[3+3] Cyclocondensation of Disubstituted Biphenyl Dialdehydes: Access to Inherently Luminescent and Optically Active Hexa-substituted C3-Symmetric and Asymmetric Trianglimine Macrocycles

Article abstract of DOI:10.1021/acs.joc.6b02868

A general synthetic route to inherently luminescent and optically active 6-fold substituted C₃-symmetric and asymmetric biphenyl-based trianglimines has been developed. The synthesis of these hexa-substituted triangular macrocycles takes advant

Full text of DOI:10.1021/acs.joc.6b02868

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Article
[3+3] Cyclocondensation of Disubstituted Biphenyl Dialdehydes:
Access to Inherently Luminescent and Optically Active Hexa-
substituted C3-Symmetric and Asymmetric Trianglimine Macrocycles
Zhenzhen Wang, Hany F. Nour, Loïc Michel Roch, Minjie Guo, Wenjiao
Li, Kim K. Baldridge, Andrew Chi-Hau Sue, and Mark Anthony Olson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02868 • Publication Date (Web): 25 Jan 2017
Downloaded from http://pubs.acs.org on January 25, 2017
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[3+3] Cyclocondensation of Disubstituted Biphenyl
Dialdehydes: Access to Inherently Luminescent and Optically
Active Hexa-substituted C3-Symmetric and Asymmetric
Trianglimine Macrocycles
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Zhenzhen Wang,a Hany F. Nour,a,b Loïc M. Roch,a,c Minjie Guo,a Wenjiao Li,a Kim K. Baldridge,a
Andrew C. –H. Suea and Mark A. Olson*a
a Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University, 92
Weijin Road, Nankai District, Tianjin, 300072, P. R. China.
b Chemical Industries Research Division, Department of Photochemistry, National Research Centre, 33 El Buhouth
Street, Giza, 12622, Egypt.
c Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
ABSTRACT:
A general synthetic route to inherently luminescent and optically active sixꢀfold substituted C3ꢀsymmetric and
asymmetric biphenylꢀbased trianglimines has been developed. The synthesis of these hexaꢀsubstituted triangular
macrocycles takes advantage of a convenient method for the synthesis of symmetrically and asymmetrically
difunctionalized biphenyl dialdehydes through a convergent twoꢀstep aromatic nucleophilic substitutionꢀoneꢀpot
Suzukiꢀcoupling reaction protocol. A modular [3+3] diamineꢀdialdehyde cyclocondensation reaction between both
the symmetrically and asymmetrically difunctionalizedꢀ4,4’ꢀbiphenyldialdehydes with enantiomerically pure
(1R,2R)ꢀ1,2ꢀdiaminocyclohexane was employed to construct the hexaꢀsubstituted triangular macrocycles.
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B97ꢀD/6ꢀ311G(2d,p) density functional theory determined structures and XꢀRay crystallographic analysis reveal
that the six substituents appended to the biphenyl legs of the trianglimine macrocycles adopt an alternating
conformation not unlike the 1,3,5ꢀalternate conformation observed for calix[6]arenes. Reduction of the imine bonds
using NaBH4 afforded the corresponding sixꢀfold substituted trianglamine without the need to alkylate the amine
nitrogen atoms which could hinder their later use as metal coordination sites and without having to introduce
asymmetric carbons.
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INTRODUCTION
Trianglimine macrocycles have attracted the interest of supramolecular chemists for more than a decade.1 On
account of their highly symmetric structure, and easily tunable cavity size; trianglimines are ideal candidates for
building larger stacked and cageꢀlike superstructures2 with potential applications in molecular recognition. By
employing a highly modular [3+3] imine cyclocondensation synthetic approach1a, the size of the cavity3, the
incorporated functional groups4, and the electronic properties5 of trianglimines can be controlled. Moreover, as a
result of their chirality, trianglamines have been employed as chiral probes for anion recognition in ionꢀtrap
ESIꢀMS6, chiral solvating and shift reagents for NMR spectra7, and as chiral ligands for various metal catalysts8
such as Cu9 and Zn10. Furthermore, Mechanically interlocked trianglamineꢀβꢀcyclodextrinꢀ[2]ꢀcatenanes have also
been reported11, providing evidence that the trianglimine macrocycle can play a role in constructing more
sophisticated molecular archtectures.
However, the trianglimine macrocycle as a scaffold upon which to build increasingly complex functional molecular
structures and superstructures, has not yet reached its full potential. The prevailing obstacle limiting the utility of
trianglimine chemistry is the lack of synthetic strategies to obtain highly substituted trianglimine macrocycles. With
regards to biphenylꢀbased trianglimines, which are particularly attractive structures owing to their large cavity
size4a, reports of synthetic strategies for obtaining various symmetrically and asymmetrically functionalized
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biphenyl dialdehyde precursors are much needed but unfortunately sparse. As a result, the ability to precisely tailor
the physical and chemical properties of biphenylꢀbased trianglimines by way of covalent modification is limited.
Herein, we report for the first time, a convergent synthetic protocol for the preparation of inherently luminescent
symmetrically and asymmetrically hexaꢀsubstituted trianglimine macrocycles.
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RESULTS AND DISCUSSION
O
O
R
O
N
O
O
N
N
O
O
B
O
HN
O
O
O
N
O
2a
F
N
K2CO3, CH3CN
8
N
Suzuki-Miyaura
Coupling
reflux, 24h
O
N
80%
O
Br
Br
O
1
3a
4a
Scheme 1. Route to Disubstituted Biphenyl Dialdehyde
Although a variety of synthetic pathways to trianglimine macrocycles have been developed12, 4a, 4b since they were
first reported1a by Gawroński and coꢀworkers, only a single protocol for the synthesis of triꢀsubstituted
trianglimines has been described13. Unfortunately, a modified pathway based on this previous work, which was
designed to proceed through the nucleophilic aromatic substitution of a 3ꢀfluoroꢀ3'ꢀsubstitutedꢀ[1, 1’ꢀbiphenyl]ꢀ4,
4’ꢀdicarbaldehyde, was not successful in affording disubstituted biphenyl dialdehydes. We then turned our attention
to intermediate 3a (Scheme 1) which could be synthesized in high yield through the nucleophilic aromatic
substitution of 4ꢀbromoꢀ2ꢀfluorobenzaldehyde 1 with ethyl piperazineꢀ1ꢀcarboxylate 2a. It was envisioned that
intermediate 3a could then be converted to the corresponding boronic ester 8 and subsequently subjected to a
SuzukiꢀMiyaura coupling (Scheme 1, Table 1) to efficiently synthesize the disubstituted biphenyl dialdehyde 4a.
Attempts to synthesize the boronic ester 8 through the borylation of 3a yielded a product which was found to be
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Table 1. Optimization of the OneꢀPot SuzukiꢀMiyaura Conditionsa
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C1 = Pd(PPh3)2Cl2, C2 = Pd(dppf)Cl2, C3 = Pd(PPh3)4
Entry
Catalyst
Base
T( oC )
Productb
1
2
3
4
5
6
C1
C1+C2
KOAc
KOAc
80
80
8
8
C1+ C2+C3
C1+ C2+C3
C1+C3
KOAc
80
8
KOAc, Na2CO3 aqueous
KOAc, Na2CO3 aqueous
KOAc, Na2CO3 aqueous
80 to 120
80 to 120
80 to 120
4a (70% )
4a (40% )
4a (86% )
C2
aReaction condition: 3a (1 mmol), bis(pinacolato)diboron (1.2 mmol), catalyst (7%), KOAc (1.5
mmol), 1,4ꢀdioxane (5 ml), 80 oC and 3 h, then Na2CO3 (2 mmol) in 1 ml H2O, 3a (1 mmol), 120
oC and 2 h. bproduct: 8 was detected through TLC; 4a was obtained through chromatography.
unstable on silica gel. Consequently, a more efficacious oneꢀpot SuzukiꢀMiyaura coupling approach (Table 1) was
adopted and optimized which effectively removed the need to isolate and purify 8. Following the simple addition of
a second equivalent of bromide 3a, the reaction was monitored by thin layer chromatography until all starting
material was consumed. Following this strategy, the desired disubstituted biphenyl dialdehydes were obtained in
good yield (Table 1, Entry 4). Screening of the palladium catalysts revealed that Pd(dppf)Cl2 was the best catalyst
for the oneꢀpot dialdehyde coupling. Under these optimized conditions, the symmetric disubstituted biphenyl
dialdehydes 4a, 4b and 4c were synthesized in good yields (Table 2, Entry 1, 2 and 3). As a testament to the
usefulness of the oneꢀpot SuzukiꢀMiyaura coupling approach, the asymmetricallyꢀdisubstituted dialdehyde 4d was
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also prepared in high yield (Table 2, Entry 4), providing the opportunity to construct various
asymmetricallyꢀdisubstituted biphenyl dialdehyde building blocks.
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The synthesis of the sixꢀfold substituted trianglimine macrocycles proceeds through a modular [3+3]
diamineꢀdialdehyde cyclocondensation reaction1a. The C3ꢀSymmetric trianglimines 5a, 5b and 5c were easily
obtained from the reactions of disubstittuted diphenyl dialdehydes 4a, 4b, and 4c with (1R,
2R)ꢀ1,2ꢀdiaminocyclohexane 2 (Scheme 2, top left) in CH2Cl2 at reflux for 2 hours. Typically, imine bonds are only
stable under anhydrous conditions as they can readily hydrolyze back to the amine and carbonyl precursors. A
commonly reported method14 to circumvent the hydrolysis of trianglimine macrocyles is to reduce the imine bonds
in order to generate the more stable trianglamine macrocycle. Therefore, to demonstrate further the usefulness of
our protocol, we subjected the trianglimines to hydride reduction. Reduction of the trianglimines 5a, 5b and 5c
Table 2. Optimized Synthesis of Disubstituted Biphenyl Dialdehydes
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Entry
R1
R2
Yield for 3
3a (80%)
Yield for 4
4a (87%)
4b (84%)
4c (70%)
1
2
3
4
3b (91%)
3c (51%)
3a (80%)
3b (91%)
4d (84%)
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Scheme 2. Synthesis of hexaꢀsubstituted C3ꢀsymmetric and asymmetric biphenylꢀbased trianglimines
using NaBH4 in a mixture of MeOH and CH2Cl2 led to the formation of hexaꢀsubstituted trianglamines 6a, 6b and
6c in excellent yield and for which no further purification was required (Scheme 2, top right).
Furthermore, we were able to also construct the asymmetric hexaꢀsubstituted trianglimine 5d in a oneꢀpot reaction
from the asymmetrically difunctionalized dialdehyde 4d. The incorporation of the asymmetric dialdehyde building
block 4d into the trianglimine macrocyclic structure leads to two regioisomeric macrocycles, 5d and 5d'. Of the
two regioisomeric macrocycles, only the asymmetric trianglimine 5d could be isolated via silica gel
1
chromatography and obtained in 9% yield. However it was determined by H NMR spectroscopy that the ratio of
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5d to 5d' is close to 3:1, which is the expected statistical distribution for the random dynamic assembly of the
trianglimine components. Therefore, the yield of 5d' was inferred to be roughly 3%.
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The chiral nature of the trianglimine macrocycles was unambiguously confirmed by circular dichroism (CD)
spectroscopy as shown in Figure 1. In accordance with the chirality of (1R,2R)ꢀ1,2ꢀdiaminocyclohexane, which
imparts its optical activity onto the macrocyclic trianglimines, the CD spectra (Figure 1a, b and d) of the allꢀR
trianglimines 5a, 5b and 5d are characterized by a strong negative Cotton effect with a zero intercept at around 318,
311, and 320 nm respectively. The observed Cotton effects are generated by exciton coupling of the allowed
transitions of the neighboring diimine. The strong positive Cotton effect around 257 nm for all R 5c (Figure 1c) is
most likely due to solvent effects15.
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Figure 1. (a) Stacked CD spectra of a 1×10ꢀ3 M solution of 5a in CH3CN, (b) of 5b in CH3CN, (c) of 5c in ethanol,
and (d) of 5d in CH3CN.
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Figure 2. (a) Photograph of vials containing solutions of 5aꢀc and 6aꢀc upon irradiation with 365 nm light, (b)
Overlaid UVꢀVis absorption and fluorescence emission spectra of solutions (1×10ꢀ5 M and 1×10ꢀ7 M respectively)
of 5a and 5b in CH3CN and 5c in ethanol, (c) Overlaid UVꢀVis absorption and fluorescence emission spectra of
solutions (1×10ꢀ5 M and 1×10ꢀ7 M respectively) of 6a and 6b in CH3CN and 6c in ethanol.
Upon irradiation with 365 nm light, macrocyclic trianglimines 5a, 5b, 5c and trianglamines 6a, 6b, 6c were found
to exhibit strong fluorescence (Figure 2a). To further characterize the photophysical properties of the triangular
macrocycles, UVꢀVis absorption and steadyꢀstate fluorescence spectroscopy measurements were carried out (Figure
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2b and 2c). Fluorescence emission (λEm) bands with maxima centered at 470, 458, and 369 nm were recorded
(Figure 2b) for trianglimines 5a and 5b in CH3CN, and 5c in ethanol, after excitation (λExc) at 252, 263, and 232
nm respectively. On account of the sixꢀfold reduction of the imine bonds of trianglimines 5aꢀc, which effectively
reduces the extent of conjugation in trianglamines 6aꢀc, both the UVꢀVis absorption and fluorescence emission
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bands for 6aꢀb (Figure 2c) are hypsochromically shifted from those observed for 5aꢀb. Fluorescence emission (λEm
)
bands with maxima centered at 406, 405, and 369 nm were recorded (Figure 2c) for trianglamines 6a and 6b in
CH3CN, and 6c in ethanol, after excitation (λExc) at 245, 250, and 235 nm respectively. Sizeable changes in Stokes’
shifts were observed for the trianglimines 5aꢀb upon reduction to trianglamines 6aꢀb. A change in the Stokes’ shift
of 57 nm was recorded (218 nm to 161 nm) for 5a upon reduction to 6a and of 40 nm (195 nm to 155 nm) for 5b
upon reduction to 6b. Only a minor change in the Stokes’ shift of 3 nm (137 nm to 134 nm) was observed15 for 5c
upon reduction to 6c.
The molecular structures and geometries of the new trianglimine and trianglamine macrocycles were assigned and
fully characterized by using various 2D NMR techniques. For example, the 2D ROESY NMR spectrum of
macrocycles 5a showed through space interactions between the protons HCꢀHD, HDꢀHI, HDꢀHH, HIꢀHH, HJꢀHK,
HHꢀHK, HEꢀHF, HGꢀHF and HEꢀHD (see SI). The through space interactions between HG and HF clearly indicates that
the conformation of the six substituents were arranged in an alternating fashion along the triangular structural
framework. The presence of these interactions were further supported by subsequent molecular modeling
calculations (Figure 3). The structures of the trianglimine macrocycles were optimized at the
B97ꢀD16/6ꢀ311G(2d,p)17 level of theory. While the alternating substituent conformation in these trianglimines is not
unlike the 1,3,5ꢀalternate conformation of calix[6]arenes18, the energy barrier for the “through the annulus” ring
inversion of their aromatic units is most likely sufficiently low enough to permit conformational switching at room
temperature.
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Figure 3. Structural formulas and the front and side views of the mixed stick and space filling representations of
the B97ꢀD/6ꢀ311G(2d,p) optimized structures of trianglimine macrocycles 5a–5d. Hydrogens have been omitted
for clarity.
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Figure 4. Mixed stick and space filling representations of the solidꢀstate crystal structure of 5c from the top view (a
and c) and the sideꢀon view (b and d), illustrating each of the two trianglimine macrocycles of 5c which comprise
the unit cell. Hydrogen atoms have been omitted for clarity.
Single crystals suitable for Xꢀray crystallographic analysis were grown from a saturated solution of 5c in DMSO.
The solidꢀstate crystal structure (Figure 4) of 5c was found to be in agreement with our energy minimized
molecular modeling calculations and confirmed that macrocycle 5c adopts a 1,3,5ꢀalternateꢀlike conformation. The
six alternating pyridine substituents of 5c form a cageꢀlike structure above and below the plane of the triangular
structural framework (Figure 4b and 4d) where a single molecule of DMSO (Connolly solvent excluded volume =
66.14 Å3) is sterically trapped within the cavity. The interaction energy between DMSO and 5c, obtained at the
ωB9719/Def2ꢀTZVP20//B97ꢀD/6ꢀ311G(2d,p) level of theory, is ꢀ22.9 kcal/mol (i.e., exothermic). Interestingly, the
deformation energy from the optimized structure depicted in Figure 3 (5c) to the conformation adopted within the
solidꢀstate hostꢀguest superstructure depicted in Figure 4 was computed to be +8.5 kcal/mol at the same level of
theory. The calculated hostꢀguest configuration shows a hydrogen bond interaction between DMSO and 5c, as
also supported by the electron density rearrangement upon interaction (See SI, Figure S66). In particular, one sees
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electron depletion (purple regions, Figure S66) around the hydrogen atom involved in the Hꢀbond, and electron
accumulation (green regions) around the nitrogen lone pairs, typical of electronic density rearrangement observed
in the formation of Hꢀbonds.21 It is also worth noting that the Xꢀray crystal structural unit cell for 5c is in fact a
πꢀstacked superstructure comprised of two unsymmetrical molecules of 5c (Figure 4aꢀ4b and Figure 4cꢀ4d).
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CONCLUSION
In conclusion, a general route to sixꢀfold substituted C3ꢀsymmetric and asymmetric biphenylꢀbased trianglimines
has been developed. Access to this class of luminescent and optically active hexaꢀsubstituted triangular
macrocycles capitalizes on a convenient method for the synthesis of symmetrically and asymmetrically
difunctionalized biphenyl dialdehydes. This route to highly derivatized biphenylꢀbased trianglimines/trianglamines,
enables the incorporation of a wide variety of functional groups into the triangular structural framework. Moreover,
these structures can be synthesized without having to introduce additional asymmetric carbons22 or the need for
alkylating the amine nitrogen atoms23 which could otherwise potentially hinder their later use as metal coordination
sites. The use of hexaꢀsubstituted trianglimines derived from this methodology as components in constructing
larger extended structures and/or superstructures is currently under investigation in our laboratory. We believe this
work will increase the attractiveness for such macrocycles in designing increasingly complex hostꢀguest functional
materials with the added benefit of also being inherently luminescent and optically active.
EXPERIMENTAL SECTION
Materials and General Methods
Starting materials, reagents and solvents were purchased as reagent grade and used without further purification. 1H
and 13C NMR spectra were recorded on a 400 MHz spectrometer at 25 oC. Chemical shifts values are given in ppm
and calibrated relative to the residual signal of the solvent. The peak patterns are defined as follows: s, singlet; d,
doublet; t, triplet; q, quartet; qui, quintet; m, multiplet; dd, doublet of doublets, and td, triplet of doublets. The
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coupling constants J, are reported in Hertz (Hz). Flash column chromatography was performed over silica gel (200–
300 mesh or 300–400 mesh) using a mixture of nꢀhexane and ethyl acetate (EtOAc) as the eluent. TLC plates
(Silica gel GF254) were visualized by exposure to ultraviolet light. High resolution mass spectrometry (HRMS)
was obtained on a QꢀTOF micro spectrometer. Melting points were determined with a melting point apparatus
without corrections. Organic solutions were concentrated by rotary evaporation below 40 °C in vacuum.
Compounds 3a and 3b were prepared according to literature.13 Single crystals suitable for Xꢀray crystallographic
analysis were selected and their Xꢀray diffraction intensity data was collected on a rotating anode diffractometer
equipped with a hybrid photon counting detector, using graphiteꢀmonochromated Mo Kα radiation (λ = 0.71073 Å)
at T = 113K. UVꢀVis absorption spectra, fluorescence spectra, infrared absorption spectra and circular dichroism
spectra were measured on the relevant instruments.
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Synthetic Procedures
Ethyl 4ꢀ(5ꢀbromoꢀ2ꢀformylphenyl) piperazineꢀ1ꢀcarboxylate (3a)
K2CO3 (8.2 g, 60 mmol) and ethyl Nꢀpiperazinecarboxylate (4.4 ml, 30 mmol) were added a stirred solution of
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4ꢀbromoꢀ2ꢀfluorobenzaldehyde (4.04 g, 20 mmol) in acetonitrile. The mixture was heated at 100 C for 40 h. The
reaction mixture was then cooled to r.t. and the solvent was removed under vacuum. Water was added to the crude
product and extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the solvent was
removed under vacuum. The residue was purified by column chromatography on silica gel (200ꢀ300 mesh) using
gradient EtOAc/nꢀhexane (from 1:9 to 3:7) as eluent to provide the desired product as a white yellow solid (5.28g,
1
87%). Rf = 0.18 (EtOAc/nꢀhexane = 1:5). Mp: 95ꢀ96 °C. H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.29 (t, J = 7.1
Hz, 3H), 3.05 (t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.8 Hz, 4H), 4.18 (q, J = 7.1 Hz, 2H), 7.23 (d, J = 1.6 Hz, 1H), 7.26 –
7.31 (m, 1H), 7.67 (d, J = 8.3 Hz, 1H), 10.24 (s, 1H). 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 14.8, 43.8, 53.6,
61.8, 122.8, 126.4, 127.5, 130.1, 132.0, 155.5, 155.8, 190.0. IR (KBr): 2856 (w), 1684 (s), 1581(m), 1249 (m),
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1191 (w), 988 (w), 937 (w), 821 (w) cmꢀ1. The 1H and 13C spectra were in accordance with the literature.13
4ꢀbromoꢀ2ꢀ((2, 2ꢀdimethoxyethyl) (methyl) amino) benzaldehyde (3b)
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K2CO3 (8.2 g, 60 mmol) and methylaminoacetaldehyde dimethyl acetal (2.5ml, 20 mmol) were added to a stirred
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solution of 4ꢀbromoꢀ2ꢀfluorobenzaldehyde (4.0 g, 20 mmol) in acetonitrile. The mixture was heated at 100 C for
40 h. The reaction mixture was then cooled to r.t. and the solvent was removed under vacuum. Water was added to
the crude product and extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the
solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (200ꢀ300
mesh) using gradient EtOAc/nꢀhexane (from 1:20 to 1:10) as the eluent to provide the desired product as a yellow
liquid (5.48g, 91%). Rf = 0.28 (EtOAc/nꢀhexane = 1:5). 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 2.97 (s, 3H), 3.29
(d, J = 5.4 Hz, 2H), 3.30 (s, 6H), 4.56 (t, J = 5.3 Hz, 1H), 7.16 (dd, J = 8.2, 1.5 Hz, 1H), 7.26 (s, 1H), 7.60 (d, J = 8
Hz, 1H), 10.18 (s, 1H). 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 43.0, 53.8, 59.2, 102.4, 123.0, 124.8, 126.7, 129.7,
132.1, 156.1, 190.4. IR (KBr): 2833 (w), 1683 (s), 1583 (s), 1190 (m), 1121 (s), 1074 (s), 960 (m), 843 (s) cmꢀ1.
The 1H and 13C spectra were in accordance with the literature.13
4ꢀbromoꢀ2ꢀ(pyridinꢀ3ꢀyloxy) benzaldehyde (3c)
K2CO3 (1.22 g, 8.9 mmol) and 3ꢀhydroxypyridine (0.5 g, 5.4 mmol) were added to a stirred solution of
4ꢀbromoꢀ2ꢀfluorobenzaldehyde (1.0 g, 4.9 mmol) in dimethylformamide. The mixture was heated at 90 oC for 12 h.
The reaction mixture was then cooled to r.t. and the solvent was removed under vacuum. Water was added to the
crude product and extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the solvent
was removed under vacuum. The residue was purified by column chromatography on silica gel (200ꢀ300 mesh)
using gradient EtOAc/nꢀhexane (from 1:5 to 1:3) as the eluent to provide the desired product as a yellow solid. (0.7
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g, 51%). Rf = 0.16 (EtOAc/nꢀhexane = 1:5). Mp: 82 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.00 (d, J = 1.7 Hz,
1H), 7.33 – 7.45 (m, 3H), 7.81 (d, J = 8.3 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.51 (dd, J = 4.5, 1.5 Hz, 1H), 10.44 (d,
J = 0.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 121.1, 124.8, 125.6, 127.0, 127.6, 130.2, 130.5, 142.2,
146.4, 152.3, 159.5, 187.9. IR (KBr): 2860 (w), 1688 (s), 1587 (s), 1472 (s), 1424 (s), 1388 (s), 1231 (s), 1201 (s),
833 (m), cmꢀ1. HRMS (ESI): m/z calcd for C12H8NO2Br: 277.9811; found: 277.9810 [M+H]+.
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Diethylꢀ4,4'ꢀ(4,4'ꢀdiformylꢀ[1,1'ꢀbiphenyl]ꢀ3,3'ꢀdiyl) bis(piperazineꢀ1ꢀcarboxylate) (4a)
3a (3.4 g, 10 mmol) and bis(pinacolato)diboron (3.0 g, 12 mmol) were dissolved in 50 ml 1,4ꢀdioxone. Argon was
then bubbled through the mixture in order to degas the solution for 20 minutes. Then Pd(dppf)Cl2 (570 mg, 0.78
mmol) and KOAc (1.47 g, 15 mmol) were added to the mixture. The mixture was stirred at 80 °C until compound
3a was no longer detected by TLC (EtOAc/nꢀhexane = 1:5). Na2CO3 (2.12 g, 20 mmol) and 3a (3.4g, 10 mmol)
were added to the mixture and the solution was heated at 120 °C for 2 hrs. The solvent was removed under vacuum.
Water was added to the crude product and extracted with CH2Cl2. The combined organic phases were dried with
Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography on silica
gel (200ꢀ300 mesh) using gradient EtOAc/ nꢀhexane (from 1:5 to 1:1) as the eluent to provide the desired product
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as a yellow solid (4.5 g, 86%). Rf = 0.40 (EtOAc/nꢀhexane = 1:1). Mp: 180ꢀ181 °C. H NMR (CDCl3, 400 MHz,
25 °C): δ = 1.28 (t, J = 7.1 Hz, 6H), 3.12 (t, J = 4.4 Hz, 8H), 3.1 (t, J = 4.4 Hz, 8H), 4.17 (q, J = 7.1 Hz, 4H), 7.25
(d, J = 1.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 10.35 (s, 2H). 13C NMR (CDCl3, 100 MHz,
25 °C): δ = 14.8, 43.9, 53.8, 61.7, 118.2, 122.2, 128.4, 131.3, 146.7, 155.55, 155.64, 190.5. IR (KBr): 1700 (s),
1596 (s), 1432 (s), 1244 (s), 1122 (m), 989 (w), 922 (w), 828 (w) cmꢀ1. HRMS (ESI): m/z calcd for C28H34N4O6:
545.2371; found: 545.2378 [M+Na]+.
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3, 3’ꢀbis ((2, 2ꢀdimethoxyethyl) (methyl) amino)ꢀ[1, 1’ꢀbiphenyl]ꢀ4, 4’ꢀdicarbaldehyde (4b)
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3b (3.00 g, 10 mmol) and bis(pinacolato)diboron (3.00 g, 12 mmol) were dissolved in 50 ml 1,4ꢀdioxone. Argon
was bubbled through the mixture in order to degas the solution for 20 minutes. Then Pd(dppf)Cl2 (570 mg, 0.78
mmol) and KOAc (1.47 g, 15 mmol) were added to the mixture. The mixture was stirred at 80 °C until compound
3b was no longer detected by TLC (EtOAc/nꢀhexane = 1:5). Na2CO3 (2.12 g, 20 mmol) and 3b (3.4g, 10 mmol)
were added to the mixture and the solution was heated at 120 °C for 2 hrs. The solvent was then removed under
vacuum. Water was added to the crude product and extracted with CH2Cl2. The combined organic phases were
dried with Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica
gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane (from 1:5 to 1:1) as the eluent to provide the desired product as
a yellow solid (4.3 g, 81%). Rf = 0.33 (EtOAc/nꢀhexane = 1:5). Mp: 80ꢀ82 °C. 1H NMR (CDCl3, 400 MHz, 25 °C):
δ = 3.05 (s, 6H), 3.33 (s, 12H), 3.36 (d, J = 5.2 Hz, 4H), 4.61 (t, J = 5.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.32 (s,
2H), 7.85 (d, J = 8.0 Hz, 2H), 10.31 (s, 2H). 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 43.6, 53.8, 59.2, 102.7, 118.8,
120.8, 127.8, 131.2, 146.5, 155.9, 191.0. IR (KBr): 2839 (w), 1688 (s), 1598 (s), 1548 (m), 1482 (m), 1418 (m),
1082 (m), 842 (w), 821 (w) cmꢀ1. HRMS (ESI): m/z calcd for C24H32N2O6: 467.2153; found: 467.2157 [M+Na]+.
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3ꢀ(pyridinꢀ3ꢀylmethyl)ꢀ3'ꢀ(pyridinꢀ3ꢀyloxy)ꢀ[1, 1’ꢀbiphenyl]ꢀ4, 4’ꢀdicarbaldehyde (4c)
3c (200 mg, 0.72 mmol) and bis(pinacolato)diboron (219 mg, 0.86 mmol) were dissolved in 4 ml
dimethylformamide. Argon was bubbled through the mixture in order to degas the solution for 20 minutes. Then
Pd(dppf)Cl2 (40 mg, 0.05 mmol) and KOAc (106 mg, 1.1 mmol) were added to the mixture. The mixture was
stirred at 80 °C until compound 3c was no longer detected by TLC (20% EtOAc in nꢀhexane). Na2CO3 (116 mg, 1.1
mmol) and 3c (3.0 g, 10 mmol) were added to the mixture and the solution was heated at 120 °C for 2 hrs. Then the
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solvent was removed under vacuum. Water was added to the crude product and the aqueous was extracted with
CH2Cl2. The combined organic phases were dried with Na2SO4 and evaporated under vacuum. The residue was
purified by column chromatography on silica gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane (from 1:3 to 2:1)
as the eluent to provide the desired product as a white solid (200 mg, 70%). Rf = 0.15 (EtOAc/nꢀhexane = 1:1). Mp:
181ꢀ182 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.00 (s, 2H), 7.32 – 7.42 (m, 6H), 8.01 (d, J = 8.1 Hz, 2H),
8.48 (s, 4H), 10.48 (s, 1H). 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 117.2, 123.2, 124.6, 126.3, 126.9, 129.9, 141.7,
145.9, 146.6, 153.0, 159.3, 188.1. IR (KBr): 1686 (s), 1603 (s), 1554 (s), 1473 (s), 1425 (s), 1390 (s), 1226 (s), 825
(s) cmꢀ1. HRMS (ESI): m/z calcd for C24H16N2O4: 397.1188; found: 397.1183 [M+H]+.
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Ethylꢀ4ꢀ(3'ꢀ((2, 2ꢀdimethoxyethyl) (methyl) amino)ꢀ4, 4’ꢀdiformylꢀ[1, 1’ꢀbiphenyl]ꢀ3ꢀyl) piperazineꢀ1ꢀcarboxylate
(4d)
3a (3.40 g, 10 mmol) and bis(pinacolato)diboron (2.79 g, 11 mmol) were dissolved in 50 ml 1,4ꢀdioxone. Argon
was bubbled through the mixture in order to degas the solution for 20 minutes. Then Pd(dppf)Cl2 (570 mg, 0.78
mmol) and KOAc (1.47 g, 15 mmol) were added to the mixture. The mixture was stirred at 80 °C until compound
3a was no longer detected by TLC (20% EtOAc in nꢀhexane). Na2CO3 (2.12 g, 20 mmol) and 3b (3.0 g, 10 mmol)
were added to the mixture and the solution was heated at 120 °C for 2 hrs. Then the solvent was removed under
vacuum. Water was added to the crude product and the aqueous was extracted with CH2Cl2. The combined organic
phases were dried with Na2SO4 and evaporated under vacuum. The residue was purified by column
chromatography on silica gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane (from 1:5 to 1:1) as the eluent to
provide the desired product as a yellow liquid (4.25 g, 88%). Rf = 0.40 (EtOAc/nꢀhexane = 1:5). 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 1.26 (td, J = 0.9, 7.1 Hz, 3H), 3.03 (s, 3H) , 3.10 (s, 4H) , 3.30 (d, J = 1.0 Hz, 6H) , 3.34 (d, J
= 5.1 Hz, 2H), 3.69 (s, 4H), 4.14 (tt, J = 3.5, 7.1Hz, 2H), 4.60 (t, J = 5.1 Hz, 1H) , 7.21 – 7.25 (m, 2H), 7.29 (s, 1H),
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7.34 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 1.1, 8.0 Hz, 1H), 7.87 (dd, J = 1.1, 8.0 Hz, 1H), 10.28 (s, 1H), 10.33 (s, 1H).
13C NMR (CDCl3, 100 MHz, 25 °C): δ = 14.7, 24.9, 43.4, 43.8, 53.7, 59.1, 61.6, 102.5, 118.1, 118.7, 120.7, 122.1,
127.7, 128.2, 131.1, 131.2, 146.1, 147.0, 155.48, 155.54, 155.9, 190.5, 190.9. IR (KBr): 2833 (w), 1683 (s), 1596
(s), 1430 (m), 1396 (m), 1288 (m), 1123 (m), 832 (m) cmꢀ1. HRMS (ESI): m/z calcd for C26H33N3O6: 506.2262;
found: 506.2264 [M+Na]+.
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Trianglimine (5a)
(1R, 2R)ꢀ1, 2ꢀdiaminocyclohexane (360 mg, 3.15 mmol) in anhydrous dichloromethane (25 mL) was added to a
solution of 4a (1100 mg, 2.1 mmol) in 25 ml of anhydrous dichloromethane. The mixture was stirred at 50 °C for 2
hrs. The solvent was then removed under vacuum. The crude mixture was purified by column chromatography on
silica gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane/trimethylamine (from 3: 7: 0.5 to 4: 6: 0.5) as the eluent
to provide the desired product as a yellow solid (200mg, 16 %). Rf = 0.33 (EtOAc/nꢀhexane/trimethylamine =
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10:10:1). Mp: 203ꢀ204 °C. H NMR (C6D6, 400 MHz, 25 °C): δ = 1.17 (t, J = 7.1 Hz, 4H), 1.41 – 1.53 (m, 6H),
1.70 – 2.14 (m, 18H), 2.20 – 2.70 (m, 24H), 3.20 – 3.80 (m, 30H), 4.05 – 4.25 (m, 12H), 6.99 (s, 6H), 7.24 (d, J =
8.1 Hz, 6H), 8.27 (d, J = 8.0 Hz, 6H), 8.77 (s, 6H). 13C NMR (C6D6, 100 MHz, 25 °C): δ = 15.0, 25.0, 33.4, 44.2,
52.2, 53.6, 61.4, 76.3, 119.1, 122.4, 128.6, 129.5, 144.2, 153.6, 155.2, 157.7. IR (KBr): 2926 (m), 1701 (s), 1598
(m), 1430 (m), 1243 (s), 1118 (m), 1081 (m), 803 (s) cmꢀ1. HRMS (ESI) m/z calcd for C102H132N18O12: 902.0226;
found 902.0233 [M+2H]2+.
Trianglimine (5b)
(1R, 2R)ꢀ1, 2ꢀdiaminocyclohexane (155 mg, 1.36 mmol) in anhydrous dichloromethane (10 mL) was added to a
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solution of 4b (500 mg, 1.2 mmol) in 10 ml anhydrous dichloromethane. The mixture was stirred at 50 °C for 2 hrs.
The solvent was then removed under vacuum. The crude mixture was purified by column chromatography on silica
gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane/trimethylamine (3:7:0.5 to 6:4:1) as the eluent to provide the
desired product as a yellow solid (310mg, 52%). Rf = 0.23 (EtOAc/nꢀhexane/trimethylamine = 10:10:1). Mp:
101ꢀ102 °C. 1H NMR (C6D6, 400 MHz, 25 °C): δ = 1.42 (t, J = 9.4 Hz, 6H), 1.64 – 2.13 (m, 18H), 2.60 (s, 18H),
2.92–3.26 (m, 48H), 3.69 – 3.77 (m, 6H), 4.47 (t, J = 4.5 Hz, 6H), 7.18 – 7.28 (m, 12H), 8.33 (d, J = 8.0 Hz, 6H),
9.03 (s, 6H); 13C NMR (C6D6, 100 MHz, 25 °C): δ = 25.1, 33.7, 44.0, 53.0, 53.1, 58.5, 75.9, 103.0, 119.5, 121.7,
129.2, 130.3, 143.2, 154.1, 158.4. IR (KBr): 2926 (m), 1633 (w), 1599 (w), 1453 (w), 1392 (w), 1261 (s), 1099 (s),
1026 (s), 804 (s) cmꢀ1. HRMS (ESI) m/z calcd for C90H126N12O12: 523.3279; found 523.3279 [M+3H]3+.
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Trianglimine (5c)
(1R, 2R)ꢀ1, 2ꢀdiaminocyclohexane (1.26 g, 9.0 mmol) in anhydrous dichloromethane (75 mL) was added to a
solution of 4c (2.45 g, 6.0 mmol) in 75 ml of anhydrous dichloromethane. The mixture was stirred at 50 °C for 2
hrs. The solvent was then removed under vacuum. The crude mixture was purified by recrystallization from
dichloromethane and cyclohexane to provide the desired product as a white solid (2.0 g, 70 %). Rf = 0.17
(EtOAc/nꢀhexane/trimethylamine = 2:1:1). Mp: 205 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.41 (s, 6H), 1.70
– 1.85 (m, 18H), 3.25 – 3.35 (m, 6H), 7.00– 7.09 (m, 18H), 7.12 (d, J = 8.3 Hz, 6H), 7.82 (d, J = 8.2 Hz, 6H), 8.10
(d, J = 4.3 Hz, 6H), 8.19 (d, J = 2.1 Hz, 6H),, 8.44 (s, 6H);13C NMR (CDCl3, 100 MHz, 25 °C): δ = 24.4, 32.6, 74.4,
117.9, 123.3, 124.2, 124.7, 127.4, 128.4, 140.6, 142.9, 144.4, 154.2, 155.40, 155.43. IR (KBr): 2927 (w), 2854 (w),
1638 (w), 1476 (w), 1423 (w), 1390 (w), 1229 (s), 821 (w) cmꢀ1. HRMS (ESI) m/z calcd for C90H78N12O6:
475.2128; found 475.2132 [M+3H]3+.
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(1R, 2R)ꢀ1, 2ꢀdiaminocyclohexane (360 mg, 3.15 mmol) in anhydrous dichloromethane (25 mL) was added to a
solution of 4d (1000 mg, 2.07 mmol) in 25 ml of anhydrous dichloromethane. The mixture was stirred at 50 °C for
4 hrs. The solvent was then removed under vacuum. The crude mixture was purified by column chromatography on
silica gel (200ꢀ300 mesh) using gradient EtOAc/nꢀhexane/trimethylamine (from 3: 7: 0.5 to 4: 6: 0.5) as the eluent
to provide the desired product as a yellow solid (100mg, 9%). Rf = 0.12 (EtOAc/nꢀhexane/trimethylamine =
3:7:0.5). Mp: 198 °C. 1H NMR (C6D6, 400 MHz, 25 °C): δ = 1.11 – 1.21 (m, 9H), 1.35 – 1.50 (m, 6H), 1.62 – 1.80
(s, 6H), 1.82 – 2.42 (m, 24H), 2.65 (s, 1H), 2.79 (s, 1H), 2.88 (s, 1H), 3.06 – 3.90 (m, 42H), 4.12 – 4.28 (m, 6H),
4.50 (t, J = 5.2 Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 6.65 (d, J = 5.8 Hz, 2H), 7.09 (t, J = 7.2
Hz, 2H), 7.19 (s, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 8.2 Hz, 2H), 7.63 (s, 1H), 7.69 (s, 1H), 8.17 – 8.28 (m,
3H), 8.32 – 8.42 (m, 3H), 8.61 (s, 1H), 8.65 (s, 1H), 8.79 (s, 1H), 9.07 (s, 2H), 9.17 (s, 1H); 13C NMR (C6D6, 100
MHz, 25 °C): δ = 14.96, 15.00, 25.0, 25.1, 33.1, 33.5, 33.7, 33.78, 33.83, 43.6, 43.7, 44.2, 44.3, 52.8, 53.0, 53.06,
53.10, 53.16, 53.24, 58.8, 59.0, 59.3, 61.3, 61.4, 61.5, 75.6, 75.9, 76.0 , 76.27, 76.31, 76.5, 103.2, 103.3, 103.4,
118.7, 119.1, 120.0, 121.1, 121.7, 121.9, 122.1, 122.2, 122.3, 122.4, 128.6, 128.7, 128.9, 129.1, 129.3, 129.4, 129.7,
130.4, 130.6, 143.0, 143.3, 143.4, 143.9, 144.3, 144.5, 153.0, 153.2, 153.3, 153.9, 154.4, 154.8, 155.2, 155.26,
155.31, 157.7, 157.99, 158.04, 158.4. Mp: 198 °C. IR (KBr): 2928 (m), 1701 (s), 1633 (m), 1432 (m), 1390 (m),
1243 (m), 1123 (m), 937 (m), 825 (m) cmꢀ1. HRMS (ESI) m/z calcd for C96H129N15O12: 843.5062; found 843.5062
[M+2H]2+.
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Trianglamine (6a)
NaBH4 (14mg, 0.39mmol) was added to a solution of trianglimine 5a (100 mg, 0.055 mmol) in the mixture of
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CH2Cl2 and MeOH (10 mL). The mixture was stirred at r.t. for 2 hrs. The solvent was then removed under vacuum.
Water was added to the crude product and the aqueous was extracted with CH2Cl2. The combined organic phases
were dried with Na2SO4 and evaporated under vacuum to give the pure product as a white solid (100mg, 100%).
Mp: 155 °C. 1H NMR (C6D6, 400 MHz, 25 °C): 1.05 (t, J = 7.1 Hz, 24H), 1.15 – 1.30 (m, 6H), 1.71 (d, J = 7.2 Hz,
6H), 1.99 (s, 6H), 2.20 – 2.35 (d, J = 8.5 Hz, 12H), 2.81 (td, J = 11.5, 6.1 Hz, 24H), 3.34 – 3.71 (m, 30H), 4.01 –
4.18 (m, 18H), 7.29 (s, 6H), 7.34 (d, J = 7.9 Hz, 6H), 7.44 (d, J = 7.9 Hz, 6H). 13C NMR (C6D6, 100 MHz, 25 °C):
δ = 14.9, 25.6, 31.9, 44.6, 47.3, 52.8, 61.3, 62.4, 119.4, 123.3, 131.1, 135.2, 141.6, 152.4, 155.4. IR (KBr): 2927
(m), 1701 (s), 1603 (w), 1431 (s), 1386 (m), 1244 (s), 1219 (m), 1122 (m), 990 (w) cmꢀ1. HRMS (ESI) m/z calcd
for C102H144N18O12: 605.7154; found 605.7152 [M+3H]3+.
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Trianglamine (6b)
NaBH4 (17mg, 0.44mmol) was added to a solution of trianglimine 5b (100 mg, 0.063 mmol) in the mixture of
CH2Cl2 and MeOH (10 mL). The mixture was stirred at r.t. for 2 hrs. The solvent was then removed under vacuum.
Water was added to the crude product and the aqueous was extracted with CH2Cl2. The combined organic phases
were dried with Na2SO4 and evaporated under vacuum to give the pure product as a white solid (100mg, 100%).
Mp: 51 °C. 1H NMR (C6D6, 400 MHz, 25 °C): 1.10 – 1.30 (m, 12H), 1.70 (d, J = 6.4 Hz, 6H), 2.25 (s, 6H), 2.34 (d,
J = 11.0 Hz, 6H), 2.44 (d, J = 7.6 Hz, 6H), 2.73 (s, 18H), 3.11 (s, 36H), 3.33 – 3.19 (m, 12H), 3.87 (d, J = 12.6 Hz,
6H), 4.24 (d, J = 12.8 Hz, 6H) 4.54 (t, J = 5.1 Hz, 6H), 7.35 (d, J = 7.8 Hz, 6H), 7.52 (s, 6H), 7.60 (d, J = 7.8 Hz,
6H). 13C NMR (C6D6, 100 MHz, 25 °C): δ = 25.7, 31.8, 43.9, 47.2, 52.78, 52.81, 58.3, 62.1, 103.0, 120.3, 122.9,
130.9, 135.8, 141.2, 152.7. IR (KBr): 2928 (s), 1603 (w), 1555 (w), 1450 (s), 1124 (s), 1071 (s), 971 (m), 816 (m)
cmꢀ1. HRMS (ESI) m/z calcd for C90H138N12O12: 527.3592; found 527.3592 [M+3H]3+.
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Trianglamine (6c)
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NaBH4 (9mg, 0.24mmol) was added to a solution of trianglimine 5c (50 mg, 0.035 mmol) in the mixture of CH2Cl2
and MeOH (8 mL). The mixture was stirred at r.t. for 2 hrs. The solvent was then removed under vacuum. Water
was added to the crude product and the aqueous was extracted with CH2Cl2. The combined organic phases were
dried with Na2SO4 and evaporated under vacuum to give the pure product as a white solid (50mg, 100%). Mp:
99 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): 0.96 (d, J = 7.8 Hz, 6H), 1.18 (t, J = 9.9 Hz, 6H), 1.69 (d, J = 7.8 Hz,
6H), 2.00 (s, 6H), 2.14 (d, J = 12.4 Hz, 6H), 2.19 – 2.24 (m, 6H), 3.65 (d, J = 13.5 Hz, 6H), 3.93 (d, J = 13.5 Hz,
6H), 7.06 (d, J = 1.6 Hz, 6H), 7.13 – 7.15 (m, 12H), 7.35 (dd, J = 7.9, 1.6 Hz, 6H), 7.52 (d, J = 7.9 Hz, 1H), 8.25 –
8.28 (m, 6H), 8.34 (t, J = 1.4 Hz, 6H). 13C NMR (C6D6, 100 MHz, 25 °C): δ = 25.0, 31.4, 45.2, 61.1, 117.9, 123.3,
124.16, 124.23, 130.9, 131.9, 140.5, 140.6, 144.1, 154.1, 154.2. IR (KBr): 3428 (s), 2925 (m), 2853 (w), 1614 (w),
1556 (w), 1475 (m), 1423 (m), 1387 (w), 1225 (s), 1102 (w), 1120 (w), 882 (w), 803 (w), 731 (w), 705 (w) cmꢀ1; IR
(KBr): 3428 (s), 2925 (m), 1475 (s), 1387 (w), 1226 (s), 1102 (m), 803 (m), 705 (m) cmꢀ1; HRMS (ESI) m/z calcd
for C90H90N12O6: 479.2447; found 479.2445 [M+3H]3+.
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Computational details
The structural and energetic analysis of the molecular systems described in this study were carried out using both
the Gaussian0924 and GAMESS 2014R1 software.25 Geometries were optimized with the former software in both
gas and solution phase with DFT 26 at the B97ꢀD16/6ꢀ311G(2d,p)17 level of theory. Full geometry optimizations
were performed in their corresponding symmetry point group representations, D3 for 5a, 5b, and 5c and C3 for 5d.
An ultra fine integration grid of 99 radial shells and 590 angular points per shell was selected. Stationary points
were determined when the maximum gradient convergence tolerance and the root mean square gradient were below
0.00045 Hartree/Bohr and 0.00030 Hartree/Bohr, respectively. Effects of solvent employed the CꢀPCM method in
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combination with the Klamt radii.27 For more accurate energetics, the interaction energy between 5c and the
encapsulated DMSO molecule was computed at the ωB9719/Def2ꢀTZVP20//B97ꢀD/6ꢀ311G(2d,p) level of theory,
using the GAMESS 2014R1 open source software. A larger number of radial points in the EulerꢀMacLaurin
quadrature and a finer Lebedev grid28 than the armyꢀgrade grid were used (nrad=155 and nleb=1202, respectively).
The SCF density convergence criterion was lowered to 2.5x 10ꢀ07 and the integral cutoff was lowered to 10ꢀ11. The
rationale for using the hybrid longꢀrange corrected ωB97 functional resulted from an exhaustive performance study
on a broad set of nonꢀcovalent interacting systems.
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In the discussions of the electronic rearrangement upon complexation, the total electronic density change caused by
the interaction between host and guest is considered and is defined as:
ꢁρ = ρcomp. − ρhost − ρguest (1)
where ρcomp. is the electronic density of the hostꢀguest complex and ρhost and ρguest are the electron densities of the
subunits forming the hostꢀguest complex in exactly the configuration adopted in the relaxed hostꢀguest complex.
Within this definition, a positive value indicates electron accumulation and a negative value indicates electron
deletion.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H, 13C, HMQC, HSQC, HMBC, ROESY NMR and Mass spectra for all new substrates and products (PDF)
Single crystal Xꢀray diffraction data for compound 5c in CIF format (CIF).
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AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: molson@tju.edu.cn
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ACKNOWLEDGMENTS
This research is supported by the National Basic Research Program of China (2015CB856500)
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