calix-Tris-Troeger's bases - A new cavitand family

Article abstract of DOI:10.1039/b706791g

The first members of a new cavitand family, represented by calix-shaped tris Troeger's base diastereoisomers, are prepared via step-by-step synthesis as well as one-pot mixed troegeration. The Royal Society of Chemistry.

Full text of DOI:10.1039/b706791g

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calix-Tris-Tro¨ger’s bases – a new cavitand family{
a
Martin Val´ık, Jan Cejka, Martin Havl´ık, Vladim´ır Kra´l and Bohumil Dolensky´*
b
a
a
a
ˇ
Received (in Cambridge, UK) 4th May 2007, Accepted 29th June 2007
First published as an Advance Article on the web 25th July 2007
DOI: 10.1039/b706791g
e.g. in TFA) of hexaamines 4 resulted in the targeted trisTBs 1.
However we found that the troegeration of hexaamine 4a does not
produce the corresponding trisTB 1a, which is obviously due to the
para position to the amine group being free (R = H). This
corresponds with the fact that aniline TB derivatives give very low
or zero yields.6a,11 Fortunately when the position was blocked by a
suitable moiety the yield increased significantly.6c Thus the
troegeration of hexaamine 4b (R = Me) gave 8% preparative
The first members of a new cavitand family, represented by
calix-shaped tris Tro¨ger’s base diastereoisomers, are prepared
via step-by-step synthesis as well as one-pot mixed troegeration.
Tro¨ger’s base (TB, 2,8-dimethyl-6H,12H-5,11-methanodiben-
zo[b,f][1,5]diazocine) is a structural motif known to almost every
chemist. The compound was first described1 by Tro¨ger in 1887, its
structure correctly suggested by Spielman in 1935,2 and its
enantiomers first separated3 by Prelog in 1944. Since then TB
derivatives have become a touchstone of chiral separation
performance and a textbook example of chiral nitrogen. At the
end of the 20th century, TB derivatives, as was reviewed recently,4
were being used as building blocks for receptor preparations. The
21st century has brought more new dimensionality for TB
derivatives with the discovery of oligoTB; the finding that an
aromatic part of one TB can be an aromatic part of another TB.5–7
We have recently published that it is even possible to annelate all
three TB units (1,5-diazabicyclo[3.3.1]nonane) to a single benzene
ring (Scheme 1), thus creating a trisTB.6a TrisTB derivatives 1 can
form two diastereoisomers, the calix-like one (calix-trisTB, Fig. 1
and 2) and the throne-like one (throne-trisTB, Fig. 3 and 4). Up
until now calix-trisTB has never been isolated or observed by
spectroscopy, steric hindrance being the unwritten reason.
However we found that calix-trisTB can be obtained by the
isomerization of throne-trisTB under acidic conditions, and
isolated as a stable compound after fast alkalization. This finding
makes the trisTB derivatives 1 unique cavitands, differing from
known cavitands (e.g. calixarenes, cyclodextrins, resorcinarenes,
cyclotriveratrylene, cucurbiturils etc.)8,9 in their ability to switch
from calix to throne isomers in acidic pH. Additionally, Lenev et al.
have recently shown10 than the ‘‘conformational’’ stability of TB
derivatives under acidic conditions can be set-up by suitable
substituents, which could be a very useful function for drug
delivery systems.
TrisTBs 1 were prepared according to the four-step amide
protocol (Scheme 1).6a The acylation of 1,3,5-triaminobenzene by
chlorides of 2-nitrobenzoic acids produced nitroamides 2. Then
catalytic reduction of the nitro groups of 2 produced aminoamides
3, which were reduced by LiAlH4 to their corresponding
hexaamines 4. The final troegeration (treatment with formalde-
hyde equivalent, e.g. paraformaldehyde, under acidic conditions,
aITC Prague, Department of Analytical Chemistry, Technicka´ 5, 16628,
Praha, Czech Republic. E-mail: dolenskb@vscht.cz;
Fax: (+420) 2 2044 4352; Tel: (+420) 2 2044 4067
bITC Prague, Department of Solid State Chemistry, Technicka´ 5, 16628,
Praha, Czech Republic. E-mail: jan.cejka@vscht.cz;
Tel: (+420) 2 2044 4200
Scheme 1 Preparation of trisTB. Reagents and conditions: (a) pyridine,
12 h, RT; (b) H2, Pd/C; (c) LiAlH4; (d) (CH2O)n, TFA, 1a (0%), 1b (8%,
overall 3%), 1c (18%, overall 6%).
{ Electronic supplementary information (ESI) available: Experimental
details, characterization of presented compounds, and detailed description
of cavity volume calculation. See DOI: 10.1039/b706791g
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3835–3837 | 3835

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Fig. 4 Spacial arrangement of two enantiomeric molecules of throne-1c
forming a nano-capsule containing two acetone molecules.
Fig. 1 ORTEP style plot of compound calix-1c. Thermal ellipsoids are
drawn at 50% probability level.
yield (3% overall yield) of the expected trisTB 1b, and the
troegeration of hexaamine 4c (R = OMe) produced 18%
preparative yield (6% overall yield) of the corresponding trisTB
1c. The low yields of the troegerations should be tolerated,
because, in total, 12 new bonds are formed in one reaction step,
which means that ‘‘yield per bond formed’’ is higher than 80%.
In addition, we have recently published6b our success with oligo-
troegeration, the mixed troegeration of amine and diamine, which
resulted in the corresponding oligoTB derivatives. Therefore we
tried one-pot preparation of trisTB 1b by the mixed troegeration of
1,3,5-triaminobenzene and p-toluidine (TFA, paraformaldehyde,
60 uC, overnight). The expected trisTB 1b was formed and isolated
in 2% yield. The fact that, in this case, 18 new bonds are formed in
one reaction step makes the yield excellent (80% yield per bond
formed). However, the preparation of trisTB 1c by this one-pot
arrangement failed.
Fig. 2 Part of calix-1c crystal packing showing intertwining of two
enantiomeric molecules, and CH2Cl2 position.
In both the trisTB 1b and trisTB 1c preparations only the
throne-like diastereoisomers were isolated, which is probably due
to the very low yields of the calix-like diastereoisomers. When the
throne-1b or throne-1c was treated in TFA, diastereoisomerisation
took place even at room temperature, within a few minutes. In
both cases (1b and 1c), the ratio of throne-trisTB to calix-trisTB at
equilibrium was 97 : 3. The calix-like diastereoisomers calix-1b and
calix-1c were isolated by chromatography, and fully identified. In
the case of trisTB 1c, single crystals of both diastereoisomers were
obtained, X-ray diffraction confirming their structures.{ Our calix-
1c (Fig. 1) and throne-1c (Fig. 3) are the first examples of X-ray
data for trisTB derivatives.
X-Ray structure determination proved that calix-1c is racemic
and cavity shaped. Probably the first thing to consider concerning
a new cavitand molecule is its volume. Unfortunately general rules
for the calculation of cavity volume do not exist, therefore, to have
some idea, we estimated the volume from the X-ray atom
coordinates. The volume of the cavity was approximated from the
truncated cone, wherein the lower rim is defined by the circle
intersecting the nitrogen atoms (d1 = 0.65 nm), and the upper rim
is defined by the circle intersecting the oxygen atoms (d2
=
0.98 nm), and the depth defined as the distance between the
oxygen atoms’ centroid and the nitrogen atoms’ centroid (h =
0.55 nm). With the measurements reduced using van der Waals
diameters, the calculated volume was approximately 0.078 nm3,
which means that the volume of the calix-1c cavity was around
Fig. 3 ORTEP style plot of compound throne-1c. Thermal ellipsoids are
drawn at 50% probability level.
3836 | Chem. Commun., 2007, 3835–3837
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44% of an a-cyclodextrin cavity9 (0.174 nm3). The cavity’s
potential to bind is demonstrated by the crystal packing (Fig. 2),
in which two molecules are intertwined with each other; one
methoxy group of one molecule being inside the cavity of the
second molecule, and vice versa. Conversely, the crystal methylene
chloride is outside the cavity, wherein its hydrogen is bound to the
center of the central benzene unit.
Notes and references
{ CCDC 640697 and 640698. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b706791g
1 J. Tro¨ger, J. Prakt. Chem., 1887, 36, 225.
2 M. A. Spielman, J. Am. Chem. Soc., 1935, 57, 583.
3 V. Prelog and P. Wieland, Helv. Chim. Acta, 1944, 27, 1127.
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1st edn, 1999, vol. 11, pp. 1–20; (b) M. Val´ık, R. M. Strongin and
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As in the case of calix-1c, the X-ray structure of throne-1c
displayed both enantiomers. Single-crystal packing showed that
two molecules formed a cavity consisting of two acetone molecules
(Fig. 4). The volume of this cavity was estimated using a cuboid
(1.10 6 0.91 6 1.06 nm), which, after correction with a van der
Waals diameter (0.16 nm), gave a cavity volume of approximately
0.63 nm3.
In summary, we herein present the first members of a new
cavitand family, the inherently chiral and calix-like oligoTB
derivatives. They are destined to become building blocks for the
construction of molecular reactors and capsules. In addition, the
ability of the TB unit to isomerize under acidic conditions means
that calix-oligoTB derivatives offer potential extra functionality,
e.g. for drug delivery systems. The cavity of the presented trisTB
derivatives, the smallest member of this cavitand family, is suitable,
e.g. for methoxy group inclusion as was observed in the solid state
(Fig. 2). Finally, we have demonstrated the new three-component
condensation reaction, which leads to formation of 18 new bonds
at once. Our future research will target calix-oligoTB derivatives
with deeper sidewalls and larger cavities, in particular focusing on
the implementation of the central-reagent approach we recently
developed for the preparation of bisTB derivatives.6e
ˇ ˇ
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This work was supported by the Ministry of Education of the
Czech Republic (MSM 6046137307 and LC06077), the Grant
Agency of Czech Republic (203/03/D049), and EU grant CIDNA
NMP4-CT-2003-505669.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3835–3837 | 3837