Reports: ND456665-ND4: Paracyclophane Self-Assembly Promoted by Transannular Hydrogen Bonding

Ronald K. Castellano, University of Florida

Background and Significance

[2.2]Paracyclophane ([2.2]pCp) is a molecule of historic intrigue due to its unique structural, chemical, physical, and optical properties – these include non-planar aromaticity, through-space conjugation, planar chirality, and rigidity. In fact, the unambiguous and stereochemically defined structure has led to it being referred to by H. Hopf as a “hexadecavalent ‘superatom’” onto which 16 substituents may be introduced, and “a core element to organize space”.1 While [2.2]pCp has been used to great effect in ligand design and conjugated polymers, it has been relatively underexplored in supramolecular constructs. With this realization, we recently reported a new derivative, [2.2]pCp-4,7,12,15-tetracarboxamide, [2.2]pCpTA ((±)-1, Figure 1), which advantageously utilizes hydrogen bonding (H-bonding) to form supramolecular 1-D “nanorods”.2 The design exploits the first pCp transannular H-bonding (to preposition the amide groups for intermolecular hydrogen bonding) and planar chirality of the monomer (to dictate the chirality of the 1-D assembly).  Also noteworthy is that the dipole moment of the monomers can cancel upon nanorod growth (which we presume affects the assembly mechanism), and the R group can be conveniently varied. The overlapped, multi-tiered aromatic core of the suprastructure is attractive for materials science applications involving charge transport.  Described here is our progress associated with the two specific aims of the funded proposal: (1) The design, synthesis, and resolution of pCps capable of transannular H-bonding for the evaluation of the consequences of these interactions on molecular pCp structure, stability, and chiroptical properties and (2) the study of the transannular H-bonding promoted solution-phase self-assembly and emergent electronic structures of selected pCps.


Figure 1. The parent [2.2]pCp is functionalized with four amides to form [2.2]pCpTA, which self-assembles via cooperative transannular and intermolecular hydrogen bonding.

Investigation of Transannular Hydrogen Bonding

In order to understand the strength and influence of transannular hydrogen bonding on the self-assembly of pCp carboxamides, model compounds 4,16-bis(amide)[2.2]pCp 2 (pseudo-para (ps-p)) and (±)-4,12-bis(amide)[2.2]pCp (±)-3 (pseudo-ortho (ps-o)) were synthesized from the corresponding acids during this reporting period.3 Compounds 2 and (±)-3 serve as the non-intramolecular hydrogen-bond control and transannular hydrogen-bonding model, respectively. These derivatives show remarkably different amide N–H 1H NMR resonances in CDCl3 (Figure 2), consistent with their expected hydrogen bond capabilities; the relative N–H chemical shift of 2 (5.5 ppm) is shifted significantly downfield for (±)-3 (7.4 ppm). This deshielding effect is due entirely to the presence of the transannular hydrogen bond in (±)-3, which is absent in 2.  With the synthetic technology in hand to prepare these bisamides, we are now prepared to evaluate their self-assembly properties and use them to establish chiral resolution conditions.


Figure 2. 1H NMR of pseudo-para [2.2]pCp bisamide 2 (top) and pseudo-ortho [2.2]pCp bisamide (±)-3 (bottom) at 30 mM in CDCl3.

Chiral Resolution

Enantiopure monomers are needed in order to fully study the pCp self-recognition process, and thus, the chiral resolution of (±)-1 and transannular H-bond comparator (±)-3 is underway. Attempts to resolve (±)-4 (Figure 3a) via derivatization with a chiral alcohol to form separable diastereomers proved troublesome; esterification does not proceed as expected under Fischer conditions or in the presence of a dehydrating agent.  

Resolution of a pseudo-ortho comparator has been accomplished by adapting a method developed by Morisaki, et. al. (Figure 3b).4 Accordingly, (±)-6 could be converted into separable sulfinate diastereomers (Rp,S)-7 and (Sp,S)-7. Subsequent lithiation and CO2 quench offered optically pure diacid (Rp)-8. Following our already established synthetic methodology from here, we should be able to synthesize enantiopure pseudo-ortho bisamide (Rp)-3. In parallel, we are currently using this procedure to access enantiopure [2.2]pCpTA (Figure 3c).


Figure 3. (a) Attempted chiral resolution of (±)-[2.2]pCpTA through derivatization, (b) resolution of (±)-3 through conversion to chiral sulfinates, and (c) planned resolution procedure for (±)-[2.2]pCpTA.

[3.3]Paracyclophane: A Strain-Relieved Scaffold

The strain of [2.2]pCp arises from ring distortions and repulsive arene-arene interactions.  We originally hypothesized that the reduced strain enthalpy of [3.3]paracyclophane, [3.3]pCp (Figures 4a and 4b), signified by a more reasonable interplanar deck distance and flatter benzene rings, should favor formation of the H-bonded assembly. Unlike [2.2]pCp, [3.3]pCp is not commercially available and must be synthesized before introducing the methodology developed for [2.2]pCpTA.5 While the derivatization of [3.3]pCp differs from that of [2.2]pCp, with significant optimization (Figure 3c), (±)-[3.3]pCpTA could be obtained. 1H NMR analysis shows the amide N–H resonance of (±)-[3.3]pCpTA occurs downfield at 7.4 ppm in CDCl3, similar to that of (±)-[2.2]pCpTA and (±)-3. This observation indicates that the transannular hydrogen bond is indeed formed in (±)-[3.3]pCpTA, and the desired assembly will likely be accommodated. We are currently scaling up the synthesis and purification of this compound to allow its characterization in the solid-state and solution.


Figure 4. (a) X-ray crystal structures of [2.2]- and [3.3]-paracyclophane with transannular deck distances and benzene deformations shown, (b) chemical structure of (±)-[3.3]pCpTA, and (c) synthesis of (±)-[3.3]pCpTA.


1.    Henning Hopf, Isr. J. Chem. 2012, 52, 18–9

2.    Fagnani, D. E.; Meese, M. J., Jr.; Abboud, K. A.; Castellano, R. K. Angew. Chem. Int. Ed. 2016, 55, 10726–10731

3.    D. Y. Antonov, E. V. Sergeeva, V. I. Rozenberg, Russ. Chem. Bull., 1997, 46  1897–1900

4.    Y. Morisaki, Y. Chujo, Chem. Lett. 2012, 41, 990–­992

5.    M. Shibahara, M. Watanabe, T. Iwanaga, T. Matsumoto, K. Ideta, T. Shinmyozu, J. Org. Chem., 2008, 73, 4433–4442