(713e) Exploring Self-Assembly Mechanism from Solution: Tolfenamic Acid in Toluene and in DMF

Authors: 
Tang, W. - Presenter, The Co-Innovation Center of Chemistry and Chemical Engineering,State Key Laboratory of Chemical Engineering
Gong, J., Tianjin University
Wang, J., National Engineering Research Center for Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University
The detailed molecular pathway of nucleation of crystalline materials largely remains unknown. The formation of solution-state assembly is suggested to be the first step of nucleation pathway, and the structure of pre-nucleation aggregates may shed lights on crystal nucleation mechanism. Herein, this study presents a systematic investigation on structure, conformation, size and shape of solution aggregates during the self-assembly process of TFA molecules from both nonpolar (toluene) and polar (n,n-dimethylformamide, DMF) solutions.

Crystallization experiments were conducted by using crash cooling method at various supersaturations and different temperatures. It was shown that both Form â? and Form â?¡of TFA with carboxylic acid homo-dimer synthons can be crystallized from toluene dependent on applied supersaturations while DMF solvate containing carboxylic acid formamide synthon is exclusively crystallized from DMF independent of supersaturations.

The solution phase self-assembly processes are investigated by FTIR spectroscopy, one- and two-dimensional 1H-NMR spectroscopy, and ab initio computations. NMR chemical shift changes of TFA in DMF indicate two events, which are likely associated to conformation change and further dimerization through weak aromatic rings interactions. By contrast, dimerization is mediated by H-bonding in toluene. FTIR spectroscopic measurements and ab initio calculations of the stability of small clusters in solution support the conclusions. Based upon concentration and temperature dependences of proton chemical shifts of TFA, the reaction constant, cooperativity, and thermodynamic parameters (enthalpy and entropy) of self-association process were determined. The detailed structures of pre-nucleation aggregates are unveiled by chemical shift changes and further conformed by 2D-NOESY NMR. The results show that the solution pre-nucleation dimers bear similar structures as those found in X-ray crystal structure. The size and shape of solution aggregates were revealed by diffusion ordered spectroscopy (DOSY) NMR measurements. It was found that TFA aggregates take on the shapes of prolate ellipsoid.