Small Twisted Oligomers

A New Path to Induce Chirality

  • Fig1: Structures that show induced axial chirality with backbone (blue) and bridge (orange). I: Bridged biphenyls as studied in our group. II) Vögtles original Geländer-oligomer, III) new designed structure from our group. The ring in red acts as a rigid joint which relays the helicity across the structure.Fig1: Structures that show induced axial chirality with backbone (blue) and bridge (orange). I: Bridged biphenyls as studied in our group. II) Vögtles original Geländer-oligomer, III) new designed structure from our group. The ring in red acts as a rigid joint which relays the helicity across the structure.
  • Fig1: Structures that show induced axial chirality with backbone (blue) and bridge (orange). I: Bridged biphenyls as studied in our group. II) Vögtles original Geländer-oligomer, III) new designed structure from our group. The ring in red acts as a rigid joint which relays the helicity across the structure.
  • Fig.2: Summarized synthesis of the target structure over 12 steps. The desired structure was finally accessed as the two enantiomers (M and P).
  • Fig.3: Solid state structures of 1 as obtained by x-ray diffraction analysis which clearly demonstrate the induced helicity. Color-code: backbone oligomer (blue), bridge oligomer (orange), oxygens (red), hydrogens (gray). TAdvAnced No compromises in technology Biometra-Thermocycler www

When thinking about activity of a molecule on a very fundamental level, a crucial element is the electronic nature of the bonds - how polarized that bond is defines directly if and how the two involved atoms will participate in a chemical reaction. The second equally important factor is what chemists describe as the spatial arrangement of the atoms in space. How an atom is arranged in space will just as much determine whether it can undergo bond formation or will, despite its reactivity, stay inert.

These findings are not limited to fundamental chemistry, we find such phenomena as well in biological systems, like e.g. the cooperative effect of hemoglobin, substrate-selectivity of enzymes, or the perception of odor in our nose. Ever since the discovery of structure-activity relationship, scientists have tried to relate function to shape, be it as biochemists with vast structures like enzymes or proteins down to the very abridged but nonetheless challenging screws, knots and propellers that have fascinated chemists and mathematicians alike. Interestingly, studying a particular system has often supported also formally unrelated fields, simply because the underlying systems showed structural or topological similarities.

What Topology Means to Us
We have been fascinated by spatial arrangements for a while now [2], especially the impact structure has on conductivity and optical activity. For instance: While it is comparably easy to state that, due to their planar delocalization, two aromatic π systems will communicate less if they are twisted out of plane, the experimental quantification remained challenging. It basically meant to design and synthetically access a number of biaryls that each showed a defined, stable twist [3]. By measuring the transport through these structures on a single molecule level, each molecule's conductivity became accessible and enabled the correlation between the twist angle or the degree of delocalization and molecular conductivity.

Towards Induced Helicity
Helical structures gained more interest in our considerations recently. They are not only structurally closely related to biological systems such as DNA, due to their uniform and continuous twist they are also of great interest for material applications.

In addition to that they are appealing model compounds from a kinetic viewpoint (i.e. how fast such helices can unwind or even invert their twist), as the stability of the helix depends on structural features like its length and number of turns. With similar objectives, we have observed and quantified the untwisting of small molecular helices (I, fig. 1) [4].

Vögtle and coworkers have designed doubly bridged terphenyls, that is three aromatic rings which are interlinked by two bridges (II, fig.1) [5], so called Geländer-oligomers. Geländer is the German word for bannister because of the resemblance to a bannister of a helical staircase. The term oligomer hints at the potential use of such structures (be it the material in itself or the incorporation of shorter substructures into materials) as highly functional materials. The key requirement is to obtain long-term, stable helices. And indeed, increased racemization barrier heights were found for these systems compared to the smaller, monobridged systems. From a topological standpoint however, these systems while being unpreceded and innovative had one major drawback. The two bridges are remotely spaced with respect to each other, meaning that they do not influence each other considerably. The problem is of a statistical nature: If each bridge can independently adopt either a left-handed or right-handed helix (or more precisely, M or P conformations), three possible isomers can occur. M,M and P,P (that is, both bridges adopt the same conformation) lead to the desired helices (M,M being the left-handed overall helix, while P,P describes a right-handed helix). However, there are also two mixed isomers possible (M,P or P,M). While they are in that case structurally identical, from a statistical point it means they are twice as likely to occur than the desired M,M or P,P helices. To make matters worse, the mixed structures no longer show a handedness, they become an achiral dead end.

Molecular Design
We were thinking about that problem and potential solutions and identified two important factors: The two bridges do not communicate the adopted helicity, which allows each of the bridge to freely choose one of the two conformations. Secondly, the adopted structure M,P is the same as P,M because the system features a point of inversion. This internal element of symmetry is the reason why these two conformations are no longer chiral (show no handedness, chemists calls such structures "meso"). To obtain systems which are suitable to study chiral behavior as well as make them available for material applications, we needed to find a way to address both of these points. The possibility of adopting a meso form can be avoided best by reducing the symmetry of the entire system. As soon as no conformation can be adopted which shows an internal symmetry element (such as a point of inversion or a mirror plane), a meso form is no longer possible. All structures obtained would therefore show chiral activity. On the downside, it would also make the synthesis significantly more laborious. The problem of communication was however considerably more challenging. How could we ensure that the bridges will always adopt the same conformation, regardless of which one is adopted first? Eventually, we realized that we needed to join the bridges by a rigid joint that would relay the adopted helicity from one end of the molecule to the other (III, fig.1), which meant to asymmetrically join the two bridges [6]. We then designed a second oligomeric strand which is shorter than the bridge as backbone (axis) of the structure. Combining the two strands at very specific points theoretically leads to induced steric strain which the system relieves by adopting a bannister type helical conformation. This entirely new concept addresses all the issues outlined for systems that show two bridges (no internal symmetry and enforced continuous helicity).

Synthesis and Properties
While the desymmetrized molecule was challenging to access, it was eventually possible by a twelve-step synthesis which concluded in a twofold intramolecular cyclization of a preorganized intermediate (Fig. 2). Isolation of the target structure 1 was laborious and we were pleased to obtain the desired structure in milligram quantities, which was enough to grow single crystals, confirming to our delight, that indeed we found the envisaged helical structure as two enantiomers only, without an achiral meso form (Fig. 3). The elongated bridge enforced a continuous twist (147° over the system), while the rigid joint relayed the conformation across the entire structure, giving - for the first time for such systems - rise to a uniform helicity. Even more excitingly we could separate the enantiomers and demonstrate that the structure showed very well behaved racemization processes with complete interconversion from one helix into the other with a half-life time of 9-10 hours.

To conclude, by further developing ideas previously described in literature, we designed and accessed a new bannister-type helical molecule which introduces a new concept on how to enforce helicity. Combining an in length mismatched pair of oligomers resulted in a helical structure as ground state conformer which was confirmed by x-ray diffraction analysis. The helix exists as two mirror images that were separable and allowed to study the racemization behavior in detail. Currently we are working on similar analogues with extended enantiomeric lifetimes.

[1] M. Gomberg: J. Am. Chem. Soc., 22, 11, 757-771 (1900)
[2] a) B. Karamzadeh et al.: Chem. Commun., 50, 14175-14178 (2014)
b) A. M. Masillamani et al.: Nanoscale, 6, 8969-8977 (2014)
[3] a) D. Vonlanthen et al.: Eur. J. Org. Chem., 120-133 (2010)
b) L. Cuin et al.: J. Am. Chem. Soc., 133, 7332-7335 (2011)
[4] a) J. Rotzler et al.: Org. Biomol. Chem, 9, 86 (2011)
b) J. Rotzler et al.: Org. Biomol. Chem., 11, 110-118 (2013)
[5] a) B. Kiupel et al.: Angew. Chem. Int. Ed., 37, 3031-3034 (1998)
b) M. Modjewski et al.: Org. Lett., 11, 4656-4659 (2009)
[6] M. Rickhaus et al.: Angew. Chem. Int. Ed., 53, 52, 14587-14591 (2014)

The synthesis is described in detail here: M. Rickhaus et al.: Eur. J. Org. 4, 786-801 (2015)





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