Synthesis and characterisation of a new naphthalene tris-Tr?ger's base derivative - A chiral molecular clip

Article abstract of DOI:10.1016/j.tetlet.2012.11.035

Serial tris-Tr?ger's base derivatives (trisTBs) are members of a recently introduced family of chiral molecular clips. Naphthalene tris-Tr?ger's base is prepared via both stepwise and one-pot approaches. All three diastereoisomers are isolated and unambiguously identified, and their NMR spectra, enantioseparation and binding ability are studied. The syn,syn-trisTB diastereoisomer, a molecular clip, is found to be a potential molecular receptor of electron-deficient cyanobenzenes. For the first time, racemic syn,syn-trisTB is resolved via preparative HPLC (chiral column) and the absolute configurations are assigned by comparison of experimental and calculated ECD spectra. General dependencies on the oligoTB stability in acid media and potential anion binding are suggested.

Full text of DOI:10.1016/j.tetlet.2012.11.035

Accepted Manuscript
Synthesis and characterisation of a new naphthalene tris-Tröger’s base deriva‐
tive – a chiral molecular clip
Bohumil Dolenský, Jiř í Kessler, Milan Jakubek, Martin Havlík, Jan Čejka, Jana
Novotná, Vladimír Král
PII:
S0040-4039(12)01965-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.035
TETL 42127
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 June 2012
19 October 2012
8 November 2012
Please cite this article as: Dolenský, B., Kessler, J., Jakubek, M., Havlík, M., Čejka, J., Novotná, J., Král, V.,
Synthesis and characterisation of a new naphthalene tris-Tröger’s base derivative – a chiral molecular clip,
Tetrahedron Letters (2012), doi: http://dx.doi.org/10.1016/j.tetlet.2012.11.035
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Bohumil Dolenský,* Jiří Kessler, Milan Jakubek, Martin Havlík, Jan Čejka, Jana Novotná, Vladimír Král

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis and characterisation of a new naphthalene tris-Tröger’s base derivative – a
chiral molecular clip
Bohumil Dolenskýa,  , Jiří Kesslera , Milan Jakubeka , Martin Havlíka , Jan Čejkab , Jana Novotnáa,
Vladimír Krála
aDepartment of Analytical Chemistry, Institute of Chemical Technology Prague, Technická 5, Praha 16628, Czech Republic
bDepartment of Solid State Chemistry, Institute of Chemical Technology Prague, Technická 5, Praha 16628, Czech Republic
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Serial tris-Tröger’s base derivatives (trisTBs) are members of a recently introduced family of
chiral molecular clips. Naphthalene tris-Tröger’s base is prepared via both stepwise and one-pot
approaches. All three diastereoisomers are isolated and unambiguously identified, and their
NMR spectra, enantioseparation and binding ability are studied. The syn,syn-trisTB
Available online
diastereoisomer, a molecular clip, is found to be a potential molecular receptor of
electron-deficient cyanobenzenes. For the first time, racemic syn,syn-trisTB is resolved via
preparative HPLC (chiral column) and the absolute configurations are assigned by comparison
of experimental and calculated ECD spectra. General dependencies on the oligoTB stability in
acid media and potential anion binding are suggested.
Keywords:
serial tris-Tröger’s base
chiral molecular clip
bis-Tröger’s base
racemisation
2009 Elsevier Ltd. All rights reserved.
anion binding
Serial tris-Tröger’s base derivatives (trisTBs) are members of
the recently introduced family of various molecular scaffolds
based on fused Tröger’s base derivatives (oligoTBs).1-3
A common Tröger’s base (TB) derivative4 consists of two arenes
R2
N
N
N
N
N
N
R1
(AR) linked via [b,f] annelation to
a 1,5-diazabicyclo-
1a R1 = CH3, R2 = NO2 ref. 5,6
[3.3.1]nonane (TB unit; TBU), figuratively AR1-TBU-AR2. A
serial trisTB consists of two TBs linked via [b,f] annelation to
another TBU, figuratively AR1-TBU-AR2-TBU-AR3-TBU-AR4.
As TBU is a chiral structural element constraining the attached
arenes about a perpendicular position (rigid V-shape, 80-114°),4 a
serial trisTB has four diastereoisomers (anti,anti-trisTB,
anti,syn-trisTB, syn,anti-trisTB and syn,syn-trisTB). To date,
only five symmetrical (AR1 = AR4 and AR2 = AR3;
anti,syn-trisTB  syn,anti-trisTB) serial trisTBs are known
(Figure 1).5-9 The syn,syn-trisTBs were recently proposed as
inherently chiral molecular clips.
1b R1 = R2 = Br
1c R1 = R2 = OCH3
ref. 7
ref. 8
CH3
R1
R2
CH3
R1
N
N
N
N
N
R1
N
R2
CH3
R1
CH3
2a R1 = CH3, R2 = H ref. 8
2b R1 = Cl, R2 = Br ref. 9
molecular shapes
of the diastereoisomers
anti,anti-trisTB
anti,syn-trisTB
syn,syn-trisTB
Figure 1. Known serial trisTBs and the profile shapes of their
diastereoisomers.
In this communication, we present the preparation and
characterisation of all three diastereoisomers of
a new
naphthalene trisTB derivative 3, the first trisTB having
———
 Corresponding author. Tel.: +420-2-2044-4110; fax: +420-2-2044-4352; e-mail: Bohumil.Dolensky@vscht.cz

2
naphthalene as the sidewall arenes (AR1, AR4). In addition, we
present the first evidence of binding abilities of each
diastereoisomer, and the first resolution and characterisation of
syn,syn-3 enantiomers.
O
NO2
NH2
HN
O
X
TrisTB 3 was prepared via one-step mixed troegeration,8,10
i.e., by treatment of naphth-2-ylamine with phenylene-1,4-
diamine and hexamethylenetetramine (HMTA) in trifluoroacetic
acid (TFA) at room temperature. While this method is simple and
inexpensive, it provided low yields (1.9% of anti,anti-3 and 0.3%
of anti,syn-3; formation of syn,syn-3 was not observed), and
required a tedious isolation process due to formation of
significant amounts of side-products, particularly, naphthalene
TB 4 and bisTB 5 (Scheme 1).
O
NH NH2
THF, 70 °C, 16 h
NO2
6, X = O (72%)
7, X = H2 (99%)
BF3, THF, 70 °C, 8 h
NH2
NH2
(CH2)6N4, TFA, rt, 16 h
HMTA
+
TFA, rt, 5 d
N
R
N
8, R = NO2 (59%)
9, R = NH2 (58%)
SnCl2, HCl, 80 °C, 5 h
NH2
N
N
(CH2)6N4, TFA, rt, 3 d
4 (75% yield)
N
N
N
N
N
N
N
N
N
N
+
anti,anti-3 58.6% yield (14.3% overall)
anti,syn-3 12.8% yield (3.1% overall)
syn,syn-3
2.6% yield (0.6% overall)
anti-5 (9% yield), syn-5 (4% yield)
Scheme 2. Stepwise preparation of trisTB 3.
+
+
+
(R*)
(R*)
(R*)
N
N
The single-crystal X-ray diffraction study of racemic
anti,syn-3 (CCDC 832257) shows that the syn part of the
molecule resembles molecular tweezers (Figure 2); the opposite
benzene cores are separated by 0.657(1) nm, and their planes
form an angle of 29°. The crystal packing shows that two
molecules having opposite absolute configurations are
interlocked by the tweezers parts; the naphthalene planes are
separated by approximately 0.36 nm and are entirely coplanar.
This parallel displaced arene-arene interaction is supported by
two simultaneous CH-π hydrogen bonds; the naphthalene
hydrogen atom of one molecule points nearly to the middle of the
benzene group of the second molecule and vice versa, and the
hydrogen is approximately 0.25 nm from the plane of the central
benzene.
N
N
(R*)
N
(R*)
N
(R*)
anti,anti-3 (1.9% yield)
(R*)
(R*)
(S*)
N
N
N
N
(R*)
N
(R*)
N
(S*)
anti,syn-3 (0.3% yield)
(S*)
(R*)
(S*)
N
N
N
N
(S*)
N
(R*)
N
(S*)
syn,syn-3 (0% yield)
Scheme 1. One-pot preparation of trisTB 3.
As a better alternative, trisTB 3 was prepared in five steps
(18% overall yield) via a known approach7,8 (Scheme 2) through
preparation of asymmetric amino-TB 9, troegeration of which
gave trisTB 3 in 74% yield as a mixture of all the possible
diastereoisomers in overall yields of: 14.3% anti,anti-3, 3.1%
anti,syn-3, and 0.6% syn,syn-3. TrisTB
3 was formed
regioselectively, i.e., formation of no other isomers was
observed. The structures of the diastereoisomers were identified
via detailed analyses of NMR spectra supported by quantum
chemical calculations, and confirmed by X-ray diffraction
analyses of anti,syn-3 and syn,syn-3.

3
Figure 2. Single-crystal structure of racemic anti,syn-3: a)
without solvent molecules; b) a view of the crystal packing
along the x axis showing acetonitrile and water (the hydrogen
atoms of the water molecules were not localised); c) a top
view of the interacting naphthalene parts of the two
molecules.
Figure 3. Structure of racemic syn,syn-3, as determined by
X-ray diffraction analysis: a) front and b) side views without
solvent molecules; c) view of the crystal packing along the y
axis showing disordered CH2Cl2 molecules. The helicity
descriptors P and M indicate the absolute configurations; (P)-
syn,syn-3  (1R,6S,18S,23R,28S,40S)-syn,syn-3, (M)-
syn,syn-3  (1S,6R,18R,23S,28R,40R)-syn,syn-3.
The single-crystal X-ray diffraction analysis of racemic
syn,syn-3 (CCDC 832258) shows the molecular clip shape and
helical character of this molecule (Figure 3). The crystal packing
indicates formation of homochiral double channels filled with
heavily disordered solvent molecules; a similar packing mode
was observed in both molecular clips syn,syn-2b9 and
methanoanthracene.11
To increase the yield of syn,syn-3, acid-catalysed
isomerisation of the major diastereoisomers was conducted. It
was found that trisTB 3 was stable in TFA at 70 °C (at least for
16 h), and slowly isomerises at 130 °C to reach an equilibrium
ratio 63:29:8 (anti,anti-3 : anti,syn-3 : syn,syn-3) in 2 days, which
is, unfortunately, not far from the ratio reached in the stepwise
preparation (79:17:4, TFA, rt). Furthermore, the addition of up to
3000 equivalents of nitrobenzene had a negligible effect.
Fortunately, we observed a high yield of the desired syn,syn-3
by isomerisation in TFA with the addition of hydrochloric acid
(1:1). The isomerisation takes place readily at 60 °C, reaching an
equilibrium ratio of 12:41:47 in approximately 16 hours.
In contrast to trisTB 2b, the high stability of trisTB 3 is
surprising because trisTB 3 has no moieties in the ortho
positions, which are known to hinder TBU isomerisation.9,12 The
following observations in TFA demonstrate that the nature of the
side arene also plays a crucial role. 4-Methoxybenzene bisTB
10a reached an equilibrium in TFA within one hour at rt,
fluorene bisTB 10b required a couple of hours at rt, while both
naphthalene bisTB 10c and anthracene bisTB 10d required
several days at 60 °C (Figure 4).

4
OCH3
CH3O
10a
syn,anti-3 or anti,anti-3 was approximately 50% less. The
N
N
N
N
molecular model (B3LYP-D/6-31G**) of syn,syn-3•TCNB
showed that TCNB was entirely in the middle of the molecular
clip but not planar since the cyano groups were out of the
benzene plane. The binding constants of syn,syn-3 with both 1,4-
and 1,3-dicyanobenzenes are approximately only 6, but the CIS
values were similar to those measured for TCNB, suggesting the
binding mode was similar. The binding of 1,2-dicyanobenzene
was negligible.
N
N
N
N
10b
10c
Finally, HPLC [column Reprosil Chiral – NR (a Whelk O1
type)], which is efficient in resolving TB derivatives,17 was used
to separate the trisTB 3 diastereoisomers. On an analytical scale,
both symmetric anti,anti-3 and syn,syn-3 were resolved
regardless of the ratio of iPrOH : CH2Cl2 (2:8, 1:1, 8:2) used as
the mobile phase; each sample of pure diastereoisomer gave two
peaks of equal integral areas. Surprisingly, no resolution was
observed in the case of unsymmetrical anti,syn-3, which suggests
that this isomer behaves as an inner racemate.17
N
N
N
N
N
N
10d
N
N
Thanks to the excellent separation, syn,syn-trisTB 3 was
resolved on a preparative scale using the column (250  25 mm,
isocratic elution by iPrOH : CH2Cl2 8:2). The pure enantiomers
were characterised by optical rotation (OR). The less retained
Figure 4. bisTB derivatives used in isomerization studies.
An increase in the yield of the syn diastereoisomer by
isomerization in hydrochloric acid was observed previously in
the case of a methoxybenzene bisTB derivative, where the anti to
syn ratio of 64:36 was reached in TFA, and was 7:93 in neat
hydrochloric acid.13 Similarly, it was observed that a syn-bisTB
derivative was not formed by reaction in TFA, but was obtained
in 50% yield by isomerisation of the corresponding anti-bisTB
isomer in ethanol with hydrochloric acid.14 In addition, we
recently found that the equilibrium composition of parallel
tris-Tröger’s base diastereoisomers can be affected by other
acids. A 1:1 mixture of TFA with hydrochloric, hydrobromic, or
phosphoric acid gave 24%, 71%, or 76% more of the
syn,syn-diastereoisomer then in neat TFA, respectively.3
20
enantiomer (tR’ = 9.99 min) had a negative OR, []D = -16.1
deg.cm2.g-1, the more retained enantiomer (tR’ = 15.41 min) had a
positive OR, []D20 = +61.1 deg.cm2.g-1. Based on comparison of
the experimental and theoretical ECD (electronic circular
dichroism) spectra (Figure 5), the P configuration (Figure 3) can
be assigned to more retained enantiomer, P-(+)-syn,syn-3.
50
(+)-syn ,syn -3 ( tR' = 15.41 min )
40
30
Calculated spectrum
of (P)-syn ,syn -3
20
This evidence led us to assume that the anion plays an
important role in the isomerization, which can be explained by
the following deliberation. Since simple TB can be
diprotonated,15 an oligoTB derivative is expected to exist as an
equilibrium mixture of multi-protonated species in a strong acid
medium. Protonation of the nitrogen atoms will cause withdrawal
of the electron density from the arenes, and make them electron-
deficient, or even positively charged. Therefore, the anti
diastereoisomers would be preferred due to repulsion of the
charged arenes of the syn diastereoisomers. However, when a
suitable anion is present, the syn diastereoisomers can be more
stable due to tweezering (chelating) of the anion by the electron-
deficient arenes. In addition, when the conditions are sufficient to
10
l
[ nm ]
0
-10
-20
-30
-40
200
250
300
350
400
(-)-syn ,syn -3 ( tR' = 9.99 min )
Figure 5. Experimental ECD spectra of syn,syn-3 enantiomers
(1.64 mol.mL in CH2Cl2), and the calculated ECD spectrum
of (P)-syn,syn-3 (B3LYP/6-311+G**).
cause isomerization, the system becomes
a
dynamic
combinatorial library, i.e., the content of the species which forms
In conclusion, we have shown that a serial trisTB derivative
with naphthalene as the side arenes can be prepared as the
syn,syn diastereoisomer, and can be easily resolved into
a stable complex will increase.16
On the contrary, templating by the ammonium cation was
suggested as the origin of the higher yield of the syn,syn
diastereoisomer of trisTB 2b, when NH4Cl was added to the
reaction mixture.9 Based on the previous deliberation, that would
be possible for reactions with a low degree of protonation. In that
case, most arenes remain electron-rich, i.e., able to bind cations.
In addition, it should be emphasised that the reaction proceeded
under milder conditions than those required for isomerisation,
therefore, an intermediate should be templated.
enantiomers on
a chiral HPLC column. This compound
represents somewhat constricted and inherently chiral
a
molecular clip. The crystal structure revealed that the molecular
clips form a channel-like structure, thus the single-crystal can be
considered as a potentially nanoporous material. For the first
time, we have shown that the syn,syn diastereoisomer of a serial
trisTB derivative has a significant ability to bind electron-
deficient compounds, thus the serial syn,syn-trisTB derivatives
have potential as chiral molecular clips in molecular and
materials engineering.
The binding ability of trisTB 3 was examined via titration
1
experiments followed by H NMR spectroscopy. This revealed
In addition, we have demonstrated that the acid-catalysed
isomerisation of Tröger’s base derivatives depends considerably
on the nature of the arenes. Based on several indirect forms of
evidence we conclude that protonated oligoTBs can bind anions
significantly. Thus, the isomerisation of oligoTBs should be
perceived as a complex process, possessing the features of a
dynamic combinatorial library.
that syn,syn-3 binds 1,2,4,5-tetracyanobenzene (TCNB) with a
binding constant 36-times higher than those of syn,anti-3 or
anti,anti-3 (Ksyn,syn = 615 ± 68, Kanti,syn = 17 ± 2, Kanti,anti = 16 ± 2).
The complexation-induced shift (CIS) of TCNB by syn,syn-3 (3.9
ppm) is similar to the CIS obtained with the analogous
methanoanthracene molecular clip (4.7 ppm),11 while the CIS by

5
Acknowledgements
This work was supported by the Grant Agency of the Czech
Republic (203/08/1445).
Supplementary Material
Detailed information about the preparation of all compounds;
analyses of NMR spectra (and their copies) including an
assignment of the signals and quantum chemical calculation, the
binding studies, molecular modelling of the complex, analytical
enantioseparation of trisTB 3 diastereoisomers, preparative
enantioseparation of syn,syn-3 and ECD spectra and their
calculation, the crystallographic data on syn,anti-3 and syn,syn-3
are provided as a supplementary material. This material is
available free of charge via the Internet at ...
References and notes
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