Can Melting Point Trends Help Us Develop New Tools To Control the Crystal Packing of Weakly Interacting Ions?

Abstract

Ionic liquid forms of biologically active molecules (e.g., active pharmaceutical ingredients or herbicides) are often designed by using weakly interacting, conformationally flexible ions. However, crystalline forms of these molecules involve strong interactions and efficient packing. The salts of biologically active molecules may completely lack the directional supramolecular synthons typically used in crystal engineering, and thus new tools must be developed to control the crystal packing without strong directional interactions and predict their structure−property relationships in advance. The crystal structures of tetrabutylammonium and phosphonium salts of two structurally related, biologically active ions, salicylate and dicamba, show systematic differences from their free acids and metal salts, which are dominated by strong directional interactions. Molecular conformation and the structure of oligomeric ions of acids and their conjugate bases are conserved across multiple structures. The use of flexible, weakly coordinating cations to make salts of high melting biologically active acids can dramatically change melting points based on the size and shape complementarity of the ions and the ability of the cations to enhance anion−anion repulsion.

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

“…[31][32][33][34][35][36][37][38][39] The Clxx isomer grid provides an illustration of Carnelley's rule, which relates the crystal melting temperature to the symmetry of the crystallized molecule. [81][82][83][84][85][86][87][88][89] An empirical function based on the substituent positions and the lattice electrostatic energy is introduced, allowing us to obtain the fitted melting temperatures which are more than 95% correlated with the experimental values. Given the high correlation, this model will be further refined in series of related benzamides and its possible predictive behaviour will be evaluated.…”

“…Conversely, methyl-substituted and meta-or orthosubstituted are preferred for lower melting point compounds. [40][41][42][43][44][45][46][81][82][83][84][85][86][87][88][89]…”

“…In an attempt to model Carnelley's rule, the ortho-/meta-/para-position descriptor f is introduced (Figure 11a). [81][82][83][84][85][86][87][88][89] The f(Clxx) function, defined as: , where E lat is the lattice electrostatic energy and E HB is the electrostatic energy between the two atoms involved in the strong hydrogen bond (N…H N or O…H N ) atoms using the transferred multipolar atom model. (c) Double linear fit of melting point using the f and E lat -E HB parameters.…”

Azolate Anions in Ionic Liquids: Promising and Under‐Utilized Components of the Ionic Liquid Toolbox

“…[38] This is an otable difference from conventional ILs (with more weakly hydrogen-bonding anions), which tend to experience increased melting pointsw ith substitution in this position. [41][42][43] Rich hydrogen-bondinge nvironmentsb etween amino groups of 5-aminotetrazolate ILs and neighboring ions are also observedi no ther SCXRD analyses, [44] and were proposed to contribute significantly to their increasedthermalstability. Similarly,interionic hydrogen bonding is an additive interaction to the coulombic cation-anion pairs of the 1,2,4-triazolium 5-nitro-tetrazolate ([tri][5-NO 2 -tet]) salt (showni nF igure 2), inducing significant order to the crystal lattice.…”

“…SCXRD analyses have also revealed the role of significant interionic hydrogen bonding in increasing the melting points of the salt, with, for example, methyl substitution of the acidic C2‐proton of an imidazolium cation lowering the salt's melting point from 137 °C to 62 °C . This is a notable difference from conventional ILs (with more weakly hydrogen‐bonding anions), which tend to experience increased melting points with substitution in this position . Rich hydrogen‐bonding environments between amino groups of 5‐aminotetrazolate ILs and neighboring ions are also observed in other SCXRD analyses, and were proposed to contribute significantly to their increased thermal stability.…”