Structure, Cohesion Energetics, and Hydrogen Bonding Cooperativity in Fumaric Acid and Alkyl Fumarates: Insights from Experiment and Theory

Fumaric acid and alkyl fumarates are a family of structurally related compounds with a wide spectrum of potential or effective therapeutic applications. The series consisting of fumaric acid (FA), monomethyl fumarate (MMF), dimethyl fumarate (DMF), monoethyl fumarate (MEF), and diethyl fumarate (DEF) was studied in this work to address the following main questions: how does the number of OH···O hydrogen bonds that may be established due to systematic differences in molecular structure impacts on the molecular packing and lattice energetics? Is there evidence of a cooperative hydrogen bond strengthening when infinite 1D chains sustained by OH···O hydrogen bonds are formed? How well can the structural and energetic features of this series of related molecules be predicted by state-of-the art force field and periodic DFT procedures that are used in the rationalization or prediction of crystal structures and physical properties of molecular organic solids? By combining results from a variety of experimental (X-ray diffraction, Raman spectroscopy, DSC, Calvet drop-sublimation calorimetry) and theoretical (quantum mechanical, molecular dynamics simulations) methods, it was found that (i) in all cases, the molecular packing leads to layered solids, where each layer consists of 1D chain motifs linked to each other through C–H···O interactions. (ii) The 1D arrangements are determined by two main motifs: the R22(8) carboxyl dimer, typically found in mono- and di-n-alkyl carboxylic acids, and the staggered CH3···H3C synthon, which is present in mono-n-alkyl carboxylic acids and n-alkanes. This leads to the formation of carboxyl–carboxyl and alkyl–alkyl domains that are structurally isolated from each other. (iii) The lattice energy, as measured by the enthalpy of sublimation (ΔsubHmo), varies according to FA > MMF ∼ MEF > DMF ∼ DEF and is linearly correlated with the number of OH···O hydrogen bonds present in the structures. (iv) The larger enthalpy of sublimation of FA compared to MMF and MEF is linked to the number of OH···O hydrogen bonds but does not seem to be related to their individual strength. Examination of O···O distance and C═O stretching frequency as well as theoretically computed dissociation energies of dimeric FA, MMF, and MEF species suggests that the OH···O interaction is weaker in FA than in MMF and MEF. As such, the present study showed no evidence of a cooperative OH···O bond strengthening in FA, relative to MMF and MEF, due to the presence of infinite 1D chains sustained by carboxylic acid dimers. (v) No evident connection between ΔsubHmo and compactness indicators such as density or Kitaigorodski packing index was also found. Finally, (vi) MD simulations and periodic DFT calculations were both able to reproduce the above-mentioned ΔsubHmo trend and capture the main structural features of the family of crystalline materials studied in this work. In terms of accuracy, better overall performance was observed for the force field method developed for this particular type of compounds.