A similar behaviour was reported169 by Philp and Comina in a mixture of
bis(borazaaromatic) compounds 14 that undergo reversible dehydration to form linear or cyclic oligomers (Figure 20). Upon addition of 4Å molecular sieves the slow process of dehydration was monitored by MALDI-TOF mass spectrometry. Not surprisingly initially the linear and cyclic dimers are the predominant species in the mixture. As the dehydration progresses higher oligomers can be observed, but after 4 days the higher molecular weight species diminish, to leave exclusively the cyclic dimer 15 in solution after 12 days. The predisposition of the specific structure to assemble exclusively into dimers is a good example of achieving selectivity in a dynamic mixture without using a template.
13
N B - H OH O N B- H OH N B- H O N B- H N B- H O O B-N H O +2 H2O -2 H2O
Figure 20. Exclusive formation of cyclic dimer 15 upon slow dehydration of a bis(boraza aromatic) compound 14.
Introducing a guest template into a dynamic library of potential receptors will result in a distribution favouring the structure that is most thermodynamically stabilised by the specific template. In other words the subunits will assemble themselves around the template automatically adopting the best combination at a highest concentration. Such process is described170
as molding when the target substrate is used as an
exo-receptor. Casting, on the other hand, utilises a target receptor to direct the assembly of the optimal substrate from the library using the target as an endo- receptor (Figure 21).
Figure 21. Assembling of a structure from DCL components upon addition of a receptor either by molding or casting.
Otto and Kubik presented171 one of the examples of optimising a neutral receptor that
binds inorganic ions. A sandwich type complex of an ion such as a halide or a sulfate and two cyclic hexapeptides was reported. If two of the cyclopeptides were to be linked by a covalent bond the complex would be even more stable. The problem was choosing the proper linker. A dynamic combinatorial approach using reversible disulfide chemistry was chosen to solve this issue (Figure 22). A range of dithiol derivative spacers 17-22 with different lengths and geometries were used to form a dynamic library of potential receptors with a compound where two peptide rings were linked by a simple disulfide bond 16. The addition of an anionic guest amplified the host with the highest affinity.
14
Figure 22. Design of a DCL for the optimisation of an ion receptor. An array of disulfide linkers 17-22
formed structures with two peptide macrocycles. The addition of an ionic guest (grey sphere) selected the most stable sandwich-type complex.
Imines were one of the first compounds that were used to create a DCL in search for inhibitors of biological macromolecules. Huc and Lehn used172
an imine based library in the presence of carbonic anhydrase (Figure 23). The parent compounds for the generation of the library were four amines 23-26 and three aldehydes 27-29. From the interchanging mixture of imines one compound 30 was amplified twofold over the other ones. In order to analyse the mixture the imines had to be reduced to the corresponding amines using sodium cyanoborohydride. It has been observed173
that the imine analogues used in the DCL are good models of the biological activity of the amines. 16 17 19 18 20 21 22
Figure 23. Selection of the best inhibitor for carbonic anhydrase using an imine-based DCL with subsequent reduction of the imine 30 to an amine 31.
Metal cation receptors have also been a target of imine-based dynamic combinatorial chemistry. Gotor174 used pyridinedicarboxaldehyde 32 with a homochiral diamine 33.
Different macrocycles were amplified depending on the size of the metal ion. Ba2+
induced the amplification of the smaller macrocycle 34 consisting of two amines and two aldehydes, while the bigger Cd2+
gave the [3+3] adduct 35 in almost quantitative yield (Figure 24). The imine compounds were also reduced to the stable amines, however the transformation resulted in a decrease in the binding affinity of the complex. NH2 NH2 N O O + N N N N N N N N N N N N N N N Ba2+ Ba2+ MeOH Cd2+ Cd2+ Cd2+ MeOH
Figure 24. Amplification of different macrocycles from an imine-based DCL using different metal ions.
Imines have been used extensively by Stoddart175
in research where DCC meets supramolecular chemistry. One of the most formidable examples of utilising the reversible imine bond is the formation of the molecular borromean rings 39
(Figure 25). This elegant assembly consists of three interwoven macrocycles 38 23 24 25 26 27 28 29 30 31 32 35 34 33
arranged in such a way that the breaking of one of the rings enables the disassembly of the other two. The imine based structure consists of six dialdehydes 36 and six diamines 37 and the assembly is templated by six Zn2+
ions. Again a way of fixing the macrocycles is a reduction of the imines to the amines, in the case of the borromean rings also a removal of the zinc ions with EDTA is possible to give a stable mechanically interlocked structure.
Figure 25. The synthesis and chemical structure of macrocycle 38 and the X-ray crystal structure of the molecular borromean rings assembly 39. Figure adapted from ref. 151.
Sanders and coworkers amplified176
a supramolecular structure from a hydrazone- based DCL. A library of peptide-hydrazone building blocks 40 when allowed to exchange in the presence of an acetylcholine template, form a [2]-catenane 41 as the most stable structure (Figure 26). Without the template the mixture consists of cyclic oligomers from a simple dimer up to a hexamer. Upon the introduction of the template and letting the mixture equilibrate the catenane 41 accounts for 70% of the mixture after 44 days. The interactions between the catenane receptor and the guest are not completely elucidated however it is sure that it is a very specific directional binding in order to create such an unexpected three dimensional structure.
36
37 38
Figure 26. Amplifying a [2]catenane 41 from a hydrazone-based DCL of oligomeric macrocycles using acetylcholine as the template.
Imine and hydrazone exchanges are the most prominent members of the family of exchange reactions based on nitrogen nucleophiles. Both the amine and the hydrazone however are not particularly good nucleophiles and the exchange mainly proceeds via the hydrolytic mechanism. Also neither of the bonds presents any utility in synthetic applications. The only useful reaction of the imine is its reduction to the secondary amine.
A logical extension of the methodology is the use of hydroxylamines. Hydroxylamines are excellent nucleophiles and react rapidly with aldehydes in non-polar solvents to form the corresponding nitrone. Unlike hydrazones, diaryl nitrones are capable of participating in a number of irreversible synthetic transformations directly, the most attractive of which are dipolar cycloadditions. A description of nitrone exchange in DCC has appeared in the patent literature177
. The reaction is, however, restricted to aqueous buffers and the generation of unreactive nitrones mostly for the development in drug discovery. Philp has reported178
that nitrones are, indeed, capable of undergoing exchange under mild conditions in chloroform. This dynamic exchange is demonstrated and exploited within the context of the selection of a receptor for a dicarboxylic acid from a mixture of nitrones. The small dynamic library consists of four nitrones two of them bearing a single aminopyridine recognition site
42 and 43, one incapable of recognition 45 and one with two aminopyridine