative and qualitative structural analysis, Journal of Molecular
Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.07.033.
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Graphical Abstract
Lattice energy involved in the intermolecular interactions in the isonicotinamide
derivatives.

ACCEPTED MANUSCRIPT
Investigation of nicotinamide and isonicotinamide derivatives: A
quantitative and qualitative structural analysis
Gayathri Purushothamana, Deekshi Angirab and Vijay Thiruvenkatama*
aDiscipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India
bDiscipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India
Correspondence email: vijay@iitgn.ac.in
Abstract An anhydrous nature of benzylidene derivatives of nicotin and isonicotinamides crystal structures
is determined and studied for their weak intermolecular interactions. The molecular structure is non-planar
in general with the pyridine ring twisted with respect to the central hydrazone moiety. The crystal
structures depict various intermolecular interactions, including N-H…O, C-H…O, N-H…N, and C-H…N
hydrogen bonding along with weak C-H…π and π…π contacts. Further, Hirshfeld surface and 2D-
fingerprint plot analysis confirm the role of intermolecular interactions in building the crystal packing in
these derivatives. The PIXELC energy calculation shows that dispersion energy plays an essential role in
stabilizing the crystal packing in all six derivatives.
Keywords: Nicotinamide, Isonicotinamide, Intermolecular interactions, Hirshfeld surface, 2D-Fingerprint
plots, and PIXELC calculations
1. Introduction
Nicotinamide and isonicotinamide have been investigated extensively in recent years because of their
biological activity, especially as potent inhibitors for many essential enzymes [1] [2] [3] and as an
antimalarial drug [4] [5]. Pyridoxal isonicotinoyl hydrazone and salicylaldehyde isonicotinoyl
hydrazone act as much stronger antimalarial agents than the Fe chelator in desferrioxamine (DFO),
which is widespread in clinical use [6]. Apart from antimalarial drugs, recently, these type of
molecules are highly used as a therapeutic invention for Alzheimer's disease. Isonicotinamide
derivatives are reported as β-Secretase inhibitors [7] [8]. These derivatives are proven inhibitor against
xanthine oxidase that is involved in the purine metabolism. The inhibition of xanthine oxidase helps in the
treatment of hyperuricemia and medical conditions like gout [9]. By considering the importance of these
molecules, we have studied a set of nicotinamide and isonicotinamide derivatives that are expected to
provide the conformational requirements of the molecules and suggests the topological inputs for the
design and synthesis of suitable inhibitors. We have studied the crystal structures of nicotinamides and

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isonicotinamides to understand the role of hydrogen bonds [10] [11] [12] [13] and π…π stacking
[14][15][16][17] in the crystal packing and the energy involved in the interactions. The study includes
four nicotin hydrazide derivatives: N-(2-methylbenzylidene)nicotinohydrazide(N1); N-(2-
nitrobenzylidene)nicotinohydrazide(N2);N-(2-bromobenzylidene)nicotinohydrazide (N3); N-(3,4,5-
trimethoxybenzylidene)nicotinohydrazide (N4) along with two isonicotin hydrazide derivatives: N-(2-
methylbenzylidene)isonicotinohydrazide (IN1); N-(4-methylbenzylidene)isonicotinohydrazide (IN2)
(Fig. 1a and 1b). Here, we present the structural features of all six compounds, both in terms of
conformational and intermolecular interactions. In the crystal structures, a strong N-H…O and weak
C-H…O, C-H…N,π…π [18] [19] intermolecular interactions have been studied for their contribution
in the crystal packing together with the energy involved in these interactions. The stability of the
crystal packing is revealed by the lattice energy calculations [20]. The crystal structures of
benzylidene derivatives of nicotin and isonicotin hydrazides endorse the occurrence of novel synthons
in the absence of water of crystallization. The presence of NH and CH in the central hydrazone moiety
generates N-H…O and C-H…O packing motifs with the neighboring carbonyl group as shown in Fig.
1c except for the O-methylbenzylidene isonicotin derivative, where the nitrogen of the pyridine ring
generates N-H…N and C-H…N packing motifs as shown in Fig. 1d.
Figure 1. Chemical structure of the compounds. a) N1: R1=CH3, R2=R3=R4=H; N2: R1=NO2, R2=R3=R4=H; N3:
R1=Br, R2=R3=R4=H; N4: R1=H, R2=R3=R4=OCH3; b) IN1: R1=CH3; R2=R3=H; IN2: R1=R2=H; R3=CH3; The
presence of NH and CH in the central hydrazone moiety generating c) N-H…O and C-H…O packing motifs with
carbonyl group; d) N-H…N and C-H…N packing motifs nitrogen of the pyridine ring
2

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2.1. Experimental methodology
To a solution of aldehyde/ ketone (1 mmol) in methanol (20ml), the corresponding acid hydrazide (1
mmol) was added. The resulting mixture was refluxed for 2hrs. In most cases, precipitation was
observed after 1 hour of refluxing. The solution was allowed to cool, the precipitate was filtered and
washed with 50ml of methanol and left for drying. For an additional purity, recrystallization was
carried out using methanol as solvent. Single crystals of desired size and quality were grown by slow
evaporation method at room temperature by dissolving the substance in various solvent combinations
like MeOH, DCM, DCM/CHCl3, and DCM/Hexane. In most of the cases, the quality of the crystals
was either a needle or a plate.
2.2. Cambridge Structural Database studies
Cambridge Structural Database (CSD, version 5.40, February 2019) was used for the detailed
evaluation of the previously reported crystal structures of nicotinamide and isonicotinamide. The
chemical scheme of both the molecules was used as a template for the search.
2.3. Crystallography
Single crystal X-ray diffraction data were collected on a Bruker AXS SMART APEX CCD
diffractometer using graphite monochromated MoKα (λ = 0.7107 Å) radiation at 290(2) K and the
intensities were measured using ω scan with a scan width of 0.3°. A total of 606 frames per set were
collected in different settings of φ (φ = 0o, 90o and 180o if the system is monoclinic; φ = 0o, 90o, 180o
and 270o if it is triclinic) keeping the sample to detector distance of 6.054 cm. Crystal data were
reduced by SAINTPLUS [21], and an empirical absorption correction was applied using the package
SADABS [21] available in the Bruker software package. All the crystal structures were solved by
direct methods using SHELXS97 [22] and refined by full-matrix least squares method using
SHELXL97 present in the program suite WinGX (Version 1.7.0) [23]. ORTEP diagrams of all the
compounds were generated using ORTEP32 [24] and packing diagrams were generated using
CAMERON and Mercury [25]. Geometrical calculations were performed using PARST and PLATON
[26].
2.4. Computational study
A quantitative and qualitative analysis of intermolecular interactions in nicotinamide and
isonictinamide derivatives were studied via Hirshfeld surface, and the short contacts were calculated
3

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by 2D fingerprint plot analysis [27] [28] [29]. The lattice energy involved in the intermolecular
interaction was calculated by CLP-PIXELC package (Version 3.0, Nov 2015) [20]. For all these
calculations crystallographic information files of the compounds were used as the input file.
3. Results and Discussion
3.1. Cambridge Structural Database studies
Cambridge Structural Database search resulted in no reports for N1, N2, N3, N4, IN1, and IN2
molecules. In the case of IN2, there are seven reported molecules, but they are crystallized either along
with water or along with solvent molecules. The CSD search with the nicotinamide moiety (Fig. 1a)
resulted in 99 hits, out of this, 70 hits were hydrated or crystallized with the solvent molecules and the rest
29 hits were with other scaffolds. Similarly, for the isonicotinamide moiety (Fig. 1b) there were 203 hits
from CSD database out of which 57 molecules were hydrated, and the rest 146 were with other scaffolds.
3.2. Crystal structure of nicotinamide and isonicotinamide derivatives
Figure 2 & 7 show the crystal structures of nicotinamide and isonicotinamide derivatives, respectively.
Table 1 & 2 lists the relevant crystallographic and intermolecular hydrogen bonding details of
nicotinamides; Table 3 & 4 lists the relevant crystallographic and intermolecular hydrogen bonding details
of isonicotinamides.
N1: The molecule (Fig. 2a) crystallizes in a centrosymmetric monoclinic space group, P21/c with Z = 4
with one molecule in the asymmetric unit. The intermolecular N-H…O, C-H…N, C-H…O hydrogen bond
forms molecular chains along the crystallographic b-axis. The packing feature shows (Fig. 3), linear C-
H…O and N-H…O interaction, which holds the molecules together. The nitrogen N1 atom of the pyridine
ring forms a dimer with the C2-H2A of the corresponding phenyl ring, with H2A…N1 distance of 2.81Å at
an angle C2-H2A…N1 of 135º. The stacking of molecules is in such a way that the pyridine ring of one
molecule is stacked parallel to the pyridine ring of the adjacent molecule along the c-axis generating π…π
weak intermolecular interactions, which adds to the stability of the crystal packing.
4

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Figure 2. ORTEP diagram of nicotinamide derivatives (a-d) drawn with 50% thermal ellipsoidal probability
Figure 3. Packing of molecules (N1) via strong N-H…O(), C-H…O, and C-H…N hydrogen bonds. The weak π…π
interaction assist the molecules to stack one on top of the other forming layered arrangement in the crystal lattice.
Unit cell viewed along the b-axis
5

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N2: The molecule (Fig. 2b) crystallizes in a centrosymmetric monoclinic space group, P21/c with Z =
4, one molecule in the asymmetric unit. The presence of C=O group generates these molecular chains
through intermolecular N-H…O, C-H…O hydrogen bonds along the crystallographic a-axis. Figure 4
shows the linear interaction by O1 atom of the C=O group generating C-H…O and N-H…O hydrogen
bonds along the a-c plane. Along with this, the para-substituted nitro group gives rise to C4-H4…O3
hydrogen bonding, where O3-H1 is having a bond distance of 2.42Å and C4-H4…O3 is at an angle of
140º. The pyridine ring N1 forms dimer with the C13-H13 of the substituted phenyl ring, with
H13…N1 distance of 2.58Å and C13-H13…N1 at an angle of 159º.
Figure 4. Packing of molecules N2 via strong N-H…O, C-H…O, and C-H…N hydrogen bonds
N3: The molecule (Fig. 2c) crystallizes in a centrosymmetric monoclinic space group, P21/c with Z = 4,
one molecule in the asymmetric unit. The packing features show (Fig. 5a), C-H…O and N-H…O
interaction, which holds the molecules together, generating molecular sheets. The stacking of molecules is
further stabilized by π…π interaction between the corresponding pyridine rings, as shown in (Fig. 5b).
6

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Figure 5. Packing molecules in N3 a) C-H…O and N-H…O intermolecular hydrogen bonding viewed along b-axis
and b) π…π interaction viewed along b-axis.
N4: The molecule crystallizes in a centrosymmetric monoclinic space group, P21/c with Z = 4 (Fig. 2d).
Figure 6 shows the C=O bifurcated interaction generating C-H…O and N-H…O hydrogen bonds; the
corresponding graph set is [R1 (6)]. Along with this, the tri-substituted methoxy group on the phenyl ring
2
form hydrogen bonds with the C=O of the central hydrazone moiety and the pyridine ring C-H.
Figure 6. a) Packing of molecules (N4) in the unit cell viewed along the a-axis. Shows N-H…O, bifurcated C-H…O
weak intermolecular interaction and b) C-H…N and C-H…O hydrogen bonding viewed along the b-axis
7

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IN1: The molecule crystallizes in a centrosymmetric monoclinic space group, P21/c with Z = 4 (Fig. 7a).
Here, the pyridine nitrogen N1 is involved in the bifurcated C-H…N and, N-H…N inter-molecular
hydrogen bonding as shown in the (Fig. 8a), the corresponding graph set notation is [R1 (7)]. The pyridine
2
ring C1-H1 forms hydrogen bonding with the corresponding carboxyl C=O group, giving rise to long chain
dimers. This layered formation further brings the molecules close enough to give weak π…π stacking
arrangement and further stabilizing the crystal packing.
Figure 7. ORTEP diagram of isonicotinamide derivatives a) IN1 and b) IN2 drawn with 50% thermal ellipsoidal
probability
Figure 8. Intermolecular interaction in isonicotinamide derivatives; a) IN1 and b) IN2
8

Table 1. Crystallographic and refin
A
em
C
e
C
nt
E
da
P
ta
T
o
E
f
D
nico
M
tin
A
am
N
id
U
e
S
de
C
riv
R
a
IPT
Crystal data
CCDC Number
Crystal size/mm
Solvent
N1
N2
N3
N4
668684
668685
668686
668688
0.6 x 0.3 x 0.25
MeOH
0.24 x 0.10 x 0.10
MeOH
0.10 x 0.10 x 0.10
MeOH
0.45 x 0.35 x 0.2
MeOH
Formula
C14 H13 N3 O1
C13 H10 N4 O3
270.25
C13 H10 N3 O1 Br1
304.14
C16 H17 N3 O4
315.33
Formula weight/g mol-1 239.27
Temperature/K
Radiation
Wavelength/Å
Crystal system
Space group
a/Å
b/Å
c/Å
α/º
290(2)
MoKα
0.71073
Monoclinic
P21/c
11.8902(12)
12.4720(13)
8.4155(9)
90
290(2)
MoKα
290(2)
MoKα
290(2)
MoKα
0.71073
Monoclinic
P21/c
5.068(3)
12.886(8)
19.123(12)
90
0.71073
Monoclinic
P21/c
12.050(2)
12.621(2)
8.309(15)
90
0.71073
Monoclinic
P21/c
9.180(4)
22.218(9)
7.625(3)
90
β/º
γ/º
91.130(2)
90
1247.7(2)
4
1.274
0.083
91.617(11)
90
1248.3(13)
4
1.438
0.106
92.964(3)
90
1262.0(4)
4
1.602
0.325
98.419(8)
90
1538.5(11)
4
1.361
0.100
Volume/Å3
Z
Density/g cm-3
µ/mm-1
F(000)
504
560
608
664
θmin,max
1.7, 25.5
1.9, 26.0
(-6,6),(-15,14),(-
23,21)
1.7, 25.0
(-14,14),(-15,13),(-
9,9)
1.8, 25.5
(-11,11),(-26,26),(-
9,9)
hmin,max, kmin,max, lmin,max (-14,13),(-15,15),(-
10,10)
Treatment
Hydrogens*
No of
measured
No
reflectionsz
of Constr
reflections 9160
of unique 2315
Constr
Constr
Constr
8052
2436
8854
2212
11398
2857
No of parameters
R_all, R_obs
Wr2_all, Wr2_obs
ꢀρmin, max/Eå-3
GoF
164
181
163
211
0.068, 0.046
0.108, 0.100
-0.137, 0.145
1.037
0.090, 0.048
0.105, 0.095
-0.163, 0.186
1.013
0.100, 0.045
0.086, 0.076
-0.272, 0.357
0.957
0.096, 0.054
0.121, 0.109
-0.193, 0.159
1.057
9

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Table 2. Intermolecular interactions in nicotinamide derivatives
Donor-H…Acceptor
N1
r(D-H)/Å
r(H…A)/Å
r(D…A)/Å
Symmetry Codes
D-H…A/º
163
141
135
170
N(2)-H(2)...O(1)i
C(7)-H(7)...O(1)ii
C(2)-H(2ª)...N(1)iii
C(11)-H(11)...N(3)iv
π…π interaction
0.86
0.93
0.93
0.93
π…π
2.06
2.48
2.81
2.74
Symmetry
Codes
2.897(16)
3.255(2)
3.529(2)
3.662(2)
i. x,1/2-y,1/2+z
ii. x,1/2-y,1/2+z
iii. –x+1,-y+1,-z-1
iv. –x,+y+1/2,-z+1/2
Cg(1)…Cg(1)i
Cg(2)…Cg(2)ii
N2
3.7999(10) i.1-x,1-y,-z
3.9903(11) ii.2-x,-,-z
N(2)-H(2ª)...O(1)i
C(7)-H(7)...O(1)ii
C(4)-H(4)...O(3)iii
C(13)-H(13)...N(1)iv
N3
0.86
0.93
0.93
0.93
2.05
2.35
2.42
2.58
2.875(3)
3.144(3)
3.189(3)
3.462(3)
159
143
140
159
i. -1+x,y,z
ii. -1+x,y,z
iii. -1-x,-1/2+y,1/2-z
iv. 1-x,-y,1-z
N(2)-H(2)...O(1)i
C(7)-H(7)...O(1)ii
C(1)-H(1)...O(1)iii
C(11)-H(11)...N(3)iv
0.86
0.93
0.93
0.93
2.04
2.52
2.84
2.73
2.882(4)
3.278(4)
3.418(4)
3.651(5)
165
139
122
170
i. x,3/2-y,-1/2+z
ii. x,3/2-y,-1/2+z
iii. x,-y+1/2,+z+1/2
iv.–x+2,+y-1/2,-
z+1/2+1
C(7)-H(7)...Br(1)
0.93
2.75
3.143(4)
106
-
Symmetric
Codes
i. 1-x,2-y,1-z
ii. –x,1-y,1-z
π...π interaction
π...π
Cg(1)…Cg(1)i
Cg(2)…Cg(2)ii
N4
3.696(2)
4.009(2)
N(2)-H(2)...O(1)i
C(7)-H(7)...O(1)ii
C(2)-H(2ª)...O(4)iii
C(4)-H(4)...O(2)iv
0.86
0.93
0.93
0.93
2.01
2.75
2.59
2.61
2.863(2)
3.500(3)
3.429(3)
3.492(3)
169
138
151
159
i. x,1/2-y,-1/2+z
ii. x,-y+1/2,+z-1/2
iii. -1+x,1/2-y,-3/2+z
iv.
–x+1,+y+1/2,-
z+1/2
C(14)-H(14B)...O(1)v
C(16)-H(16C)...N(3)vi
C(16)-H(16B)...N(1)vii
0.96
0.96
0.96
2.61
2.67
2.69
3.549(3)
3.323(3)
3.549(3)
165
126
149
v. –x+1,+y-1/2,-z+1/2
vi. x,-y+1/2,+z+1/2
vii.x+1,-
y+1/2,+z+1/2+1
viii. x+1,+y,+z+1
ix. x,-y+1/2,+z+1/2
-
C(16)-H(16ª)...N(1)viii
C(16)-H(16C)...O(1)ix
C(15)-H(15C)...O(4)
0.96
0.96
0.96
2.80
2.79
2.53
3.631(3)
3.746(3)
3.030(3)
145
172
113
10

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IN2: The molecule crystallizes in a centrosymmetric monoclinic space group, P21/c with Z = 4 (Fig.
7b). In Figure 8b, the molecules are packed to form C-H…O and C-H…N hydrogen bonds; the
corresponding graph-set notation is [R1 (6)]. Besides, π…π interaction further stabilizes the layered
2
arrangement forming extended chain dimers. The interaction pattern of IN2 is compared with the
reported molecules (SAYPAL; SAYQEQ; YUJJOE; YUJJOEO1; YUJRAY; OLECOZand 2AQMIP
[30]. It is interesting to observe that the graph-set analysis of previously reported molecules depicts
the interaction pattern and crystal packing driven by the solvent molecules. This indicates that the
anhydrous form of crystal structure might help to design more potent compounds since the interaction
pattern has arisen from the intermolecular interaction between the molecules.
Further, analyzing the nature of planarity of the molecules, the twist observed in both the nicotinamide
and isonicotinamide derivatives give rise to short contacts N2-H2A…O1 and C7-H7…O1 with the
carboxyl O1 of the adjacent molecule in the crystal packing. The strong hydrogen bonding interaction
with H2A…O1 has values ranging from 1.8 Å – 3.0 Å and the angle N2-H2A…O1 in the range of
148° - 172° and C7-H7…O1 intermolecular hydrogen bond values ranges from (H7…O1) 2.0 Å- 3.0 Å
and angle C7-H7…O1 in the range 122°-144° respectively. The molecules form elongated sheets held
in a zigzag manner giving rise to a unique supramolecular arrangement. In isonicotinamide, one can
see the molecules stacked in sheets/ layers which give rise to C-H…π, π…π weak intermolecular
interaction. In general, all the compounds show N-H…O, C-H…O, N-H…N, and C-H…N hydrogen
bonds dominating the packing with N…N, N…O, and C…O values ranging from 1.7 Å – 3.5 Å, and
the angle of N-H…N, N-H…O in the range 150°-172°.
11

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Table 3. Crystallographic and refinement data of isonicotinamide derivatives
Crystal data
CCDC Number
IN1
IN2
681130
681131
Crystal size/mm
Solvent
0.35 x 0.25 x 0.1
DCM
0.5 x 0.45 x 0.2
DCM
Formula
C14 H13 N3 O1
239.27
290(2)
C14 H13 N3 O1
239.27
290(2)
Formula weight/g mol-1
Temperature/K
Radiation
MoKα
MoKα
Wavelength/Å
Crystal system
Space group
a/Å
b/Å
c/Å
0.71073
Monoclinic
P21/c
7.480(2)
10.847(3)
15.226(5)
90
0.71073
Monoclinic
P21/c
18.618(5)
6.442(18)
10.213(3)
90
α/º
β/º
γ/º
96.796(6)
90
1226.7(6)
4
1.296
0.085
95.873(5)
90
1218.5(6)
4
1.304
0.085
Volume/Å3
Z
Density/g cm-3
µ/mm-1
F(000)
757
504
θmin,max
2.3, 26.0
(-9,9),(-13,13),(-18,18)
Constr
9348
2410
2.2, 25.0
(-22,22),(-7,7),(-12,11)
Constr
8291
2150
hmin,max, kmin,max, lmin,max
Treatment of Hydrogens*
No of reflections measured
No of unique reflections
No of parameters
R_all, R_obs
wR2_all, wR2_obs
ꢀρmin, max/eÅ-3
GoF
164
164
0.087, 0.054
0.123, 0.112
-0.136, 0.151
1.056
0.088, 0.057
0.139, 0.128
-0.160, 0.237
1.086
12

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Table 4. Intermolecular interactions in isonicotinamide derivatives
Donor-H…Acceptor r(D-H)/Å r(H…A)/Å
IN1
r(D…A)/Å
Symmetry Codes
D-H…A/º
161
161
152
N(2)-H(2)...N(1)i
C(1)-H(1)...O(1)ii
C(2)-H(2A)...N(1)iii
π...π interaction
Cg(1)-Cg(2)i
0.86
0.93
0.93
π...π
2.27
2.59
2.62
3.098(2)
3.481(3)
3.467(3)
i. 2-x,1/2+y,1/2-z
ii. x,1/2-y,1/2+z
iii. 2-x,1/2+y,1/2-z
Symmetry Codes
3.7589(17) i. 2-x,1-y,-z
3.7588(17) ii. 2-x,1-y,-z
Cg(2)-Cg(1)ii
IN2
N(2)-H(2)...O(1)i
C(4 )-H(4)...O(1)ii
C(7)-H(7)...O(1)iii
C(9)-H(9)...O(1)iv
C(9)-H(9)...N(3)v
C(5)-H(5)...N(1)vi
π...π interaction
Cg(1)-Cg(1)i
0.86
0.93
0.93
0.93
0.93
0.93
π...π
2.18
2.81
2.65
2.89
2.73
2.69
3.006(2)
3.424(2)
3.423(3)
3.451(3)
3.573(3)
3.491(3)
161
125
141
120
151
144
i. x,3/2-y,-1/2+z
ii. x,-y+1/2+1,+z-1/2
iii. x,-y+1/2+1,+z-1/2
iv. x,-y+1/2,+z-1/2
v. x,-y+1/2,+z-1/2
vi. -x+1,+y-1/2,-z+1/2
Symmetric Codes
3.6859(17) i. 1-x,2-y,1-z
3.3. Computational analysis of intermolecular interactions
The Hirshfeld surface (HS) and 2D fingerprint analysis of the molecules result in the thorough
investigation of intermolecular interactions. As a result, the HS was mapped with dnorm, shape index and
curvedness to visualize the major intermolecular interactions, π...π interactions and crystal stacking
respectively. Figure 9 shows the HS of nicotinamide derivatives mapped with dnorm that highlights the
major interacting atoms in the molecules. In all the nicotinamide derivatives, N-H…O is the major
interactions, and it is visualized by the presence of red color either in the donor molecule (nitrogen) or
acceptor (oxygen) molecules. Next, to N-H…O, C-H…O interaction plays a major role in the molecular
packing, and it can be seen by the presence of red color in the carbon (donor) or oxygen (acceptor)
molecule (Fig. S1). In N1 and N3 molecules, the contribution of π...π interactions is confirmed by the
presence of red and adjacent blue triangles in the HS surface mapped with the shape index (Fig. S2). The
similar interaction patterns with N-H...O followed by C-H...O, and π...π are observed in isonicotinamide
molecules (Fig. S3&S4). The major intermolecular interactions in the isonicatinamide derivatives are
mapped with dnorm in the HS of the molecules(Fig 10).
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Figure 9. Intermolecular interactions in a) N1 b) N2 c) N3, and d) N4 via Hirshfeld surface mapped with dnorm
Figure 10. Intermolecular interactions in the isonicotinamide derivatives a) IN1 b) IN2 via Hirshfeld surface mapped
with dnorm
14

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Further, the intermolecular interactions in the derivatives are analyzed by 2D fingerprint plot. The H-H, N-
H, C-H and O-H are the major short contacts in both nicotinamide and isonicotinamide derivatives (Table
5) which supports that N-H...O and C-H...O are the major interactions for the crystal packing. The
contribution of H...H (~50%) contacts is relatively more in N1 and N4. In N2, O...H (28%) and H...H
(23%) contribute almost equally to the interactions. In N3, H...H (33%), Br...H (14%), and C...H (14%)
contribute to the overall intermolecular interactions. IN1 and IN2 also follow the same pattern of short
contacts. A relatively higher contribution of C...C in N1, N3, and IN1 confirms the presence of π…π
interactions in the crystal packing (Fig S5 &S6).
Table 5. Contribution of different short contacts for the overall intermolecular interactions in nicotinamide and
isonicotinamide derivatives
Compounds
H…H (%)
N…H (%)
C…H (%)
O…H (%)
C…C (%)
N1
50
13
14
11
9
N2
23
16
20
29
2
N3
33
11
14
11
9
N4
44
10
15
23
4
IN1
47
13
17
12
8
IN2
46
13
19
12
5
Figure 11. Lattice energy involved in the intermolecular interactions in the nicotinamide derivatives a) N1 b) N2 c)
N3, and d) N4
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Figure 12. Lattice energy involved in the intermolecular interactions in the isonicotinamide derivatives; a) IN1 b)
IN2
3.4. Lattice energy calculation
The lattice energy involved in the stability of the crystal packing for all the reported nicotinamide and
isonicotinamide derivatives is shown in Table 6. The resulted lattice energy is partitioned into
dispersion, coulombic, polarisation, and repulsion components. The analysis indicates that both
nicotinamide and isonicotinamide derivatives are having the same pattern of energy distribution for
crystal packing. The total energy for the molecules is in the range from -150 to -200 kJmol-1 (Table
6). Amongst all, the dispersion energy plays a significant role in the stability of the packing in all the
derivatives. The energy provided by each molecular pair involved in the interaction is also analyzed
by the CLP, which is listed in Table 7. The results shows that in N1, N(2)-H(2)…O(1) (70.3 kJmol-1)
and C(11)-H(11)…N(3) (70.3 kJmol-1) (Fig. 11a) interactions contribute equally and significantly to
the stability of the molecule, followed by π…π interactions (-50 kJmol-1). In case of N2, N(2)-
H(2A)…O(1) (-65.6 kJmol-1) provides the maximum stabilisation energy followed by C(13)-
H(13)…N(1) (-59.6 kJmol-1) (Fig. 11b). In N3, the equal contribution of stabilization energy is given
by N(2)-H(2)…O(1) and C(7)-H(7)…O(1) interactions with -66.3 kJmol-1 each. The π…π interactions
also provide stabilization energy with the value of -46.4 kJmol-1 (Fig. 11c). Similar to N3, N4 also has
the maximum and equal contribution from N(2)-H(2)…O(1) and C(7)-H(7)…O(1) with the value of -
87.4 kJmol-1. Altogether the C-H…O interactions provide 80% of the total stabilization (Fig. 11d). It
is very interesting to observe in IN1, that the π…π interactions are providing the maximum
contribution (-120 kJmol-1) followed by N-H...N and C-H...N with -46 kJmol-1 (Fig. 12a). In IN2, the
stabilization energy pattern is similar to nicotinamide derivatives, where the N-H..O and C-H…O are
contributing more to the stability of the crystal packing (Fig. 12b).
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Table 6. Total lattice energy (kJmol-1) for nicotinamide and isonicotinamide derivatives
Compounds
Coul
-43.1
-56.6
-39.8
-67.4
-41.0
-45.2
Pol
Disp
Rep
43.9
61.7
45.5
65.1
42.8
41.4
Tot
N1
N2
N3
N4
IN1
IN2
-23.4
-29.2
-17.5
-36.2
-24.1
-24.6
-137.5
-148.9
-141.0
-176.0
-142.3
-139.9
-160.0
-173.0
-152.8
-214.5
-164.6
-168.4
Table 7. Total energy (kJmol-1) contribution from molecular pairs involved in intermolecular interactions in
nicotinamide and isonicotinamide derivatives
Compounds
Coul
Pol
Disp
Rep
Tot
Symmetry codes
N1
N(2)-H(2)...O(1)i
C(11)-H(11)...N(3)iv
Cg(1)…Cg(1)i
Cg(2)…Cg(2)ii
N2
-47.3
-47.3
-5.2
-17.2
-17.2
-3.4
-47.5
-47.5
-24.6
-41.4
41.8
41.8
13.0
20.1
-70.3
-70.3
-20.3
-29.8
x,1/2-y,1/2+z
x,1/2-y,1/2+z
–x+1,-y+1,-z-1
–x,+y+1/2,-z+1/2
-4.4
-4.0
N(2)-H(2A)...O(1)i
C(4)-H(4)...O(3)iii
C(13)-H(13)...N(1)iv
N3
-43.6
-12.1
-32.4
-16.6
-3.5
-12.3
-47.1
-13.5
-38.8
41.7
8.0
23.8
-65.6
-21.1
-59.6
-1+x,y,z
-1-x,-1/2+y,1/2-z
1-x,-y,1-z
N(2)-H(2)...O(1)i
C(7)-H(7)...O(1)ii
C(1)-H(1)...O(1)iii
Cg(1)…Cg(1)i
Cg(2)…Cg(2)ii
N4
-43.9
-43.9
-0.7
-4.9
-0.8
-15.4
-15.4
-2.5
-2.4
-1.8
-44.4
-44.4
-14.6
-21.4
-33.7
37.2
37.2
8.8
8.2
9.8
-66.4
-66.4
-9.0
-20.5
-26.4
x,3/2-y,-1/2+z
x,3/2-y,-1/2+z
x,-y+1/2,+z+1/2
1-x,2-y,1-z
-x,1-y,1-z
N(2)-H(2)...O(1)i
C(7)-H(7)...O(1)ii
C(2)-H(2A)...O(4)iii
C(4)-H(4)...O(2)iv
-56.4
-56.4
-9.9
-22.8
-22.8
-3.1
-69.2
-69.2
-14.9
-17.1
62.5
62.5
9.6
-85.8
-85.8
-18.4
-28.1
x,1/2-y,-1/2+z
x,-y+1/2,+z-1/2
-1+x,1/2-y,-3/2+z
-x+1,+y+1/2,-
z+1/2
-x+1,+y-1/2,-
z+1/2
x,-y+1/2,+z+1/2
-15.7
-4.7
9.4
C(14)-H(14B)...O(1)v
-2.2
-9.9
-9.9
-7.7
-56.4
-2.4
-3.1
3.1
-24.5
-14.9
-149
10
9.6
-19.1
-18.4
-18.4
-33.7
-85.8
C(16)-
H(16C)...N(3)vi
C(16)-
9.5
x+1,-
y+1/2,+z+1/2+1
x+1,+y,+z+1
H(16B)...N(1)vii
C(16)-
-5.6
-22.8
-31.1
-69.2
10.7
62.5
H(16A)...N(1)viii
C(16)-
x,-y+1/2,+z+1/2
H(16C)...O(1)ix
IN1
N(2)-H(2)...N(1)i
C(1)-H(1)...O(1)ii
C(2)-H(2A)...N(1)iii
Cg(1)-Cg(2)i
Cg(2)-Cg(1)ii
IN2
-33.6
-10.8
-33.6
-26.0
-26.0
-13.8
-3.6
-13.8
-9.1
-29.2
-13.8
-29.2
-69.0
-69.0
30.4
5.8
30.4
42.0
42.0
-46.2
-22.4
-46.2
-62.1
-62.1
2-x,1/2+y,1/2-z
x,1/2-y,1/2+z
2-x,1/2+y,1/2-z
2-x,1-y,-z
-9.1
2-x,1-y,-z
N(2)-H(2)...O(1)i
C(4 )-H(4)...O(1)ii
C(9)-H(9)...O(1)iv
-27.7
-27.7
-10.7
-9.9
-9.9
-6.2
-19.9
-19.9
-20.4
16.7
16.7
11.0
-40.7
-40.7
-26.4
x,3/2-y,-1/2+z
x,-y+1/2+1,+z-1/2
x,-y+1/2,+z-1/2
17

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C(9)-H(9)...N(3)v
C(5)-H(5)...N(1)vi
-10.7
-7.2
-6.2
-2. 9
-20.4
-10.4
11.0
5.3
-26.4
-15.2
x,-y+1/2,+z-1/2
-x+1,+y-1/2,-
z+1/2
Cg(1)-Cg(1)i
-1.6
-1.9
-20.5
9.6
-14.3
1-x,2-y,1-z
4. Conclusions
A series of substituted nicotinamide and isonicotinamide derivatives were crystallized in anhydrous
form and structures were determined. The crystallographic analysis shows different packing
arrangements in the unit cell due to different substitutions present on the function groups generating
various packing arrangements in the crystal lattice. From the experimental and computational studies
of the crystal structure, it is found that N-H...O hydrogen bonds play an important role in the
stabilization of the crystal packing along with C-H…N, C-H…O and π…π interactions. It clearly
shows that the presence of N-H and C-H in the central hydrazone moiety helps in generating N-H…O
and C-H…O packing motifs with the neighbouring carbonyl group with an exception, O-
methylbenzylidene isonicotinamide derivative, where the nitrogen of the pyridine ring generates N-
H…N and C-H…N packing motifs. The quantitative analysis of interactions via 2D fingerprint plot
shows the important role of weak intermolecular interactions in the crystal structure. The energy
calculation by PIXELC analysis highlighted the role of dispersion energy in governing the
stabilization in all the 6 crystal structures followed by coulombic and polarisation energies. The
examination of the intermolecular interactions allows for the analysis of the interaction strength and
energy with respect to the functional group. This work dealing with the extensive information on
various substitutions on the phenyl ring and the effectiveness of the weak interactions would throw
light on the binding site affinity of similar chemical scaffolds. It will also highlight the importance of
better design and synthesis of drug-like molecules that will ultimately aid for the understanding of the
interaction between the drug and their target enzyme.
Acknowledgement
The authors thank DST-FIST for Single crystal X-ray facility at IIT Gandhinagar. GP, DA & VT thank
IITGN and SERB for the lab infrastructure and funding.
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Highlights:
ꢀ Anhydrous nature of benzylidene derivatives of nicotinamides and isonicotinamides crystal
structures and their weak intermolecular interactions.
ꢀ A number of intermolecular interactions including N-H…O, C-H…O, N-H…N and C-H…N
hydrogen bonding along with weak C-H…π and π…π contacts are studied here.
ꢀ Hirshfeld surface and 2D-fingerprint plot analysis confirm the role of intermolecular
interactions in building the crystal packing.
ꢀ PIXELC energy calculation shows that dispersion energy plays an essential role in stabilizing
the crystal packing in all six derivatives.