Facile acetal dynamic combinatorial library

Article abstract of DOI:10.1039/b800384j

We herein report our first results on the use of simple acetalation chemistry in the service of dynamic combinatorial libraries (DCLs); the reaction between triethylene glycol and 4-nitrobenzaldehyde afforded a DCL of more than 15 cyclic and acyclic species; all of which were separated and characterized; the smaller macrocyclic compounds were successfully amplified by the use of ammonium ions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800384j

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COMMUNICATION
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Facile acetal dynamic combinatorial librarywz
Dvora Berkovich-Berger and N. Gabriel Lemcoff*
Received (in Cambridge, UK) 10th January 2008, Accepted 25th January 2008
First published as an Advance Article on the web 7th February 2008
DOI: 10.1039/b800384j
We herein report our first results on the use of simple acetalation
chemistry in the service of dynamic combinatorial libraries
(DCLs); the reaction between triethylene glycol and 4-nitro-
benzaldehyde afforded a DCL of more than 15 cyclic and acyclic
species; all of which were separated and characterized; the
smaller macrocyclic compounds were successfully amplified by
the use of ammonium ions.
reversible reaction can be used in the same library,3 and also
that the number of components in a DCL can be vast, for
example, Miller and co-workers recently reported a library
containing more than 10 000 molecules, the largest DCL to
date.4
The acid-catalyzed reaction between carbonyls and alcohols
to give acetals is a classical and much studied reaction with
several synthetic applications,5 although somewhat secluded
to the protective group role. Rapid equilibrium, accessible and
inexpensive reagents and well-known methodologies make it
an extremely good candidate for creating DCLs. Furthermore,
‘‘freezing’’ a dynamic library of acetals is readily achieved by
addition of base and neutralization of the acid catalyst. None-
theless, the detrimental lability of acetals and the formation of
water during the equilibration period present a challenging
problem when creating an acetal DCL. Perhaps because of this
there are but a few reports in the literature for the use of this
type of simple bonding in DCLs. Up to date, only two
examples of cyclic acetal DCLs are known. The first was put
forward by Fuchs, Stoddart and co-workers and produced
chiral polyethers based on threitol6 while the second example
was a DCL of cyclophane Ag+ receptors equilibrated by
means of acid-catalyzed transacetalation of formaldehyde
acetals by the Mandolini group.7 To the best of our knowl-
edge, there are no examples in the literature for the creation of
acetal DCLs by straightforward combination of aldehydes and
alcohols.
At the basis of any recognition process we usually come across
well defined, preassembled cavities of the right dimensions and
shapes, i.e., the lock-and-key principle. Small structural
changes between the free and complexed host brings about
small entropic changes that may, in consequence, produce a
more stable assembly. Many key processes in chemical and
biological mechanisms are based on this principle and have
major consequences on the reaction outcome. Thus, finding
the precise host for the specific guest has significant implica-
tions and much effort has been directed towards this area of
research. A dynamic combinatorial chemistry1 provides a
useful mechanism for the search of the right supramolecular
assembly. Reversible bonding of the initial building blocks,
and the consequent complex equilibria which are established,
form the dynamic library components. The DCLs thus formed
are an attractive tool for screening molecules with molecular
recognition properties and amplifying them. The increase of
the concentration of selected species in response to the intro-
duction of a template is commonly referred to as ‘‘amplifica-
tion’’ (Scheme 1).
Thus, commercially available triethylene glycol and 4-nitro-
benzaldehyde were employed to generate an acetal dynamic
library that could theoretically contain both oligomers and
macrocycles (denoted On and Mm, respectively) using sulfuric
acid as the catalyst (Scheme 2). The presence of hemiacetal
species was discounted due to the lower stability of the
hemiacetal function.
Dynamic combinatorial chemistry has been applied success-
fully in the development of synthetic receptors and has proven
to be a practical method that not only allows the identification
of new host molecules but also provides a facile synthetic route
towards these sometimes complex molecules. Fitting examples
are the macrocyclic receptors produced by hydrazone ex-
change,2 such as the [2]-catenane isolated by Sanders, Otto
and co-workers,2e an extremely complex receptor with a
remarkable affinity and selectivity for acetylcholine. These
results highlight the power of the DCL strategy by effectively
amplifying an unpredictable candidate as a very strong recep-
tor for a biologically active compound. DCLs are also very
versatile. It has been shown, for instance, that more than one
Electron-poor aromatic aldehydes were chosen as starting
materials because of their inherent propensity to form stable
Department of Chemistry, Ben-Gurion University of the Negev, P.O.
Box 653, Beer-Sheva, 84105, Israel. E-mail: lemcoff@bgu.ac.il; Fax:
(+97)-8-6461740; Tel: (+97)-8-6461196
w CCDC 661726 and 674793. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b800384j
Scheme 1 Illustration of amplification in a dynamic combinatorial
library upon external addition of a specific template to an equilibrated
mixture.
z Electronic supplementary information (ESI) available: Characteri-
zation and experimental details. See DOI: 10.1039/b800384j
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Scheme 2 A DCL built by acetalation of p-nitrobenzaldehyde using
triethyleneglycol. O1 is the 2 + 1 oligomer and M1 is the 1 + 1
macrocycle (smallest possible members).
acetals. The effect of electron-withdrawing groups on aromatic
acetals has been covered in the relevant literature and it has
been shown that the destabilization of the benzylic carbo-
cation hinders acetal hydrolysis.8–11 Triethyleneglycol was
selected as the alcohol counterpart since the smallest cyclic
member of such a library would contain an 11-membered ring,
a thermodynamically disfavored moiety, diminishing the for-
mation of an entropically favored 1 : 1 cyclic compound (M1).
Additionally the macrocycles formed by ethylene glycol oligo-
mers have the advantage of mimicking crown ethers and their
cation complexation ability,12 an advantageous property when
designing host compounds.
Fig. 2 1H NMR spectra (acetal region) of the library mixture after
separation by preparative HPLC.
To generate the library, the mixture was refluxed in toluene
with a catalytic amount of sulfuric acid under azeotropic
distillation conditions. After 20 h the library was fully equili-
brated and 70% of the aldehyde had been converted into
subgroup we exposed an acetalic oligomer to library equili-
bration conditions. Accordingly, a fraction taken from pre-
parative HPLC containing 13 mg of the O6 oligomer was
heated in deuterated toluene for 48 h with sulfuric acid as
catalyst. NMR and MALDI-TOF analysis before and after
the addition of catalyst show the regeneration of the library,
albeit not exactly the same library was obtained due to the
different stoichiometry of starting materials (see ESIz).
Finally the effect of organic cations as possible amplification
templates was tested. Several ammonium ions were used to test
the generality of the effect: dibenzyl ammonium hexafluoro-
phosphate (DBAPF6), tetrabutyl ammonium iodide (TBAI);
tetraoctylammonium bromide (TOAB) and paraquat (DMV).
After reaching equilibrium a 25 molar percent of ammonium
ion template was added to the library mixture. Samples were
taken 24 h and 3 days after the salt addition. To our satisfac-
tion, significant changes in concentrations were observed. For
most templates used an amplification of the macrocycles M1,
M2 and M3 were detected at the expense of other library
members (see ESIw). For DBAPF6 M1 was amplified about
10-fold and M2 was augmented 2.5-fold. Table 1 and Fig. 3
display the results obtained for DBAPF6. The amplification of
the macrocycles provided a larger amount of compounds M1
and M2 which were readily crystallized and their structures
solvedy (Fig. 3, right side insets).
1
acetals (according to H NMR analysis). A series of distinct
acetal peaks were observed (Fig. 1) indicating that several
acetalic compounds were obtained. The library was then
quenched by the addition of potassium carbonate and the
mixture separated by preparative HPLC. Most gratifyingly,
we were able to separate and fully characterize the complex
mixture that contained more than 15 library members; both
cyclic and acyclic. The different fractions were analyzed both
by MALDI-TOF (see ESIz) and 1H NMR as shown in Fig. 2.
As one of the main attributes of dynamic combinatorial
libraries is the ability to regenerate a full library out of a small
The association constant for DBAPF6 with M2 was calcu-
lated by NMR titration to be about 2 ꢁ 102 Mꢂ1 (see ESIz) in
accordance to similar complexes of crown ether analogs with
quaternary ammonium ions shown in the literature.13 No shift
of the benzyl signal could be observed when DBAPF6 was
titrated with O2.
Fig. 1 1H NMR of p-nitrobenzaldehyde and triethyleneglycol DCL.
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Table 1 Several library members before and after amplification by DBAPF6
Library member
HPLC tR/min
% in equilibrated librarya
% after 24 h templation
% after 3 days templation
O1
M1
O5
M2
O6
M3
O7
M4
O9
a
3
14.7
5.6
2.6
2.0
5.4
1.6
2.1
0.8
0.15
2.1
51.9
0.7
5.6
1.3
1.05
0.2
0.5
0.1
1.5
56.4
0.5
4.35
2.1
0.65
0.36
0.5
4.3
5.15
5.3
6.4
7.2
8.2
9.6
14.5
0.2
Due to a B6-fold absorbance coefficient of 4-nitrobenzaldehyde over acetal derivatives, calculations were done by combining integrals of peaks
both in the full HPLC chromatograms and NMR spectra of the fractions that contained all the 4-nitrobenzaldehyde.
Notes and references
y Crystal data: M1 structure: C13H17NO6, M = 283.28, orthorhombic,
space group Pbca, a = 15.714(3), b = 8.2622(15), c = 20.989(4) A,
V = 2725.1(9) A3, Z = 8, 14 250 reflections measured, 2704 unique
(Rint = 0.060), from which 1288 were used in the calculations. The
final R was 0.0484. M2 structure: C26H34N2O12, M = 566.55, triclinic,
ꢀ
space group P1, a = 7.166(3), b = 7.306(3), c = 13.515(6) A, V =
687.7(5) A, Z = 1, 4010 reflections measured, 2721 unique (Rint =
0.025), from which 2047 were used in the calculations. The final R was
0.0728.
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Fig. 3 Preparative HPLC of the library before (top) and after
amplification by DBAPF6 template (bottom). The X-ray structures
of M1 and M2 are shown on the right side insets.
In conclusion we have shown that the simple reaction
between alcohols and aldehydes is fitting for creating dynamic
combinatorial libraries and may be used as the structural
framework for this type of assemblies. A new acetal dynamic
combinatorial library was thus established and analyzed. The
library at equilibrium is composed of at least 15 members,
either oligomers or macrocycles, as shown by NMR and mass
spectra. The dynamic nature of the DCL was demonstrated by
re-equilibration of a single library member to regenerate a full
library. Furthermore, the anticipated association and amplifi-
cation of macrocycles was detected by the addition of
ammonium ions, as expected for crown ether analogues.
The simplicity of acetalation reactions paves the way for an
extensive use of this method in the creation of novel dynamic
combinatorial libraries. We are currently working on raising
the degree of complexity of the acetal libraries by using tri- and
tetrafunctional starting materials (alcohols and aldehydes),
and also by the introduction of additional recognition func-
tions orthogonal to the acetal equilibrium conditions.
We thank Dr Mark Sigalov for technical assistance in the
NMR titrations. This research was partially supported by the
Israel Science Foundation (227/05).
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This journal is The Royal Society of Chemistry 2008
1688 | Chem. Commun., 2008, 1686–1688