Density Functional Theory and Quantum Theory of Atoms in Molecules Analysis: Influence of Intramolecular Interactions on Pirouetting Movement in Tetraalkylsuccinamide[2]rotaxanes

Article abstract of DOI:10.1021/acs.cgd.7b00944

The first Quantum Theory of Atoms in Molecules (QTAIM) analysis of [2]rotaxanes was used in combination with quantum mechanical calculations and variable temperature NMR experiments. The study shows all the intramolecular interactions of tetraalkylsuccinamide[2]rotaxanes with different templates. The threads have different stoppers [R¹R²NC(O)-CH₂CH₂-C(O)NR²R¹, in which R²/R¹ = CH₂cy-Hex/CH₂Ph, i-Bu, Bu, and Pr]. The different threads used allowed us verify that the contact area between the submolecular components (C_Mcy···Thr) is closely correlated with the interaction energy (G_Mcy···Thr) in the [2]rotaxanes studied. Furthermore, the QTAIM data and quantum mechanical calculations confirmed that, in all of the compounds, the hydrogen bonds are responsible for most of the energy from the intramolecular interactions that follow the C-H···π and H···H interactions, independent of the thread used. In the liquid state, using NMR ¹H some intramolecular interactions were observed, which is in agreement with the data obtained in the solid state, thus making possible a comparison between the energy data obtained via the quantum mechanical calculations and the molecular movements of the [2]rotaxanes in solution. Consequently, a new way of understanding the intramolecular interactions in [2]rotaxanes and the influence they have on the movement of molecular machines is presented.

Full text of DOI:10.1021/acs.cgd.7b00944

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Article
DFT and QTAIM analysis: Influence of intramolecular interactions
on pirouetting movement in tetraalkylsuccinamide[2]rotaxanes
Marcos A. P. Martins, Leticia V. Rodrigues, Alexandre R. Meyer, Clarissa P. Frizzo,
Manfredo Hörner, Nilo Zanatta, Helio G. Bonacorso, José Berná, and Mateo Alajarín
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00944 • Publication Date (Web): 26 Sep 2017
Downloaded from http://pubs.acs.org on September 28, 2017
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DFT and QTAIM analysis: Influence of
intramolecular interactions on pirouetting movement
in tetraalkylsuccinamide[2]rotaxanes
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Marcos A. P. Martins , Leticia V. Rodrigues , Alexandre R. Meyer , Clarissa P. Frizzo ,
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Manfredo Hörner , Nilo Zanatta , Helio G. Bonacorso , Jose Berná , and Mateo Alajarín
†
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade
Federal de Santa Maria, 97105ꢀ900 Santa Maria, RS, Brazil.
‡
Núcleo de Investigação de Triazenos (NITRICO), Departamento de Química, Universidade
Federal de Santa Maria, 97105ꢀ900 Santa Maria, RS, Brazil.
§
Departamento de Química Orgánica, Facultad de Química Regional Campus of International
Excellence “Campus Mare Nostrum”, Universidad de Murcia, Eꢀ30100 Murcia, Spain.
KEYWORDS: [2]rotaxanes, QTAIM analysis, intramolecular interactions, VTꢀNMR
experiments, Xꢀray crystal.
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ABSTRACT: The first Quantum Theory of Atoms in Molecules (QTAIM) analysis of
[
2]rotaxanes was used in combination with quantum mechanical calculations and VTꢀNMR
experiments. The study shows all the intramolecular interactions of
tetraalkylsuccinamide[2]rotaxanes with different templates. The threads have different stoppers
R R NC(O)ꢀCH CH ꢀC(O)NR R , in which R /R = CH cyꢀHex/CH Ph, iꢀBu, Bu, and Pr]. The
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[
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different threads used let us verify that the contact area between the submolecular components
CMcy Thr) is closely correlated with the interaction energy (GMcy Thr) in the [2]rotaxanes studied.
(
⋯
⋯
Furthermore the QTAIM data and quantum mechanical calculations confirmed that, in all of the
compounds, the hydrogen bonds are responsible for most of the energy from the intramolecular
interactions that follow the C–Hꢁꢁꢁπ and HꢁꢁꢁH interactions, independent of the thread used. In the
1
liquid state, using NMR H some intramolecular interactions were observed, which is in
agreement with the data obtained in the solid state, thus making possible a comparison between
the energy data obtained via the quantum mechanical calculations and the molecular movements
of the [2]rotaxanes in solution. Consequently, a new way of understanding the intramolecular
interactions in [2]rotaxanes and the influence they have on the movement of molecular machines
is presented.
Introduction
Mechanically interlocked architectures, such as catenanes and rotaxanes, offer very attractive
access to intramolecular interactions, due to the submolecular components being connected by a
mechanical bond, and the molecular interactions being present from the moment that their
1
–3
synthesis begins with the selfꢀassembly of multiꢀcomponents.
In particular, the rotaxanes
consist of two or more submolecular components, with at least one macrocycle locked onto a
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linear component (thread). In principle, the submolecular components can move relative to one
another without breaking covalent bonds, and this fact makes these compounds similar to
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molecular machines.
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Recently, we showed: the dynamic behaviour of succinamide templates in the preparation of
[2]rotaxanes containing benzylic amide macrocycle and cyclohexylmethyl substituents as
stoppers, and how the stoppers cause interference in the pirouetting submolecular motion of
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these interlocked molecules. Additionally, another study we show the relationship between the
size of the components and the stability of the [2]rotaxanes, indicating the influence of the
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straight and branched alkyl stopper groups in the deslipping reactions. In particular, in previous
works we used techniques to demonstrate how the stopper can have an influence in the
deslipping and the pirouetting movement. Considering that these submolecular movements are
correlated to the intramolecular interactions, a complete study of these interactions is necessary.
The large family of rotaxanes that is based on a thread containing a hydrogenꢀbonding template
for the benzylic amide macrocycle has the shuttling and pirouetting movements wellꢀestablished
9–12
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in solution,
but only once have these rotaxanes been studied in the solid state. Soon these
compounds have rarely been investigated in the literature within static quantum chemical
1
4,15
calculations.
Another attractive feature of Leighꢀtype [2]rotaxanes is that they are excellent molecules for
the study of intramolecular interactions, due to them having donor and acceptor hydrogenꢀbond
groups and πꢀelectrons that allow various interactions involving πꢀsystems; for example πꢁꢁꢁπ,
CHꢁꢁꢁπ, πholeꢁꢁꢁπ, and loneꢀpairꢁꢁꢁπ interactions. In this sense, supramolecular chemistry has
grown and been developed in recent years in an effort to explain how molecules interact with
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each other by intramolecular and intermolecular interactions;
however, there is a lack of
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supramolecular studies of [2]rotaxanes in the literature. Literature works
have established
only hydrogen bonding in [2]rotaxanes, via purely geometrical criteria that do not give due
attention to the other intramolecular interactions existing in these compounds.
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Consequently, Quantum Theory of Atoms in Molecules (QTAIM) is a useful tool for
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characterizing nonꢀcovalent interactions.
For the pair of atoms that are interacting, there is
the bond path (BP) with the corresponding bond critical point (BCP), where the electron density
(
ρBCP) is established. Several studies have shown that the energy of an atom⋯atom interaction
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5
can be estimated from the electron density at the BCP.
Thus, this present study was to demonstrate the existence of complementary regions between
thread and macrocycle in [2]rotaxanes. In order to achieve this, the molecular electrostatic
potential (MEP) and the correlation between the contact area of the threadꢀmacrocycle and the
⋯
interaction energy (GMcy Thr) were used. In this paper, our main objective was to quantitatively
and qualitatively establish all the intramolecular interactions — via QTAIM and calculations
1
using density functional theory (DFT) — in the compounds studied. The H NMR experiments
were used in order to compare the interactions in the solid state with those in the liquid state,
thereby correlating the energy of the pirouetting in the compounds studied and showing how the
intramolecular interactions can affect the movement of molecular machines.
Experimental Section
General: All reagents and solvents were commercially available and were used without further
purification. Column chromatography was carried out using silica gel (60 Å, 40ꢀ60 µm, SDS) as
stationary phase, and TLC was carried out using silica gel on aluminun cards (0.25 mm thick,
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with fluorescent indicator 254 nm, Fluka) and observed under UV light. The H and C NMR
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spectroscopic data were recorded with a Bruker AVANCE 400 ( H NMR at 400.13 MHz and C
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NMR at 100.62 MHz) in CDCl /TMS solutions, and the VTꢀNMR experiments were recorded
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with a Bruker DPX 400 ( H NMR at 400.13 MHz and C NMR at 100.62 MHz) or AVANCE
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00 ( H NMR at 600.13 MHz and C NMR at 150.62 MHz), in CDCl /TMS or C D Cl /TMS
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solutions. The chemical shifts (δ values) are given in ppm. Signals in the H and C NMR
spectra of the synthesized compounds were assigned with the aid of twoꢀdimensional NMR
experiments (COSY, HMBC, NOESY and HMQC). Analyses exact mass of the [2]rotaxane was
performed on a mass spectrometer HP HPLC / MS 6220 TOF with direct insertion mode
electrosprey positive.
Materials
and
Methods:
To
prepare
the
[2]–[N,N’ꢀbisbenzylꢀN,N’ꢀ
tetraoxoꢀ
bisciclohexylmetylsuccinamide]–
rotaxa–[1,7,14,20ꢀtetraazaꢀ2,6,15,19ꢀ
3,5,9,12,16,18,22,25ꢀtetrabenzocicloexacosano] (compound 4) the reaction steps described
below are required.
Nꢀ(ciclohexylmetyl)(fenyl)metanamine: The mixture of benzylamine (1.96 mL, 18 mmol ) ,
cyclohexane carboxaldehyde (2.18 mL, 18 mmol ) and CH Cl (40 mL ) was added to a flask
2
2
and was subsequently added sodium triacetoxyborohydride (5.70 g, 27 mmol ) . The mixture was
stirred at 25 ° C for 4 h under N atmosphere. After completion of the reaction time was added
2
slowly a saturated solution of NaHCO (30 mL) and the resulting mixture was stirred at 25 ° C
3
for 30 minutes . The resulting mixture was extracted with ethyl acetate and the organic phase
was washed with saturated NaCl solution (3 × 30 ml) . Then , the organic phase was dried with
anhydrous sodium sulfate (Na SO ), filtered and the solvent was evaporated under reduced
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4
pressure. The product was purified by column chromatography, using hexane/ethyl acetate (98:2)
1
as eluent. The product was obtained with 84 % yield. HꢀNMR (400 MHz, CDCl ): δ , J (Hz):
3
HH
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.83ꢀ1.79 (m, 11H); 2.48 (d, J =7, 2H); 3.79 (s, 2H); 7.73 (s, 5H). The compound has been
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characterized in the literature.
N,N’ꢀbisbenzylꢀN,N’ꢀbisciclohexylmetylsuccinamide: To
a
solution of the Nꢀ
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(
ciclohexylmetyl)(fenyl)metanamine (8 mmol), triethylamine (8 mmol) in CH Cl (50 mL),
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succinyl dichloride (4 mmol) in CH Cl (10 mL) was added droppwise at 0ºC. The reaction
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mixture was stirred for 20 hours at room temperature under N atmosphere. After this time the
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solution was washed with NaOH 1M (2 × 30mL), HCl 1M (2 × 30 mL) and brine (2 × 30 mL).
The organic phase was dried over anhydrous MgSO and concentrated under reduced pressure.
4
The residue was subjected to column chromatography on silica gel using using CHCl /MeOH
3
(95:5) as eluent to give the corresponding thread. The product was obtained with 85 % yield.
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2
HꢀNMR (400 MHz, CDCl3):
δ
0.95ꢀ1.28 (m,11H); 1.68 (brs, 11H); 2.76 (d, J = 16, 4H); 3.24
2
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(dd, J = 13, J = 7, 4H,); 4.62 (s, 4H); 7.23 (m, 10 H). / 0.95ꢀ1.28 (m,11H); 1.68 (brs, 11H);
2
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3
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2.75 (d, J = 16, 4H); 3.14 (dd, J = 12, J = 7, 4H,); 4.65 (s, 4H); 7.23 (m, 10 H). CNMR
(100 MHz, CDCl ): δ 25.; 26.3; 28.6; 29.6; 36.4; 49; 53.2; 127; 127.7; 128.7; 137.8; 172.5;
3
172.7. / 25.9; 26.4; 28.8; 30.96; 37.1; 52.3; 52.4; 126.6; 127.2; 128.4; 137.2; 172.6; 172.8.
+
LCMSꢀMS [(M+H) , 489]
[
2]–[N,N’ꢀbisbenzylꢀN,N’ꢀbisciclohexylmetylsuccinamide]–
rotaxa–[1,7,14,20ꢀtetraazaꢀ
2,6,15,19ꢀ tetraoxoꢀ3,5,9,12,16,18,22,25ꢀ tetrabenzocicloexacosane]: The thread was solubilized
in anhydrous chloroform (300 mL) in the presence of triethylamine (24 mmol). Stirred
vigorously whilst solutions of pꢀxylylenediamine (8 mmol), in anhydrous chloroform (20 mL)
and the isophthaloyl dichloride (8 mmol) in anhydrous chloroform (20 mL) were simultaneously
added over a period of 4 h using motorꢀdriven syringe pumps. After a further 4 h the resulting
suspension was filtered through a Celite and the solvent removed under reduced pressure. The
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resulting solid was subjected to column cromatography (silica gel) using CHCl /MeOH (99:1)
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mixture as eluent to give the [2]rotaxanes. The product was obtained with 28 % yield. HꢀNMR
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(400 MHz, CDCl3):
δ
0.22ꢀ0.96 (m, 11H); 1.05 (s, 4H); 1.07ꢀ1.47 (m, 11H); 2.80 (d, J = 7, 4H);
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.39 (s, 4H,); 6.88 (s, 10H); 7.33 (s, 8H); 7.49 (t, J = 6, 4H); 7.68 (t, J = 7 2H); 8.40 (d, J = 8,
3
2H,); 8.78 (s, 2H)./ 0.22ꢀ0.96 (m, 11H); 1.07ꢀ1.47 (m, 11H); 1.78 (s, 4H); 2.76 (d, J = 7, 2H);
3
3
3
7
1
.37 (d, J = 7, 2H); 4.10 (s, 2H); 4.29 (s, 2H); 6.75 (s, 5H); 6.73 (s, 5H); 7.17 (t, J = 7, 4H);
3
3
.29 (s, 8H), 7.64 (t, J = 7, 2H); 8.37 (d, J = 8, 2H); 8.65 (s, 2H)./ 0.22ꢀ0.96 (m, 11H); 1.07ꢀ
3
.47 (m, 11H); 1.26 (s, 4H); 3.25 (d, J = 6, 4H); 4.06 (s, 4H,); 6.88 (s, 10H); 7.03 (t, 4H); 7.33
3
3
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(
s, 8H); 7.61 (t, J = 8, 4H); 8.30 (d, J = 8, 2H); 8.47 (s, 2H). CNMR (100 MHz, CDCl3):
δ
25.3; 31.3; 36.3; 42.8; 51.1; 55.1; 122; 125.5; 128.4; 129.9; 132.2; 133.2; 135.5; 138.1; 165,0;
1
73,3./25.3; 31.3; 36.4; 43.2; 52.6; 52.7; 55.5; 56.0; 122.4; 128.1; 128.4; 129.9; 132.4; 133.3;
36.8; 138.3; 165.2; 173.5. / 25.3; 31.3; 37.4; 43.5; 54.2; 54.7; 122.5; 128.2; 128.4; 129.9; 132.5;
33.4; 136.9; 138.5; 165.5; 174.5. HRMS (ESI) calcd for C H N O [M + H]+ 1020,5518,
1
1
6
4
72
6
6
found 1021,5618.
The spectra of the synthesized compounds are given in Supportin Information Figure S1ꢀS5.
Crystallographic data collection and structure determination: The diffraction measurements of
compound 1 was carried out by graphite monochromatized Mo Kα radiation with λ = 0.71073
Å on a Bruker D8 VENTURE diffractometer with a goniometer KAPPA four circles, equipped
with PHOTON II CPAD area detector, at 100 K. The compounds 2ꢀ4 were carried out by
graphite monochromatized Mo Kα radiation with λ = 0.71073 Å on a Bruker SMART CCD
29
diffractometer. The structures were solved with direct methods using the SHELXS program,
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0
and refined on F2 by fullꢀmatrix leastꢀsquares with the SHELXL package. Absorption
3
1
correction was performed by the Gaussian method. Anisotropic displacement parameters for
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nonꢀhydrogen atoms were applied. The hydrogen atoms were placed at calculated positions with
.96 (methyl CH ), 0.97 (methylene CH ), 0.98 (methyne CH), 0.93 (aromatic CH), and 0.82 Å
0
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(OH) using a riding model. Hydrogen isotropic thermal parameters were kept equal to Uiso(H) =
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xUeq (carrier C atom), with x = 1.5 for methyl groups and x = 1.2 otherwise. The valence angles
C–C–H and H–C–H of methyl groups were set to 109.5°, and H atoms were allowed to rotate
around the C–C bond. Graphic projections were constructed using Ortep3 for Windows program
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included in WinGx program package. Parameters in CIF format are available as an electronic
supplementary publication from the Cambridge Crystallographic Data Centre (CCDC 1539700
(1), 1542403 (2) and 1550499 (3) 1539696 (4)). The crystal data and details concerning data
collection and structure refinement are given in Table 1. The micrographics of the compounds 1ꢀ
4 given in Supportin Information Figure S6.
Table 1. Data collection and structure refinement for structure of 1-4.
Compound
1
2
3
4
CCDC Number
Empirical formula
Formula weight
Temperature (K)
Wavelenght (Å)
Crystal system
Space group
a (Å)
1539700
C H N O
1542403
C H N O
1550499
C H N O
1539696
C H Cl N O
32
36
3
3
26 34
436.56
296(3)
3
3
52 68
873.12
293(2)
6
6
26 28
572.31
293(2)
4
3
3
510.64
293(2)
0.71073
Triclinic
0.71073
Triclinic
0.71073
Triclinic
0.71073
Triclinic
P 1
ꢀ
ꢀ
ꢀ
ꢀ
P 1
P 1
P 1
10.065 (5)
11.064(5)
12.664(5)
10.3051(6)
11.0239(7)
11.6493(8)
12.3496(10)
13.1703 (11)
15.7235(13)
10.0010(3)
11.6711(4)
13.1113(4)
b (Å)
c (Å)
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
α (deg)
β (deg)
γ (deg)
103.731(5)
80.705(4)
67.383(4)
77.728(4)
1189.02(13)
2, 1.219
85.736(5)
82.630(5)
73.470(5)
2429.5
76.249(2)
73.972(2)
83.515(2)
1426.90(8)
2, 1.332
98.250(5)
92.239(5)
1351.8(11)
2, 1.254
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Volume (Å )
Z/density (calcd)(Mg/m )
3
2, 1.194
Absorption
coefficient
ꢀ
1
0.081
546.0
0.080
470
0.078
940
0.446
594
(
mm )
F(000) (e)
0
0
.41 × 0.36 × 0.22 × 0.17 × 0.548 × 0.348 0.582 × 0.474 ×
.18
3
Crystal size (mm )
0.12
× 0.186
0.204
θ range of data collection
(deg)
2.20 to 30.10 1.90 to 26.91 1.31 to 26.91
1.80 to 27.16
53309 / 7901 32265 / 5067 68942 / 10372
Reflections
collected/unique
39993 / 6281
[R(int) = 0.0402]
[
0
R(int)
.027
= [R(int)
0.0755]
= [R(int)
0.0736]
=
(30.10) 99.1
Completeness to θ (%)
(26.91) 98.5% (26.91) 98.7% (27.16) 99.4%
%
Absorption correction
Gaussian
Gaussian
Gaussian
Gaussian
Max.
transmission
and
min. 0.9906
0.9616
and 0.9904
0.9826
and 0.99937 and
0.99830
0.928 and 0.793
Fullꢀmatrix
Fullꢀmatrix
Fullꢀmatrix
Fullꢀmatrix
Refinement method
leastꢀsquares
leastꢀsquares
leastꢀsquares
leastꢀsquares on
2
2
2
2
on F
on F
on F
F
1
5
0372 / 0 /
78
Data/restraints/parameters 7901 / 0 / 343 5067 / 4 / 288
6281 / 0 / 316
1.065
2
Goodnessꢀofꢀfit on F
1.038
0.996
0.958
Final R indices [I ≥ 2σ R
= 0.0619, R1 = 0.0527, R1 = 0.0720, R
= 0.0820,
= 0.2369
2
1
1
a
(I)]
wR
2
= 0.1509 wR2 = 0.1180 wR2 = 0.1977 wR
a
R
1
= 0.0744, R1 = 0.1334, R1 = 0.2330, R
1
=
0.1312,
R (all data)
1
wR = 0.1613 wR2 = 0.1494 wR2 = 0.2831 wR = 0.2769
2
2
Larges diff. peak and hole 0.973
and 0.162
ꢀ0.174
and 0.295
ꢀ0.205
and
ꢀ
3
1.446 and ꢀ0.517
(
e A )
ꢀ0.570
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Computational Computational Details: All quantum mechanical calculations were
©
33
performed with the aid of the Gaussian 09 software package. To obtain the interaction energy
between thread and macrocycle Density Functional Theory (DFT) with the level of theory
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34
ωB97XD/ccꢀpVDZ was used. The counterpoise method of Boys and Bernardi was employed
to minimize the error of overlapping bases (BSSE). Dihedral amide angle of the compound (1)
were changed from 0 to 360° in steps of 10° optimizing the geometry at the PM6 level. The
geometry of the most stable conformers was fully reꢀoptimized without any constrain at the
ωB97XꢀD/ccꢀpVDZ level of theory. All geometries were verified as minima on the potential
energy by calculating the Hessian matrices by harmonic frequency calculations. The atomic
coordinates used in theoretical calculations are given in Supporting Information Table S1.
Quantum Theory of Atoms In Molecules (QTAIM) Data: All QTAIM analyses were
35
performed with the aid of the AIMALL program package. The wave functions used in the
QTAIM analyses were generated at the ωB97XD/ccꢀpVDZ level of theory. The bond paths show
which atoms are interacting and the analyses of the electron density at the BCP provide
important information about the intramolecular interactions. The electron density (ρ) value at the
BCP is related to the intermolecular interaction strength; the greater the ρ value, the greater the
2
interaction energy. The Laplacian of the electron density (∇ ρ) shows the nature of the
2
interaction. Positive ∇ ρ values indicate that the interaction is electrostatic in nature (ionic
interactions, hydrogen bonds and halogen bonds), while negative Laplacian values indicate that
23,24
the interaction is covalent in nature.
The QTAIM data and details concerning data collection
and structure refinement are given in Supporting Information Table S2ꢀS6.
Molecular Electrostatic Potential (MEP): Considering the electrostatic nature of the
interactions, the electrostatic potential in compounds 1-4 is distributed along the molecular
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5
5
6
regions of high and low molecular electrostatic potential (MEP)—the red areas indicate that the
36
MEP is negative while the blue ones indicate that it is positive. The Electrostatic Potential
3
3
Maps were generated with a value of 0.001 a.u. of isodensity surface with The GaussView®
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
program from wave functions generated at the theory level ωB97XD/ccꢀpVDZ. These
calculations were made from geometries obtained by Xꢀray diffractometry without singleꢀpoint
optimization.
Voronoi–Dirichlet polyhedron (VDP): The contact area between the thread and the
®
37
macrocycle were constructed and TOPOS version 4.0 software, were taken directly from the
CIF file generated by Xꢀray diffraction. The molecular Voronoi–Dirichlet polyhedron (VDP)
concept was introduced in order to find the contact between the thread and macrocycle. This
introduced the idea of the face of the one subcomponent molecular as a set of atomic VDP faces
corresponding to the adjacent contacts between the atoms of the other subcomponent molecular.
®
The datas obtained by TOPOS are given in Supporting Information Table S7.
38
NCI analysis: The NCIPLOT program was used to identify and visualize nonꢀcovalent
interaction. As input of the program were used the wave functions generated at the ωB97XꢀD/ccꢀ
pVDZ level of theory. Reduced density gradient isosurfaces have been generated with NCIPLOT
39
program and visualized with VMD . A density cutꢀoff of 0.1 a.u was applied and NCI figures
have been generated with an isosurface of 0.4 and color scale of ꢀ0.02 < ρ < 0.02 a.u.
Results and Discussion
We chose four compounds for this work, in order to study the intramolecular interactions in
[
2]rotaxanes. All of the rotaxane tetralactam macrocycles in this report are comprised of two 1,4ꢀ
phenylene sideꢀwalls that are connected by two identical isophthalamide units. The threads have
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a succinamide station and different stoppers (e.g., CH cyꢀHex/CH Ph, iꢀBu, Bu, or Pr — see
2
2
Figure 1). The [2]rotaxanes 2–4 — which have symmetrical stoppers and were completely
8
characterized in a previous work — were prepared by the clipping method. The [2]rotaxane 1
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has a thread with unsymmetrical stoppers (CH cyꢀHex and CH Ph), and it is described for the
2
2
first time here (see Experimental Sections and Supporting Information for full details).
It is worth mentioning that unsymmetrical amides typically fluctuate between different
conformational forms through the rotation of C(O)ꢀN covalent bonds. Thus, for compound 1,
three different conformers were identified in solution (Figure 2), for which the following
1
percentages of unsymmetrical amides were detected by integrating the H NMR signal: 72% for
conformer 1a (ZꢀZ), 22% for conformer 1b (ZꢀE), and 6% for conformer 1c (EꢀE).
Figure 1. Structures of compounds 1–4 used in this study.
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0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Conformers identified for compound 1.
Compounds 1–4 were firstly crystallized and their structures were subsequently determined by
Xꢀray diffraction (Figure 3). The crystals were obtained by slow evaporation of a solvent or a
mixture of solvents: a mixture of chloroform and methanol (1:1) for compound 1; only
chloroform for compounds 2 and 3; and tetrachloroethane (1:1) for compound 4. The Xꢀray
structure showed a number of notable features: (i) all the compounds have the macrocycle in a
4
0–43
chair conformation that is commonly observed with Leighꢀtype rotaxanes;
(ii) the chair
macrocycles are located centrally and symmetrically over the succinamide station, which
suggests two possible sets of bifurcated hydrogen bonds between the amide groups of the
4
4,45
macrocycle and the carbonyl groups of the succinamide system;
(iii) there is spatial
proximity between the antiꢀalkyl chain group of the stoppers and the isophthalamide unit of the
7
macrocycle, which suggests the existence of CHꢁꢁꢁπ intramolecular interaction; (iv) from the
three different tertiary amide conformers present in solution for compound 1 (see Figure 2), only
conformer 1a is found in the crystal; (v) due to small differences in the conformation of the alkyl
chain of the stoppers (see red circle in Figure 3), compound 3 crystallized with two independent
molecules in the asymmetric unit, which is why the intramolecular interactions for the two
molecules will be studied (compounds 3a and 3b); and (vi) the [2]rotaxane 4 crystallized with a
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solvent molecule in the asymmetric unit, but this will not spoil this study, because in this work
we are only interested in intramolecular interactions between the thread and the macrocycle.
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®
Figure 3. Molecular structures of compounds 1–4 represented by ORTEP diagrams, with
thermal ellipsoids drawn at the 50% probability level.
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1
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3
4
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4
4
4
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5
5
5
5
5
6
Additionally, singleꢀpoint calculations were performed in order to determine the interaction
energies (GMcy Thr) between thread and macrocycle for all compounds, using DFT at the
ωB97XꢀD/ccꢀpVDZ level of theory with BSSE correction. The contact area between thread and
macrocycle (CMcy Thr) for compounds 1–4 was also determined in order to correlate with the
interaction energies (GMcy Thr). Data regarding the contact area (CMcy Thr) — which were
Thr) for compounds 1—4 are
⋯
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
⋯
⋯
⋯
37
obtained using TOPOS® — and the interaction energies (GMcy
⋯
shown in Table 2. It was possible to establish that the increase in the interaction energies is
closely related to the increase in the size of the stoppers, and the consequent increase in the
contact area is due to the greater possibility of intramolecular interactions between stoppers and
macrocycles. Thus, we found a good correlation between the GMcy Thr
⋯
⋯
and CMcy data
Thr
(
CMcy = ꢀ4.9 GMcy = ꢀ 80.6; r = 0.942 — see Figure S13 in Supporting Information). In
⋯
⋯
Thr
Thr
4
6
previous works we showed that when the compounds present classical hydrogen bonds, there
is no good correlation between the contact area and energy; however, this fact is diluted in all
compounds, because all the compounds of the series studied have strong hydrogen bonds.
Table 2. Interaction energies and contact surfaces for compounds 1–4.
a
Thr
b
Cpd
GMcy
⋯
CMcy
⋯
Thr
1
2
3
3
4
ꢀ58.31
ꢀ52.84
ꢀ52.87
ꢀ52.06
ꢀ51.65
204.62
187.02
178.26
173.57
168.69
a
b
a
ꢀ1
In kcal mol , determined using the equation G
⋯
= ERotax ꢀ (EThr + EMcy)
Mcy Thr
b
2
®
In Å , determined using TOPOS
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Accordingly, the MEP of compounds 1–4 is a useful tool for analysing complementary regions
between zones with negative and positive potentials, and suggesting how the molecules interact
with one other. In the study of the intramolecular interactions, it is more valid to generate the
MEP for the thread and the macrocycle separately. Through analysis of the MEP we found a
common pattern in all of the compounds, which demonstrates the negative electrostatic potential
in the carbonyl oxygens atoms (red, in the thread) and the positive electrostatic potential in the
nitrogens of the amides (blue, in the macrocycle). This electrostatic complementarity confirms
that the Leighꢀtype [2]rotaxanes are formed by hydrogen bonds formed between the NH
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(macrocycle) and the O (thread) — see Figure 4. On the other hand, Figure 5 shows the MEP for
compound 1, with an isosurface value of 0.01 — when observing the two isosurfaces at the same
time in this figure, it is possible to see that the thread is interpenetrated in the macrocycle.
Figure 4. View of the MEPs of the thread and macrocycle for compounds 1–4, obtained with an
isodensity value of 0.001 (red = ꢀ0.02 a.u., yellow = ꢀ0.01 a.u., green = 0.00 a.u., and blue = 0.02
a.u.).
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1
1
1
1
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1
1
1
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2
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2
2
2
3
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0
1
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1
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0
1
2
3
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9
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1
2
3
4
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7
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9
0
Figure 5. View of the MEP of rotaxane 1 with an isodensity value of 0.01 (red = ꢀ0.02 a.u.,
yellow = ꢀ0.01 a.u., green = 0.00 a.u., and blue = 0.02 a.u): a) side view of the chair macrocycle
in the [2]rotaxane 1; and b) internal view of the chair macrocycle in the [2]rotaxane 1.
In order to identify all intramolecular interactions and understand how they affect the G of
int
®
each molecule, calculations based on QTAIM were performed with the aid of the AIMAL
program. From the QTAIM analysis, the presence of the intramolecular interaction is given by a
2
2,46,47
BCP along the bond path connecting two interacting atoms.
The results are shown in Table
S2ꢀS6 (see Supporting Information) — the threads and macrocycle showed bond paths, which
confirms the interlocked nature of the molecules, and the number of interaction paths increased
proportionately with the volume of the stoppers (Figure 6), thus corroborating the data discussed
in Table 2. Another important observation is that all the [2]rotaxanes studied are symmetric
molecules, so the interactions appear in pairs, thus confirming the perfect symmetry of the
molecule.
4
6–48
In previous works
we showed a good correlation between the sum of the electron density
(
∑ρ ) at the BCP and the interaction energy. In other words, the energy contribution of
INT
⋯
atom atom interactions is proportional to the ρINT, which allows the portioning of the energy into
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⋯
atom atom interactions so that we can derive the energy value for the intramolecular interaction
⋯
(G ). The types of atom atom interactions and energy values of the intramolecular interactions
AI
(
G ) of all the compounds are listed in Supporting Information. The ρINT values used in the
AI
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determination of the GAI of each intramolecular interaction are given in the Supporting
Information.
Based on the literature, it is known that hydrogen bonds are the most important interactions for
4
5,49–51
the formation of Leighꢀtype amide [2]rotaxanes,
because they are the ones that drive the
formation of the mechanically interlocked molecules. Although QTAIM analysis has never been
done before on [2]rotaxanes, it confirms the importance of the hydrogen bonds in these
compounds. This is evident when we observe Figure 7, which shows the energy contribution (in
percentage) and how much each type of interaction contributed to the total energy of the
⋯
⋯
intramolecular interactions. Additionally, other important contributions like CH π, H H, and
πhole⋯π interactions were observed.
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0
Figure 6. View of the intramolecular interactions with the BCP's connecting interacting atoms.
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Figure 7. Energetic contribution (in percentage) of Thr⋅⋅⋅Mcy intramolecular interactions in
compounds 1–4, obtained from the fragmentation of QTAIM.
The QTAIM analysis (Table S2ꢀS6 and Figure 7) showed that in all of the compounds, most of
the atom⋯atom interaction energies (G ) are related to the hydrogen bonds between the
AI
carbonyl of the thread and the macrocycle. These interactions can be classified as: (i) two sets of
.
..
NꢀH O interactions, between the NH of the macrocycle and the carbonyl oxygens of the thread
ꢀ1
ꢀ1
...
(
ꢀ3.22 to ꢀ6.42 kcal mol , except for compound 2 with ꢀ1.76 kcal mol ); and (ii) a set of CꢀH O
interactions, between the CH belonging to the isophthalamide unit of the macrocycle and the
ꢀ1
carbonyl oxygens of the thread (ꢀ4.50 to ꢀ6.32 kcal mol ) — see Figure 8.
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Figure 8. Trifurcated hydrogen bonds in compounds 1–4.
More properties relevant to all of the hydrogen bondings are given in the Supporting
Information (Table S2ꢀS6). These data let us discuss whether these hydrogen bonding fit the
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three main topological criteria established by Koch and Popelier. A first necessary condition to
confirm the presence of a hydrogen bond is the observation of a BCP between the hydrogen atom
and the acceptor atom. The second necessary condition involves a local property, namely, the
charge density evaluated at the BCP, referred to as ρ. The values were in the range of 0.002–
0.034 au, and typically are smaller than those found for a covalent bond. The third necessary
criterion focuses on another local property, namely, the Laplacian of the charge density
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evaluated at the BCP, referred to as ∇ ρ. It is crucial that ∇ ρ be positive, but also that the values
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range from 0.024 to 0.139 a.u (allowing for small differences in basis set). Thus, all the hydrogen
bonding in compounds 1–4 follow criteria established by Koch and Popelier.
.
..
After the hydrogen bonds, the most important interactions are the CH π type. These
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interactions can be classified as: (i) two sets of interactions between the succinamide station and
ꢀ1
the 1,4ꢀphenylenediamine ring (with energies in the range of ꢀ2.72 to ꢀ0.98 kcal.mol for each
interaction — see Figure 9); (ii) interactions between the stoppers’ alkyl chains and the
isophthalamide ring — four sets of interactions for compound 1 (with energies in the range of ꢀ
ꢀ1
2
.33 to ꢀ0.93 kcal mol for each interaction), three sets of interactions for compound 2 (with
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energies in the range of ꢀ2.34 to ꢀ 0.82 kcal mol for each interaction), and two sets of
interactions for compounds 3a and 3b (with energy values in the range of ꢀ2.28 to ꢀ 1.71 kcal
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ꢀ1
mol for each interaction), one set of interactions for compound 4 (with ꢀ1.47 kcal mol for each
interaction) (Figure 10); and (iii) interactions between the stoppers’ alkyl chains and the
phenylenediamine ring — one set of interactions for compounds 1 and 2 (ꢀ1.53 and ꢀ1.16,
respectively) (Figure 11). It is very important to note that these interactions do not occur in
.
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compounds 3a and 3b. The total energies of the CH π interactions were ꢀ27.34, ꢀ18.88, ꢀ17.10, ꢀ
ꢀ1
1
4.86, and ꢀ11.62 kcal mol for compounds 1–4, respectively. Thus, we can say that the larger
.
..
and more branched the alkyl chain of the stoppers, the greater the number of CH π interaction
paths between the thread and the macrocycle, which again confirms the data previously
discussed in Table 2.
It is worth mentioning that CꢀH···π interactions are also unique if they refer to the typical
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hydrogen bonds. According to Pauling’s definition of hydrogen bonding, such an interaction is
formed if the covalently bound hydrogen atom (XꢀH bond, in which X is an electronegative
.
..
atom) interacts with the other electronegative centre (designated as Y). In the case of CꢀH π
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interactions, the πꢀelectrons act as acceptors (Y). A later statistical study, based on the
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...
Cambridge Structural Database, definitively proved that CꢀH π interactions are attributed to
...
hydrogen bonds. There are numerous studies stating that CꢀH π interactions may be classified as
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hydrogen bonds with multicentre proton acceptors.
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Figure 9. CH π interactions, between the succinamide station and the 1,4ꢀphenylenediamine
ring, for all of the compounds.
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Figure 10. CH π interactions, between the stoppers’ alkyl chains and the isophthalamide ring.
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Figure 11. CH π interactions, between the stoppers’ alkyl chains and the phenylenediamine
ring.
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Finally, H H interactions were found in all of the compounds, and they appear as weak
ꢀ1
interactions — with energies in the range of ꢀ1.77 to ꢀ0.43 kcal mol — that occur between the
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stoppers and the macrocycle. Added together, all these H H interactions represent ꢀ4.72, ꢀ5.64,
ꢀ1
ꢀ2.88, ꢀ7.17, and ꢀ5.80 kcal mol , for compounds 1–4, respectively (Figure 12).
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Figure 12. H H interactions, between the stoppers and macrocycles, for all of the compounds.
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Compounds 3a and 4 show only these intramolecular interactions. On the other hand, there
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were πhole π interactions — between the carbon carbonyl of the thread station and the 1,4ꢀ
phenylenediamine ring — for compounds 1, 2, and 3b, with energy values of ꢀ1.61, ꢀ1.47, and ꢀ
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.12 kcal mol , respectively (Figure 13).
...
Figure 13. πhole π interaction , between the succinamide station and macrocycles.
An important feature of the bonding interactions in terms of the AIM theory is the ellipticity
(
ε) values. The ellipticity was suggested by Bader et al. for the quantitative description of the
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electron density deviation from the cylindrical symmetry in the CP of the (3, ꢀ1) type . In fact,
the value of ε characterizes the cycle susceptibility to opening. In this sense, the contacts with
high ellipticity are potentially unstable. In such cases there is a high probability of bifurcation
catastrophe, i.e. fusion of bond and ring critical points (CP (3, ꢀ1) and (3 + 1),respectively),
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which leads to unstable degenerate CP occurrence (w < 3).
Thus, the analysis of the
ellipticity (ε) values for compounds 1-4 allows (see Supporting Information, Table S2ꢀS6) to
predicted that some CH⋅⋅⋅π interactions in all compounds and one set of H⋅⋅⋅H interactions in the
compound 3b are unstable, but can be experimentally determined. However these interactions
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was not neglected because these was proven using NCIPLOT program (for NCI data see
Supporting Information, Figures S8ꢀS12 ), furthermore manifestations of these interactions in the
1
compounds studied will be investigated by NMR H experiments, described below. For these
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reasons the energies of these interactions were considered.
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In this sense, in order to provide an insight into the intramolecular interactions in solution, H
NMR experiments were used. The experiments were done in CDCl , and they showed the large
3
temperatureꢀdependent changes in chemical shifts for some of the signals that are involved in
.
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CH π interactions and hydrogen bonding. In particular, the downfield shift of the amide proton
signal is characteristic of hydrogen bonding interactions between the amide groups, when atoms
that are involved in hydrogen bonds have the effect of decreasing the electron density around the
hydrogen atom, which leads to deshielding. On the other hand, the upfield shift of the methylene
.
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signals is characteristic of CH π interactions and is due to the proximity at the phenyl ring. The
upfield shift is probably a result of the anisotropic effect due to the aromatic ring’s proximity.
Thus, in order to prove that the intramolecular interactions observed in the solid state can also
be verified in solution, all of the compounds were subjected to variable temperature (VT) NMR
experiments in CDCl solutions. The concentration of the samples was fixed (0.04 M) in all of
3
the experiments, within a range of 238–323 K, with increments of 5 K. For the macrocycle, the
D
signals that were analysed were: (i) the NH amide group (H , Figure 14); and (ii) the CH group
C
...
...
belonging to isophthalamide (H , Figure 14), both of which are involved in NꢀH O and CꢀH O
hydrogen bonds. For the thread, the signals that were analysed were: (i) the methyl group
a
belonging to the succinamide portion of the thread (H , Figure 14); and (ii) the methyl group
d
e
belonging to the stoppers (H for compounds 1, 3, and 4; and H for compound 2 — see Figure
...
14), both of which are involved in CH π interactions with the phenyl units of the macrocycle. It
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