Molecular Mechanism Of Conformational Polymorph Nucleation And Transformation Ofα,ω-Alkanedicarboxylic Acids

The research on the molecular mechanism of polymorphic nucleation and transformation has become a hot and difficult point in the field of crystallization.Aiming at the current problems such as unclear molecular mechanism and the lack of research methods,this paper selects α,ω-alkanedicarboxylic acids with special analogous and comparable structures as a series of research models.The nucleation pathway was uncovered that difficulty in desolvation had a remarkable effect on the result of rearrangement and nucleation outcome,which was then used to guide the design of additives to achieve polymorph nucleation regulation and mechanism verification.Besides,a comparative study clarifies the key role of weak molecular interactions in polymorph transformation behavior,and improves the mechanism model of solid-solid phase transformation.Firstly,we explored the molecular mechanism of solvent-dependent conformational polymorph selectivity as a case of undecanedioic acid(DA11,the number refers to the carbon number).Based on binary solvent design,it is confirmed that DA11 form II is easy to form in solvents with strong hydrogen bond donor ability(HBD),otherwise it is form I.Spectroscopy studies show that the solute-solvent interactions are strongly correlated with polymorphic nucleation of DA11.The analysis of crystal and solution structures shows that solutes in different solvents undergo different conformational rearrangements during the nucleation process,resulting in the formation of two conformational polymorphs.The difficulty of solute desolvation is closely related to the solute-solvent interactions,which affects the conformational rearrangement mode and then the nucleation crystal form.Secondly,the research models were expanded to DA5/7/9/11/13/15 to reveal the nucleation mechanism by studying their relationships and distinctions.Except for DA5,the nucleation behavior has the same solvent dependence as DA11,but DA5 only forms crystal form I.Quantum mechanical computation showed that there was no direct conformational link between the solvents and the resultant polymorphic outcomes.Surprisingly,solute aggregates were found in no-HBD solvents by Fourier transform infrared spectroscopy,and only monomers could be detected in HBD solvents,suggesting stronger solvation.Furthermore,it was found that all six compounds including DA5 followed the same pattern in solution.Moreover,crystal-packing efficiency calculations and stability tests stated that dimorphs of DA5 bear a greater stability difference than others.These suggest the rearrangement from conformation II to I could not be limited by hard desolvation in HBD solvents,where form I was also obtained.In other systems,metastable II was produced in the same solvents,probably as a result of the rearrangement being limited by hard desolvation.A comparative study uncovers the proposed nucleation pathway: difficulty in desolvation has a remarkable effect on the extent of rearrangement and nucleation outcome.Subsequently,based on the above mechanism,DA2/3/4/5/6/8/9/10/11 was designed as homologous additives to interfere with the self-assembly of pimelic acid(DA7)to further induce the form II compound,which differs from form I only in conformation.Interestingly,longer-chain additives(DA6–11)have a stronger form IIinducing ability than short-chain ones(DA2–4).In addition,an apparent gradient of the degree of interference with solute self-assembly,consistent with form II-inducing ability,was detected by infrared and nuclear magnetic resonance spectroscopy combining with quantum mechanical calculations.This novel use of additives demonstrates a direct link between solvation/solute aggregation and conformational polymorph nucleation.Finally,the comparative method is also introduced to study the molecular mechanism of solid-solid thermal transitions of the series.It was found that DA5/7/15/17 could transform from form I to II,but DA9/11/13 does not transform during heating up.The result that the energy barrier of conformational change increases with the chain length increasing indicates that the energy barrier of packing change is the key to determining whether or not to transform.Combined with the analysis of the new crystal structures of DA13/15/17,the comparative analysis of energy framework,the proportion of the forces and the structural stackings reveals that the balance of the alkane chain length and the molecular intralayer/interlayer O-O interactions play an important role in determining whether the transition could happen.The related transformation model was perfected to clarify the mechanism of the difference in the transformation behavior of DA7→DA9/11/13→DA15/17.