Synthesis and amino acids complexation of tripodal hexasubstituted benzene chiral receptors

Article abstract of DOI:10.1016/j.molstruc.2014.10.059

(Chemical Equation Presented). The parent 1,3,5-triacetyl-2,4,6-trihydroxybenzene was prepared in up to 91% yield using a one-pot, one step reaction catalyzed by aluminum chloride. Its alkylations with 1,5-dibromopentane generated a symmetric tripodal hex

Full text of DOI:10.1016/j.molstruc.2014.10.059

Accepted Manuscript
Synthesis and Amino Acids Complexation ofTripodalHexasubstituted Benzene
Chiral Receptors
Saowanaporn Choksakulporn, Auradee Punkvang, Yongsak Sritana-anant
PII:
S0022-2860(14)01072-2
DOI:
http://dx.doi.org/10.1016/j.molstruc.2014.10.059
MOLSTR 21055
Reference:
Journal of Molecular Structure
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 June 2014
18 September 2014
23 October 2014
Please cite this article as: S. Choksakulporn, A. Punkvang, Y. Sritana-anant, Synthesis and Amino Acids
Complexation of Tripodal Hexasubstituted Benzene Chiral Receptors, Journal of Molecular Structure (2014), doi:
http://dx.doi.org/10.1016/j.molstruc.2014.10.059
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Synthesis and Amino Acids Complexation of Tripodal
Hexasubstituted Benzene Chiral Receptors
a
Saowanaporn Choksakulporn , Auradee Punkvang , Yongsak Sritana-anant *
b
a
a
Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Rd, Pathumwan,
Bangkok 10330, Thailand
b
Division of Chemistry, Faculty of Sciences, Nakhon Phanom University, Nakhon Phanom 48000,
Thailand
E-mail: yongsak.s@chula.ac.th; Tel. +662 2187632; Fax +662 2187598
Abstract
The parent 1,3,5-triacetyl-2,4,6-trihydroxybenzene was prepared in up to 91% yield using a
one-pot, one step reaction catalyzed by aluminum chloride. Its alkylations with 1,5-dibromopentane
generated a symmetric tripodal hexasubstituted benzene precursor in the alternated conformer
predicted by a theoretical calculation. Subsequent substitutions and reductions provided the
corresponding tris-amine in 59% yield. Aminations of the tripodal precursor with (R)-(+)-1-
1
phenylethylamine obtained a chiral tris-amine ligand in 44% yield. H-NMR titrations of this ligand
with each of three L-amino acid derivatives as guest molecules confirmed the presence of their
complexes, in which the complex with alanine derivative displayed the strongest interactions with
the ligand. Job plots suggested that all complexes composed of 1:2 ratios of the ligand and these
guests. Theoretical calculations additionally revealed the structures and the associated binding
parameters of the complexes.
Keywords: Hexasubstituted benzene scaffold; tripodal ligand; amino acid receptor
Introduction
Molecular scaffolds and their structural diversity building upon the scaffolds are at the heart
of supramolecular chemistry with the goal to achieve effective bindings towards guest molecules by
the aligned interactive arms on the respective scaffolds. The design of these hosts and their
complementary guests would involve many related factors such as size, charge density,
polarizability, position and shape.[1-3] When an equal number of interactive arms is present, multi-
macrocycles or three-dimensional cryptates are known to create very stable inclusion complexes
with better selectivity and binding strength towards their guests than the non-cyclic or even
monocyclic counterparts.[4,5] The rigidity imposed upon the cycles helps situate the binding arms
and facilitate some degrees of preorganization. Nevertheless, the painstaking synthetic efforts

towards such rigidity and the usually required multidentate groups are the major hurdles and hinder
the advance of the field.
With relatively simple synthetic access and highly diverse varieties, tripodal ligands are
among the most frequently investigated and successful host scaffolds.[6-11] One of the platforms
that has particularly caught our interests is the hexasubstituted benzene scaffold.[12,13] Each pair of
adjacent substituents minimizes their steric repulsion by adopting the thermodynamically favored
conformation in which all subunits are arranged in fully up-down alternating configuration or the
“ababab” geometry (Figure 1).[14-16] Such arrangement projected three groups perpendicularly on
one face of benzene plane while the others turn toward the opposite direction. This facially
segregated feature creates rigidity on this non-cyclic ligand, but allows some flexibility upon guest
binding and avoids the difficulty of macrocyclic synthesis.
Figure 1 preorganized geometry of hexasubstituted benzene scaffold
Most of the ligand designs based on hexasubstituted benzene focused on those derived
from 1,3,5-trisubstituted-2,4,6-triethylbenzene precursor.[17-25] Some restrictions could be noticed
from this scaffold. The synthetic strategies employed for incorporation of the binding arms onto the
scaffold are relatively limited, and only three arms can be functionalized due to the unreactive ethyl
groups. Such limitations can be sidestepped by employing 1,3,5-triacyl-2,4,6-trihydroxybenzene as
the parent. The compound can be prepared simply in one step and further derivatized, similarly or
differently, on both sides of the benzene plane. However, designs of ligands derived from this
platform were relatively scarce and underutilized.[26-30] In this context, we wish to report our
recent attempts to employ the scaffold towards molecular recognition especially those involves
chiral biological related molecules such as amino acid derivatives.
Experimental section
1
13
General information: H and C NMR spectra were recorded on Varian Mercury 400 or Bruker
1
13
Avance 400 spectrometers, operated at 400 MHz for H and 100 MHz for C nuclei. The FT-IR
spectra were recorded on a Perkin-Elmer spectrum RXI spectrometer. High resolution mass spectra
were determined on Bruker Daltonik GmbH micrOTOF-Q II. All reagents and solvents were used as
purchased or distilled prior to use.

Syntheses
Synthesis of 1,3,5-triacetyl-2,4,6-trihydroxybenzene 1
Acetyl chloride (50 mL) was added to the mixture of phloroglucinol dihydrate (5.01 g, 30.9
mmol) and anhydrous AlCl (20.47 g, 154.5 mmol). The reaction was stirred under reflux for 1 h and
3
quenched with 10% HCl (10 mL), water (150 mL) and filtered. The collected precipitate was
recrystallized from ethanol to give colorless needle crystals of the product in 7.09 g, 91% yield, mp
1
155-156 °C (lit. mp 156 °C [31,32]); H NMR (CDCl ) δ: 17.16 (3H, s, -OH), 2.72 (9H, s, -C(O)CH );
13
C
3
3
-1
NMR (CDCl ) δ: 205.1, 175.9, 103.3, 33.0; IR (KBr, cm ): 3427.0, 1620.2, 1579.8, 1296.7; HRMS
3
+
(ESI/methanol) m/z: (M+Na) 275.0539 (Calcd for C H NaO : 275.0532).
12 12
6
Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-bromopentyloxy)benzene 2
Compound 1 (5.01 g, 19.9 mmol) was dissolved in acetonitrile (200 mL). 1,5-
Dibromopentane (32.7 mL, 238.8 mmol) and K CO (41.15 g, 298.2 mmol) were added and the
2
3
mixture was stirred under reflux for 48 h. The solvent was then removed and water (100 mL) was
added. The solution was extracted with ethyl acetate. The organic layers were separated, combined,
dried over anhydrous Na SO and evaporated the solvent. The concentrated crude product was
2
4
purified by column chromatography (90:10 hexane/ethyl acetate) to give colorless oil product in
1
10.7 g, 77% yield; H-NMR (CDCl ) δ: 3.82 (t, J = 6.4 Hz, 6H, -OCH -), 3.40 (t, J = 6.7 Hz, 6H, -CH Br),
3
2
2
2.52 (s, 9H, -C(O)CH ), 1.86 (m, 6H, -OCH CH -), 1.64 (m, 6H, -CH CH Br), 1.48 (m, 6H, -CH CH CH -);
3 2 2 2 2
2
2
2
13
-1
C-NMR (CDCl ) δ: 201.1, 153.9, 135.8, 129.1, 128.8, 128.8, 80.1, 32.8; IR (KBr, cm ): 3031.9, 2920.0,
3
+
1698.9, 1572.4, 1197.8, 1081.1; HRMS (ESI/methanol) m/z: (M+H) 701.0323 (Calcd for C H Br O :
27 39
3
6
701.0334).
Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-azidopentyloxy)benzene 3
Compound 2 (3.69 g, 5.3 mmol) was dissolved in acetone (24 mL). Sodium azide (1.37 g, 21.1
mmol) in water (6 mL) was added and the mixture was stirred under reflux for 8 h. The solvent was
then removed and water (30 mL) was added. The mixture was extracted with ethyl acetate. The
combined organic layers were dried over anhydrous Na SO and evaporated the solvent. The crude
2
4
product was purified by column chromatography (CH Cl ) to give the yellow oil product in 2.82 g,
2 2
1
85% yield; H NMR (CDCl ) δ: 3.82 (t, J = 6.4 Hz, 6H, -OCH -), 3.27 (t, J = 6.8 Hz, 6H, -CH N ), 2.52 (s,
3
2
2
3
9H, -C(O)CH ), 1.62 (m, 12H, -OCH CH - and -CH CH N ), 1.43 (dt, J = 12.6, 6.8 Hz, 6H, -CH CH CH -);
3 2 2 2 2
2
2
3
2
13
-1
C NMR (CDCl ) δ: 201.1, 154.2, 127.8, 77.6, 51.4, 32.8, 29.5, 28.6, 23.0; IR (neat, cm ): 2943.4,
3
+
2867.9, 2084.1, 1700.8, 1570.2, 1349; HRMS (ESI/methanol) m/z: (M+H-N ) 558.3101 (Calcd for
2
C H N O : 558.3040).
27 39 7 6
Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-aminopentyloxy)benzene trihydrochloride 4
Compound 3 (0.3 g, 0.5 mmol) and ammonium chloride (0.23 g, 3.6 mmol) were dissolved in
ethanol (3 mL) and water (10 mL) and then added zinc powder (0.14 g, 2.0 mmol). The mixture was

stirred vigorously at reflux temperature for 15 min. Ethyl acetate (15 mL) and 30% ammonia (5 mL)
were added. The mixture was filtered, and the filtrate was washed with brine, dried over anhydrous
Na SO and removed the solvent. The concentrated crude product was converted into hydrochloride
2
4
salt by adding methanol (5 mL) and 10% HCl (1 mL) and stirred for 3 h. The salt product 4 was
purified by column chromatography using Sephadex LH-20 and methanol as the eluent. The product
was obtained as yellow oil in 0.23 g, 90% yield.
This compound was characterized as N-acetylated derivative using the following procedure.
Compound 4 (0.18 g, 0.35 mmol) was treated with acetic anhydride (1 mL), DMAP (0.039 g, 0.35
mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature overnight. It was
quenched with water (10 mL) and then extracted with ethyl acetate. The combined organic layer
was dried over anhydrous Na SO , concentrated and purified by column chromatography (80:20
2
4
ethyl acetate/methanol). The N-acetylated product was obtained as a white solid in 0.15 g, 69%
1
yield; H NMR (Acetone-d ) δ: 7.06 (s, 3H, -NH-), 3.84 (t, J = 6.4 Hz, 6H, -OCH -), 3.16 (q, J = 6.5 Hz,
6
2
6H, -CH NH-), 2.51 (s, 9H, ArC(O)CH ), 1.84 (s, 9H, -NHC(O)CH ), 1.64 (m, 6H, -OCH CH -), 1.47 (dd, J =
2 3 3 2 2
13
14.7, 7.1 Hz, 6H, -CH CH NH-), 1.38 (dd, J = 14.9, 7.8 Hz, 6H, -CH CH CH -); C NMR (Acetone-d ) δ:
2
2
2
2
2
6
-1
201.0, 169.8, 154.8, 128.3, 77.9, 39.6, 32.9, 30.27, 30.1, 23.8, 22.9; IR (neat, cm ): 3722.4, 3627.9,
2929.2, 2866.2, 1766.6, 1655.0, 1569.1, 1417.3, 1256.8, 1196.8, 1085.1; HRMS (ESI/methanol) m/z:
+
(M+H) 634.3750 (Calcd for C H N O : 634.3704).
33 51
3
9
Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-((R)-1-phenylethylamino)pentyloxy)benzene 5
Compound 2 (0.51 g, 0.7 mmol) was dissolved in in acetonitrile (25 mL). 1,5-(R)-
(+)Phenylethylamine (0.3 mL, 2.4 mmol) and K CO (0.5 g, 3.5 mmol) were added and the mixture
2
3
was stirred under reflux for 13 h. The solvent was then removed and water (20 mL) was added. The
solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous
Na SO and evaporated the solvent. The concentrated crude product was purified by column
2
4
chromatography using Sephadex LH-20 (80:20 methanol/water) to give the yellow oil product in 0.26
1
g, 44% yield; H NMR (400 MHz, CD OD) δ 7.60 (d, J = 7.1 Hz, 1H, o-ArH), 7.54 – 7.41 (m, 14H, ArH),
3
4.58 (dd, J = 13.3, 6.5 Hz, 1H, -NH-C*HCH ), 4.39 (q, J = 6.5 Hz, 2H, -NHC*HCH ), 3.81 (t, J = 5.4 Hz,
3 3
6H, -OCH -), 3.17-2.99 (m, 2H, -CH NH-), 3.00-2.68 (ddd, J = 78.8, 16.5, 11.1 Hz, 4H, -CH NH-), 2.48 (s,
2 2 2
9H, -C(O)-CH ), 1.69 (d, J = 6.7 Hz, 9H), 1.79 – 1.56 (m, 12H, -CH -CH - CH -), 1.41 – 1.34 (m, 6H, -CH -
3 2 2 2 2
13
CH - CH -); C NMR (100 MHz, CD OD) δ 202.6, 155.4, 137.9, 130.7, 130.5, 130.4, 130.0, 128.7, 78.2,
2
2
3
-1
59.7, 51.8, 46.9, 33.0, 30.7, 30.3, 26.9, 25.0, 24.0, 23.9, 19.8, 17.2; IR (neat, cm ): 3401.7, 2943.4,
+
2867.9, 1700.8, 1569.1, 1417.2, 1256.8, 1196.8, 1085.1 (C-N st); HRMS (ESI/methanol) m/z: (M+H)
820.5286 (Calcd for C H N O : 820.5265).
51 69 3 6
Binding studies

1
H NMR titrations and Job’s plots were used to determine the binding ratios between the
ligand and guests.[33] The selected guests are the enantiomeric pairs of alanine methylester
1
hydrochloride (6), N-Boc-tryptophan (7) and N-Boc-valine (8). H NMR spectrum of the mixture was
recorded after each addition of exact equivalent of guest solution until no change was observed in
the spectrum. Complexes of ligand 5 with guests 6 and 8 were investigated in CDCl while those with
3
guest 7 were studied in acetone-d due to its low solubility in CDCl . The association constants (K )
6 3 assoc
and predicted complex structures were computationally assessed using Autodock 3.05 program.
Computational methods
Structures of 2, ligand 5 and the selected guests including alanine methylester hydrochloride
(6), N-Boc-tryptophan (7) and N-Boc-valine (8) were constructed using the standard tools available in
GaussView 3.07 program. They were fully optimized by Hartree fock (HF) method with 6-31G* basis
set (HF/6-31G*) implemented in the Gaussian 03 program. Two different conformers of 2, the
abaabb and the fully alternated ababab conformers, were similarly constructed and fully optimized
by HF/6-31G* method. The structures of 1:1 and 1:2 complexes of ligand 5 with guests 6, 7 and 8
were predicted by the molecular docking calculations using Autodock 3.05 program.[34] The
optimized structure of each guest was first docked into the pocket of ligand 5 to generate the 1:1
complex. The obtained structure was then taken as the receptor, and another guest molecule was
docked into its corresponding 1:1 complex to generate the 1:2 complex. With an exception of the
number of genetic algorithm (GA) runs set to 50, all other parameters were set at default values. The
structure with the lowest docked energy was selected as the best binding mode of each complex.
The corresponding estimated free energy of binding (ΔG) and binding constants (K ) of these
assoc
complexes were then calculated and reported.
Results and Discussion
Synthesis
The parent 1,3,5-triacetyl-2,4,6-trihydroxybenzene 1 was successfully synthesized in one-
pot, one step process using the process modified from previous reports (Scheme 1).[31-32] The
reaction was assumed to go through triple O-acylations of phloroglucinol followed by Fries
rearrangements to the hexasubstituted product. Aluminum chloride was found to be the most
efficient acid catalyst, yielding the product up to 91% (Table 1). Much lower yields were obtained
with other acids in which incompletely rearranged intermediates and large amount of recovered
substrate were observed in some cases. The optimum reaction time was approximately at 1 h.

Prolonged reflux may convert the highly steric crowded product back to the intermediate or other
1
byproducts. The H-NMR signal of the phenolic protons of 1 appeared as a singlet at δ 17.16 ppm,
indicating that the molecule is relatively flat with strong three intramolecular hydrogen bonds
between the three hydroxy groups and the adjacent carbonyls.[35]
Scheme 1 Reagents and conditions: (i) AcCl, AlCl ; (ii) 1,5-dibromopentane, K CO , CH CN; (iii) NaN ,
3 2 3 3 3
acetone/H O; (iv) Zn, NH Cl; (v) 10% HCl, MeOH; (vi) (R)-(+)-1-phenylethylamine, K CO , CH CN
2 4 2 3 3
Table 1 The syntheses of 1,3,5-triacyl-2,4,6-trihydroxybenzene
Entry
Catalyst
Time (h)
%Yield
91
1
2
3
4
5
6
AlCl
1
1
2
1
4
4
3
TiCl
40
4
FeCl 1 3
3
BF ·OEt
3
17
14
70
2
conc.H SO
2
4
AlCl
3
The precursor 1 was alkylated at the hydroxyl groups to generate the symmetric tripodal
scaffold. The synthesis of 2 was accomplished using 1,5-dibromopentane as the alkylating agents
(Scheme 1). Based on our HF/6-31G* calculations, the energy of the optimized structure of 2 in its
fully alternated ababab conformation was lower than that of the next most stable abaabb
conformer by 6.3 kcal/mol (Figure 2). In this conformation, all bromopentoxy groups were oriented
out of the same face of the central benzene plane, in the opposite direction to the methyl groups of

the three acetyl substituents. This result was later used as the guideline to computationally build the
structure of the related ligand 5 as its fully alternated conformation in the following complexation
study.
Figure 2 The most stable ababab (left) and the next most stable abaabb (right) conformers of 2
Nucleophilic substitutions of the scaffold 2 with sodium azide provided tris-azide 3 in 85%
yield.[36] The subsequent reductions with Zn/NH Cl turned the tris-azide intermediate to the
4
corresponding tris-amine 4 in 90% yield.[37] The structure of the product 4 was confirmed as its tris-
N-acetyl derivatives from further excessive acylations. The overall yield of 4 calculated from the
starting platform 1 was 59%. In another route, direct aminations of 2 with (R)-(+)-1-
phenylethylamine generated the chiral ligand 5 in 44% yield.
Compound 5 was investigated for its ability to form complexes and discriminate enantiomers
of three amino acid derivatives: alanine methylester hydrochloride 6, N-Boc-tryptophan 7 and N-
Boc-valine 8. The more abundant L-isomers of the amino acids were first selected for the
1
investigation using H-NMR titration with increasing amount of guests. Ligand 5 showed significant
downfield complexation-induced chemical shifts (CICS) in all cases especially around the stereogenic
centers. On the other hand, the proton signals of guests immediately shifted upfield at the beginning
of the titration, and gradually moved downfield upon further additions of guests. This wavering shift
could arise from the initial hydrophobic environment surrounding the guest molecules upon
complexation within the binding pocket of the ligand. As more guest molecules were added,
interactions among themselves diminished the effect from the ligand and moved the NMR chemical
shifts of the proton signals downfield. Because of the uncertain directions of the CICS of the NMR
signals of the guests, the chemical shifts of the signals of two moieties of the ligand: the methine
protons at the stereogenic centers and the adjacent methyl groups were chosen to be monitored.
During the titration, the signals of the methine and the methyl protons of ligand 5 upon
complexation with 6 displayed the strongest downfield shifts of 0.43 and 0.49 ppm, respectively
(Figure 3). In comparison, the complexes with 7 and 8 gave the values of downfield shifts of these
two signals to be 0.25, 0.20 and 0.38, 0.27 ppm, respectively. This indicated that the binding arms of

ligand 5 could interact with guest 6 stronger than the other two compounds. It could be assumed
that the free amino and the ester groups on 6 could attract to the binding groups of the ligand
better than the amide and the free carboxyl groups on 7 and 8.
1
Figure 3 Stack plots of H-NMR titration spectra of complex between ligand 5 and guest 6
Job plots of all complexes were obtained by the continuous variations method (Figure 4).[33]
The aligned maxima of all plots at about 0.67 mole fraction of the guest suggested that the binding
ratios between this ligand and these amino acid derivatives were 1:2. The tight hydrogen bonds
between two guest molecules may prevail over the weaker interaction yet sufficient for
complexation with the binding groups of ligand 5. This dimeric self-attraction of amino acid
derivatives weakened the interactions with the host and reflected in the gradual downfield shifts of
the proton signals of the guests observed in the NMR titrations.
0.160
6
0.120
7
8
0.080
0.040
0.000
0.000
0.200
0.400
0.600
0.800
1.000
mole fraction of guest
Figure 4 Job plots of CICS of the methine protons of ligand 5 from NMR titrations with guests 6, 7, 8

Computational studies revealed the relatively modest association constants of the
complexes of ligand 5 and the three guests (Table 2). The results partly agreed with the experimental
data that suggested better complexations of ligand 5 with the guests in 1:2 ratios except with
compound 8. In fact, the difference between the calculated ΔG values of the 1:1 and 1:2 complexes
with 7 and 8 were insignificant. Only the complex with 6 clearly preferred the 1:2 ratio, probably due
to the presence of the free amino group. Part of the complex stabilization may arise from the
possibility that the two guest molecules could also bind to each other within the pocket of the
ligand. The predicted structures of the 1:2 complexes of ligand 5 and each of the three guests are
shown in Figure 5.
Table 2 Association constants of the complexes of ligand 5 with guests
-ΔG(1:1)
kcal/mol
1.47
Kassoc (1:1)
-ΔG(1:2)
kcal/mol
1.61
Kassoc (1:2)
Guest
-1
(M )
-1
(M )
6
7
8
11.97
52.03
10.28
15.17
54.74
9.14
2.34
2.37
1.38
1.31
a)
b)
c)
Figure 5 Predicted 1:2 complex structures of ligand 5 with a) 6, b) 7 and c) 8

The less abundant D-isomers of amino acid derivatives 6, 7 and 8 were next used as the
guests to form complexes with ligand 5 in order to investigate the enantiomeric discrimination
ability of the ligand. Surprisingly, the results from NMR titrations of the D- form of these guests also
all preferred 1:2 complexes and were similar to those obtained from the previous experiments on
the L-form. It could be deduced that the diastereomeric differentiations from ligand 5 were
unfortunately too small to overcome the main attractive interactions that involved no chiral
components. This lack of chiral distinction may be explained from the calculated structures of the
complexes in Figure 5. The three arms of ligand 5 carrying the asymmetric moieties were extended
away from the central core, where the dimeric pairs of the guest molecules preferentially situated
and interacted with the host. The flexible long hydrocarbon chains that link the asymmetric groups
to the core would be the reason for the failure to create an effective chiral binding pocket for the
guests. It may be suggested that more rigidity on the linkers would be required to build a better
ligand for chiral discrimination on this platform.
Conclusion
The synthesis of hexasubstituted benzene derivatives based on the parent 1,3,5-triacetyl-
2,4,6-trihydroxybenzene 1 have been achieved. The synthetic procedure of the parent compound
was optimized into one-pot, one step reflux using aluminum chloride catalyst. Alkylations of 1 with
1,5-dibromopentane produced the symmetric tripodal 2, which was theoretically predicted to be in
fully alternated conformation. Substitutions of 2 with sodium azide provided tris-azide 3, which was
reduced to the corresponding tris-amine 4. Direct aminations of 2 with (R)-(+)-1-phenylethylamine
generated the desired chiral ligand 5. These relatively straightforward procedures provide a general
access to functionalize the three hydroxyl groups directed toward one side of the hexasubstituted
benzene plane. The other three alternated acetyl groups could then be modified to incorporate
another set of functional moieties that pointed to the opposite side,[30] thereby creating a
potentially ditopic bifunctional host on one platform.
1
H-NMR titrations of ligand 5 with each of three selected L-amino acid derivatives confirmed
the presence of their complexations, in which the complex with alanine derivative 6 displayed the
strongest interactions with the ligand. Job plots of all complexes suggested that the preferred
binding ratios between ligand 5 and these guests were 1:2, which partly agreed with the
computational studies. Unfortunately, complexations of ligand 5 with the D-isomers of the guests
gave similar results to those of their enantiomers, indicating that the ligand possessed no chiral
discrimination ability among the amino acid derivatives being tested. The low rigidity of the aliphatic
chain linking the binding moieties may be the reason for such ineffective enantiomeric

differentiation. One may envision that incorporating rigid groups such as aromatic rings or gem-
dimethyl groups as part of the linkers could improve the binding stability and chiral discriminating
property. Such attempts would apparently add difficulties into the synthetic process and become a
challenge for future design and synthesis of potential ligands from this platform.
Acknowledgment
The research funds from Thailand Research Fund (MRG4880176), and the National Research
University project of CHE and the Ratchada phiseksomphot Endowment Fund (HR1155A),
Chulalongkorn University, are highly appreciated. S. C. would like to thank the Development and
Promotion of Science and Technology Talents Project (DPST) for the scholarship during the study.
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Graphical abstract
Binding of alanine derivative as 1:2 complex by a new chiral tripodal ligand based on hexasubstituted
benzene platform revealed by both experiment and theoretical calculation.

Highlights
·
New chiral and achiral ligands based on hexasubstituted benzene scaffold starting from
phloroglucinol were prepared.
·
·
The chiral ligand formed stable complexes with amino acid derivatives.
The structures of the ligand and its complexes were confirmed both by experimental
(NMR, IR) and computational studies.