Inclusion complexes of selected amines with pillar[5]arenes: experimental and molecular dynamics study

Article abstract of DOI:10.1007/s10847-019-00971-1

Selected amines were allowed to form inclusion complexes with selected synthesized pillar[5]arenes. Formation of inclusion complexes were confirmed by MALDI–TOF, ESI–MS analyses and ¹H NMR spectroscopy. The complexation was supported by molecul

Full text of DOI:10.1007/s10847-019-00971-1

Journal of Inclusion Phenomena and Macrocyclic Chemistry
https://doi.org/10.1007/s10847-019-00971-1
ORIGINAL ARTICLE
Inclusion complexes of selected amines with pillar[5]arenes:
experimental and molecular dynamics study
Hamad H. Al Mamari1 · Iman Al Harrasi · Khulood Al Hadhrami · Yousuf Al Lawati · Fakhreldin O. Suliman
1
1
1
1
Received: 4 November 2019 / Accepted: 17 December 2019
©
Springer Nature B.V. 2019
Abstract
Selected amines were allowed to form inclusion complexes with selected synthesized pillar[5]arenes. Formation of inclu-
1
sion complexes were conꢀrmed by MALDI–TOF, ESI–MS analyses and H NMR spectroscopy. The complexation was
supported by molecular dynamics calculations. Various pillar[5]arenes have been synthesized by BF ·OE (Lewis acid)
3
t2
catalyzed cyclization of 1,4-disubstitutedbenzenes with paraformaldehyde. Selected synthesized host macrocycles; DMpil-
lar[5]arene (7), DPpillar[5]arene (8a), DPGpillar[5]arene (8b) were allowed to form inclusion complexes with N-containing
guests; hexamethylenediamine (GA), di-n-octyl amine (GB) and diethyl amine (GC). Host–guest complex formation of
1
the selected pillar[5]arenes with the N-containing guests has been conꢀrmed by MALDI–TOF, ESI–MS analyses and H
+
NMR spectroscopy. ESI–MS revealed highly intense ion peaks that correspond to [pillar[5]arene@GA+Na] for inclu-
sion complexes of pillar[5]arenes with hexamethylenediamine (GA). ESI–MS conꢀrmed formation of inclusion complexes
between pillar[5]arenes with di-n-octyl amine (GB) and diethyl amine (GC) as evidenced by intense peaks that corresponds
+
+
to [pillar[5]arene@GB+H] and [pillar[5]arene@GC+H] , respectively. Performed molecular dynamics (MD) simula-
tions provided supportive results that indicate the formation of stable complexes between the three pillar[5]arene hosts and
the guests included in this study. Hydrogen bonding and CH–π interactions were found amongst the factors that contribute
signiꢀcantly to the stability of these complexes.
Keywords Pillar[5]arenes · Host–guest chemsitry · Macrocycles · Inclusion complexes
Introduction
but highly symmetric cucurbiturils [5], and the structurally
ꢁ
exible nonsymmetric calixarenes [6].
Macrocycles are fascinating molecules with various macro-
molecular sizes and cavity sizes. They display various struc-
tural, conformational and symmetrical features that exhibit
various chemical, physical, physiochemcial and host–guest
properties. Their remarkable selective binding is exempliꢀed
by crown ethers [1, 2], their structural versatility is dem-
onstrated by the structurally rigid, well-deꢀned nonsym-
metric cyclodextrins [3, 4], the similarly structurally rigid
Pillar[n]arenes (1, Fig. 1) are intriguing cyclophane-type
macrocyclic molecules that contain 1,4-disubstituted (typi-
cally 1,4-dialkoxy) hydroquinone units connected by meth-
ylene bridges at the 2 and 5 positions [7–18]. They diꢂer
from calix[n]arenes (2, Fig. 1) in their highly symmetrical
1,4-disubstituted para-bridged structure compared to the
2,6-disubstituted meta-bridged structured calix[n]arenes.
The importance of pillar[n]arenes lies in their ability to
demonstrate interesting chemical, physical and host–guest
properties [7–24]. This is attributed to their rigid and sym-
metrical pillar structure and the electron-rich cavities which
enable them function as hosts. These host properties can
allow them bind with neutral and electron-poor guests.
These unique structural features enable pillar[n]arenes to
demonstrate host–guest complexation and with notable
binding selectivity. These macrocycles are possible to syn-
thesize and based on their possession of 1,4-dialkoxy sub-
stituents, they can undergo further functionalization. The
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10847-019-00971-1) contains
supplementary material, which is available to authorized users.
*
Hamad H. Al Mamari
halmamari@squ.edu.om
1
Department of Chemistry, College of Science, Sultan
Qaboos University, PO Box 36, Al Khoudh 123, Muscat,
Sultanate of Oman
Vol.:(0
1
123456789)
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
OH
macrocycles, their fascinating modularity and functionali-
zation versatility and the great potential of their chemical,
physical and host–guest properties, we embarked on adven-
turous research in the ꢀeld. Our goal is to synthesize new
pillar[5]arenes with various electronic properties and thus
modular electron-richness in their cavities. An intertwined
goal was to enable host pillar[n]arenes complex with guest
molecules thus allow formation of host–guest inclusion
complexes. Our incentive to the desire to study complexation
and binding of the host pillar[n]arenes with amine guests.
Moreover, we utilized molecular dynamic (MD) simulations
to cast an additional light on the inclusion process and on the
stability of the complexes in solution. Through MD simula-
tions we also hoped to determine the factors that contribute
to the stability of these complexes.
4
OH
5
3
2
6
1
H
2
5
*
*
6
n
1
OH
H
4
3
HO
n
Pillar[n]arenes
Calix[n]arenes
1
2
Fig. 1 General structures of pillar[n]arenes and calix[n]arenes
alkoxy groups at C1 and C4 positions can undergo Lewis-
acid or Lowry-BrØnsted acid-catalyzed cleavage reactions
to give the corresponding 1,4-dihydroxyarene. Alternatively,
the alkoxy groups can be converted into sulfonate (such as
mesylates, tosylates or trꢀlates) groups which can, in turn,
enable the arene undergo cross-coupling reactions with orga-
nometallic reagents. Therefore, pillar[n]arenes are modular
macrocycles that can undergo versatile functionalization and
variation in cavity size which in turn can enable tuning of
their host–guest properties. A common example of pillar[n]
arene macrocycles is pillar[5]arenes that consists of ꢀve hyd-
roquinone units linked at 2 and 5 positions and that exhibit
conformational stability [7–24].
Results and discussion
Synthesis and formation of inclusion complexes
of pillar[5]arenes with amines
Various 1,4-disubstituted benzenes (6) were synthesized
from hydroquinone (5) using standard procedures (see Sup-
porting Information for details). With various 1,4-disubsti-
tuted benzenes in hand, pillararene formation was carried
out. At the outset of our work, our emphasis was placed on
the synthesis of pillar[5]arenes. Toward that end, the pil-
lar[5]arene synthesis protocol found by Ogoshi was used
(Scheme 2) [7–14]. Thus, various 1,4-disubstituted benzenes
(6) were treated with paraformaldehyde in the presence of
the Lewis-acid BF ·OEt in 1,2-dichloroethane as a solvent
Pillar[n]arenes can possibly be synthesized in diꢂerent
methods [7–20]. The pioneering work of Ogoshi involves
the synthesis of pillar[5]arenes by Lewis-acid catalyzed con-
densation of 1,4-dialkoxybenzene with paraformaldehyde
(
Scheme 1) [7–14]. Removal of the ether protecting group
by a suitable deprotection method should aꢂord the pillar[n]
arenes (Scheme 1) [7–14].
3
2
Many 1,4-disubstituted pillar[5]arenes are now known.
Pillar[5]arenes containing methyl, ethyl, n-propyl, n-butyl,
n-pentyl, n-hexyl, n-dodecyl have been synthesized using
the method outlined above (Scheme 1) [7–24]. Inclusion
complexes of host pillar[n]aranes with various guests have
been made and their host–guest properties have been stud-
ied [7–24]. Despite the development made in the ꢀeld of
pillar[n]arenes, various novel macrocycles are yet to be
synthesized. Through structural and electronic of pillar[n]
arenes, new avenues for host–guest properties could be
opened. Inspired by the intriguing structure of pillar[n]arene
to give the corresponding pillar[5]arenes (Scheme 2). Mac-
rocycles; DMpillar[5]arene (7), DPpillar[5]arene (8a), and
DPGpillar[5]arene (8e) were successfully obtained in the
respective yields shown (Scheme 2).
With pillar[5]arenes in hand, we turned our attention
into investigating their host–guest properties. Thus certain
selected pillar[5]arenes were allowed to complex and form
inclusion complexes with certain selected guests (Fig. 2).
In this contest, DMpillar[5]arene (7), DPpillar[5]arene
(8a), and DPGpillar[5]arene (8b) were selected to form the
corresponding inclusion complexes with selected guests;
Scheme 1 Synthesis of pillar[5]
OR
arenes
OR
OH
6
1
6
1
(
H CO)n
2
H
deprotection
H
2
2
5
5
Lewis-acid
H
H
4
3
4 3
OR
3
RO
HO
n
n
4
1
1
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
Scheme 2 Synthesis of pillar[5]
OR
arenes in the present study
OR
6
1
(
H CO)
H
2
n
2
5
BF .OEt
3
2
H
4
3
OR
6
1
,2-dichloroethane
RO
5
o
25 C, 24 h
8
OMe
H
On-Pr
O
H
H
H
H
H
MeO
n-PrO
O
5
5
7
: 27%
8a: 25%
8b: 26%
5
Selected hosts:
5
4
4
2
2
2
OCH
H
O
O
3
1
1
1
H
H
3
3
3
H
H
H
H CO
3
O
O
5
5
5
DMpillar[5], 7
DPpillar[5], 8a
DPGpillar[5]arene, 8b
Selected guests:
Ha
Ha
Hc
Hb
Ha
Hc
Hb
NH2
N
N
H
H N
2
Hd
Hb
H
GA
GB
GC
Fig. 2 Selected pillar[5]arenes and amine guests for inclusion complexes formation
hexamethylenediamine (GA), di-n-octyl amine (GB) and
diethyl amine (GC) (Fig. 2).
(Fig. 2) were prepared. To investigate the complexation
of various alkyl-amine guests with the pillararenes hosts
prepared in this study we used ESI–MS in the positive
mode. The ESI–MS results for all complexes are sum-
marized in Table 1. From these results it is obvious that
DMpillar[5]arene (7) forms 1:1 complexes with all the
guests studied here. The existence of DMpillar[5]arene@
GA and DMpillar[5]arene@GC complexes is discerned
by the formation of the singly charged species [DMpil-
Electrospray ionization–mass spectrometry (ESI–MS)
of pillar[5]arene inclusion complexes
Inclusion complexes of the selected pillararenes, DMpil-
lar[5]arene (7), DPpillar[5]arene (8a), and DPGpillar[5]
arene (8b) with selected guests; hexamethylenediamine
+
+
(
GA), di-n-octyl amine (GB) and diethyl amine (GC)
lar[5]arene@GA+Na] and [DMpillar[5]arene@GC+H]
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Table 1 ESI-MS results for the inclusion complexes of the DMP5,
Inclusion complexes of 1,4‑DMpillar[5]arene (7)
DPP5 and DPGP5 with various hosts
Experimental m/z Calculated m/z Species
The inclusion complexe of DMpillar[5]arene@GA revealed
changes in chemical shifts as a result upon complexation
8
9
8
5
7
1
1
1
1
1
1
89.2
92.5
24.2
19.2
889.50
992.76
824.12
518.87
773.3
1169.86
1273.31
1104.81
1129.29
1232.55
1064.22
[DMpillar[5]arene@GA+Na]+
[
29–33]. For instance, phenyl protons H1 on DMpillar[5]
+
[DMpillar[5]arene@GB+H]
arene (7) shifted slightly upꢀeld (−0.02 ppm) while chemi-
cal shifts of the methoxy protons remained unaꢂected and
the methylene bridge protons H3 shifted slightly upꢀeld
[DMpillar[5]arene@GC+H]+
2
+
[DMpillar[5]arene@GB+2Na]
73.2
[DMpillar[5]arene+Na]+
(
− 0.01 ppm). The above observations were a result of
+
169.8
272.9
104.6
129.3
232.5
064.3
[DPpillar[5]arene@GA+Na]
shielding eꢂects induced by inclusion of the guest inside
the host cavity (Table 2) [33]. Similar trends in chemical
shifts’ changes were observed in the cases of DMpillar[5]
arene@GB and DMpillar[5]arene@GC. Phenyl protons and
methylene bridge protons underwent upꢀeld chemical shift
changes (Δδ) while those of the methoxy protons remained
unchanged (Table 2).
+
[DPpillar[5]arene@GB+H]
[DPpillar[5]arene@GC+H]+
+
[DPGpillar[5]arene@GA+Na]
[DPGpillar[5]arene@GB+H]+
[DPGpillar[5]arene@GC+H]+
Inclusion of DMpillar[5]arene with the selected guests
resulted also in changes of the chemical shifts the guests
(Table 3). For instance, in the case of DMpillar[5]arene@
GA, the GA Ha protons show a downfeld chemical shifts
changes of 0.03 ppm while Hb and Hc protons shifted
upꢀeld by 0.03 and 0.04 ppm respectively (Table 3). These
observations indicate that Ha protons were deshielded sug-
gesting interactions of the methyl protons on the rims of
DMpillar[5]arene (7) [29]. Upon formation of DMpillar[5]
arene@GB inclusion complex, GB protons, Ha, Hb, Hc and
Hd, underwent upꢀeld changes in chemical shifts 0.01, 0.02,
0.01 and 0.02 respectively (Table 3). For guest DMpillar[5]
arene@GC, the chemical shift changes of the GC Ha pro-
tons shifted downfeld by 0.02 ppm. This indicates that these
methylene protons were located in the deshielding area of
the host molecule, which can be explained in terms of the
interactions with the methyl protons on the rims of DMpil-
lar[5]arene (7).
at m/z 8892.2 and m/z 824.2, respectively. On the other
hand, DMpillar[5]arene@GB is represented by the singly
+
and doubly charged cations [DMpillar[5]arene@GB+H] ,
2
+
[
DMpillar[5]arene@GA+2Na] , at m/z 992.5 and 519.2
respectively. The existence of sodium and potassium
adducts in ESI–MS spectra is inescapable especially in
presence of macrocyclic molecules. Inspection of Table 1
shows a signal at m/z 773.2 which corresponds to [DMpil-
+
lar[5]arene+Na] ion representing the sodium adduct of
the host.
DPpillar[5]arene (8a), and DPGpillar[5]arene (8b)
(
Table 1) form singly charged ions with all guest mole-
cules. The experimental m/z values of all complexes are in
good agreement with the calculated values indicating that
all hosts form stable inclusion complexes with the guest
molecules included in this study in acetonitrile. It is worth
mentioning here, that the formation of stable complex ions
in the gas phase suggest that such complexes already exist
in the solution. Similar observations have been previously
reported for other macrocyclic systems such as cyclodex-
trins and cucrbit[n]urils [25–28].
Inclusion complexes of 1,4‑DPpillar[5]arene (8a)
Inclusion complexes of DPpillar[5]arene (8a) with the three
1
guests were also studies by H NMR. Upon addition of GA
Typical ESI–MS spectra of DPGpillar[5]arene com-
plexes with GA, GB and GC are shown in Fig. 3.
to the host, phenyl protons H1, H4 and H5 on DPpillar[5]
arene (8a) shifted downꢀeld chemical shift changes (Δδ) of
0
.01, 0.01 and 0.02, respectively (Table 2). The methylene
bridge protons underwent upꢀeld chemical shift change of
0.01 while C2 protons (next to oxygen) remained unchanged.
The inclusion complex also resulted in changes of the chemi-
cal shifts of the guest, GA. Notably, Ha, Hb and Hc protons
of the guest underwent upꢀeld changes in chemical shifts
by 0.05, 0.07 and 0.09 ppm respectively (Table 3). These
observations suggest that these methylene protons are deeply
inserted into the cavity of the DPpillar[5]arene (8a).
Nuclear magnetic resonance spectroscopy (NMR)
1
1
D NMR H NMR spectroscopy is a powerful technique
used to study inclusion complexes of the selected pillar[5]
arene complexes. Inclusion of guest molecules is usually
associated with changes in NMR spectra. The changes in
chemical shifts of the pillararene host as a result of compl-
exation with the selected guests are summarized in Table 2,
whereas the eꢂects of complexation on chemical shifts of
the guest peaks are summarized in Table 3.
1
The H NMR of DPpillar[5]arene@GB revealed upꢀeld
chemical shift changes for the methylene bridge and C2
protons, by 0.01 ppm, while other protons remained
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 3 ESI-MS spectrum of
a DPGpillar[5]arene@GA,
b DPGpillar[5]arene@GB, c
DPGpillar[5]arene@GC in ace-
tonitrile in the positive mode
unaꢂected (Table 2). The guest, GB, protons, Ha, Hb, Hc
and Hd underwent upꢀeld chemical shift changes of 0.02,
formation of inclusion complex, DPpillar[5]arene@GC,
1
H NMR revealed upꢀeld changes in the chemical shifts of
0
.02, 0.03 and 0.02 ppm, respectively (Table 3). Upon
C2, C3 and C4 protons. While such changes occurred with
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Table 2 Changes in chemical
shifts of pillar[5]arene peaks as
a result of complexation with
guests
Pillar[5]arene
Phenyl
protons
C2 protons (Δδ) Methylene C4 protons (Δδ) C5 protons (Δδ)
bridge (Δδ)
(
Δδ)
DMpillar[5]arene@GA − 0.02
DMpillar[5]arene@GB − 0.03
DMpillar[5]arene@GC − 0.02
DPpillar[5]arene@GA
DPpillar[5]arene@GB
DPpillar[5]arene@GC
DPGpillar[5]arene@GA
DPGpillar[5]arene@GB
DPGpillar[5]arene@GC
–
–
–
–
− 0.01
− 0.02
− 0.01
− 0.01
− 0.01
− 0.01
–
+0.01
+0.01
–
− 0.01
+0.01
+0.01
–
+0.02
–
–
–
–
–
–
–
− 0.01
− 0.01
–
–
–
−0.02
–
Table 3 Changes in chemical shifts of the guest peaks as a result of
complexation with guests
Pillar[5]arene
Ha (Δδ) Hb (Δδ) Hc (Δδ) Hd (Δδ)
DMpillar[5]arene@GA
DMpillar[5]arene@GB
DMpillar[5]arene@GC
DPpillar[5]arene@GA
DPpillar[5]arene@GB
DPpillar[5]arene@GC
DPGpillar[5]arene@GA −0.03
DPGpillar[5]arene@GB
DPGpillar[5]arene@GC
+0.03
−0.01
+0.02
−0.05
− 0.02
− 0.01
−0.03
−0.02
+0.01
−0.07
− 0.02
− 0.02
−0.03
− 0.03
− 0.01
−0.04
−0.01
−0.02
− 0.02
− 0.02
−0.09
− 0.03
−0.04
− 0.02
− 0.02
− 0.01
The bolded entries show the biggest changes in chemcial shifts
Fig. 4 RMSD of (a) DMpillar[5]arene@GA (b) DPpillar[5]arene@
GA (c) DPGpillar[5]arene@GA
upꢀeld shifts of 0.01 ppm each, the phenyl protons (H1)
and C5 protons did not undergo chemical shoft changes
(
Table 2). Complexation was also accompanied by upꢀeld
chemical shift changes of Ha and Hb protons of the guest
Table 3).
Molecular dynamic simulations
(
Molecular dynamic (MD) simulations has been employed
in this study to cast more light on the inclusion process at
atomistic levels and to have a deeper understanding of the
diꢂerent forces contributing to the stability of these com-
plexes. The energy optimized structure of the complexes
were immersed in an orthorhombic box containing dimethyl
sulfoxide (DMSO) solvent molecules. Simulation runs of
20–50 ns at a pressure of 1 atm and a temperature of 300 K
were carried out. To follow the stability of the complexes
during the simulation time the root mean square devia-
tions (RMSD) from the energy minimized structures were
obtained for all complexes (Fig. 4).
Inclusion complexes of 1,4‑dipropargyloxypillar[5]
arene (8b)
Addition of the hexylmethylene diamine guest GA to the
DPGpillar[5]arene (8e) in CDCl results in changes in inten-
3
sity of the host peaks, which indicates complex formation.
While C4 protons of the pillararene underwent downꢀeld
chemical shift of 0.01 ppm, the other protons remained unaf-
fected (Table 2). Formation of the DPGpillar[5]arene@GA
complex resulted in notable chemical shift changes of the
guest. Ha, Hb and Hc underwent upꢀeld changes of 0.03,
GA forms stable complexes with the three pillararenes
studied here is inferred from the RMSD plots shown in
Fig. 6. In the three cases, the complex is stabilized within
less than a nanosecond and the RMSD remained stable
throughout the simulation time (Fig. 4). We also calculated
0
.03 and 0.04 ppm respectively (Table 3). Formation of
DPGpillar[5]arene@GB and DPGpillar[5]arene@GC inclu-
sion complexes was accompanied with upꢀeld changes in
the chemical shifts of the guests (Table 3).
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
the radius of gyration, r , of guest, host and the complexes
The RMSD for the interactions of GB with the three hosts
(Supporting Information, Fig. S70) shows that GB forms
stable complex with DMpillar[5]arene during the ꢀrst ten
nanoseconds of the simulation after which the guest leaves
the host as represented by the snapshots (Supporting Infor-
mation, Fig. S70a). On the other hand, DPpillar[5]arene@
GB exhibits stable trajectory over the 50 ns of the simulation
with the guest inserted into the cavity of the host as shown
in the snapshots (Supporting Information, Fig. S71). Scru-
pulous examination of these snapshots shows that the octyl
arm outside the cavity rotates around the host resulting in
the formation of various conformers and at some instances
with scorpion-like structures. These structures are formed
due to the ꢁexibility of the long guest.
gyr
averaged over the simulation time and the results are sum-
marized in Table 4. Examination of r values for GA com-
gyr
plexes reveals the fact that r for the complexes are always
gyr
less than the sum of r of the individual host and the guest
gyr
and in all casesits value is close to that of the host. These
observations clearly show that GA form compact and stable
complexes in solution with these hosts.
To ascertain these results, we collected snapshots during
the simulation for the three complexes of GA (Supporting
Information, Figs. S67–S69). It is clear that GA as a small
guest molecule ꢀts easily into the nanocavity of the indi-
vidual hosts and the complexes remain stable during the
simulation.
DPGpillar[5]arene@GB exhibits a more fluctuating
RMDS pattern compared to that of DPpillar[5]arene@GB.
Snapshots for DPGpillar[5]arene@GB complexes show
conformations similar to DPpillar[5]arene@GB rotating to
maximize interaction with the host (Supporting Informa-
tion, Fig. S70). The radii of gyration of the GB-pillararene
complexes are close to those of the hosts indicating that the
complexes are compact in DMSO solution suggesting the
formation of stable complexes.
Table 4 RMSD and radius of gyration values obtained from the MD
simulations
Compound
RMSD (Å)
rgyr (Å)
DMpillar[5]arene@GA
DPpillar[5]arene@GA
DPGpillar[5]arene@GA
DMpillar[5]arene@GB
DPpillar[5]arene@GB
DPGpillar[5]arene@GB
1.04± 0.29
1.14± 0.15
1.01± 0.21
1.48± 0.48
2.10± 0.68
2.09± 1.15
3.24± 1.33
2.60± 1.13
3.79± 0.71
–
–
–
–
–
4.63± 0.07
5.36± 0.05
5.22± 0.04
5.63± 0.35
5.91± 0.22
5.75± 0.21
7.69± 0.69
8.68± 0.25
8.60± 0.33
4.77± 0.04
5.53± 0.05
5.39± 0.04
2.98± 0.03
5.40± 0.04
To have a better insight into the factors involved in the
stabilization of these complexes we calculated the radial
distribution functions (RDF), g(r), as a function of the dis-
tance between NH-group on GB and the center of mass of
DPGpillar[5]arene as shown in Fig. 5. This ꢀgure tells us
that GB, a long straight chain molecule, exists in various
conformations while tumbling in the nanocavity of the host
molecule. The most probable conformation is represented by
the peak with the maximum at r~0.6 Å where one octyl arm
of the di-n-octyl amine is inserted completely into the cavity.
The other possible structures are represented by the peak at
r~4.0 Å where most of the guest molecule is left outside the
a
(
(
(
DMpillar[5]arene) @GB
2
DPpillar[5]arene) @GB
2
DPGpillar[5]arene) @GB
2
DMpillar[5]arene
DPpillar[5]arene
DPGpillar[5]arene
GA
GB
Fig. 5 RDF of the distance
between NH and the center of
mass of DPGpillar[5]arene
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
cavity. This observation, however, prompted us to investigate
the possibility of formation of the 1:2 GB: host complexes
by checking the stability of these complexes using MD simu-
lations. Figure 6 shows relatively stable RMSD values were
obtained for the three ternary complexes throughout the
simulation. On the other hand, the r values also suggest
gyr
stable complexes are obtained (Table 4) notwithstanding
the ꢁuctuations observed in the RMSD. These ꢁuctuations,
however, originate from the ꢁexibility of the guest molecule
that allows it to adopt several stable conformations as can
be inferred from the snapshots taken during the simulation
of these complexes (Supporting Information, Fig. S72). The
guest molecule adopts straight chain conformations as well
as twisted conformations and even sometimes forces the two
hosts to adopt a v-shaped structure with each other.
It has been reported, using quantum mechanics calcula-
tions, that DMpillar[5]arene inner cavity exhibits a strongly
negative electrostatic potential [34]. This negative atmos-
phere is mainly due the delocalized π-electrons of the phenyl
rings located at the central belt of the host. Additionally, the
methyl groups decorating the openings of the host’s cavi-
ties show slightly positive electrostatic potentials. There-
fore, electrostatic interactions and hydrogen bonding are the
main driving forces for the formation of pillararene-guest
complexes.
Fig. 6 RMSD of (a) DMpillar[5]arene@GA (b) DPpillar[5]arene@
GA (c) DPGpillar[5]arene@GA
to investigate the contribution of such interactions to the
stability of our complexes. The RDFs of the distances from
the CH -protons on the octyl groups of GB to the center of
2
each benzene ring on the pillararene are shown in Fig. 7. The
peaks at r~2.6 Å indicate the presence of the guest protons
at a distance that allows for the formation of CH–π bond pro-
viding additional stability to these complexes. Interestingly,
it was reported that ethylbenzene forms stable complexes
with perethylated pillar[5]arene by inserting the ethyl group
into the center of the cavity of the host [14]. It is clear that
DMpillar[5]arene, DPpillar[5]arene and DPGpillar[5]arene
are capable of forming stable complexes with molecules
carrying normal alkane chain moieties in organic solvents
(Fig. 8).
Given the nature of the guest and hosts included in this
work, the most predominant interactions are expected to
involve electrostatic and hydrogen bond interactions, how-
ever, other non-covalent interactions cannot be ruled out.
To this end, we decided to investigate the interaction of NH
and NH groups on the guests with the oxygen atoms on
2
the host for potential contributions from hydrogen bonds.
Figure 7 shows the RDF plots for the NH–O distances for
GA complexes with the three hosts. The results shown here
imply that weak to moderate hydrogen bonding exists by
virtue of the peak at r ~ 2.8–3.0 Å. On the other hand, a
weaker NH–O interaction is observed for pillar[5]arene@
GB complexes (Supporting Information, Figs. S71–S74).
Probably the longer octyl group for GB may be responsible
for such a diꢂerence in interactions. Interestingly, for the 1:
Conclusion
Inclusion complexes of selected amines with selected
synthesized pillar[5]arenes were formed and conꢀrmed
1
by MALDI–TOF, ESI–MS analyses and H NMR spec-
2
complexes this interaction is greatly diminished, indicat-
troscopy. The complexation was supported by molecular
dynamics calculations. Various symmetrical pillar[5]
arenes have been synthesized BF ·OE (Lewis acid) cata-
ing that other non-covalent interactions are more important
in this case.
3
t2
CH–π interactions are well known for their signiꢀcant
role in crystal packing of organic molecules and for their
contributions in supramolecular chemistry and molecu-
lar aggregations [34, 35]. These interactions are weak in
nature, and it has been determined by quantum mechanics
calculations that the binding energies for the interaction
of methyl and ethyl groups with benzene are −1.45 and
lyzed cyclization of 1,4-disubstitutedbenzenes with para-
formaldehyde. Selected synthesized host macrocycles;
DMpillar[5]arene (7), DPpillar[5]arene (8a), DPGpillar[5]
arene (8b) were allowed to form inclusion complexes with
N-containing guests; hexamethylenediamine (GA), di-
n-octyl amine (GB) and diethyl amine (GC.) Host–guest
complex formation of the selected pillar[5]arenes with the
N-containing guests has been conꢀrmed by MALDI–TOF,
−
1
−
1.82 kcal mol , respectively. These interaction energies
1
were found to increase with the presence of methyl substitu-
ents on the benzene ring [35]. In this work, we were tempted
ESI–MS analyses and H NMR spectroscopy. ESI–MS
revealed highly intense ion peaks that correspond to
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 7 RDF of the distance
between NH of GA and the
oxygen atoms on the pillararene.
Solid lines DMpillararene@GA,
dashed lines DPpillararene@
GA, dashed dotted lines DGP-
pillararene@GA
Fig. 8 RDF of the distance
between CH–π of GB@pil-
lararene. Solid lines (DGPpil-
lararene) @GB, dashed lines
2
DGPpillararene @GB, dashed
dotted lines DPpillararene @GB
inclusion complexes of pillar[5]arenes with amine guests.
References
1
H NMR spectral data revealed upꢀeld-chemical shifts for
certain peaks on the pillar[5]arene hosts and N-containing
guests which provided another evidence for formation of
inclusion complexes. Some peaks underwent broadening
as a result of inclusion of the guests inside the cavity of the
guest. MD simulations have shown that these N-containing
guest molecules are capable of forming stable complexes
with the three synthesized hosts. Additionally, the simula-
tion results suggested the presence of hydrogen bonding
interactions as well as strong CH–π interactions which
add additional stability to these supramolecular struc-
tures. Work is currently underway to further investigate
host–guest properties of pillar[n]arenes.
1. Bradshaw, J.S., Izatt, R.M.: Crown ethers: the search for selec-
tive ion ligating agents. Acc. Chem. Res. 30, 338–345 (1997)
2
.
Gokel, G.W., Leevy, W.M., Weber, M.E.: Crown ethers: sensors
for ions and molecular scaꢂolds for materials and biological
models. Chem. Rev. 104, 2723–2750 (2004)
3. Harada, A., Hashidzume, A., Yamaguchi, H., Takashima, Y.:
Polymeric rotaxanes. Chem. Rev. 109, 5974–6023 (2009)
4
.
Chen, G., Jiang, M.: Cyclodextrin-based inclusion complexa-
tion bridging supramolecular chemistry and macromolecular
self-assembly. Chem. Soc. Rev. 40, 2254–2266 (2011)
5. Bhasikuttan, A.C., Pal, H., Mohanty, J.: Cucurbit[n]uril based
supramolecular assemblies: tunable physico-chemical properties
and their prospects. Chem. Commun. 47, 9959–9971 (2011)
1
3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
6
7
.
.
Botana, E., Da Silva, E., Benet-Buchholz, J., Ballester, P., de
Mendoza, J.: Inclusion of cavitands and calix[4]arenes into a
metallobridged para-(1H-imidazo[4,5-f][3,8]phenanthrolin-2-yl)-
expanded Calix[4]arene. Angew. Chem. Int. Ed. 46, 198–201
negatively charged carboxylatopillar[5]arene. J. Org. Chem. 76,
8458–8465 (2011)
23. Shu, X., Fan, J., Li, J., Wang, X., Chen, W., Jia, X., Li, C.: Com-
plexation of neutral 1,4-dihalobutanes with simple pillar[5]arenes
that is dominated by dispersion forces. Org. Biomol. Chem. 10,
3393–3397 (2012)
(
2007)
Ogoshi, T., Kanai, S., Fujinam, S., Yamagishi, T.-A., Nakamoto,
Y.: para-bridged symmetrical Pillar[5]arenes: their lewis acid
catalyzed synthesis and host–guest property. J. Am. Chem. Soc.
24. Zhang, H., Strutt, N.L., Stoll, R.S., Li, H., Zhu, Z., Stoddart, J.F.:
Dynamic clicked surfaces based on functionalised pillar[5]arene.
Chem. Commun. 47, 11420–11422 (2011)
1
30, 5022–5023 (2008)
8
9
.
.
Ogoshi, T., Hashizume, M., Yamagishi, T.-A., Nakamoto, Y.: Syn-
thesis, conformational and host–guest properties of water-soluble
pillar[5]arene. Chem. Commun. 46, 3708–3710 (2010)
Ogoshi, T., Aoki, T., Kitajima, K., Fujinami, S., Yamagishi, T.-A.,
Nakamoto, Y.: Facile, rapid, and high-yield synthesis of pillar[5]
arene from commercially available reagents and its x-ray crystal
structure. J. Org. Chem. 76, 328–331 (2011)
25. Al-Burtomani, S.K.S., Suliman, F.O.: Deciphering ephedrine
inclusion complexes with β-cyclodextrin, 18-crown-6 and cucur-
bit[7]uril using spectral and molecular modeling methods. J. Incl.
Phenom. Macrocycl. Chem. 93, 157–172 (2019)
26. Mokhtar, M.S., Suliman, F.O., Elbashir, A.A.: Experimental and
molecular modleing investigations of inclusion complexes of
imazapyr with 2-hydroxypropyl(β/γ) cyclodextrin. J. Mol. Liq.
262, 504–513 (2018)
1
1
1
1
1
0. Ogoshi, T., Nishida, Y., Yamagishi, T.-A., Nakamoto, Y.: Polyp-
seudorotaxane constructed from pillar[5]arene and viologen poly-
mer. Macromolecules 43, 3145–3147 (2010)
27. Al-Burtomani, S.K.S., Suliman, F.O.: Experimental and theo-
retical study of the inclusion complexes of epinephrine with
β-cyclodextrin, 18-crown-6 and cucurbit[7]uril. N. J. Chem. 42,
5785–5797 (2018)
1. Ogoshi, T., Demachi, K., Kitajima, K., Yamagishi, T.-A.: Mono-
functionalized pillar[5]arenes: synthesis and supramolecular
structure. Chem. Commun. 47, 7164–7166 (2011)
28. Varghese, B., Suliman, F.O., Al-Hajri, A., Al Bishri, N.S.S., Al-
Rwashda, N.: Spectral and theoretical study on complexation of
sulfamethoxazole with β- and HPβ-cyclodextrins in binary and
ternary systems. Spectrochim. Acta Part A 190, 392–401 (2018)
29. Han, C., Yu, G., Zheng, B., Huang, F.: Complexation between
pillar[5]arenes and a secondary ammonium salt. Org. Lett. 14(7),
1712–1715 (2012)
2. Ogoshi, T., Kitajima, K., Aoki, S., Yamagishi, T.-A., Nakamoto,
Y.: Synthesis and conformational characteristics of alkyl-substi-
tuted pillar[5]arenes. J. Org. Chem. 75, 3268–3273 (2010)
3. Ogoshi, T., Kitajima, K., Yamagishi, T.-A., Nakamoto, T.: Synthe-
sis and conformational characteristics of nonsymmetric pillar[5]
arene. Org. Lett. 12, 636–638 (2010)
4. Ogoshi, T., Shiga, R., Yamagishi, T.-A., Nakamoto, Y.: Planar-
chiral pillar[5]arene: chiral switches induced by multiexternal
stimulus of temperature, solvents, and addition of achiral Guest
molecule. J. Org. Chem. 76, 618–622 (2011)
30. Ramdas, M.R., Kumar, K.S., Nair, C.P.R.: Synthesis, structure and
tunable shape memory properties of polytriazoles: dual-trigger
temperature and repeatable shape recovery. J. Mater. Chem. A
3(21), 11596–11606 (2015)
1
5. Xue, M., Yang, Y., Chi, X., Zhang, Z., Huang, F.: Pillararenes,
a new class of macrocycles for supramolecular chemistry. Acc.
Chem. Res. 45, 1294–1308 (2012). and references therein
6. Cragg, P.J., Sharma, K.: Pillar[5]arenes: fascinating cyclophanes
with a bright future. Chem. Soc. Rev. 41, 597–607 (2012)
7. Li, C., Xu, Q., Li, J., Yao, F., Jia, X.: Complex interactions of
pillar [5] arene with paraquats and bis (pyridinium) derivatives.
Org. Biomol. Chem. 8, 1568–1576 (2010)
31. Deng, H., Shu, X., Hu, X., Li, J., Jia, X., Li, C.: Synthesis of
a fully functionalized pillar[5]arene by ‘click chemistry’ and its
eꢂective binding toward neutral alkanediamines. Tetrahedron Lett.
53(34), 4609–4612 (2012)
1
1
32. Cheng, X., Li, H., Zheng, F., Lin, Q., Zhang, Y., Yao, H., Wei, T.:
A pillar[5]arene-based cyanide sensor bearing on a novel cyanide-
induced self-assemble mechanism. Dyes Pigments 127, 59–66
(2016)
1
1
8. Shu, X., Chen, S., Li, J., Chen, Z., Weng, L., Jia, X., Li, C.: Highly
eꢂective binding of neutral dinitriles by simple pillar[5]arenes.
Chem. Commun. 48, 2967–2969 (2012)
33. Mock, W.L., Cucurbituril, W.L.: Top. Curr. Chem. 175, 1–24
(1995)
34. Schönbeck, C., Li, H., Han, B.-H., Laursen, B.W.: Solvent eꢂects
and driving forces in pillararene inclusion complexes. J. Phys.
Chem. B 119, 6711–6720 (2015)
9. Kou, Y., Tao, H., Cao, D., Fu, Z., Schollmeyer, D., Meier, H.: Syn-
thesis and conformational properties of nonsymmetric pillar[5]
arenes and their acetonitrile inclusion compounds. Eur. J. Org.
Chem. 2010, 6464–6470 (2010)
35. Karthikeyan, S., Ramanathan, V., Mishra, B.K.: inꢁuence of the
substituents on the CH…π interaction: benzene–methane com-
plex. J. Phys. Chem. A 117, 6687–6694 (2013)
2
0. Hu, X.-B., Chen, L., Si, W., Yu, Y., Hou, J.-L.: Pillar[5]arene
decaamine: synthesis, encapsulation of very long linear diacids
and formation of ion pair-stopped [2]rotaxanes. Chem. Commun.
Publisher’s Note Springer Nature remains neutral with regard to
4
7, 4694–4696 (2011)
jurisdictional claims in published maps and institutional aꢃliations.
2
2
1. Han, C., Yu, G., Zheng, B., Huang, F.: Complexation between
pillar[5]arenes and a secondary ammonium salt. Org. Lett. 14,
1
712–1715 (2012)
2. Li, C., Shu, X., Li, J., Chen, S., Han, K., Xu, M., Hu, B., Yu,
Y., Jia, X.: Complexation of 1,4-Bis(pyridinium)butanes by
1
3