Supramolecular Naphthalenediimide Nanotubes
Amino acid functionalized naphthalenediimides (NDIs) when dissolved in chloroform form a dynamic combinatorial library (DCL) in which the NDI building blocks are connected through reversible hydrogen bonds forming a versatile new supramolecular assembly in solution with intriguing host–guest properties. In chlorinated solvents the NDIs form supramolecular nanotubes which complex C60, ion-pairs, and extended aromatic molecules. In the presence of C70 a new hexameric receptor is formed at the expense of the nanotube; the equilibrium nanotube – hexameric receptor can be influenced by acid–base reactions. Achiral NDIs are incorporated in nanotubes formed by either dichiral or monochiral NDIs experiencing the “sergeants-and-soldiers” effect.
KeywordsCircular dichroism Fullerenes Host–guest Ion-pairs Sergeants-and-soldiers Supramolecular chemistry Supramolecular polymers
Dynamic combinatorial chemistry is defined as combinatorial chemistry under thermodynamic control; that is, in a dynamic combinatorial library (DCL), all constituents are in equilibrium with each other [1, 2, 3, 4, 5, 6]. This requires the interconversion of library members into one another through a reversible chemical process, which can involve covalent bonds or non-covalent interactions such as hydrogen bonds. The composition of the library is determined by minimising the free energy of the whole system, which often is dominated by the thermodynamic stability of each of the library members under the particular conditions of the experiment. If a particular library member can be stabilised, either by binding to an external template, mutual interactions with other library members or due to a change in the DCL conditions, its free energy is lowered and consequently, in general, the equilibrium shifts towards its formation.
Hydrogen bonds between neutral partners in solution typically have energies between 0 kJ/mol and 20 kJ/mol  and have a preference for a linear arrangement of the three atoms involved (X−H···A angle ~180°). Due to its labile nature, equilibrium is often reached rapidly. Reinhoudt, Timmerman and co-workers were the first to describe a DCL based on hydrogen-bonded assemblies: using combinations of donor and acceptor hydrogen-bonded motifs, they built complex superstructures held together by an impressive number of hydrogen bonds [8, 9]. Rebek and co-workers have also utilised multiple hydrogen-bonding interactions to generate dynamic libraries composed of closed and spherical capsules [10, 11].
Amino acid functionalized naphthalenediimides (NDIs) when dissolved in chloroform form a DCL in which the NDI building blocks are connected through reversible hydrogen bonds forming a versatile new supramolecular assembly in solution with intriguing host–guest properties. These studies were prompted by the observation of an unusual arrangement of NDIs in a crystal structure and this chapter summarises the results and insights obtained to date.
Microwave dielectric heating is a mild and efficient method for the one-pot and stepwise synthesis of symmetrical and N-desymmetrised NDI derivatives of amines and α-amino acids. For the synthesis of symmetrical NDI derivatives, the reaction is carried out at 140 °C for 5 min in a dedicated microwave reactor in a pressure-resistant reaction vessel. Using this method, the products are obtained in high yield and purity after a simple aqueous workup; the acid-labile protecting groups (trityl, benzyl, tert-butyl, Boc and Pmc) are stable under the mild reaction conditions and undesired self-condensation side-products of amino acid esters, such as dipeptides, diketopiperazines and higher oligomers, are not observed. In the case of unprotected tyrosine and serine, the reaction is completely selective for the formation of the symmetrical imide without any trace of ester formation .
Selected examples of amino acid derived symmetrical NDIs. For more examples see 
Selected examples of NMIs and N-desymmetrised NDIs. For more examples see 
NMI yield (%)
NDI yield (%)
A higher degree of selectivity in favour of NMI was obtained when the amino acid derivatives contained aromatic side chains: trityl (100% selectivity), benzyl (70–90% selectivity) and alkyl (<60% selectivity). Also the amino acid esters gave higher selectivity towards NMI than the corresponding amino acids. This trend was rationalised by considering the solubility of the amino acid derivative and its reactivity towards NDA in DMF at room temperature. The NDA is insoluble in DMF at room temperature, but is rapidly solubilized by an amino acid containing aromatic side chains, which is itself soluble in DMF. It was proposed that the dissolution of NDA in DMF is probably due to π–π interactions between its extended aromatic core and the amino acid aromatic side chains. This enhanced solubility of NDA in DMF leads to a 1:1 mixture of NDA and the amino acid in solution and hence promotes the selective formation of the NMI. In the cases where sonication and heating were required in order to dissolve the reagents completely, a strong preference for the formation of the NDI was observed. The N-desymmetrised synthesis was primarily used to synthesise monochiral NDIs for their use in “sergeant-and-soldiers” experiments (see below).
3 Solid State Characterisation of α-Amino Acid Functionalised Naphthalenediimides
X-ray structures and crystallisation conditions of molecules 1, 3–8
In this arrangement, the angle between the central N1–N2 axis of the NDI core and the central axis of the nanotube is 60°, whereas the distance between two sequential aromatic cores is on average 4.8 Å. The nanotube has an average inner diameter of 12.4 Å and it contains diffuse electron density attributed to disordered water molecules.
A derivative that stands apart in this analysis is NDI 7, in which the carboxylic acids (or esters) have been replaced by amide groups, thus allowing the possibility of a new type of hydrogen bonding interaction. The crystal structure of molecule 7 was obtained by slow evaporation of an acetone solution and the analysis showed a complex network of molecules connected via a large number of hydrogen bonds.
4 Nanotube Characterisation
The helical supramolecular nanotubes of NDI 1, observed in the solid state, were identified in CHCl3 and 1,1,2,2-tetrachloroethane (TCE) solution by means of circular dichroism (CD) and NMR spectroscopies, and were further studied using molecular modelling.
4.1 Solution State Characterisation
The first evidence for the presence in solution of NDI nanotubes of 1 came from CD spectroscopy, which measures the optical rotation of circular polarised light by chiral molecules and therefore is an indicator of chirality. A molecule with a chiral centre usually produces a small intrinsic CD signal; however, if the molecule can aggregate to form a chiral supramolecular species, then a much stronger CD signal can be generated, as the entire structure expresses chirality. In chloroform, 1 had an intense CD signal at 383 nm, corresponding to the absorbance of the naphthalene core. By contrast, the corresponding methyl ester derivative of 1 (l-1 ester) was CD silent at this wavelength. The l,l-enantiomer of 1 (l-1) derived from the corresponding l-amino acid forms P-helices with a positive CD signal, while the d,d-enantiomer (d-1) forms M-helices with a negative CD signal .
4.2 Majority Rules Study
4.3 Theoretical Studies of the CD of NDI
In order to correlate the solid state and solution phase structures, molecular modelling using the exciton matrix method was used to predict the CD spectrum of 1 from its crystal structure and was compared to the CD spectrum obtained in CHCl3 solutions . The matrix parameters for NDI were created using the Franck–Condon data derived from complete-active space self-consistent fields (CASSCF) calculations, combined with multi-configurational second-order perturbation theory (CASPT2).
4.4 The “Sergeants-and-Soldiers” Effect
The “sergeants-and-soldiers” effect was first proposed in the field of polymer chemistry in the 1960s and was named by M.M. Green and co-workers in 1989 . Since that time, E.W. Meijer and others have broadened the scope of the concept to take in many facets of supramolecular as well as polymer chemistry . In a system displaying “sergeants-and-soldiers” behaviour a chiral derivative, the “sergeant”, imposes its chirality on a structure formed mainly out of achiral derivatives, the “soldiers”. In the case of NDI nanotubes, investigating the possibility of a “sergeants-and-soldiers” effect requires the synthesis of NDIs derived from achiral amino acids. Glycine is perhaps the most obvious choice, but the resulting NDI had previously been found to be highly insoluble in organic solvents. Several different achiral amino acids were therefore employed to synthesise a range of achiral NDIs. The NDIs derived from S-trityl cysteine (1 and 1-ester), or N-Boc lysine (2 and 2-ester) were employed as the sergeant, while achiral derivatives 8–11 were used as soldiers (Table 1).
As can be seen in Fig. 21, solutions of chiral NDIs 1 containing small percentages of 8 tend to show stronger CD signals than 100% chiral solutions of the same total NDI concentration. The effect is small but reproducible, and must be the outcome of subtle geometrical changes in the size of the exciton coupling between adjacent chromophores, thus leading to an increased CD signal .
5 C60 Encapsulation
The nanotubular cavities (mean diameter: 12.4 Å) were found to be effective hosts for C60 molecules (van der Waals radius: 10.3 Å), and were capable of solubilising C60 in solvents such as chloroform, where the fullerene has poor solubility. UV–vis, CD, 13C-NMR and molecular modelling were used to characterize this NDI nanotube-C60 host–guest complex .
5.1 UV–Vis Spectroscopy
The uptake of C60 corresponds to the increase in absorbance at 258 and 328 nm in the absorption spectrum of 1 + C60 (Fig. 23). Comparison of a solution of 1 + C60 with a saturated solution of C60 in chloroform showed that the C60 concentration increased 16-fold in the presence of NDI nanotubes (1). In contrast with these results, the methyl ester of 1, which is unable to form hydrogen-bonded supramolecular nanotubes, did not enhance the solubility of C60 in chloroform, supporting the thesis that the C60 molecules are complexed in the inner nanotubular cavity. The increase in absorbance at 258 nm also led to an estimate of [NDI]/[C60] stoichiometry, revealing that an average of 3.6 NDI units were encapsulating one C60 molecule. Similar results were also obtained with other amino acid derivatives of NDI.
5.2 CD Spectroscopy
5.3 13C-NMR Experiments
13C NMR experiments in TCE-d2 confirmed that this functional behaviour of the nanotubes is also present in hybrid nanotubes composed of a mixture of chiral 1 and achiral 8 . The C60 uptake is lower for the hybrid nanotubes with increasing amounts of incorporated achiral NDIs. A similar effect was observed for the monochiral NDI, in which nanotubes containing the cyclopropyl side chain 12 are better receptors for C60 than the analogues formed from 13. These observations highlight the importance of the rigidity in the NDIs derived from achiral amino acids.
5.4 Self-Sorting of Nanotubes
Complexation of C60 also remarkably demonstrated the self-sorting of nanotubes of opposite helicity. A 1:1 mixture of l-1 and d-1 is capable of encapsulating C60 as shown by UV–vis spectroscopy: the [NDI]/[C60] ratio of 3.9 matches (within experimental error) that is obtained for optically pure samples of either l-1 or d-1, and the 13C signal of C60 is shielded by 1.4 ppm, indicating that nanotubes are still present (even though they are inevitably invisible by CD). This quantitative self-sorting of the two helical nanotube enantiomers shows that one NDI enantiomer cannot be incorporated into a helix made of the other enantiomer as the directionality created at the chiral centre is critical to self-assembly and is in agreement with the “majority-rule” experiments (see above).
6 Self-Assembled C70 Receptors
A detailed symmetry analysis based on spectroscopic data showed that a 6:1 stoichiometry with a D3 point-group symmetry is the only plausible structural class of the C70 receptor. Thus, at the “poles” of the C70 receptor, three NDI molecules have to bind to each other in a C3-symmetrical manner, requiring angles of 120o (Fig. 28). Weak CH···O hydrogen bonding to an imide or carboxylic acid carbonyl group could explain the chemical shift change of more than 0.7 ppm for one aromatic proton in the C70 receptor (Fig. 26b). Indeed, such an arrangement can give rise to a favourable trimeric interaction mode (Fig. 28), accounting for formation of one trimeric “half” of the receptor. In the proposed arrangement, consistent with D3 point symmetry for the complex, one carboxylic residue per NDI unit would remain free for carboxylic acid dimerization with the NDI counterpart of the other hemisphere, at the equator of the C70 receptor.
In chloroform, the monochiral NDIs were found to form the C70 receptor in the presence of an excess of C70. However, unlike 1, they did not form the receptor exclusively, rather the equilibrium position between receptor and nanotube is different for each monochiral NDI, as indicated by 1H NMR experiments. As expected, 12 NDI was the most efficient at forming the hexameric capsule with 70% of the material being incorporated, while only 30% of 14 forms the receptor. Figure 28 shows a cartoon representation of the proposed geometry of the C70 receptor including the possible orientations for an N-desymmetrised NDI .
Only one α-proton signal is seen in the 1H NMR spectrum of the C70 receptor formed from 12, which means that all the chiral ends of the NDIs are in the same environment. It is unclear whether the single α-proton signal of the monochiral component is associated with the equatorial or axial position, but this demonstrates that the arrangement of NDIs in the receptor is ordered rather than random (Fig. 28).
7 Proton-Driven Switching Between C60 and C70 Receptors
8 Complexation of Polyaromatic Hydrocarbons
9 Complexation of Ion Pairs
Increasing the amount of XIV·Cl in a solution containing 2 + C60 complex also resulted in the rapid decrease of absorption at 452 nm (attributed to fullerene–fullerene interactions in a closed-packed one-dimensional array of C60 inside the nanotubular cavity), indicating that the encapsulation of ammonium ions led to partial disruption of the close-packed C60 array resulting in the formation of a mixed complex ion-pair/C60 host–guest complex, where the ion pair is intercalating between the fullerenes.
The reverse experiments, in which C60 was added to solutions of XIV·Cl encapsulated 2, also led to the formation of the same nanotube–fullerene–ion pair mixed complex. UV and NMR experiments confirmed that C60 partially displaced ion pairs from the nanotube’s cavity. This is indicative of the dynamic nature of the systems and the propensity of these nanotubes to form mixed complexes.
The serendipitous discovery that amino acid derived NDIs form supramolecular nanotubes in the solid state led to the unravelling of a very rich vein of supramolecular assemblies in organic solvents. This chemistry highlights how a very simple and versatile building block can form hydrogen-bonded dynamic combinatorial libraries that allow the co-existence of small oligomers, nanotubes and hexameric capsules. Achiral and mono-chiral derivatives allowed us to discover how very small changes in their structure influenced incorporation into chiral supramolecular structures. The formation of a dynamic nanoreceptor whose morphology and recognition properties can be tuned by a simple acid–base equilibrium highlighted the importance of the amino acid side chains in the formation of these supramolecular structures. The remarkable ability of NDIs to self-assemble in a receptor for C60, C70, polyaromatic molecules and ion pairs is unprecedented and should inspire chemists to investigate other “simple” systems whose abundant supramolecular chemistry is yet to be discovered.
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