Unlocking Supramolecular Chemistry: A New 2D-COS Approach to Intermolecular Interactions

Kwansei Gakuin University in Osaka, Japan. © Eric Akashi - stock.adobe.com

Kwansei Gakuin University in Osaka, Japan. © Eric Akashi - stock.adobe.com

Researchers collaborating from Peking University in China, Kwansei Gakuin University in Japan, and the University of Delaware in the United States have developed a new approach to analyzing intermolecular interactions using two-dimensional correlation spectroscopy (2D-COS). This method could lead to a deeper understanding of complex chemical processes and open doors to new discoveries in supramolecular chemistry.

Two-dimensional correlation spectroscopy (2D-COS) is gaining traction among chemists for its ability to examine intermolecular interactions in complex systems. However, analyzing these interactions can be challenging due to overlapping spectral peaks. Yi-Wei Zeng, An-Qi He, Li-Min Yang, Yukihiro Ozaki, Isao Noda, and Yi-Zhuang Xu have tackled this problem by employing a double asynchronous orthogonal sample design (DAOSD), which allows them to study cross-peaks in 2D-COS​ (1).

By focusing on intermolecular interactions between two substances, termed P and Q, the researchers observed two reversible reactions, resulting in two supramolecular aggregates, PQ and PQ2. Traditional one-dimensional (1D) spectroscopy often struggles with severe overlapping among characteristic peaks, making it challenging to accurately reflect the physiochemical nature of the interaction. The 2D-COS method, however, provides a clearer view of these interactions, revealing intricate patterns that would otherwise be obscured (1).

The research team examined cross-peaks generated via the DAOSD approach, uncovering much more complex patterns than those described by only a single reaction. In their analysis, they identified four major groups of cross-peaks with unique characteristic patterns:

  • No Cross-Peak: This pattern suggests that the peak position and peak widths of P, PQ, and PQ2 are identical. It indicates that the interactions among these substances do not cause significant changes in their spectral characteristics.
  • Cross-Peaks in ΨQ Only: This pattern indicates that two of the three species—P, PQ, and PQ2—have identical peak positions and peak widths, while the third experiences changes in peak position or width. This pattern is helpful in distinguishing subtle variations in intermolecular interactions.
  • Double Crescent Patterns in ΨP: This pattern signifies that P, PQ, and PQ2 have identical peak widths and intensities, but their peak positions vary. This pattern is useful for identifying significant shifts in peak positions due to intermolecular interactions.
  • Octet Patterns in ΨP: This pattern suggests that P, PQ, and PQ2 have identical peak positions and intensities, but their peak widths are different. This pattern could indicate variations in the molecular structure or conformation due to intermolecular interactions (1).

These patterns offer valuable insights into the physicochemical nature of intermolecular interactions between P and Q. By analyzing the spectral features of these cross-peaks, scientists can extract additional information about the changes in peak positions and widths, aiding in the understanding of supramolecular chemistry at a deeper level.

The research team acknowledges that while their work represents significant progress in understanding intermolecular interactions, much remains to be explored. The complex patterns of cross-peaks require further analysis, and artificial intelligence (AI) techniques could play a crucial role in unraveling these complexities. AI's ability to analyze large datasets and identify patterns may help decipher the more intricate aspects of 2D-COS.

This new approach to 2D-COS, combined with the DAOSD technique, could be instrumental in advancing our understanding of supramolecular chemistry. This advancement may lead to innovations in molecular recognition, catalysis, and other critical chemical processes. As scientists continue to explore these interactions, the potential for discovering new supramolecular compounds with unique structures and functionalities becomes increasingly likely (1).

Two-dimensional correlation spectroscopy (2D-COS) has a range of applications in chemistry and materials science, offering unique insights into molecular structures and dynamics. It is particularly useful for probing complex systems where traditional one-dimensional spectroscopy might struggle due to overlapping spectral peaks. By analyzing cross-peaks in 2D-COS, scientists can distinguish subtle differences in molecular interactions, making this technique invaluable for studying chemical reactions, conformational changes, and intermolecular forces. The high resolution and detailed information provided by 2D-COS can assist in advancing research in supramolecular chemistry, drug development, polymer science, and biomolecular studies. Additionally, 2D-COS can be used to monitor reactions in real-time, helping researchers understand reaction mechanisms and the formation of complex structures, leading to more informed decisions in experimental design and analysis (1–3).


  1. Zeng Y-W, He A-Q, Yang L-M, Ozaki Y, Noda I, Xu Y-Z. Patterns of Cross-Peaks in Two-Dimensional Correlation Spectra to Probe Intermolecular Interactions Described by Two Reversible Reactions. Appl. Spectrosc. 2024, 0 (0). doi:10.1177/00037028241245136
  2. Adar, F. Raman Analysis of Ethylene Vinyl Acetate Copolymers–Using 2D-COS for Identifying Structural Changes. Spectroscopy 2019, 34 (11), 12–21. https://www.spectroscopyonline.com/view/raman-analysis-ethylene-vinyl-acetate-copolymers-using-2d-cos-identifying-structural-changes (accessed 2024-05-01).
  3. Adar, F. Use of 2D-COS to Tease Out Structural Information on Polymers. Spectroscopy 2018, 33 (2), 14–18. https://www.spectroscopyonline.com/view/use-2d-cos-tease-out-structural-information-polymers (accessed 2024-05-01).