Anagostic interactions in chiral separation. Polymorphism in a [Co(II)(L)] complex: Crystallographic and theoretical studies

Article abstract of DOI:10.1016/j.molstruc.2017.10.073

Syntheses and crystal structures of two polymorphs of the complex [Co(II)(L)], where H₂L = 2,2’-[cis-1,2-diaminocyclohexanediylbis (nitrilo-methylidyne)]bis (5-dimethyl-amino]phenol, have been studied. The two polymorphs concomitantly crystallized by vapour diffusion of solvent. The first polymorph (I) crystallized as a racemate in the centrosymmetric tetragonal I4₁/a space group. The second polymorph (II) crystallized in the chiral orthorhombic space group P2₁2₁2₁. The chiral conformers of symmetrical cis-1,2-disubstituted cyclohexane molecules cannot be resolved in the liquid or gas phases, due to the rapid ring inversion. In the present study, the two chiral conformers are present in crystals of polymorph I, whereas, only one chiral conformer is present in crystals of polymorph II. Crystal structure analysis indicated that the formation of two different polymorphs of [Co(II)(L)] complex can be rationalized based on C–H?Co anagostic interactions. Density Functional Theory (DFT) calculations indicated that C–H?Co interactions are due to HOMO-LUMO interactions.

Full text of DOI:10.1016/j.molstruc.2017.10.073

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Journal of Molecular Structure 1154 (2018) 373e381
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Anagostic interactions in chiral separation. Polymorphism in a
[Co(II)(L)] complex: Crystallographic and theoretical studies
Firas F. Awwadi*, Hamdallah A. Hodali
Department of Chemistry, The University of Jordan, Amman 11942, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses and crystal structures of two polymorphs of the complex [Co(II)(L)], where H2L ¼ 2,2’-[cis-1,2-
diaminocyclohexanediylbis (nitrilo-methylidyne)]bis (5-dimethyl-amino]phenol, have been studied. The
two polymorphs concomitantly crystallized by vapour diffusion of solvent. The first polymorph (I)
crystallized as a racemate in the centrosymmetric tetragonal I41/a space group. The second polymorph
(II) crystallized in the chiral orthorhombic space group P212121. The chiral conformers of symmetrical cis-
1,2-disubstituted cyclohexane molecules cannot be resolved in the liquid or gas phases, due to the rapid
ring inversion. In the present study, the two chiral conformers are present in crystals of polymorph I,
whereas, only one chiral conformer is present in crystals of polymorph II. Crystal structure analysis
indicated that the formation of two different polymorphs of [Co(II)(L)] complex can be rationalized based
on CeH/Co anagostic interactions. Density Functional Theory (DFT) calculations indicated that CeH/Co
interactions are due to HOMO-LUMO interactions.
Received 21 June 2017
Received in revised form
19 October 2017
Accepted 19 October 2017
Available online 20 October 2017
Keywords:
Chiral separation
Polymorphism
cis-1,2-Disubstituted cyclohexane
conformers
Anagostic interactions
Conformation analysis
DFT calculations
© 2017 Elsevier B.V. All rights reserved.
1. Introduction
However, there is significant progress in the area of crystal struc-
ture prediction [6]. Different crystallization conditions may results
Solid state polymorphism refers to different arrangements of
crystalline species inside crystalline lattices. Different polymorphs,
especially conformational polymorphs, are expected to have
different physical properties [1e3] including solubility, density,
optical, magnetic … etc. Variation in solubility caused by different
polymorphs is important in pharmacology as it leads to different
pharmacokinetics. A well-known example of the effect of poly-
morphism on solubility is the drug Ritonavir which is used to treat
Acquired Immunodeficiency Syndrome (AIDS). The formation of a
new stable conformational polymorph of Ritonavir with reduced
solubility leads to reduced bioavailability, which required refor-
mulation of the drug [2].
in the formation of different polymorphs including solvent of
crystallization [7e9], temperature [10,11], pH [12], pressure [13,14]
and the use of auxiliary molecules [7].
The arrangement of different conformers leads to the formation
of conformational polymorphs [1], whereas different arrangements
of a conformer result in the formation of packing polymorphs.
Thirty-six percent of the reported polymorphs in the Cambridge
Structural Database is conformational polymorphs [1]. Symmetrical
cis-1,2-disubstituted cyclohexane molecules exist as two equivalent
non-separable conformers in the liquid and gas phases due to the
rapid inversion of the cyclohexane ring. As shown in Fig. 1, A and B0
are identical enantiomers and so are B and A’.
The polymorphism phenomenon is not very well understood
yet. The general methodology of studying polymorphism is either
by preparing different polymorphs serendipitously or intentionally
and then rationalizing the supramolecular structure of the different
polymorphs using the weak noncovalent interactions connecting
the crystalline units or conformational differences [4]. So far, there
is no guaranteed method to obtain different polymorphs [3,5].
Crystallization of symmetrical cis-1,2-disubstituted cyclohexane
as pure enantiomer is rare, only nine organic and one organome-
tallic examples are known [15e23]. None of these ten examples
crystallizes as different polymorphs. In this paper, we report the
synthesis and crystal structure of two polymorphs of [Co(II)(L)]
where H2L
¼
2,2’-[cis-1,2-diamino-cyclohexanediylbis (nitrilo-
methylidyne)]bis (5-dimethyl-amino]phenol (Fig. 2). Polymorph (I)
crystallizes as a racemate in the centrosymmetric space group I41/a
space group, while polymorph (II) crystalizes as pure enantiomers
in the chiral space group P212121. The two polymorphs crystallize
concomitantly from the same solution with approximately 1:1 ratio
* Corresponding author.
E-mail address: fawwadi@yahoo.com (F.F. Awwadi).
https://doi.org/10.1016/j.molstruc.2017.10.073
0022-2860/© 2017 Elsevier B.V. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
374
F.F. Awwadi, H.A. Hodali / Journal of Molecular Structure 1154 (2018) 373e381
with some modifications [24]. The Vilsmeier Haack adduct was
prepared by addition of POCl3 (15.0 mL, 0.16 mol) dropwise to dry
DMF (30 mL) at 0 ꢀC, and the mixture was then stirred for 30 min at
the same temperature. To the adduct, a solution of 3-(N,N-dime-
thylamino)phenol (11.0 g, 80.3 mmol) in dry DMF (23 mL) was
added dropwise at 0 ꢀC. The reaction mixture was slowly warmed
to room temperature, stirred for 4 h, and then heated at 85e90 ꢀC
for 30 min. The reaction mixture was allowed to cool to room
temperature and kept at that temperature with stirring overnight.
It was then poured into crushed ice and neutralized with saturated
aqueous solution of Na2CO3 (120 mL). The precipitate was filtered
off, washed with water and dried in a vacuum oven at 25 ꢀC for 4 h.
Yield: 9.00 g (68%), m.p. 78e79 ꢀC (lit. 80.5e81 ꢀC). The compound
was used without further purification. 1H NMR (500 MHz, CDCl3)
(Fig. S1-S3):
d
¼ 11.56 (1H, s, OH), 9.47 (1H, s, CHO), 7.24 (1H, d,
J ¼ 9 Hz, H-6), 6.24 (1H, dd, J ¼ 9, 2.1 Hz, H-5), 6.03 (1H, d, J ¼ 2.1 Hz,
H-3), 3.02 (6H, s, CH3); 13C NMR (125 MHz, CDCl3) (Fig. S4):
d
n
¼ 192.4, 164.1, 156.2, 135.2, 111.7, 104.6, 97.2, 40.1. FT-IR:
CO ¼ 1628 cmꢁ1
.
2.2. Preparation of 2,2’-[cis-1,2-diaminocyclohexanediylbis(nitrilo-
methylidyne)]-bis(5-dimethyl-amino]phenol, (H2L)
A solution of 4-(N,N-dimethylamino)-2-benzaldehyde (1.00 g,
6.05 mmol) in dry ethanol (25 mL) was introduced into a 150-mL
two-necked round bottomed flask equipped with a dropping fun-
nel, a condenser, a nitrogen inlet and connected to a bubbler. cis-
1,2-Diaminocyclohexane (0.346 g, 3.03 mmol) in dry ethanol
(20 mL) was added dropwise. After the addition was complete, the
reaction mixture was refluxed for 2 h. The reaction mixture was
allowed to cool to room temperature and the solid was filtered off
and washed with ethanol (2 ꢂ 10 mL). The yellow product was
dried in a vacuum oven at 50 ꢀC for 4 h. Yield: 1.16 g (94%), m.p.
Fig. 1. The enantiomeric conformers of symmetrical cis-1,2- disubstituted cyclohexane
molecules. The assignment of R and S configuration for the two chiral centers in (A) is
arbitrary.
190e192 ꢀC. 1H NMR (500 MHz, CDCl3) (Fig. S5-S7).:
d
¼ 13.93 (2H,
s, OH), 8.07 (2H, s, CHO), 7.03 (2H, d, J ¼ 8.2 Hz, H-6, H-60), 6.18 (2H,
dd, 8.2, 2.0 Hz, H-7,H-70), 6.13 (s, 2H, H9,H90), 3.55 (2H, m, H-1,H-10),
3.00 (12H, s, CH3), 1.56e1.97 (8H, m, cyclohexyl); 13C NMR
(125 MHz, CDCl3) (Fig. S8):
103.4, 99.1, 67.4, 40.1, 30.4, 22.6. FT-IR:
Calcd for C24 H32 N4 O2: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.17;
H, 8.36; N, 13.75. HRMS ((þ)-ESI): m/z ¼ 409.25980 (calcd. 408.54
for C24 H33 N4 O2, [M þ H]þ).
d
¼ 166.0, 162.4, 153.9, 132.7, 109.0,
n
C ¼ N ¼ 1614 cmꢁ1. Anal.
2.3. Preparation of the cobalt complex, [Co(II)(L)]
A solution of the Schiff base H2L (0.500 g, 1.22 mmol) in dry
methanol (25 mL) was introduced into a 150-mL two-necked round
bottomed flask equipped with a dropping funnel, a condenser and a
nitrogen inlet and connected to a bubbler. Cobalt acetate tetrahy-
drate (0.304 g, 1.22 mmol) in dry methanol (20 mL) was added
dropwise. After the addition was completed, the dark-brown re-
action mixture was refluxed for 4 h. It was then cooled to room
temperature and the solid precipitate was collected and washed
with small amount of methanol. The orange-red product was dried
in a vacuum oven at 50 ꢀC for 4 h. Yield: 88%, m.p. 275e280 ꢀC
Fig. 2. The two chiral conformers of [Co(II)(L)]. The assignment of R and S configu-
ration for the two chiral centers in the left image is arbitrary.
as inspected under microscopy. To our knowledge, these two
polymorphs are the first examples in the literature in which sym-
metrical cis-1,2-disubstituted cyclohexane complexes crystallizes
as a racemate (Polymorph I) and pure enantiomer (Polymorph II).
(dec.). . FT-IR:
n
C ¼ N ¼ 1575 cmꢁ1. Suitable crystals for single x-ray
analysis were obtained by a vapour diffusion method, using the
combination CH2Cl2/diethyl ether with diffusion of diethyl ether
vapour into dichloromethane solution.
2. Experimental
2.4. Crystal structure determinations
2.1. Preparation of 4-N,N-dimethylamino-2-hydroxybenzaldehyde
The compound was prepared following the literature procedure
The crystal structures of cobalt polymorphs (I) and (II) were
determined at room temperature using 'Xcalibur, Eos'

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
F.F. Awwadi, H.A. Hodali / Journal of Molecular Structure 1154 (2018) 373e381
375
Table 1
lanl2dz basis set with pseudo potential was assigned for Co atom.
The starting geometry was extracted from the crystal structure
data.
Summary of data collection and refinement parameters for two polymorphs of
[Co(II)(L)] complex.
Crystal
Formula
Polymorph I
C24 H30 Co N4 O2
465.45
Polymorph II
C24 H30 Co N4 O2
465.45
3. Results and discussion
Mr
rcalc (Mg/m3)
1.427
1.378
Crystal system
Space group
Tetragonal
I41/a
Orthorhombic
P212121
3.1. Synthesis
a (Å)
b (Å)
18.2420 (6)
18.2420 (6)
26.0404 (11)
8665.5 (5)
1556534
4400
4400/0/283
0.0406
16
9.0553 (10)
11.790 (2)
21.021 (2)
2244.3 (5)
1556533
4338
4338/0/284
0.0533
4
1.024
0.001 (19)
0.0507
0.0828
0.793
The ligand resulting from the condensation of 4-(N,N-dime-
thylamino)-2-hydroxybenzaldehyde with trans-diaminocyclohex-
c (Å)
V (Å3)
ane
(2,2’-[trans-1,2-diaminocyclohexanediylbis
(5-dimethyl-amino]phenol) was
(nitrilo-
briefly
CCDC
methylidyne)]bis
ind. Reflections
Data/restraints/parameters
R (int)
mentioned in only one report [21]. However, no reports were found
on the preparation and characterization of the corresponding
ligand with cis-1,2-diaminocyclohexane. This ligand was prepared
by refluxing 4-N,N-dimethylamino-2-hydroxybenzaldehyde and
cis-1,2-diaminocyclohexane in dry ethanol (Scheme 1). The
condensation was confirmed by the appearance of the stretching
Z
Goodness of fit
Absolute structure parameter
1.045
e
R1a [I > 2
s
]
s
0.0464
0.0932
0.821
0.382 and ꢁ0.229
b
wR2 [I > 2
]
, mmꢁ1
band for
n
C ¼ N at 1614 cmꢁ1. The ligand was fully characterized by
m
Largest diff. peak and hole (e/Å3)
0.545 and ꢁ0.307
elemental analysis, 1H and 13C NMR and mass spectrometry. The
Schiff base formed behaves as a tetradentate ligand binding to the
metal ion through the imine nitrogen atoms and phenolic oxygen
atoms. Reaction of the ligand (H2L) with cobalt (II) acetate in dry
methanol results in the formation of [Co(II)(L)] complex which was
confirmed by the appearance of the ligand-related peaks, which are
slightly shifted in the IR spectrum of the complex. However, the
a
R1 ¼ SjjFoj - jFcjj/jS jFoj.
b
wR2 ¼ { S w (Fo2 - Fc2)2/Sw (Fo2)2,1/2
.
diffractometer (Mo K
a
radiation,
l
¼ 0.7107 Å). Data were acquired
and processed to give hkl files using CrysAlisPro software [25]. A
preliminary solution was obtained using Olex2 program [26], then
the structure solution and refinements were finished using
SHELXTL program package [27]. Atoms other than hydrogen were
refined anisotropically, hydrogen atoms were placed in the calcu-
lated positions using a riding model. Data collection parameters
and refinement results are given in Table 1.
peak at 1614 cmꢁ1 assigned to
n
C ¼ N in the ligand spectrum was
significantly shifted to lower frequency (1575 cmꢁ1) in the complex
due to cobalt bonding to the azomethine nitrogen. The complex
was fully characterized by single crystal X-ray analysis (Fig. 3).
3.2. Crystallographic results
2.5. Theoretical calculations
Crystals of [Co(II)(L)] were grown by gas diffusion of diethyl
ether into a dichloromethane solution of the [Co(II)(L)] complex.
Examination of the crystals of the [Co(II)(L)] complex under a mi-
croscope indicated the presence of two types of crystals which
concomitantly crystallized, with an approximately 1:1 ratio; (a)
dark red sword-shaped crystals (Fig. S9 left), henceforth polymorph
Gaussian 09 was used to optimize the molecular structure of the
[Co(II)(L)] complex on the (DFT/UB3LYP) level, (DFT ¼ Density
Functional Theory and B3LYP ¼ Becke, 3-parameter, Lee-Yang-Parr
[28]. cc-pvdz basis set was assigned for all atoms except Co atom,
Scheme 1. Stepwise synthesis of [Co(II)(L)] complex.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
376
F.F. Awwadi, H.A. Hodali / Journal of Molecular Structure 1154 (2018) 373e381
chiral space group P212121. The molecular structures of the two
polymorphs are shown in Fig. 3.
The cyclohexane rings in both structures are in the chair
conformation. X-ray analysis indicated that the molecules in the
I41/a phase are racemates with (50:50) of the two cyclohexane
conformers, since I41/a is a centrosymmetric space group, whereas
they are pure enantiomers in the P212121 phase as indicated by
absolute structure parameters (Flack ¼ 0.001 (19) (Table 2) and
Hooft parameter ¼ ꢁ0.024 (15)) [29,30]. The chiral center at C1 is of
S configuration and that at C2 is of R configuration (Fig. 3) as
determined by Platon software [31]. As expected, inverting the
structure of Polymorph I does not change the refining parameters,
whereas, upon inverting structure of Polymorph II the refining
parameters [I > 2sigma(I)] rise from R1 ¼ 0.0507 and wR2 ¼ 0.0828
to R1 ¼ 0.0617and wR2 ¼ 0.1048 When the structure of both mirror
images of polymorph I were overlaid on the structure of polymorph
II (Fig. 4, only one structure of the mirror images of polymorph I is
superimposable with the structure of polymorph II (Fig. 4).
The geometry around the metal center in the complexes is
nearly square planar as indicated by the cis O1eCoeN1,
O2eCoeN2, N1eCoeN2 and O1eCoeO2 angles and trans
O1eCoeN2 and O2eCoeN1 angles; the average of the cis angles is
90.1ꢀ(range 83.6e94.1ꢀ) and the average of the trans angles is
174.7ꢀ(range 171.8e177.8ꢀ) (Fig. 3).it is noteworthy that the Oe
CoeN cis angles are larger than the OeCoeO or NeCoeO cis angles,
Fig. 3. Molecular structure of polymorph I (top) and polymorph II (bottom). Thermal
ellipsoids are shown at 30% probability. In the case of Polymorph I, the structure
represented corresponds to one enantiomer and the other enantiomer present in the
structure is obtained by inversion.
I and, (b) lighter red parallelepiped-shaped crystals (Fig. S9 right),
henceforth polymorph II. The sword-shaped crystals crystallize in
the centrosymmetric tetragonal I41/a space group, while, the
parallelepiped crystals crystallized in the chiral orthorhombic
Fig. 4. Overlaid molecular structure of Polymorph II and the molecular structure of the
two enantiomeric molecules found in the crystal structure of Polymorph I.
Table 2
Selected bond length (Å) and angles (ꢀ).
Polymorph I
Polymorph II
Optimized
Table 3
CoeO1
CoeO2
CoeN1
CoeN2
N1eC1
N2eC6
C1eC6
1.866 (2)
1.868 (2)
1.874 (2)
1.863 (2)
1.491 (4)
1.468 (4)
1.522 (4)
176.0 (1)
88.09 (8)
93.26 (10)
94.05 (10)
85.11 (11)
172.3 (1)
104.9 (2)
105.5 (2)
110.3 (3)
117.6 (3)
112.5 (3)
112.4 (3)
110.2 (3)
111.7 (3)
110.7 (3)
111.2 (3)
43.2 (3)
1.850 (3)
1.861 (2)
1.872 (3)
1.850 (4)
1.501 (5)
1.478 (4)
1.532 (5)
171.8 (1)
87.35 (10)
93.46 (12)
94.10 (12)
85.87 (14)
174.4 (1)
104.5 (3)
105.8 (3)
109.6 (3)
117.5 (3)
112.5 (3)
114.7 (4)
110.9 (4)
111.4 (4)
109.9 (4)
110.3 (4)
42.6 (4)
1.862
1.866
1.902
1.888
1.484
1.467
1.541
175.8
87.7
CeH/Co anagostic interaction distances (Å) and angles (ꢀ). These interactions are
depicted in Fig. 6.
Polymorph I
Polymorph II
H24C/Co1
C24/Co1
C24eH24C/Co1
H24A … Co1
C24/Co1
2.970
3.315
103
2.939
3.315
105
H1/Co1
C1/Co1
C1eH1/Co1
H5A … Co1
C5/Co1
2.829
3.665
144
3.199
3.951
136
O (1)-Co(1)-N (2)
O (1)-Co(1)-O (2)
N (2)-Co(1)-O (2)
O (1)-Co(1)-N (1)
N (2)-Co(1)-N (1)
O (2)-Co(1)-N (1)
N (1)-C (1)-C (6)
N (2)-C (6)-C (1)
N (2)-C (6)-C (5)
N (1)-C (1)-C (2)
C (1)-C (6)-C (5)
C (3)-C (2)-C (1)
C (2)-C (3)-C (4)
C (4)-C (5)-C (6)
C (3)-C (4)-C (5)
C (6)-C (1)-C (2)
N1eC1eC6eN2
C2eC1eC6eC5
93.1
93.9
85.7
C24eH24A … Co1
C5eH5A … Co1
174.7
105.8
106.5
110.6
117.6
112.0
113.6
110.6
112.1
110.9
111.3
42.9
Table 4
CeH/O interaction distances (Å) and angles (ꢀ).These interactions are depicted in
Fig. 7.
Polymorph I
Polymorph II
H2B/O
C2/O1
C2eH2B/O1
2.628
3.566
163
H6/O1
C6/O1
C6eH6/O1
H15B/O1
C15 / O1
C15eH15B/O1
2.445
3.339
152
2.459
3.153
129
50.9 (4)
50.0 (5)
50.7