Weak Alignment Liquid Crystal Media from Colloidal Dispersion and Self-assembled Oligopeptide for Anisotropic NMR

ConspectusAcquiring anisotropic NMR parameters such as residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) has been demonstrated as a powerful route to elucidate the three-dimensional structure of organic molecules in organic and medicinal chemistry. However, this methodology is somewhat compromised by the limited availability of alignment media, which are indispensable to induce the partial orientation of analytes for anisotropic data acquisition. Given the feature of inherent anisotropy, lyotropic liquid crystals (LLCs) have been documented as excellent candidates to act as alignment media. This Account aims to review the research progress of developing LLCs to obtain anisotropic NMR data. We mainly focus on two complementary LC media, i.e., two-dimensional (2D) colloidal dispersions and self-assembled peptides, that are generated by a “top-down” approach and “bottom-up” approach, respectively.Our laboratory has been at the forefront of developing 2D colloidal dispersions as alignment media. We first demonstrated the applicability of graphene oxide (GO) LLCs in the RDC-based structural elucidation of small molecules. When used as alignment media, GO LLCs showed a striking feature of no background signals. Clean NMR spectra enable accurate data assignment without disturbances and even effective RDC measurements of rare natural products. To circumvent the limitation that preparing GO LLC media needs tedious solvent exchange to remove nondeuterated solvents for NMR experiments, we subsequently developed MXene LLCs. Different from GO media whose anisotropy would be destroyed after direct freeze-drying, MXene can self-align in the redispersed solution to recover LC behavior. This feature provides great convenience for sample preservation and rapid medium preparation. Another advantage of MXene LLCs over GO media is the applicability to directly measure RDCs of aromatic solutes with no need for chemical modification on MXenes.To complement the 2D colloidal media that are only compatible with strong polar solvents, we further develop supramolecular LLCs. Oligopeptides, due to their mature synthesis strategy, structural designability, and robust self-assembly ability, have been exploited to create supramolecular alignment media in different solvents. We first reported CH3OH-, DMSO-, and multiple solvent-compatible peptide media, which show the broad applicability of their corresponding analytes. Meanwhile, the chiral amino acids confer oligopeptide LLCs with potential chirality, and we have demonstrated their relative application of enantiodiscrimination. Arising from the structural diversity of oligopeptides, several distinct LLC media are constructed and applied to measure independent sets of RDCs. This offers an opportunity for de novo structural determination of organic molecules.In light of the good fluidity of these media, analytes can rapidly penetrate the LLC phases for self-alignment, facilitating simple and fast NMR experiments. Moreover, the alignment degree can be easily scaled through varying LC concentrations. This enables precise and accurate data acquisition at an optimal alignment strength. In addition to describing the design and LC preparation, we show the applicability of these weak alignment media for acquiring anisotropic NMR parameters. We hope it can serve as an inspiration source for the exploration of new alignment media, NMR methodology, and related material science.