Toward dynamic combinatorial libraries of cryptands

Article abstract of DOI:10.1016/j.tetlet.2011.06.075

The first examples of dynamic combinatorial libraries of cryptands, created using the chemistry of imines is presented. Experiments, in which two trialdehydes compete for one triamine in a small library, show the full reversibility of cryptand formation,

Full text of DOI:10.1016/j.tetlet.2011.06.075

Tetrahedron Letters 52 (2011) 4452–4455
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward dynamic combinatorial libraries of cryptands
Krzysztof Ziach a, Magdalena Ceborska a, Janusz Jurczak a,b,
⇑
a Department of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 March 2011
Revised 9 June 2011
Accepted 17 June 2011
Available online 25 June 2011
The first examples of dynamic combinatorial libraries of cryptands, created using the chemistry of imines
is presented. Experiments, in which two trialdehydes compete for one triamine in a small library, show
the full reversibility of cryptand formation, since the library composition is the same irrespective of the
sequence of introducing the building blocks to the mixture.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Dynamic combinatorial chemistry
Dynamic combinatorial libraries
Cryptands
Imines
Since their first synthesis by Lehn and co-workers,1,2 bicyclic
cryptands are a center of interest in supramolecular chemistry.3,4
They are widely known for their complexing properties, especially
toward organic and inorganic cations,5 although there are exam-
ples of the binding of anions4 and neutral molecules.6 Cryptands
are prepared using various types of reactions, including amida-
tion,7,8 amine alkylation,9 quaternization/demethylation,10,11 Man-
nich12 reactions, and ring-closing metathesis.13 Following the work
of Lehn and co-workers,14 one of the most convenient reactions for
their synthesis is imination.15–17 We believe that a particular
strongpoint of Schiff base formation (among other possible chem-
istries) lies in its reversibility that can combine cryptand-type
receptors into dynamic combinatorial chemistry (DCC).18,19 The
major benefit will be the information about cryptand–guest inter-
actions that can be derived from amplification in template-direc-
ted libraries under thermodynamic equilibrium. However, the
imination reaction, when used to prepare macrobicyclic molecules,
has some difficulties that need to be overcome to fulfill the DCC
requirements and allow for ease of operation. These are, for exam-
ple, low cryptand solubility,20 a tendency to polymerization21 and,
frequently, the necessity of applying high dilution conditions and a
properly chosen solvent.22
tripodal aldehydes (3a–d, Scheme 1) and a tripodal amine tris(2-
aminoethyl)amine (TREN, 4) were chosen.
Synthesis of tripodal aldehydes: The tripodal aldehydes 3, used in
this project as carbonyl substrates for the imination reaction, were
prepared from tris(2-chloroethyl)amine (1) and the corresponding
hydroxybenzaldehyde 2 in the presence of NaOH as reported by
Bharadwaj et al. (Scheme 1).23–25 We faced severe problems in
reproducing the original procedure in which boiling ethanol or
n-propanol was used as the solvent. ESI-MS showed that, under
the strongly basic conditions, by-products were formed in the reac-
tion between tris(2-chloroethyl)amine and the alkoxylate anions,
decreasing the yield of the tripodal aldehydes and making their
isolation difficult. We found that changing the protic solvent to
an aprotic one (DMF) greatly facilitated the purification process
and afforded the desired aldehydes in good yields.
Synthesis of cryptands: The syntheses of cryptands by the reac-
tions of trialdehydes with the general formula 3 with tris(2-amino-
ethyl)amine (TREN) were presented by Bharadwaj et al.25,26 The
reactions were carried out in a THF/MeOH solution, either under
high dilution at 5 °C or in the presence of cesium cations and pro-
vided the desired [1+1] bicyclic products. However, when the reac-
tion was carried out under high concentration, tricyclic or
oligomeric products were formed.21 Our first aim was to adjust
the imination reaction conditions to meet DCC requirements,
mainly by eliminating the necessity of using a specific Cs+ salt, to
give freedom of choice of the templates for future experiments.
We found that reactions conducted in methylene chloride as a sol-
vent enabled formation of all the imine cryptands (Scheme 2).
Moreover, neither a lower temperature nor high dilution condi-
tions were needed for a successful double cyclization process in
CH2Cl2 that significantly simplified the original procedure and
Our goal was to find simple and practical protocols that can be
used to create libraries of macrobicyclic imines. We first focused
our attention on the verification of the reversibility of the imina-
tion reaction, necessary to assure unbiased thermodynamic control
over the whole system. As library building blocks, four aromatic
⇑
Corresponding author. Fax: +48 22 8230944.
E-mail addresses: jurczak@icho.edu.pl, jjurczak@chem.uw.edu.pl (J. Jurczak).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.06.075

K. Ziach et al. / Tetrahedron Letters 52 (2011) 4452–4455
4453
(o)
X
CHO
CHO
(p)
O
Cl
(o)
CHO
(o)
X
OH
+
N
O
(p)
N
Cl
Cl
(p)
O
X
X
(p)
1
2
X = H, CH3, Br
CHO
(o)
3
Br
O
O
O
O
Br
O
O
O
O
O
O
N
O
O
O
N
N
O
O
N
O
O
O
O
O
O
O
O
O
Br
3'o' (78%)
3'p' (88%)
3'Me' (62%)
3'Br' (36%)
Scheme 1.
N
O
N
O
O
O
O
O
O
O
H2N
CH2Cl2
O
OH
NaBH4
MeOH
NaBH4
MeOH
H2N
N
+
N
O
N
O
O
H2N
OH
OH
O
HN
N
O
N
O
HN
NH
N
N
N
7'p'
3'p'
4
5'p'
6'p' (74%)
N
O
N
O
N
O
O
O
O
O
O
O
Br
Br
Br
NH
NH
HN
HN
NH
HN
NH
N
NH
N
NH
N
6'Me' (72%)
6'Br' (75%)
6'o' (65%)
Scheme 2.
allowed easy creation of dynamic combinatorial libraries of crypt-
ands. In particular, all reactions, except for 4+30p0, maintained
homogeneity. The bicyclic imines 5 were reduced in situ to the cor-
responding amines 6 (Scheme 2) by NaBH4 with addition of MeOH
to facilitate the reduction.27 The overall yields were similar or bet-
ter than those reported in the literature (60o0: 65% vs 65–70%,26
60p0: 74% vs 36–45%28) and proved the preference of the substrates
for the double cyclization reaction. Altering the ratio of substrates
did not improve the yields of the cryptands. When excesses of the
aldehydes 5 were used, the corresponding alcohols 7 were ob-
served after reduction (NMR), although without any significant
decrease in the amount of cryptands. This proved the general ten-
dency of the substrates to undergo the double cyclization reac-
tions, even under non-stoichiometric conditions and opened up
the possibility to investigate competition in ‘many aldehydes—
one amine’ libraries.
Dynamic combinatorial libraries of cryptands: The main goal of
our research was to form libraries of cryptands and to study their
behavior. The libraries were formed by mixing two tripodal alde-
hydes and TREN (4) (1:1:1) in a competitive mode (Scheme 3). Un-
der such a protocol, the ratio of the cryptands at equilibrium
represents their relative stability. Half of the carbonyl reagents

4454
K. Ziach et al. / Tetrahedron Letters 52 (2011) 4452–4455
N
O
N
O
N
O
O
O
O
O
O
O
+
+
OH
HO
O
NH
HN
O
O
OH
NH
N
H2N
H2N
1. CH2Cl2
3'o' (1 equiv.)
6'o'
7'o'
H2N
N
+
2. NaBH4, MeOH
4 (1 equiv.)
N
O
N
O
N
O
+
O
O
O
O
O
O
Br
Br
Br
Br
Br
Br
Br
OH
HO
NH
Br
HN
O
O
O
OH
NH
N
6'Br'
7'Br'
3'Br' (1 equiv.)
Scheme 3.
‘by definition’ cannot form imines and, in turn, is converted into
corresponding triols in the reduction step. The ratio of alcohols
should be opposite to the ratio of cryptands.
governed by thermodynamics, the final state should not depend
on addition sequence. Thus, a 4+30o0 library was created and, after
equilibration and formation of the cryptand 50o0, the aldehyde 30Br0
was added and the mixture left for equilibration. After reduction
with NaBH4, the 1H NMR spectrum was almost identical to the pre-
viously described ones, revealing alcohols 70o0 and 70Br0 in an
approximately 4:1 ratio, and cryptands 60Br0 to 60o0 in an approxi-
mately 1:3.5 ratio (Fig. 1b). Similarly, the 4+30Br0 library was pre-
pared, equilibrated, and ‘doped’ with the aldehyde 30o0 to
compete with the initially formed cryptand 50Br0. Again, the com-
position of the library changed and, after reduction, both the crypt-
and 60Br0 and the alcohol 70o0 were observed as main products
(Fig. 1c).
The NMR analysis, due to the peaks overlapping and bias from
side-products (other library members), did not allow precise deter-
mination of the ratio of the cryptands. However, the spectral data
for the triols and cryptands gave a consistent picture and demon-
strated the same composition of libraries, independently of the se-
quence in which the aldehydes were introduced to the reaction
mixture, which proved the reversibility of the imination reaction
and thus the possibility of the application in the DCC of cryptands.
Similar experiments, utilizing simultaneous mixing of sub-
strates and ‘cryptand doping’ with a competing aldehyde, were
performed using 30p0 and 30Br0 and TREN. In this case, however,
equilibrium is strongly shifted toward the cryptand 50Br0, since
We followed previous experiments and analyzed the composi-
tion of the ‘crude’ libraries ‘frozen’ by means of NaBH4 reduction.
We decided to sacrifice precision of measurement to benefit from
1H NMR robustness and ease of operation in these early experi-
ments. Since in their 1H NMR spectra most of cryptand signals
overlap, and the CH2OH resonances of the corresponding alcohols
(d (ppm) = 4.52 for 70o0; 4.58 for 70p0; 4.45 for 70Br0) are better re-
solved for the selected pairs of substrates, we used these signals
for an indirect analysis of the compositions of the libraries.
The library built from TREN, 30o0 and 30Br0 gave the best resolu-
tion. In the first experiments involving these reagents, all the sub-
strates were mixed simultaneously in CH2Cl2 and left to equilibrate
for 2 days, then reduced and subjected to 1H NMR analysis. The
alcohol resonances showed a significant domination of 70o0 over
70Br0 in an approximately 4:1 ratio (Fig. 1a). On this basis, we
assumed that the cryptand ratio should be the opposite, giving
approximately 1:4 for 60Br0:60o0. This was actually supported by
the Ar–CH2–N cryptand resonances, that were partially resolved
[d (ppm) = 3.73 (60o0); 3.66 (60Br0)] for this pair of substrates and
roughly estimated to be 1:3.5. This proved that a library had
indeed been formed. In the next experiments, the reversibility of
formation of imine cryptands was investigated. If the system is
a
b
c
4.6
4.5
4.4
3.7
3.6
4.6
4.5
4.4
3.7
3.6
4.6
4.5
4.4
3.7
3.6
1
Figure 1. H NMR spectra of the (30o0+30Br0+4) libraries after NaBH4 reduction. (a) All substrates were mixed simultaneously, (b) 30Br0 was added to the equilibrated (30o0+4)
library and left to equilibrate, (c) 30o0 was added to the equilibrated (30Br0+4) library and left to equilibrate.

K. Ziach et al. / Tetrahedron Letters 52 (2011) 4452–4455
4455
no resonance of Ar–CH2–N from cryptand 60p0 was found in the
spectra. Accordingly, no 70Br0 Ar–CH2–OH resonances were pres-
ent. This experiment showed that, at least in certain cases, the
low solubility of a library member is not necessarily the limiting
factor. The cryptand 50p0 precipitated from the CH2Cl2 solution,
but after addition of the aldehyde 30Br0, the solution clarified again
since 50p0 was redissolved and hydrolyzed, serving as a source of
the amine 4 to build the more stable cryptand 50Br0 and well as
the soluble aldehyde 30p0.
This NMR methodology was applied to other combinations of
aldehydes 3 and TREN 4, but peak broadening and overlapping
did not allow even a semi-qualitative analysis. Presumably, a
whole group of aldehydes and amines can be used and the size
of the libraries can be easily extended, although a reliable analyti-
cal technique is needed for quantitative determination of the ratio
of the library members. An HPLC methodology is now under
development.
days for equilibration. The reduction and further workup were per-
formed according to the general procedure used for the synthesis
of cryptands. NaBH4 was used in 2 M excess (in respect to the
sum of trialdehydes). The crude mixture of products was subjected
to 1H NMR analysis.
Supplementary data
Supplementary data (general procedures, procedure for the
preparation of tripodal aldehydes 3, and spectral data (1H NMR,
13C NMR, HRMS) for all new compounds (aldehydes 30Me0, 30Br0;
cryptand 60Me0, 60Br0 and alcohols 70o0, 70p0, 70Br0) and 1H NMR
for cryptands 60o0, 60p0) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.06.075.
References and notes
In this communication, we present the first examples of
dynamic combinatorial libraries of cryptands, created using
controlled and reversible imine formation. We have developed a
convenient procedure that fulfilled the DCC requirements, assuring
true reversibility of cryptand formation. The imination reaction
takes place under ambient conditions and requires neither addi-
tion of templates, low temperature, nor high dilution conditions.
This makes it also a convenient way of preparing cryptands on a
large scale. The imines obtained were then converted into the cor-
responding amines applying a fast reduction protocol.27 An HPLC
methodology that allows dealing with larger libraries and templa-
tion experiments are currently under development.
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resulting mixture was stirred at rt for 48 h in a closed flask. Then it
was diluted with 5 ml of methanol and, immediately, NaBH4
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