Diketopiperazines as Monomers in Macromolecules

Diketopiperazines Assembled via Non-covalent Bonds (Crystal Engineering)

The conformations of DKPs possessing up to four substituents have been studied [61-67] and reviewed [3, 68]. Although constrained, DKPs are not completely rigid, because of the similar energies of their planar and boat conformations, in the solid state, intermolecular hydrogen bonding between two amides permits formation of supermolecular structures. Linear tape orientations of DKPs without N-substituents have been observed to exist in hydrogen-bonded cyclic eight- membered rings. Substituted DKPs may adopt layer structures contingent on ring substitution. One-dimensional hydrogen-bonded tapes and dimers are generally observed for mono-N-substituted DKPs.

By virtue of its rigidity, synthetic accessibility, structural diversity, and resistance to proteolytic enzymes, the DKP moiety has been extensively studied as a building block in supramolecular chemistry. Symmetrical DKPs 92 with cycloalkyl substituents were shown to form tapes by Whitesides and Palmore (Fig. 16a) [6971]. Mash and co-workers postulated that three geometrically and chemically independent elements may be used to make ordered three-dimensional organic crystals: amide-to-amide hydrogen bonding between DKPs along the z-axis; van der Waals forces shared by R1, R4, R5, and R8 substituents along the y-axis; and other interactions between the R2, R3, R6, and R7 groups in the x-axis (Fig. 16b). A series of studies toward such designs have been reported [72-76] and reviewed [77].

(a) Assembly of symmetric cycloalkyl-substituted DKP reported by Whitesides and Palmore;

Fig. 16 (a) Assembly of symmetric cycloalkyl-substituted DKP reported by Whitesides and Palmore; (b) Mash’s postulate that three independent sets of interactions between groups displayed on diketopiperazine containing compounds can generate three-dimensional networks and control crystal formation

Emphasizing the importance of aromatic side chain substituents in DKP ensembles, Verma and co-workers chose four different model systems 93-96 to form two-dimensional extended structures employing п—п interactions from the aromatic groups to create intermolecular interactions orthogonal to the hydrogen bonding between amides (Fig. 17a) [78]. Employing similar п—п interaction in the self-assembly of DKPs 97 and 98, Govindaraju and co-workers prepared two-dimensional nano- and mesosheets (Fig. 17b) [79]. These networks that combine п—п interactions and hydrogen bonding have been characterized by NMR spectroscopy and X-ray diffraction. Similarly, low-molecular-weight gelator soft materials were formed by sequential heating and cooling DKPs 99 (Fig. 17c) [80]. Chemical shift values in NMR analyses at various concentrations and temperatures revealed the formation of intermolecular ladders through hydrogen bonds, respectively, between DKP amides and side chain carbamates. In addition, aromatic п—п interactions were crucial for the self-assembly process. Similarly, gelation of DKP 100 was observed in a number of solvents including water using agitation with ultrasound (Fig. 17d) [81]. These organic hydrogels may be applied as entrapping agents, drug delivery systems, and thermo-responsive soft materials.

Helical chirality, which is ubiquitous in proteins, was adopted by naphthalene- diimide (NDI)-DKP supramolecular assemblies designed by Govindaraju and co-workers (Fig. 18) [82]. For example, the monosignate negative CD signal of NDI-DKP 101 in hexafluoroisopropanol (HFIP) indicated a left-handed M-helical assembly, which on titration with DMSO underwent a reversible transition from M- to P-helicity leading to a bisignate positive Cotton signal. On the other hand, NDI- DKP diastereomer 102 exhibited no preference to adopt helical geometry in mixture of DMSO and HFIP.

Substituted DKPs used in crystal engineering

Fig. 17 Substituted DKPs used in crystal engineering

Solvent and stereochemistry-dependent helical conformations formed from NDI-DKP

Fig. 18 Solvent and stereochemistry-dependent helical conformations formed from NDI-DKP

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