Structural Investigation of Substituent Effect on Hydrogen Bonding in (S)-Phenylglycine Amide Benzaldimines

Article abstract of DOI:10.1021/acs.cgd.5b00621

A detailed structural analysis of 23 new crystal structures of (S)-phenylglycine amide benzaldimines with various substituents (CH₃, Ph, OCH₃, F, Cl, Br, NO₂) on the benzylidene is performed in this contribution. These compounds belong to the highly studied family of Schiff bases. Etter's nomenclature and Hirshfeld surfaces are used to describe respectively the strong hydrogen bonds and the secondary interactions existing in these compounds. Surprisingly, all 23 obtained structures can be sorted into five types according to their hydrogen bonding motifs. The potential interplay of steric and electronic effects of the substituents on the resulting bonding patterns, conformational features and packing was investigated. Our analysis revealed that neither mesomeric/inductive factors of halogens nor π-π stacking, C-H···π, and other hydrophobic interactions affect the structural outcome. The type affiliation is rather due to the interplay of three parameters: (1) the number of strong hydrogen bonds forming the motif (thermodynamic factor), (2) the ease with which the motif is formed (kinetic factor), and (3) the capacity of the motif to accommodate substituents on the different positions (steric factor). It was thus possible to suggest a stability ranking of the five structural types and to identify stable forms when polymorphism was encountered. (Figure Presented).

Full text of DOI:10.1021/acs.cgd.5b00621

Subscriber access provided by UNIV OF MISSISSIPPI
Article
Structural investigation of substituent effect on hydrogen
bonding in (S)-phenylglycine amide benzaldimines
Fanny George, Bernadette Norberg, Johan Wouters, and Tom Leyssens
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00621 • Publication Date (Web): 25 Jun 2015
Downloaded from http://pubs.acs.org on July 10, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Crystal Growth & Design is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 42
Crystal Growth & Design
1
2
3
4
5
Structural investigation of substituent effect on hydrogen bonding in (S)-phenylglycine
amide benzaldimines
6
7
8
Fanny George †, Bernadette Norberg ‡, Johan Wouters ‡, Tom Leyssens †*
† Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348 LouvainꢀlaꢀNeuve,
Belgium
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡ Unité de chimie physique, théorique et structurale, University of Namur, Namur, Belgium
* Corresponding author: tom.leyssens@uclouvain.be.
Abstract
A detailed structural analysis of twentyꢀthree new crystal structures of (S)ꢀphenylglycine amide
benzaldimines with various substituents (CH3, Ph, OCH3, F, Cl, Br, NO2) on the benzylidene is
performed in this contribution. These compounds belong to the highly studied family of Schiff
bases. Etter’s nomenclature and Hirshfeld surfaces are used to describe respectively the strong
hydrogen bonds and the secondary interactions existing in these compounds. Surprisingly, all 23
obtained structures can be sorted in five types according to their hydrogen bonding motifs. The
potential interplay of steric and electronic effects of the substituents on the resulting bonding
patterns, conformational features and packing was investigated. Our analysis revealed that
neither mesomeric/inductive factors of halogens nor πꢀπ stacking, CꢀH…π and other
hydrophobic interactions affect the structural outcome. The type affiliation is rather due to the
interplay of three parameters: (1) the number of strong hydrogen bonds forming the motif
(thermodynamic factor), (2) the ease with which the motif is formed (kinetic factor) and (3) the
capacity of the motif to accommodate substituents on the different positions (steric factor). It was
thus possible to suggest a stability ranking of the five structural types and to identify stable forms
when polymorphism was encountered.
*Corresponding author:
Tom Leyssens
Institute of Condensed Matter and Nanosciences
Molecules, Solids and Reactivity
Université Catholique de Louvain
Place Louis Pasteur 1, bte L4.01.03
Bꢀ1348 LouvainꢀLaꢀNeuve
Tel: +32 10 47 2811 Fax: +32 10 47 27 07
tom.leyssens@uclouvain.be
http://www.uclouvain.be/leyssensꢀgroup
ACS Paragon Plus Environment
1

Crystal Growth & Design
Page 2 of 42
1
2
3
4
5
6
7
8
9
Structural investigation of substituent effect on
hydrogen bonding in (S)-phenylglycine amide
benzaldimines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fanny George †, Bernadette Norberg ‡, Johan Wouters ‡, Tom Leyssens †*
† Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348
LouvainꢀlaꢀNeuve, Belgium
‡ Unité de chimie physique, théorique et structurale, University of Namur, Namur, Belgium
Abstract
A detailed structural analysis of twentyꢀthree new crystal structures of (S)ꢀphenylglycine amide
benzaldimines with various substituents (CH3, Ph, OCH3, F, Cl, Br, NO2) on the benzylidene is
performed in this contribution. These compounds belong to the highly studied family of Schiff
bases.
Etter’s nomenclature and Hirshfeld surfaces are used to describe respectively the strong
hydrogen bonds and the secondary interactions existing in these compounds. Surprisingly, all 23
obtained structures can be sorted in five types according to their hydrogen bonding motifs.
The potential interplay of steric and electronic effects of the substituents on the resulting bonding
patterns, conformational features and packing was investigated. Our analysis revealed that
ACS Paragon Plus Environment
2

Page 3 of 42
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
neither mesomeric/inductive factors of halogens nor πꢀπ stacking, CꢀH…π and other
hydrophobic interactions affect the structural outcome. The type affiliation is rather due to the
interplay of three parameters: (1) the number of strong hydrogen bonds forming the motif
(thermodynamic factor), (2) the ease with which the motif is formed (kinetic factor) and (3) the
capacity of the motif to accommodate substituents on the different positions (steric factor). It was
thus possible to suggest a stability ranking of the five structural types and to identify stable forms
when polymorphism was encountered.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Introduction
During the past years, Schiff bases have received much attention due to their wide range of
biological activities1,2 and industrial applications. Among their pharmacological properties, they
show antibacterial,3 anticancer,4 antifungal,5 and radical scavenging6 activities. They can also be
used as enzymatic intermediates or inhibitor.7 Stable and easily synthesized, chiral Schiff bases
are widely used in organic chemistry as intermediates in the formation of chiral amines and
various carbonyl compounds. Due to the πꢀacceptor properties of the imine nitrogen, they are
commonly encountered ligands in coordination chemistry.8,9 Furthermore, they have shown their
use in asymmetric catalysis.10 Among Schiff bases, Nꢀ(2ꢀMethylbenzylidene)phenylglycine
amide has recently been used as a model compound for deracemization through abrasive
11–15
grinding
while 2ꢀ(benzylideneamino)ꢀ2ꢀ(2ꢀchlorophenyl)acetamide helped to demonstrate
the possibility of using attritionꢀenhanced deracemization in an upꢀscaled process.16 Both these
compounds fulfill the requirements for the deracemization technique to work; they form racemic
conglomerates in the solid phase (i.e. R and S molecules crystallize in different crystals) and they
are easily racemizable in solution.
ACS Paragon Plus Environment
3

Crystal Growth & Design
Page 4 of 42
1
2
Schiff bases have extensively been structurally characterized17–22 but only a limited amount of
studies investigate the relationship between supramolecular motifs and nature/position of
different substituents on a molecular framework.23,24
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the current contribution, we analyze the crystal structures of twenty (S)ꢀphenylglycine
amide benzaldimines having various substituents located on different positions on the
benzylidene. This study will help to understand the solid state behavior of this type of imines,
and yield insight into how the nature, size and position of the substituent impact the hydrogen
bonding patterns.
All compounds were synthesized by condensation of (S)ꢀphenylglycine amide ((S)ꢀPGA) and
the corresponding monosubstituted benzaldehyde (Scheme 1). Etter’s nomenclature25 was used
to describe the strong hydrogen bonds existing in the twentyꢀthree crystal structures presented
here, while Hirshfeld surfaces26 served to identify their secondary interactions. The potential
interplay of steric and electronic effects of the substituents on the resulting bonding patterns,
conformational features and packing, was investigated in detail.
Scheme 1. Synthesis of (S)ꢀphenylgycine derivatives (3) by condensation of (S)ꢀPGA (1) and a
monosubstituted benzaldehyde (2), in dichloromethane at room temperature. R = CH3, Ph,
OCH3, F, Cl, Br, NO2.
ACS Paragon Plus Environment
4

Page 5 of 42
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
Starting Materials. (S)ꢀPhenylglycine amide, 2ꢀanisaldehyde, 3ꢀanisaldehyde, 3ꢀ
nitrobenzaldehyde and 4ꢀnitrobenzaldehyde were purchased from Acros Organics. 2ꢀ
Tolualdehyde, 3ꢀtolualdehyde, 4ꢀtolualdehyde, 2ꢀbromobenzaldehyde, 3ꢀbromobenzaldehyde, 2ꢀ
chlorobenzaldehyde, 4ꢀchlorobenzaldehyde, 3ꢀfluorobenzaldehyde, 4ꢀchlorobenzaldehyde and
biphenylꢀ 2ꢀcarboxaldehyde were purchased from SigmaꢀAldrich. 4ꢀAnisaldehyde and 2ꢀ
fluorobenzaldehyde were purchased from Alfa Aesar. 4ꢀBromobenzaldehyde and 2ꢀ
nitrobenzaldehyde were purchased from Maybridge. 3ꢀ Chlorobenzaldehyde and biphenylꢀ 4ꢀ
carboxaldehyde were purchased from TCI.
Synthesis. (S)ꢀPGAꢀaldimines were prepared by addition of the substituted benzaldehyde to a
suspension of (S)ꢀPGA in dichloromethane and left to stirr overnight at room temperature, as
described by Dalmolen et al.27
Single Crystals. Most single crystals were grown by slow evaporation of the corresponding
solution or by cooling crystallization to 3°C. Different solvents (methanol, acetonitrile, ethyl
acetate, dichloromethane and acetone) were used as polymorphism was suspected for some
compounds (see below). For the 2ꢀchlorobenzaldehyde derivative, different polymorphs were
obtained when using acetonitrile, acetone or methanol as crystallization solvent. Those were
ACS Paragon Plus Environment
5

Crystal Growth & Design
Page 6 of 42
1
2
3
4
5
6
7
8
9
named FI, FII and FIII respectively. Similarly, two polymorphs were isolated for the 2ꢀ
anisaldehyde product when using methanol and dichloromethane, and named FI and FII
respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Single Crystal X-ray Diffraction. Single crystal Xꢀray diffraction was performed on a
Gemini Ultra R system (4ꢀcircle kappa platform, Ruby CCD detector) using Cu Kα radiation (λ
= 1.54056 Å). Cell parameters were estimated from a preꢀexperiment run and full data sets
collected at room temperature. The structures were solved by direct methods with the SHELXSꢀ
97 program and then refined on |F|2 using SHELXLꢀ97 software28. The final reported R1 value is
calculated on |F| for the observed reflections (I > 2 sigma(I)). Nonꢀhydrogen atoms were
anisotropically refined, and the hydrogen atoms in the riding mode with isotropic temperature
factors were fixed at 1.2 times U(eq) of the parent atoms (1.5 times for methyl groups).
Hydrogen atoms implicated in Hꢀbonds were located in the Fourier difference maps and freely
refined.
Hirshfeld surfaces. Hirshfeld surfaces are among other techniques29 that allow the
visualisation of intermolecular interactions formed by a molecule in a given crystal structure.
The Hirshfeld surface of a molecule in a crystal is the surface delimiting « the region where the
electron distribution of a sum of spherical atoms for the molecule dominates the corresponding
sum over the crystal ».26 This surface can be mapped with different functions. Here, we used
only the Hirshfeld surface mapped with de (distance external to the surface), the distance from
the surface to the nearest nucleus in another molecule, which give information of close
intermolecular contacts. The surface colour reflects the proximity of the neighbours : 0.55
angstrom (red) – 1.5 angstrom (green) – 2.4 angstrom (blue). Hydrogen bonds are visible on the
ACS Paragon Plus Environment
6

Page 7 of 42
Crystal Growth & Design
1
2
3
4
5
6
de surface as large red regions adjacent to the H bond acceptor and as smaller orangeꢀred dot
adjacent to the H bond donor.
7
8
9
A 2D fingerprint plot is a plot of de in function of di, the distance from the surface to the
nearest atom in the molecule itself (distance internal to the surface). It summarizes all the
intermolecular interactions in a given crystal and provides the relative area of the surface
corresponding to each such interaction. Points are coloured from blue, corresponding to the
smallest nonꢀzero contribution to the total surface, to red, for contribution of 0.1% or greater to
the total surface.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hirshfeld surfaces and 2D fingerprint plots were generated using the licenced freeꢀofꢀcharge
CrystalExplorer software.30
Results
All twenty synthesized aldimines are labelled according to the nature (CH3, Ph, OCH3, F, Cl,
Br, NO2) and position (ortho, meta, para) of the substituent on the benzylydene. They were
structurally characterized through single crystal analysis. Crystallographic parameters of all
compounds are displayed in Table 1. The crystal structure of oꢀMe at 208K has already been
reported in the CSD31,32 and shows similar parameters.
Overall, in every structure type, the imine adopts a trans configuration with respect to the C=N
bond. Moreover, except for what we will define later on as type IV structures, the amide
hydrogen H2B always faces the imine nitrogen N1 (Figure 1). In type IV structures, the carbonyl
occupies this position. Although this might seem unfavorable due to the proximity of the lone
pairs of the carbonyl and imine groups, this orientation allows H2B to form a hydrogen bond
ACS Paragon Plus Environment
7

Crystal Growth & Design
Page 8 of 42
1
2
3
4
5
6
7
8
9
with the imine nitrogen in an intermolecular way. This conformation and the overall hydrogen
bonding pattern of type IV structures also occurs in 2ꢀ(Benzylideneamino)ꢀ2ꢀ(2ꢀ
chlorophenyl)acetamide, which is the only related structure reported in the CSD.33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A further general feature is the presence of the substituents in ortho and meta positions on the
H7 side and not on the imine nitrogen side. This conformation is expected to be favored, as most
of the hydrogen bonding partners are located on the nitrogen side, and substituents on this side
would prevent strong hydrogen bonding interaction due to steric effects. Furthermore, orthoꢀ
substituents on the nitrogen side would lead to steric hindrance between the substituent and the
nitrogen lone pair.
The only exception to the above observation is mꢀF for which some rotational disorder around
the C1ꢀC7 bond can be found, with about 75% of all molecules having the fluorine on the C3
atom (H7 side) and 25% on the C5 (nitrogen side). This can be explained by the small size of the
fluorine atom and the reduced steric effect.
Figure 1. ORTEP plot (Mercury software 3.0) of mꢀCl showing crystallographic numbering
scheme on the atoms potentially involved in interꢀ and intramolecular interactions in the various
structures.
ACS Paragon Plus Environment
8

Page 9 of 42
Crystal Growth & Design
1
2
3
4
5
6
Surprisingly, we were able to categorize all 23 obtained structures (20 different compounds
and respective polymorphs) in five structurally based types, according to their main hydrogen
7
8
9
25
bonding motifs. The structural analysis below uses graph sets to describe each type of main
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bonding pattern encountered and Hirshfeld surfaces to consider all secondary contacts which,
given their number, play a key role in the structure building and packing efficiency. Indeed,
according to Desiraju,34 the presence or absence of those weaker interactions could even be
determinant for the patterns formed by the stronger hydrogen bonds in the crystal.
ACS Paragon Plus Environment
9

Crystal Growth & Design
Page 10 of 42
1
2
3
4
Table 1. Crystallographic parameters of the 23 new structures sorted by type
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
10

Page 11 of 42
Crystal Growth & Design
1
2
3
Type III
Type IV
Type V
4
Compounds
p-Me
p-Ph
Compounds
m-OMe
Compounds
o-OMe FII
5
6
7
8
Structural
formula
Formula weight
(g/mol)
Structural
formula
Formula
Structural
formula
Formula weight
(g/mol)
C16H16N2O
252.31
C21H18N2O
314.37
C16H16N2O2
268.31
C16H16N2O2
268,31
weight (g/mol)
9
Space system
Space group
a (Å)
monoclinic
monoclinic
Space system
Space group
a (Å)
monoclinic
Space system
Space group
a (Å)
monoclinic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P21
P21
P21
C 2/c
8.2225(4)
5.7932(3)
14.5687(6)
90
8.3299(3)
5.7214(2)
17.5391(5)
90
8.6581(7)
5.1375(3)
15.7993(10)
90
25.096(2)
5.6957(4)
20.3318(15)
90
b (Å)
b (Å)
b (Å)
c (Å)
c (Å)
c (Å)
α (°)
β (°)
α (°)
β (°)
α (°)
β (°)
90.377(4)
90
91.143(3)
90
100.982(7)
90
107.199(6)
90
γ (°)
V (Å3 )
γ (°)
V (Å3 )
γ (°)
V (Å3 )
639.959
2
835.724
2
689.899
2
2776.26
8
Z
Z
Z
R1ꢀfactor (%)
d (g.cmꢀ3 )
3.09
3.29
R1ꢀfactor (%)
d (g.cmꢀ3 )
4.27
R1ꢀfactor (%)
d (g.cmꢀ3 )
3.62
1.207
1.249
1.292
1.284
Type I : pꢀOMe, oꢀPh, mꢀF, pꢀF, mꢀCl, pꢀCl, mꢀBr, pꢀBr, mꢀNO2, pꢀNO2
Type I structures are characterized by repeating [R2 (9)] ring motifs (Figure 2): the imine lone
2
pair of a first molecule (A) accepts a H bond from an amide hydrogen of a second molecule (B),
while the amide hydrogen of the first molecule donates a hydrogen bond to the carbonyl of the
second molecule. Each molecule is therefore involved in four different hydrogen bonds, with
every potential H bond former being used.
A
I
B
Figure 2. Type I motif displaying a [R2 (9)] ring between two molecules (A and B) of pꢀCl.
2
ACS Paragon Plus Environment
11

Crystal Growth & Design
Page 12 of 42
1
2
3
4
Consecutive ring motifs produce zigzag ladders, containing two parallel infinite hydrogenꢀ
5
6
bond chains, described in graph set notation as [C2 (7)] and directed along the bꢀaxis. From one
2
7
8
9
sport of the ladder to the other, molecules are rotated by 180° around the bꢀaxis; all phenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
groups pointing outwards.
The oneꢀdimensional ladders are stacked periodically along the a and c axes (Figure 3).
a
c
b
a
b
c
Figure 3. Stacking of pꢀCl in the bc (left) and ab (right) planes, displaying zigzag ladders with
[C2 (7)] graph set notation, forming undulating one dimensional ribbons.
2
Type I structures crystallize either in the monoclinic P21 or in the orthorhombic P212121 space
groups.
Concerning the weaker hydrogen bonds, a particularly strong C—H…O interaction is found
between C6—H6 and O1 (Figure 4 and Table 4). This is in accordance with the results of Lo
Presti et al. (2006) stating that CꢀꢀH…O bonds of comparable strength to OꢀꢀH…O bonds can
exist in organic molecules.35
ACS Paragon Plus Environment
12

Page 13 of 42
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. C6—H6…O1 intermolecular bond in type I structures (mꢀCl)
One can also note the presence of a weaker CꢀH…O bond (C7ꢀH7…O1) directed along the aꢀ
axis connecting the carbonyl of one ladder to the imine hydrogen H7 of another ladder and
influencing the tridimensional arrangement. However, this additional interaction does not occur
in oꢀPh because the biphenyl group prevents a sufficient proximity between adjacent ladders; the
packing stability being due supposedly to hydrophobic interactions in this case (see below). This
interꢀladder interaction is not present either in mꢀNO2, which rather shows a C5ꢀH5…O3 bond,
involving the nitro group holding ladders together (Figure 5).
c
b
a
Figure 5. C5ꢀH5…O3 bond in mꢀNO2
ACS Paragon Plus Environment
13

Crystal Growth & Design
Page 14 of 42
1
2
3
4
5
6
7
8
9
In addition, comparison of πꢀ π stacking, CꢀH…π and other hydrophobic interactions in the
different structures can easily be performed by analyzing the 2D fingerprint plot and the
corresponding Hirshfeld surfaces of the molecules in the different structures. Indeed, they gives
us a complete view of intermolecular interactions, focusing not solely on 'assumed important
interactions'.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Among type I structures, disparities are found within the secondary interactions.
For example, the 2D plot of mꢀF (Figure 6, left and middle) displays soꢀcalled « horns »
between the spikes while other metaꢀsubstituted type I structures do not. Those account for the
presence of the short CꢀF…H interaction present in mꢀF.
In addition, comparing it with the 2D fingerprint plot of mꢀBr (Figure 6, right), one observes
that the latter structure is less efficiently packed, as illustrated by the presence of a diffuse blue
region at high distances.
Figure 6. 2D fingerprint plots of mꢀF (left and central figure) displaying the “horns”
corresponding to the short CꢀH…F interaction (highlighted on the central figure). On the right,
the 2D fingerprint plots of mꢀBr with no horns and less efficient packing.
Similarly, the 2D fingerprint plot of oꢀPh differs significantly from the others by the presence
of a bump between the spikes and of a pair of wings on the other side of the spikes (Figure 7).
ACS Paragon Plus Environment
14

Page 15 of 42
Crystal Growth & Design
1
2
The central bump corresponds to all the hydrophobic H...H contacts while the external wings
represent the CꢀH...π interactions which are highly represented in this particular structure, visible
as orange zones above the rings on the de Hirshfeld surface (Figure 8).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. 2D fingerprint plot of oꢀPh displaying a central bump, corresponding to H...H contacts,
and a pair of external wings corresponding to the CꢀH...π interactions.
Figure 8. Hirshfeld surface of oꢀPh mapped with de and displaying bright orange regions above
the rings, corresponding to various CꢀH...π interactions.
Type II: mꢀMe, oꢀMe, oꢀOMe FI, oꢀF, oꢀCl (FI, FII, FIII), oꢀBr, oꢀNO2
As for type I structures, type II structures are also organized in ladders but this time running
along the aꢀaxis. The ladders are constituted by the succession of inverted [R2 (8)] ring motifs
3
involving three molecules (two adjacent ones, A & C, and one on the other side of the ladder, B).
ACS Paragon Plus Environment
15

Crystal Growth & Design
Page 16 of 42
1
2
3
4
5
6
7
8
9
The carbonyl of the first molecule (A) forms a bifurcated H bond with one amide hydrogen of
the second (B) and the third (C) molecule. In addition, the second amide hydrogen of the third
molecule is linked to the carbonyl of the second molecule (Figure 9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As for type I structures, each molecule takes part in four H bonds, but this time two donating
hydrogen bonds using the amide hydrogens and two accepting bonds through the carbonyl group.
Contrary to the type I structures, the imine is not included in any H bonding pattern in type II
structures.
C
B
II
A
Figure 9. Type II motif displaying a [R2 (8)] ring formed by three molecules (A,B & C) of oꢀBr.
3
Contrary to type I, no distinctive interꢀladder interaction is reported. However, when the
substituent is a halogen/nitro group, an extra intramolecular hydrogen bond is formed between
the substituent and the imine hydrogen H7.
The successive ring motifs form two parallel hydrogenꢀbonded infinite chains C(4) directed
along the aꢀaxis (Figure 10). Ladders are almost planar, except in oꢀF structure, in which ladders
are slightly undulating.
ACS Paragon Plus Environment
16

Page 17 of 42
Crystal Growth & Design
1
2
3
4
c
b
5
6
7
8
a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ladder plane
Figure 10. oꢀBr stacking in the ac plane, displaying infinite chains C(4) creating almost planar
ladders.
Although all motif II structures display the same hydrogen bonding patterns, their overall
molecular packing is less homogenous. Therefore the type II structures can be sorted in three
different subꢀgroups according to the stacking of the ladders along the b and c axes.
A first subꢀgroup includes structures mꢀMe, oꢀCl (FI, FII) and oꢀNO2. Ladders are stacked in
alternating rows along the cꢀaxis (Figure 11); except for oꢀCl FI, in which rows alternate along
the aꢀaxis. The ladders planes are parallel within a row but form an angle with ladders planes
situated in the next row. On top, consecutive ladders rows are interpenetrating (Fig. 11).
ACS Paragon Plus Environment
17

Crystal Growth & Design
Page 18 of 42
1
2
3
4
b
a
5
6
7
8
9
1st row
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2nd row
c
Figure 11. oꢀNO2 rows stacking in the bc plane.
In the second subꢀgroup (oꢀMe, oꢀOMe FI, oꢀCl FIII and oꢀBr), one observes the same packing
as in the first subꢀgroup, except that subsequent rows do not interpenetrate, but form herringbone
arrangements (Figure 12).
b
a
1st row
2nd row
c
Figure 12. oꢀCl (FIII) stacking in the bc plane exhibiting herringbone arrangement.
ACS Paragon Plus Environment
18

Page 19 of 42
Crystal Growth & Design
1
2
3
4
This is due to the fact that the inclination angle of the ladders planes with respect to the bꢀaxis
5
6
is more pronounced in this last subꢀgroup (Figure 13).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 13. The inclination angle of the ladders planes in the bc plane with respect to the bꢀaxis is
smaller in the first subꢀgroup (right, oꢀNO2) than in the second (left, oꢀCl (FIII)).
In the last subꢀgroup (oꢀF), ladders planes are parallel within and between rows (Figure 14).
This is therefore the only compound that crystallizes in the monoclinic space group C2; all the
other compounds in type II belonging to orthorhombic space groups.
c
b
a
Figure 14. oꢀF stacking in the ac plane.
ACS Paragon Plus Environment
19

Crystal Growth & Design
Page 20 of 42
1
2
3
4
5
6
7
8
9
The analysis of the secondary interactions also reveals disparities among type II structures.
For most ortho substituted type II structures, there is a spike on the diagonal of the 2D fingerprint
plot. This accounts for the directional H...H interactions found in those structures. Those
interactions are depicted by orange areas on the bottom left and right of the Hirshfled surface of
oꢀCl FII, together with the interacting molecules (Figure 15). The strength of those interactions
varies tremendously according to the nature of the substituent as well as the nature of the
polymorph as shown by the three oꢀCl structures (Figure 16).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 15. Hirshfeld surface of oꢀCl (FII) mapped with de function. Directional H...H contacts
are represented.
Figure 16. 2D fingerprint plot of oꢀCl FII (left), FI (middle) and FIII (right).
Type III: pꢀMe and pꢀPh
ACS Paragon Plus Environment
20

Page 21 of 42
Crystal Growth & Design
1
2
3
4
These structures are characterized by headꢀtoꢀtail catemers, propagating along the bꢀaxis and
5
6
characterized by a [C2 (8)] infinite hydrogenꢀbonded chain motif: a H bond connects the
2
7
8
9
carbonyl of a molecule to one amide hydrogen of a second molecule, related to the first one by
the twofold screw axis in P21 (Figure 17). The imine is not participating in any supramolecular
motif and only one hydrogen on the amide nitrogen atom is involved in H bond formation.
Hence, unlike type I and II structures, only two hydrogen bonds are formed per molecule in this
type.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C
B
III
A
Figure 17. Type III motif displaying [C2 (8)] hydrogenꢀbonded infinite chains formed by three
2
molecules (A, B & C) of pꢀMe.
Type III structures exhibit an interꢀchain link joining the carbonyl and the para hydrogen on
the phenyl group, providing chain cohesion along the aꢀaxis (Figure 18). The same connection is
present in type IV albeit with greater strength (see Table 4 below).
ACS Paragon Plus Environment
21

Crystal Growth & Design
Page 22 of 42
1
2
3
4
c
b
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Figure 18. C13ꢀH13…O1 bond in pꢀMe.
Besides, an additional C8—H8…O1 interaction is present in pꢀPh (but not in pꢀMe).
Accordingly, the catemer formed by pꢀMe molecules is planar (Figure 17) while it is angular
(113° between successive hydrogen bonds in the catemer) in the pꢀPh structure (Figure 19).
b
c
a
Figure 19. C8—H8…O1 intermolecular interaction and angular catemer in pꢀPh (type III).
ACS Paragon Plus Environment
22

Page 23 of 42
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
The network can be described by the stacking of nonꢀinteracting chains along the a and c axes.
As in oꢀF (type II), chains are intercalated and chains planes parallel within and between rows in
the bc plane (Figure 20).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b
a
c
b
c
a
Figure 20. pꢀMe stacking in bc and ac planes.
Both pꢀMe and pꢀPh structures belong to the monoclinic space group P21.
As for the other types, the two type III structures differ significantly from one another with
respect to the hydrophobic contacts. The pꢀMe 2D fingerprint plot is characterized by a central
bump and external wings, corresponding to the presence of H...H contacts and CꢀH...π interactions
respectively, while pꢀPh does not have any of these features (Figure 21).
ACS Paragon Plus Environment
23

Crystal Growth & Design
Page 24 of 42
1
2
3
4
Figure 21. 2D fingerprint plot of pꢀMe (left) and pꢀPh (right). pꢀMe plot displays a central bump
5
6
and a pair of external wings corresponding to H...H contacts and CꢀH...π interactions respectively.
7
8
9
Type IV: mꢀOMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This type of structures exhibit succession of [R3 (11)] ring motifs involving three molecules
3
(Figure 22). A H bond joins one amide hydrogen of a first molecule (A) to the imine of a second
molecule (C). Another H bond links the second molecule carbonyl to the third molecule’s amide
hydrogen (B). A last H bond exists between the third molecule’s carbonyl (B) and the first
molecule’s amide hydrogen (A).
IV
C
B
A
Figure 22. Type IV motif displaying a [R3 (11)] ring formed by three molecules (A, B & C) of
3
mꢀOMe.
Those successive motifs form one inner [C2 (8)] and two outer C(5) hydrogenꢀbonded infinite
2
chains directed along the bꢀaxis (Figure 23).
ACS Paragon Plus Environment
24

Page 25 of 42
Crystal Growth & Design
1
2
3
4
b
a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
Figure 23. Inner [C2 (8)] and outer C(5) hydrogenꢀbonded infinite chains constituted by
2
successive motifs.
Contrary to the type II structures, the imine takes part in the hydrogen bonding patterns and
each carbonyl accepts only one H bond. Furthermore, unlike the type III structures, both amide
hydrogens are involved in such interactions. Thus, as in type I, each molecule is involved in 4
different hydrogen bonds.
Those motifs generate one dimensional hydrogen bonded twisted ladders stacked along the a
and c directions. Once again, those twisted ladders are intercalated and ladders planes are parallel
within and between rows in the ac plane (Figure 24).
ACS Paragon Plus Environment
25

Crystal Growth & Design
Page 26 of 42
1
2
3
4
b
a
5
6
c
b
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
a
Figure 24. Stacking of mꢀOMe in the bc and ac planes exhibiting one dimensional hydrogen
bonded tapes.
Concerning other interactions, one can denote the presence of particularly strong C13—
H13…O1 (Figure 25 and Table 4) interaction.
Figure 25. C13—H13…O1 interchain bond in type IV structure (mꢀOMe).
The type IV structure also crystallizes in the monoclinic spaceꢀgroup P21.
On the 2D fingerprint plot of type IV, the only significant feature concerning the hydrophobic
contacts is the presence of horns near the diagonal, which are due to the fact that in the [R3 (11)]
3
ACS Paragon Plus Environment
26

Page 27 of 42
Crystal Growth & Design
1
2
3
4
5
6
hydrogen bonding pattern of this structure, the amide hydrogens of two interacting molecules are
very close and hence provide a nonꢀdirectional H...H contact (Figure 26).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 26. 2D fingerprint plot of mꢀOMe displaying a pair of horns near the diagonal,
corresponding to close nonꢀdirectional H...H contact in the hydrogen bonding pattern.
Type V: oꢀOMe FII
The type V structure has a dimer motif as main pattern. The dimers are formed by amideꢀ
amide homosynthons [R2 (8)] joining the amides of two molecules (A & B, Figure 27). It is the
2
only type in which no infinite motifs (i.e. chains) are present. As in type II and III, the imine lone
pair does not take part in any intermolecular hydrogen bonding and as in type III, only one amide
hydrogen gives a hydrogen bond. Hence, as in type III, each molecule forms only two distinct
intermolecular hydrogen bonds. However, a weak intraꢀmolecular hydrogen bond is formed
between the imine hydrogen H7 and the oxygen O2 on the substituent.
V
B
A
ACS Paragon Plus Environment
27

Crystal Growth & Design
Page 28 of 42
1
2
3
4
Figure 27. Type V motif displaying a [R2 (8)] ring formed by two molecules (A & B) of oꢀOMe.
2
5
6
7
8
9
Overall, the packing is as in type II first subgroup: dimers are stacked in alternating and
intercalated rows along the cꢀaxis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Type V structure belongs to the monoclinic space group C 2/c.
As main feature, the 2D fingerprint of type V structure shows a central bump corresponding to
the hydrophobic H...H contacts. Furthermore, the structure seems to be less tightly packed
according to the presence of a sparse region at the high distances on Figure 28.
Figure 28. 2D fingerprint plot of oꢀOMe displaying a central bump and a diffuse region at the
high distances.
Discussion
The allocation of structures in different types (displayed in Table 2) reveals that:
ꢀ
ꢀ
ꢀ
ꢀ
All halogen/nitro meta/para substituted compounds show type I structures;
All halogen/nitro ortho substituted compounds show type II structures;
Structures with an alkyl/methoxy substituent are encountered in various types.
Type I and II motifs are by far the most frequently encountered, with 19 out of the 23
structures belonging to these types.
ACS Paragon Plus Environment
28

Page 29 of 42
Crystal Growth & Design
1
2
3
4
Table 2. Graph sets and bond nature of the most prominent features in each type, along with all
5
6
structures belonging to those types.
7
8
9
a
Main interactions
Types
I
Compounds
oꢀPh, pꢀOMe, pꢀF, pꢀCl, pꢀBr, mꢀF,
pꢀNO2, mꢀCl, mꢀBr, mꢀNO2
Hydrogen Bonding Patterns
Interactions localisation
intermolecular
intermolecular
intramolecular
intermolecular
intermolecular
intramolecular
intermolecular
intramolecular
intermolecular
intermolecular
intermolecular
intermolecular
intramolecular
2
2
[R (9)] , [C 2 (7)]
N2 ꢀꢀ H2A .. N1
N2 ꢀꢀ H2B .. O1
N2 ꢀꢀ H2B .. N1
N2 ꢀꢀ H2A .. O1
N2 ꢀꢀ H2B .. O1
N2 ꢀꢀ H2B .. N1
N2 ꢀꢀ H2A .. O1
N2 ꢀꢀ H2B .. N1
N2 ꢀꢀ H2B .. N1
N2 ꢀꢀ H2A .. O1
N2 ꢀꢀ H2B .. O1
N2 ꢀꢀ H2A .. O1
N2 ꢀꢀ H2B .. N1
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
II
mꢀMe, oꢀMe, oꢀOme FI, oꢀF, oꢀCl,
oꢀBr, oꢀNO2
[R (8)] , C(4)
3
III
IV
pꢀMe, pꢀPh
mꢀOMe
C(8)
3
2
[R (11)] , [C (7)], C(5)
3
2
V
oꢀOMe FII
[R2 (8)]
2
a CꢀꢀH..O interactions not taken into account
This leads to the question whether the attribution to a given type is mostly due to electronic or
rather steric effects specific to the substituents or their position on the benzylidene.
Concerning the electronic effects, we note that both meta and para halogen substituted moieties
exhibit type I structures. However, theoretical charges generated by mesomeric and inductive
effects of halogens are located at different positions on the benzylidene for meta and paraꢀ
substituted compounds. In other words, these charges do not impact the formation of hydrogen
bonds involving the benzylidene hydrogens or the imine nitrogen. This result is in agreement
with DFT calculations, showing the charges present on the benzylidene atoms are very similar
regardless of the nature and position of the substituent on the ring. One can thus conclude that
mesomeric and inductive factors of halogens do not significantly affect the structural outcome
and that their position (and subsequent steric occupation) on the ring may play a more important
role.
ACS Paragon Plus Environment
29