Synthesis and solid state self-assembly of a 1,4-diazepine derivative: Water cluster as molecular glue and conformational isomerism

Article abstract of DOI:10.1016/j.molstruc.2020.127811

Diazepine (a seven membered heterocycle) derivatives have emerged as “privileged structures” in chemical biology and medicinal chemistry. In this article, synthesis of a 1, 4-diazepine derivative 4 from flavone 3 in excellent yield is described. The solid state self-assembly pertaining to diazepine derivative 4 was investigated with X-ray crystallography. Fascinatingly, the solid state structure of 4 represents a remarkable example of water cluster acting as structural glue to instigate conformational isomerism and hence facilitate the crystallization process by compensating the imbalance of hydrogen-bond donors and acceptors. NBO and QTAIM based calculations show that the hydrogen-bonding network of water molecules and hyper conjugative interactions play a vital role for stabilization of structure in the solid state. To our knowledge, presented here is the first illustration of any solvent cluster stabilizing the solid-state structure in a diazepine family. In addition, the crystal structure of flavone 3 hitherto not reported is also reported.

Full text of DOI:10.1016/j.molstruc.2020.127811

Journal Pre-proof
Synthesis and solid state self-assembly of a 1,4-diazepine derivative: Water cluster as
molecular glue and conformational isomerism
Mehwash Zia, Muhammad Khalid, Shahid Hameed, Elisabeth Irran, Muhammad
Moazzam Naseer
PII:
S0022-2860(20)30135-6
DOI:
https://doi.org/10.1016/j.molstruc.2020.127811
MOLSTR 127811
Reference:
To appear in: Journal of Molecular Structure
Received Date: 1 December 2019
Revised Date: 29 December 2019
Accepted Date: 28 January 2020
Please cite this article as: M. Zia, M. Khalid, S. Hameed, E. Irran, M.M. Naseer, Synthesis and solid
state self-assembly of a 1,4-diazepine derivative: Water cluster as molecular glue and conformational
isomerism, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.127811.
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Synthesis and solid state self-assembly of a 1,4-diazepine derivative:
water cluster as molecular glue and conformational isomerism
Mehwash Zia,a,bMuhammad Khalid,c ShahidHameeda,*, Elisabeth Irrand and
Muhammad Moazzam Naseera,*
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
bDepartment of Chemistry, Allama Iqbal Open University, Islamabad-44000, Pakistan
cDepartment Of Chemistry, Khwaja Fareed University of Engineering & Information Technology
64200-Rahim Yar Khan, Pakistan
dFakultät II Institutfür Chemie, TechnischeUniversität, Berlin-10623, Germany
*Email: shameed@qau.edu.pk (S.H.); moazzam@qau.edu.pk (M.M.N.)
Abstract:
Diazepine (a seven membered heterocycle) derivatives have emerged as “privileged structures”
in chemical biology and medicinal chemistry. In this article, synthesis of a 1, 4-diazepine
derivative 4 from flavone 3 in excellent yield is described. The solid state self-assembly
pertaining to diazepine derivative 4 was investigated with X-ray crystallography. Fascinatingly,
the solid state structure of 4represents a remarkable example of water cluster acting as structural
glue to instigate conformational isomerism and hence facilitate the crystallization process by
compensating the imbalance of hydrogen-bond donors and acceptors. NBO and QTAIM based
calculations show that the hydrogen-bonding network of water molecules and hyper conjugative
interactions play a vital role for stabilization of structure in the solid state. To our knowledge,
presented here is the first illustration of any solvent cluster stabilizing the solid-state structure in
a diazepine family. In addition, the crystal structure of flavone 3 hitherto not reported is also
reported.
Keywords: 1,4-Diazipine derivative, Synthesis, Self-assembly, Structural glue, Water cluster
1

Introduction
Diazepines are a significant class of bioactive heterocycles having numerous biological
applications [1-6]. Diazepine scaffold is in fact present in a number of drugs that has been used
for anxiolytic, sedative and anticonvulsant purposes for decades [7-10].Therefore, this is
regarded as the “privileged scaffold” in medicinal chemistry. Recently, the diazipine derivatives
have been found to inhibit acetyl-lysine bonding action related to bromodomain-comprising
proteins, that has importance as gene transcriptional activation for inflammation as well as
cancer [11]. Some of the diazipine derivatives have also been reported to be used as dyes for
acrylic fibers and in the synthesis of several other heterocyclic systems as intermediates [12-14].
Knowledge of the solid state self-assembly of molecular building blocks is important area of
research in crystal engineering, structural and supramolecular chemistry, as the assembly of
component molecules determine the material properties [15-19]. This is the only way to
purposely engineer the materials of required properties and activity. However, it is still
challenging to guess the solid state self-assembly processes due to the limited knowledge of
intermolecular forces and also due to the poor understanding of the role of different factors such
as temperature and solvent in crystallization [15-19].
The solid state self-assemblies involving water clusters have attracted considerable
attentionin the recent past [20-25]. The existence of well ordered water agglomerates in active
cleft of proteins such as Scarpharca dimeric haemoglobin [26], crambin [27], actinidin [28], and
carbonic anhydrase [29] have also been identified. Water also exhibit an important function in
stabilizing the conformation of native biopolymers and various other biological self-assembly
processes [30, 31]. Despite of the progress and extensive research both theoretical and
experimental on water clusters, the formation of water clusters and their role in stabilizing
2

especially the solid state self-assemblies of organic molecules is still poorly understood [20-25].
Therefore, the solid state self-assemblies of organic molecules driven by water clusters provide
an important platform for crystal engineers, structural and supramolecular chemists to understand
the underlying principles. Herein, as continuation of our interest in the supramolecular features
of solid state-self-assemblies [32-43], reported here is synthesis and solid state self-assembly of a
new diazepine derivative where water cluster serve as the molecular glue and is responsible for
the origin of conformational isomerism and hence crystallization by fulfilling the requirements of
extra hydrogen bond acceptors and donors.
Results and Discussion
Synthesis of seven membered 1,4-diazepine derivative 4 (Scheme 1 & Scheme 2) was initially
attempted from β-diketone 2 which was prepared from o-hydroxyacetphenone by its reaction
with o-methoxybenzoyl chloride in dry pyridine. Interestingly, our attempts to obtain 1,4-
diazepine derivative 4 from β-diketone 2 in ethanol solvent or in large excess of ethylene
diamine resulted in complex mixtures. However, when the acid was used as catalyst, the flavone
3was isolated along with mixture of byproducts. The flavone 3 was not only characterized by
spectroscopic techniques but also unambiguously through single crystal diffraction. Crystal
details, data acquisition and structure processing parameters of 3 are outlined inside Table 1. The
crystal structure (ORTEP picture) for 3 with crystallographic numbering procedure is shown in
Figure 1. Fascinatingly though, when flavone 3 was refluxed with large excess of ethylene
diamine, 1,4-diazepine 4 was obtained in 86% yield after recrystallization from ethanol solvent.
3

Scheme 1. Synthesis of a 1,4-diazipine derivatives 4
Scheme 2. Proposed reaction mechanism for the formation of 1,4-diazipine derivatives 4 from
flavone 3
4

Table 1. X-ray crystallography specifications of flavone 3 and1,4-diazepine 4
Crystal data
3
4
CCDC
1960580
C16H12O3
1960581
C18H20N2O3
312.36
Chemical formula
Mr
252.26
Crystal system, space group
Temperature (K)
a, b, c (Å)
Orthorhombic, Pna21
150
Monoclinic, P21/n
150
24.6478 (9), 3.9674 (1), 24.2477 (8) 13.6318 (2), 16.8648 (4), 13.7981 (3)
-
2371.13 (13)
8
101.5617 (18)
3107.78 (11)
8
β (°)
V (Å3)
Z
Radiation type
µ (mm-1)
Cu Kα
Cu Kα
0.80
0.74
Crystal size (mm)
Data collection
Diffractometer
0.49 × 0.12 × 0.07
0.22 × 0.19 × 0.15
SuperNova, Single source at offset,
Atlas
SuperNova, Single source at offset,
Atlas
Absorption correction
Multi-scan
Multi-scan
CrysAlis PRO 1.171.38.46 (Rigaku
Oxford Diffraction, 2015) Empirical
CrysAlis PRO 1.171.38.46 (Rigaku
Oxford Diffraction, 2015) Empirical
absorption correction using spherical absorption correction using spherical
harmonics, implemented in SCALE3 harmonics, implemented in SCALE3
ABSPACK scaling algorithm.
ABSPACK scaling algorithm.
Tmin, Tmax
0.698, 0.944
0.857, 0.897
No. of measured, independent and
8612, 3931, 3527
12277, 5612, 4462
observed [I> 2σ(I)] reflections
Rint
0.031
0.599
0.029
0.599
(sin θ/λ)max (Å-1)
Refinement
R[F2> 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
H-atom treatment
0.076, 0.181, 1.05
0.037, 0.095, 1.04
3931
345
5612
443
H-atom parameters constrained
H atoms treated by a mixture of
independent and constrained refinement
∆〉max, ∆〉min (e Å-3)
0.94, -0.28
0.18, -0.23
5

Absolute structure
Flack H D (1983), ActaCryst. A39,
876-881
-
-
Absolute structure parameter
0.3 (4)
Figure 1. X-ray crystal structure for flavone3 having two conformational isomers in the solid
state. Selected bond lengths(Å):conformer A/B;O(1)-C(1)/O(4)-C(17) 1.376(6)/1.369(6),O(1)-
C(5)/O(4)-C(21)1.384(6)/1.379(6),
C(27)1.374(6)/1.368(6); Selected bond angles (°): conformer A/B;C(1)-O(1)-C(5)/C(17)-O(4)-
C(21)119.5(4)/120.2(4), O(2)-C(3)-C(2)/O(5)-C(19)-C(18)123.4(5)/123.2(5),O(2)-C(3)-
O(2)-C(3)/O(5)-C(19)1.229(6)/1.243(6),O(3)-C(11)/O(6)-
C(4)/O(5)-C(19)-C(20)122.7(5)/121.8(5).
Single crystals of 1,4-diazepine 4, appropriate to X-ray study were produced from slow
vaporisation of ethanolic solution, they exhibited monoclinic crystal lattice having P21/n space
group. Crystal structure refinement details and data collection for 4 are summed up in Table 1.
The crystal structure (ORTEP diagram) of 1,4-diazepine 4 along with crystallographic
numbering scheme be depicted in Figure 2.
6

Figure 2. Molecular framework for 1,4-diazepine 4 (ORTEP diagram).
A unit cell consists of two independent molecules of 1,4-diazepine 4 (conformer A & B,
possessing faintly unsimilar bond angles and bond lengths) as well as two hydrate water
molecules. The diazepine ring acquires twist half-chair conformation having N(1)-C(2)-C(1)-
C(5)-N(2) (conformer A) and N(3)-C(20)-C(19)-C(23)-N(4) (conformer B) atoms in nearly one
plane. Dihedral angles among C(2)-C(1)-C(5)-N(2), C(20)-C(19)-C(23)-N(4),N(1)-C(2)-C(1)-
C(5)-N(2) and N(3)-C(20)-C(19)-C(23) are11.66°, -8.15°, 13.48° and -19.01°, respectively. The
methoxy bearing aryl substituent is more tilted to this plane of diazepine ring as compared to the
other aryl substituent which is almost present in the same plane[C(11)-C(6)-C(2)-N(1) 17.91°
and C(29)-C(24)-C(20)-N(3)-8.60° vs C(17)-C(12)-C(5)-N(2) -121.96° and C(35)-C(30)-C(23)-
N(4)132.78°]. This planarity with slight distortions is most probably due to the extensive
7

electron delocalization between various tautomeric forms of 4(Figure 3) and/or because of strong
intramolecular hydrogen bond [N(1)-H(1)···O(1) 1.793 Å in conformer A and N(3)-H(3)···O(3)
1.671 Å in conformer B]. The equilibrium between different tautomeric forms and electron
delocalization as highlighted in Figure 3 is further supported by the partial double bond character
of C(1)-C(2), C(1)-C(5), C(19)-C(20) and C(19)-C(23) which is evident from their shorter bond
distances (please see Table 2 for details of bond angles and bond distances).
Figure 3. Tautomeric forms of 1,4-diazipine derivative 4.
Table 2.Selected structural parameters of 1,4-diazepine derivative 4; bond lengths (Å) along
with bond angles (°) by the X-ray crystallography.
Conformer A/B
Conformer A
1.3238(19)
1.4430(19)
1.333(2)
Conformer B
1.3213(19)
1.441(2)
N(1)-C(2)/N(3)-C(20)
N(1)-C3/N(3)-C(21)
N(2)-C(5)/ N(4)-C(23)
N(2)-C(4)/N(4)-C(22)
1.338(2)
1.4457(18)
1.4447(17)
8

O(1)-C(11) /O(3)-C(29)
1.3122(19)
1.383(2)
1.3032(19)
1.383(2)
C(1)-C(5)/ C(19)-C(23)
C(1)-C(2)/ C(19)-C(20)
1.4220(19)
1.472(2)
1.4320(18)
1.472(2)
C(2)-C(6)/ C(20)-C(24)
C(6)-C(11)/ C(24)-C(29)
1.434(2)
1.4445(19)
1.528(2)
C(3)-C(4)/C(21)-C(22)
1.526(2)
C(2)-N(1)-C(3)/ C(20)-N(3)-C(21)
C(5)-N(2)-C(4)/ C(23)-N(4)-C(22)
N(1)-C(2)-C(1)/ N(3)-C(20)-C(19)
N(1)-C(2)-C(6)/ N(3)-C(20)-C(24)
C(1)-C(2)-C(6)/C(19)-C(20)-C(24)
N(1)-C(3)-C(4)/ N(3)-C(21)-C(22)
N(2)-C(4)-C(3)/ N(4)-C(22)-C(21)
N(2)-C(5)-C(1)/ N(4)-C(23)-C(19)
N(2)-C(5)-C(12)/ N(4)-C(23)-C(30)
C(1)-C(5)-C(12)/C(19)-C(23)-C(30)
125.10(12)
123.61(13)
124.06(13)
116.24(12)
119.66(13)
112.11(12)
112.49(12)
127.86(13)
114.52(13)
117.57(13)
125.02(12)
123.84(13)
124.00(14)
115.41(12)
120.58(13)
111.91(13)
111.87(13)
126.87(12)
113.74(12)
119.15(13)
The most remarkable feature of seven-membered diazepine 4 is its molecular packing in solid
form, maintained by water cluster. Two water molecules in this solid state self-assembly in fact
are acting as structural glue by providing the additional hydrogen bond donors/acceptors required
to form a crystalline solid, hence enabling crystallization. Furthermore, the shift of hydrogen
9

from oxygen [O(1)/O(3)] to nitrogen [N(1)/N(3)]in the solid state structure of 4 and appearance
of two conformational isomers (Figure 2) resulted most probably to compensate the imbalance of
required hydrogen bond donors and acceptors. To very best by our comprehension, this
represents the first case of structure stabilization by water cluster in a diazepine family; although
the water molecule as hemihydrate has previously been found stabilizing the solid state packing
[44]. Thus, the majority of hydrogen bonds forming the intermolecular networks are formed by
crystal water. In solid state self-assembly of diazipine4, the four water molecules connected to
each other[O(6)-H(6B)···O(5) 1.909 Å]and with eight molecules of diazipines (four conformer A
& four conformer B)[O(5)-H(5A)···O(1) 1.908 Å, O(6)-H(6A)···O(1) 1.845 Å, O(5)-
H(5B)···O(3) 1.804 Å, O(5)-H(5A)···N(1) 2.738 Å, N(4)-H(4)···O(5) 1.984 Å, N(2)-
H(2)···O(6) 1.837 Å] represent the fundamental supramolecular unit of the crystal construction
(Figure 4a).It is interesting to see that four water molecules in this entity along with O(1) of two
aryl rings appear like a cyclohexane in its chair conformation (Figure 4b). Similar
supramolecular entities extend in three dimensions to furnish general 3D frame work of 4 (Figure
5a & 5b). The other notable weak non-covalent interactions involve in this solid state self-
assembly are CH···O [C(36)-H(36A)···O(3) 2.525 Å] and CH···π [C(36)-H(36C)···C(6)
interactions.
10

(a)
(b)
Figure 4.a) Showing water cluster surrounded by eight molecules of 1,4-diazepine, four each of
conformer A and B; b) showing chair-like conformation involving four water molecules and two
11

O(1) atoms of diazipine, and close view of non-covalent interactions of water cluster with eight
neighboring molecules in solid state self-assembly pertaining to 1,4-diazepine 4
(a)
(b)
Figure 5. Showing 1D-extension of basic supramolecular entity in solid state structure regarding
1,4-diazepine 4; a) along c-axis; b) along b-axis
To evaluate the thermal stability of the crystal structure of 1,4-diazepine 4, thermogravimetric
analysis [45-49] was carried out. The TGA and its differential curve (DTG) is shown in Figure 6
and depicted three decomposition steps. The first step showed a mass loss of 5.6% in the range
of 89-158 °C. The second step exhibited a large mass loss of 75% at temperature range 221-419
°C. In addition mass loss of 19.4% has been observed in temperature interval of 475-800 °C.
Three DTG curves maxima for the three decomposition steps were observed at 110 °C, 320 °C
12

and 627 °C respectively. The first decomposition step is suggested to be due to the elimination of
trapped water molecules and decomposition of the aliphatic moiety in the crystals of compound
4. The char residues at 600 °C, 700 °C and 800 °C were observed to be 16%, 7% and 2%
respectively.
Figure 6. TGA/DTG curves of 1,4-diazepine 4 at 20 °C/min heating rate.
The DSC curve (figure 7) obtained for heating amount of 20 °C exhibited two endothermic
maxima at 119.3 °C and 199.8 °C which may be attributed to the phase changes of compound 4.
13

Figure 7. DSC curve of 1,4-diazepine 4 obtained at heating rate of 20 °C/min
To further highlight the role of water cluster in stabilizing the solid-state self-assembly, the NBO
and QTAIM analysis were carried out.
Natural bond orbital (NBO) analysis
NBO analysis is frequently used for unveiling atomic charges, orbital hybridization and orbital
interactions in investigated molecules [50]. Moreover, bonds interactions, existence of hydrogen
bonding (H.B) and non-covalent interactions (NCIs) initiated by hyper-conjugative interactions
(HCI) are successfully explored using NBO analysis [51-55]. In this context, NBO analysis has
become an attractive method for chemist community to rationalize the intermolecular as well as
intramolecular transitions established by filled and virtual orbitals [56]. The tremendous
interactions of donors and acceptors are become the reason of precedence to substantial
stabilization energy [57]. The NBO based studies for investigated 1,4-diazepine 4 were
performed by B3LYP/6-31G(d,p) level of DFT (Figure 8). The significant NBO interactions are
elaborated in Table S1. Moreover, some NBO representative values for 4 can be seen in Table 3.
14

Figure 8: NBO numbering scheme of 1,4-diazepine derivative 4.
Table 3: Second order perturbation theory analysis of Fock matrix on NBO basis for 1,4-diazepine 4
Donor(i)
Type
Acceptor(j)
Type
E(2)
E(J)-E(i)
F(I,j)
∗
C74-C76
C47-C56
C7 - C16
C18-C20
C30-C32
C34-C36
C74-C76
N3
σ
0.05
0.81
0.35
0.34
0.38
0.35
0.37
0.37
0.38
0.013
0.104
0.111
0.095
0.097
0.100
0.099
0.156
C18-H19
N41-C49
N1-C9
∂
π
π
π
π
π
π
π
π
*
*
*
*
*
*
*
33.87
40.68
29.18
32.82
33.19
33.41
78.83
π
π
C22-C24
C27-C28
C30-C32
C70-C72
C7-C16
π
π
π
LP(1)
15

N43
O46
O6
LP (1)
LP(2)
LP(2)
LP(1)
π
π
π
*
*
*
70.61
38.07
37.70
6.64
0.39
0.43
0.43
1.68
0.149
0.122
0.121
0.095
C47-C56
C74-C76
C34-C36
O84-H85
O5
σ*
(i) donor, (j) acceptor, E(2) illustrates energy of hyper conjugative interaction (stabilization energy)., E(j) _ E(i) is
the difference in energy between donor and acceptor i and j NBO orbitals., F(i, j) is the Fock matrix element
between i and j NBO orbitals.
The NBO findings mentioned in Table 3 depict that four kind of transitions including π→π*,
σ→σ*, LP→π* and LP→σ* are generally found for the title compound. It is generally believed
that stabilization of investigated molecule is predominantly governed by intra-molecular charge
transfer which leads to powerful intra-molecular HCIs [58, 59]. The most prominent values for
stabilization for the investigated molecule is observed for π→π* transitions, while intermediate
type stabilization energy values are offered by LP→σ* and LP→π* transitions. Contrarily,
transitions in the domain of σ→σ* having less magnitude of stabilization energy values are
noticed for investigated compound.
Among all transitions, π→π* plausible electronic transitions π(C7-C16)→ π*(N1-C9) is uncovered
with highest magnitude of stabilization energy value 40.68 kcal/mol in 1,4-diazepine 4(Table 3).
The subsistence of conjugation in investigated molecule is proven from π→π* probable
transitions which stabilized the rings due to HCIs bonding orbitals from C-C to anti-bonding
orbitals of C-C. Transitions exposed as π(C47-C56)→π*(N41-C49), π(C18-C20)→π*( C22-
C24), π(C30-C32)→π*(C27-C28), π(C34-C36)→π*(C30-C32) and π(C74-C76)→π*(C70-C72)
yielding 33.87, 29.18, 32.82, 33.19 and 33.41 kcal/mol stabilization energy values respectively
in1,4-diazepine 4 unveiling the presence of conjugation (Table3). The σ→σ* transitions initiate
from emasculate donor (σ)-acceptor (σ*) interactivity leads to smaller stabilization energy values
16

in comparison to π→π* transitions. The somewhat smaller stabilization energy amount of 0.05
kcal/mol is noticed because of σ(C74-C76)→σ*(C18-H19) transition in1,4-diazepine 4. This,
stabilization energy value is found smaller ones among all stabilization energies owing to weak
interactions among electron acceptor and donor groups.
The transitions in case of resonance are found to be LP(1)-N3→π*(C7-C16), LP(1)-
N43→π*(C47-C56), LP(2)-O46→π*(C74-C76), LP(2)-O6→π*(C34-C36) and LP(1)-
O5→σ*(C84-H85) which yield the stabilization energies of 78.07, 70.61, 38.07, 37.70 and 6.64
kcal/mol respectively in 1,4-diazepine 4. Overall, the charge transfer (π→π*) interactions have
been examined for all sorts of bonds as C-C, C-N, C-O and N-N which is a strong proof for
existence of conjugation for 1,4-diazepine 4. From NBO findings, it might be concluded that
extended conjugation, intermolecular charge transfer and hyperconjugative interactions are main
causes for stability of studied compound.
Exploration of hydrogen bonding by NBO Analysis
NBO calculations were also accomplished to explore the strengths of the hydrogen-
bonding interactions which could be estimated from the delocalization of electron density
flanked by antibonding and natural bonding orbitals (Table 4). The N-H…O=C hydrogen-bond
energies are calculated in terms of stabilization energy E(2) in the gas phase. The favorable
stabilization energies are obtained in present study owing to strong intermolecular hydrogen
bonding (Table 4)
.
Table 4: Inter and intramolecular hydrogen bonds (IHB) for 1,4-diazepine 4by NBO method
E(2)a
[kcal/mol]
5.07
E(j)_E(i) b
[a.u.]
1.47
F(i; j)c
[a.u.]
0.078
0.150
0.075
0.040
Donor(i)
Type
Acceptor(j)
Type
O45
O45
O5
LP (1)
LP (2)
LP (1)
LP (2)
N41-H42
N41-H42
O81-H82
O81-H82
σ
σ
σ
σ
*
*
*
*
25.61
4.50
1.73
1.07
1.56
1.11
O5
17

O5
O5
O5
O5
O5
O5
O5
LP(3)
LP(1)
LP(2)
LP(3)
LP(1)
LP(2)
LP(3)
O81-H82
O84-H85
O84-H85
O84-H85
N1-H2
σ
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
*
5.43
6.64
2.90
2.44
3.75
12.07
0.71
1.07
1.68
1.24
1.19
1.56
1.11
1.07
0.074
0.095
0.054
0.052
0.068
0.105
0.027
N1-H2
N1-H2
a
ED=electron density, Comp =compound, E(2) shows hyper conjugative interaction energy (stabilization energy in
b
c
kcal/mol), E depicts difference in energy between donor along with acceptor i and j NBO orbitals, F(i; j) is Fock
matrix element among i and j NBO orbitals.
For 1,4-diazepine 4, the network of intermolecular hydrogen bonds (IHB) was established
owing to delocalization of electron charge density through lone pairs [LP(1) and LP(2)] of O45
to σ* bond of N41-H42 which bring about 5.07 and 25.61 kcal/mol stabilization energies
respectively. In similar fashion, 4.50, 1.73 and 5.43 kcal/mol stabilization energy is noted when
LP(1), LP(2) and LP(3) of O5 delocalized their charge density to the σ* of O81-H82 respectively
(Table 4 and Figure S1). The delocalization of charge density from LP(1), LP(2) and LP(3) of
O5 to σ* of O84-H85 offer stabilization energy values of 6.64, 2.90 and 2.44 kcal/mol
respectively. Similarly, the delocalization of LP(1), LP(2) and LP(3) of O5 to σ* of N1-H2
having stabilization energies: 3.75, 12.07 and 0.71 kcal/mol respectively (Table 4 and Figure
S1). On the basis of above-mentioned findings, it is evident that the cohesive H-bond assembly
instigates conformational isomerism in the solid-state structure of 1,4-diazepine 4. It is also the
explicit depiction for good harmony among NBO and SC-XRD findings. The significant
intermolecular hydrogen bonds (IHBs) are shown by NBO plots in Figure 9.
18

[LP(1)(O5)
→
σ
σ
*(O81-H82)+
LP(2)(O5)
*(O81-H82)]
LP(2)(O5)
→
+
[LP(1)(O5)
→
σ
σ
*(O81-H82)+
*(O84-H85)+
LP(2)(O5)
→
→
σ*(O81-H82)+ LP(3)(O5)
→
σ
σ
*(O81-H82)+ LP(3)(O5)→ σ*(O81-H82)] +
[LP(1)(O5)
→
*(O84-H85)+
→
[LP(1)(O5)→
LP(2)(O5)
σ*(O84-H85)+ LP(3)(O5)→ σ*(O84-H85)]
σ
*(O84-H85)+ LP(3)(O5)→ σ*(O84-H85)] +
[LP(1)(O45) *(N41-H42)
LP(2)(O45)→σ*(N41-H42)]
→
σ
+
Figure 9: Network of Hydrogen bond illustrated by donor–acceptor interaction among the lone
pair and anti-bonding orbitals of 1, 4-diazepine derivative 4.
QTAIM Analysis
Richard Bader [60, 61] developed quantum theory of atoms in molecules (QTAIM). QTAIM
investigation is recognized as sophisticated approach for characterization of hydrogen bonds plus
non-covalent interactions (NCIs) [62]. Electron density Rho ρ(r) is main ingredient of this theory
and it is usually used to elucidate the atomic properties of any chemical system. The Atoms in
Molecules (AIM) approaches chances of topological examination for bonds that are marked by
ꢁ ꢃ
coming across of vector ∇ꢀ ꢂ path lines for two distinct attractors is called Bond Critical Point
19

(BCP). Thus, the line which joins two atoms with the help of same BCP is known Bond Path
(BP). We performed QTAIM analysis of 1, 4-diazepine derivative 4 to characterize the
topological structure by using AIMAll package [63]. The analysis of BCPs are shown in Table
S2 while some selected values have been shown here in Table 5 and its schematic structure
diagram is shown in Figure 10.
Table 5: Electronic density (ꢀ), Laplacian of density (∇ꢄꢀ), ellipticity (ε) and density of
potential energy (V). (Selected Values)
ꢆꢇꢅ (e/a5)
+0.147509
-0.426129
-0.286178
-0.233589
+0.088579
+0.009431
+0.010758
+0.015043
+0.178879
+0.006700
-0.382692
-0.299307
-0.267732
+0.063451
+0.017308
+0.014235
Bond
ꢅ (e/a3)
ꢈ
ꢉ (hartree.e/a3)
-0.036359
-0.967310
-0.798038
-0.626966
-0.022619
-0.001526
-0.001210
-0.002090
-0.048067
-0.000906
-1.007595
-0.789176
-0.611270
-0.008012
-0.002409
-0.001845
+0.040223
+0.331259
+0.285737
+0.242286
+0.026762
+0.003532
+0.002842
+0.004681
+0.052925
+0.002330
+0.338322
+0.284403
+0.241295
+0.012144
+0.005239
+0.004031
+0.096342
+0.003544
+0.023994
+0.025475
+0.078214
+1.196881
+0.750252
+0.227573
+0.050143
+1.332569
+0.019531
+0.020065
+0.025804
+1.910077
+0.453863
+1.021840
H2 - O5
O5 - C26
O6 - C36
O6 - C37
O5 - H82
C7 - C70
H29 - H71
C28 - H73
H42 - O45
C20 - H48
O45 - C66
O46 - C76
O46 - C77
H48 - H59
C22 - H59
C22 - H61
20

+0.005584
+0.001892
+0.031255
+0.000018
+0.016405
+0.006863
+0.111925
+0.000115
+0.639310
+0.085646
+0.016599
+0.130796
-0.002631
-0.000818
-0.026988
-0.000008
H19 - C74
H21 - H80
O5 - H85
H38 - H83
Figure 10: Schematic Structure Diagram for the 1, 4-diazepine derivative 4
We performed AIM calculations on conformational isomers of 1, 4-diazepine derivative 4 to
ensure the existence of hydrogen bonds and additional non-covalent interactions (NCIs). AIM
measurements revealed that the strongest hydrogen bond (ρ=0.0529) is observed due to H42-O45
among all types of interactions. Moreover, the molecules of water interacted with the molecule
of substrate through two hydrogen bonds, such as O5-H85 (ρ=0.0312) and O5-H82 (ρ=0.0268)
21

as shown in Table 5. However, the hydrogen bonds O5-H82 (ρ=0.0268) was found a weakened
hydrogen bond due to the presence of another hydrogen bond at O5 atom, i.e., O5-H2
(ρ=0.0402). Apart from the hydrogen bonds, the AIM analysis showed bunch of non-classical
interactions between the individual conformers with less ellipticity values, depicting dispersive
interactions having higher directionality. These non-classical interactions such as the C28-H73
(ρ=0.0047), C20-H48 (ρ=0.0023), C22-H59 (ρ=0.0052), C22-H61 (ρ=0.004) and H19-C74
(ρ=0.0056) bonds found in conformational isomers might also be playing some role in the
stabilization of structure.
Conclusions
In conclusion, we have described synthesis and solid state-self-assembly attributed to a diazipine
(a privileged seven membered heterocycle) derivative 4, driven mainly by water clusters. The
major supramolecular force that is responsible for the stabilization of intermolecular networks of
this self-assembly is hydrogen bonding and almost all the intermolecular hydrogen bonds are
developed either among water-water or diazipine-water molecules. Therefore, crystal water
cluster act as a structural glue in the solid state to bring about conformational isomerism and a
balance of hydrogen-bond donors and acceptors. This crystal structure particularly highlights the
crucial role of solvents in the formation of crystal structures which is an important consideration
for crystal engineers and structural chemists to design a solid of desired properties. The
hydrogen-bond energies of this water cluster driven self-assembly have been calculated by NBO
and QTAIM analysis. The maximum stabilization energies reached up to 5.43, 6.64, 12.07 and
25.61 kcal/mol for C26-O5…..H82-O81, C26-O5…..H85-O84, C26-O5…..H1-N2 and C66-
O45…..H42-N41,respectively. On account of these stabilization energies, it can safely be inferred
that water cluster acts as structural glue bymeans of cohesive H-bonds leading to the
22

conformational isomerism in the solid state self-assembly of 4. All our attempts to obtain solvent
less crystals of this diazepine have failed so far. New diazepine derivative 4 presented in this
paper having two binding pockets is an interesting prospect for coordination chemistry. We are
currently exploring its biological potential and its potential in coordination chemistry.
Experimental
General
All reagents and solvents were utilized as acquired from the supplier and purified when required.
Thin layer chromatography was carried out by using silica gel 60 F254 (Merck) coated aluminium
sheets. Melting points were obtained in open capillaries using Gallen Kamp melting point
apparatus. IR spectra were gained from Schimadzu Fourier Transform Infra Red
13
Spectrophotometer Model 270 employing ATR facility. 1H and C NMR spectra were obtained
on Bruker spectrometer at 300 and 75 MHz in d6-DMSO taking tetramethylsilane (TMS) as
standard. . Thermal stability was determined using thermogravimetric analyzer model TGA-7 by
Perkin Elmer (USA). TGA analysis experiments were carried out at a scanning rate of 20°C/min
from room temperature to 850ºC under Nitrogen atmosphere. CHNS analysis was done on Leco
CHNS-932, Model 601-800-500.
Synthesis of 2-acetylphenyl-2´-methoxybenzoate 1
2-Substitutedbenzoyloxyactophenone 1 was prepared according to reported procedure [64]. To
the o-hydroxyacetphenone (1.36 g, 10 mmol) dissolved in 10 ml of dry pyridine at ambient
temperature, the o-methoxybenzoyl chloride (15 mmol) was added while stirring in about 5
minutes. The reaction mixture which became hot, was further stirred for another 30 minutes.
Then it was poured onto crushed ice containing 3% HCl (125 mL) and stirred at room
temperature overnight. The solid appeared was filtered, washed out with ice cold water (~
23

10mL), cold methanol (~5mL) and again with water (~20mL). The obtained crude product was
finally recrystallised with ethanol to get pure product.
Colorless solid, m.p: 88oC, Yield: 74 %; FTIR: (ʋ /cm-1) 2964, 2837(sp3 C-H stretch), 1739(C=O
stretch), 1475 (aromatic C=C stretch), 1448(sp3 C-H bend), 1261 (C-O stretch), 754 (sp2 C-H
1
bend). H NMR (300 MHz, DMSO-d6) δ ppm: 2.50(s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.09 (m,
1H, Ar-H), 7.21 (d, 1H, J=8.1, Ar-H), 7.31 (dd, 1H, J=0.9, 7.2, Ar-H), 7.41 (m, 1H, Ar-H), 7.61
(m, 1H, Ar-H), 7.91 (dd, 1H, J=1.8, 6, Ar-H), 7.98 (dd, 1H, J=1.8, 6, Ar-H). 13C NMR (300
MHz, DMSO-d6) δ ppm: 198.1, 163.9, 159.6, 148.9, 135.1, 134.0, 132.2, 131.6, 130.6, 126.7,
124.5, 120.6, 118.7, 113.1, 56.3, 29.9. [59].
Synthesis of 1-(2-hydroxyphenyl)-3-(2-methoxyphenyl)propane-1,3-dione 2
In a round bottom flask of 250 ml capacity equipped with a condenser, drying tube, mechanical
stirrer and side arm funnel, compounds 1 (20 mmol) was added and dissolved in pyridine (20mL)
and kept below 5°C with ice bath. Then powdered potassium tertiary butoxide (10 g) was added
to the reaction flask and stirred the resulting mixture for 2 hours. During this time thick yellow
precipitate appeared which were acidified with 3% HCl and extracted the reaction mixture with
THF (3×50 mL). After removal of THF under vacuum, the solid obtained was purified by
column employing petroleum ether and ethyl acetate as eluent.
Yellow solid, m.p. 79-80 oC Yield: 73 %; FTIR: (ʋ /cm-1) 2962 (sp3 C-H stretch), 1595 (sp2 C=C
1
stretch), 1487 (C=C stretch), 1240 (C-O stretch), 758 (sp2 C-H bend). H NMR (300 MHz,
CDCl3) δ ppm: 3.67(s, 1H, CH2), 3.99 (s, 3H, OCH3), 4.63 (s, 1H, -CH=), 6.90 (m, 1H, Ar-H),
7.00 (m, 3H, Ar-H), 7.43 (m, 2H, Ar-H), 7.71 (m, 1H, Ar-H), 7.95 (m, 1H, Ar-H), 12.00 (s, 1H,
phenolic H), 15.61 (s, 1H, enolic H). 13C NMR (300 MHz, DMSO-d6) δ ppm:188.0, 181.5, 159.4
158.7, 136.4, 134.9, 134.0, 129.9, 129.8, 123.8, 121.0, 119.8, 118.0, 112.9, 101.4, 56.3. [60]
Synthesis of 2-(2-methoxyphenyl)-4H-chromen-4-one
3
24

Flavone 3 was synthesized according to reported procedure [44]. In a 500 mL round bottom
flask, the compound 2 (2 g) was dissolved in glacial acetic acid (20 mL) and to it concentrated
H2SO4 (5 mL) was added with stirring. The mixture was warmed on water bath for 2h with
continuous stirring at 80°C. The mixture was then poured onto crushed ice (~100 g) and stirred
the mixture for 10 minutes and then stored at room temperature overnight. The solid obtained
was filtered, washed with distilled water and recrystallized the crude solid obtained from ethanol
to get pure product.
Off white solid , m. p. 98ºC, Yield: 91%; FTIR, ῡ, (cm-1) 3076 (sp2 C-H stretch), 2949, 2842 (sp3
C-H stretch), 1638 (C=O pyrone ring), 1477, 1607 (sp2 C=C stretch), 1466, 1371 (sp3 C-H bend),
1
1253 (C-O stretch), 754 (sp2 C-H bend); H NMR (300 MHz, DMSO-d6) δ ppm: 3.92(s, 3H,
OCH3), 6.93 (s, 1H, C2-H), 7.12 (m, 1H, Ar-H), 7.23 (d, 1H, J=8.4, Ar-H), 7.46 (m, 1H, Ar-H),
7.53 (m, 1H, Ar-H), 7.70 (d, 1H, J=7.8, Ar-H), 7.78 (m, 1H, Ar-H), 7.90 (dd, 1H, J=6.5, 1.5, Ar-
H), 8.03 (dd, 1H, J=6.3, 1.5, Ar-H); 13C NMR (300 MHz, DMSO-d6) δ ppm: 177.5, 161.1,
158.1, 156.3, 134.6, 133.3, 129.6, 125.8, 125.1, 123.5, 121.2, 120.3, 118.9, 112.9, 112.0, 56.4.
Anal. found (calcd.) for C16H12O3: C, 75.99(76.18); H, 4.48(4.79); O, 18.31(19.03).
Synthesis of 5(2´-Hydroxyphenyl)-7(2´´-methoxyphenyl)-2, 3-dihydro-1H-1, 4-diazepine 4
In 250 mL round bottom flask having reflux condenser, the compound 3 (1g) and
ethylenediamine (20 mL) were refluxed for 2 h with continuous stirring. The resulting mixture
was then added to a 100 mL ice cold water and kept overnight at room temperature. The obtained
crude solid was filtered, washed with water and purified by recrystallization from ethanol to
afford pure 4.
Yellow solid, m. p. 205ºC,
Yield: 86%, FTIR, ῡ, (cm-1) 3211 (N-H stretch), 2958 (sp3 C-H
stretch), 1591 (C=N stretch), 1491 (sp2 C=C stretch), 1456 (sp3 C-H bend), 1259 (C-O stretch),
25

747 (sp2 C-H bend); 1H NMR (300 MHz, DMSO-d6) δ ppm: 3.56(s, 2H, diazepine-C2-H), 3.81(s,
3H, OCH3), 3.86(s, 2H, diazepine-C3-H), 5.38(s, 1H, diazepine-C6-H), 6.31(m, 1H, Ar-H),
6.53(dd, J=7.2, 1.2, 1H, Ar-H), 7.00(m, 3H, Ar-H), 7.39(m, 3H, Ar-H), 8.21(s, 1H, OH); 13C
NMR (300 MHz, DMSO-d6) δ ppm: 171.1, 168.5, 157.2, 156.6, 132.5, 131.1, 130.1, 128.6,
127.9, 121.7, 120.7, 116.8, 112.9, 112.3, 87.7, 56.2, 49.5, 49.2. Anal. found (calcd.) for
C18H18N2O2.H2O: C, 68.89 (69.21); H, 6.10 (6.45); N, 9.17 (8.97).
Compuational procedure
The quantum chemical calculations for 4 have been performed with the help of DFT
employing Gaussian 09 program package [61]. The initial geometry of 4 was optimized without
symmetry restrictions at DFT/ B3LYP/6-31(d,p) level. The optimized structure of 4 was further
subjected to NBO analysis at same functional to explore NCIs. Theory of Atoms in Molecules
(QTAIM) calculations were carried out using the AIMAll package [62].
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