**5. The special cases: concomitant, vanishing (or disappearing) and intergrowth polymorphism**

The terms *Vanishing or disappearing polymorphs* were renowned during the second half of the twentieth century by referring to the evolving nature of some crystal forms over time that caused their unrepeatability. In the course of the subsequent years, researchers realized that every crystal form can be repeated being the finding of the proper conditions (control over nucleation and crystal growth) the main trouble.

Within the polymorphism landscape, the presence of mixtures of crystalline phases has brought a profound attention whereby, many efforts were devoted to the understanding of such circumstances. Reproducibility and purity have always been a requisite for chemists, so such demonstration of lack of control led them to seek to comprehend and identify the source of these phenomena. These two closely related special cases, named as *Concomitant* and *Vanishing* polymorphs, refers to a condition describing all the forms involved. *Concomitant* polymorphs are those simultaneously formed at the exactly same conditions. This assertion is not trivial since many factors contribute to the crystallization process. The case of *vanishing* or *disappearing* polymorphs describes the formation of a metastable phase which undergoes transformation into a more thermodynamically stable one. This phenomenon is quite thorny since as mentioned, reproducibility of the results is often intricated. Such conversions can be found by redissolution of the former crystal or in solid-state. In the solution-mediated process, the formation and disappearing of a metastable product can be quenched by *seeding*. A crucial statement is to be noted, once seeds of one polymorph are formed, the other form will no longer be formed. By using this criterion, seeding *crystallites* of the desired polymorph will lead to the growth of its crystals, even though it is a metastable form [60]. This method allows to avoid both undesirable cases, *concomitancy* and *vanishing*, if phase-pure materials are to be achieved. *Vanishing* by solid-state transformations is even less evident, indeed, any slight appliance of an external stimuli can promote this phase change and routinely sample treatments required for many characterization techniques as grinding, milling or pressure and temperature changes could be sufficient to trigger it. Both phenomena have probably been less reported than occurs and just a curious point is that the first recognized example of *polymorphism* in an organic substance

described by Wöhler [10] the *dimorphism* of benzamide, that was also the first precedent of *concomitancy*.

The critical point describing *concomitant* and *vanishing* polymorphs is based on the same kinetic/thermodynamic factors, better understandable by the mentioned E/T plots and promoted by the kinetic govern. In fact, *concomitancy* is dependent on where from the diagram the polymorphs are growing. Having this data, one can also design a strategy to favor the nucleation of one polymorphic form instead of the other.

Identification of concomitant polymorphs is as always, initially assessed by visual recognition. Thus far, careful inspection during hot-stage microscopy has been the most reliable method. Differences in crystal habit and variable melting point suggesting crystalline mixtures could provide a clue as to trace *concomitancy*. Also broadening signals in solid-state NMR or FTIR-ATR may be a symptom of this.

Reported cases of *vanishing* polymorphs in metal–organic compounds are in large part still unfathomed. The phenomenon of *concomitant* polymorphs is equally meager being only few examples reported hitherto. Oliver [96] in 2012 reported the special case of two Cd(II) coordination polymers concomitantly formed from which the less stable form was subsequently identified as a disappearing polymorph. Both products crystallize in the monoclinic crystal system but the stable form (2) exhibited a C2/c space group and bigger unit cell parameters than the vanishing form (1), which displayed a P2/c space group. Their main dissimilarity was the slightly different orientation of the dipicolinate ligands (**Figure 6**), which improved the inter-chain π···π interactions in the structure of the stable form and provoked a different packing.

In the case of organic structures, several examples can be found in literature. Chalcones are a class of natural products widely used in medicinal chemistry. For instance, the (E)-3′-dimethylamino-nitrochalcone has demonstrated *concomitant polymorphism*, easily detectable by the different colors associated to each form [97].

In spite of topologically flexible MOFs as ZIFs and other azolates are prone to manifest *polymorphism*, the scarce monitoring of *in situ* structure formation thwart its recognition. An example of concomitant polymorphism has been recently reported by Sánchez and Fernández [98] with two Pt(II) metallosupramolecular polymers. Both products were formed by self-assembly of monomeric units but

#### **Figure 6.**

*(a) Overlapping representation of the two Cd(II) polymeric chains in the two polymorphs. Different disposition of dipicolinate ligands: front chain (1) and back chain in dark (2). (b) c axis view of the packing of the less stable form 1 and (c) a axis view of the packing of the more stable form 2 [96].*

*Polymorphism and Supramolecular Isomerism: The Impasse of Coordination Polymers DOI: http://dx.doi.org/10.5772/intechopen.96930*

differed in presenting slipped or pseudoparallel packings. In 2020, a new study from Hanusa and Friščić [99] identified the presence of a *disappearing* polymorph during the formation of two different Hg(II) imidazolate (Hg(Im)2) phases, synthesizing a new layered structure (*sql*) with the consequent disappearing of a previously reported interpenetrated dense phase (*dia*) Hg(Im)2 [100]. Both forms exhibited an orthorhombic crystal system but having evident structural differences driven by an *agostic* interaction (C-H··Hg) in the *sql* form. The *dia*-Hg(Im)2 contained tetrahedral Hg(II) nodes in a Pbca space group and cell parameters of *a* = 14.5899(3) Å; *b* = 10.8076(2) Å; *c* = 9.8200(2) Å while the *sql*-Hg(Im)2 form presented a tetrahedral *see-saw* geometry in the space group P21212, with *a* = 9.4089(4) Å, *b* = 7.6414(3) Å, *c* = 5.3625(2) Å. The transient nature of the *dia* form was tracked by PXRD during the mechanochemical synthesis of *sql* form, being inaccessible to reach *dia* form as a final product.

*Intergrowth polymorphism* was firstly reported by Bond, Boese and Desiraju [101] in 2007 during a study about the doubtful crystalline forms of aspirin and the related difficulties of its structural refinement. It was conceived *to refer to the existence of distinct structural domains within a single crystal of a compound*. When analyzing the one-dimensionally diffuse diffraction data, using Bürgi [102] method, they noticed some diffuse streaks between the Bragg reflections. Considering the reported results of Bürgi, this would be associated with the presence of a less ordered domain. Careful inspection of such results led them to identify two differently ordered domains in the same crystal of aspirin. They also demonstrated by a nanoindentation study in 2014, a bimodal mechanical response depending on which of the crystal faces were measured [103]. From the metal–organic perspective, there had already been examples reported by Ciani of *coordination polymers* of cobalt(II) *intergrowth supramolecular isomers* [104] and copper (II) *intergrowth polymorphs* [105] due to the presence of conformational non-rigid linkers.

## **6. Interest of polymorphism in organic and metal–organic structures**

*Polymorphism* has an implicit interest since it represents a special situation for the study of structure-properties relationship with limited number of variables as well as provides essential information to understand and control the crystalline inception. The special case of *concomitant polymorphs*, is in turn, an even more worthwhile situation. From a unique reaction, one could establish direct relations between structure modifications and properties. They are also benchmark products for computational analysis as well as for verification of structure-prediction softwares. All this beneficial knowledge can be fruitfully employed throughout the industrial and academic landscape.

### **6.1 Industrial interest**

In the industrial field, stability and purity are mandatory equal for organic and metal–organic materials. Properties of organic solids reflected in their processability and storage as well as solubility and dissolution rates are directly related with bioavailability of a drug and hence are of prime interest to the pharmaceutical industry. For instance, an important concern in the manufacturing, storage and transport of energetic materials is that polymorphic modifications alter the energetics and safety risks associated to them. A representative case is 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX), in which higher compact crystal packings lead to the safer form [106]. In addition, *polymorphism* has relevant commercial impact in the patenting of drugs [107] as in the renowned case of Ranitidine, a drug for the treatment of stomach and intestines ulcers. The subsequent discovery of the polymorphic form 2, having an easier manufacturing procedure, after the patenting of form 1, originated a lengthy court process [108]. *Concomitant* polymorphs are regularly found in industrial precipitation processes in the pharmaceutical and fine-chemicals sectors as in the case of L-histidine, to which anti-solvent crystallization became an inevitable proceeding [109]. *Coordination polymers* has special interest for waste water treatment, protective coatings and fluorescent chemosensors [110]. For instance, in MOFs the thermo-mechanical stability is crucial to move towards the industrial segment. Among the most promising applications, those of industrial interest are adsorption, separation, purification and catalysis. They are being exhaustively tested to supersede, by improved performance, the extensively exploited zeolitic molecular sieves, activated carbon and base metal oxides [111]. Furthermore, ZIFs materials have exhibited remarkable efficiency in separation of olefin/paraffin mixtures [112] and emerged as appropriate candidates to adsorb and retain radioactive iodine [113]. All of these applications depend on the structural arrangement of the materials and thus, control over crystal structure formation is imperative.

### **6.2 Academic interest**

The interest of *polymorphism* in *coordination polymers* lies on the always present structure-properties relationship. The exact control of their structural arrangement is reflected in the achievement of the desired chemical and physical properties. Despite being known as promising functional materials their modular nature can result in polymorphic forms and thus, hampering their application. This is emphasized in applications demanding a high selectivity as enantiomeric separation, gas storage, sensing, molecular recognition, ionic exchange [114], heterogeneous catalysis [115] or non-linear optics. The rise of MOFs, a remarkable case of ordered coordination polymers with potential voids and permanent porosity was driven by the breakthrough of the archetypal MOF-5 [116]. Their main attribute is the controlled porosity to which the formation of cages allows their controlled use in such applications. Currently research is devoted to study structural transformations in Zr-based MOFs. Also a particular family of MOFs essentially constructed with zinc(II) or cobalt(II) metal ions, the Zeolitic Imidazolate Frameworks (ZIFs), have been explored for their superior thermal and chemical stability but as zeolites, the ZIF family displays rich polymorphism [117]. The Zn(Im)2 itself can accommodate 18 polymorphic forms, being essential towards its application the finding of controlled synthesis as the recently established template-mediated route [118]. As afore mentioned, there has been evidence in the recent cases of Cd(II) *coordination polymers* or especially in the ZIF material *dia*-Hg(Im)2 of the undesirable scenario of *vanishing polymorphs.* In the latter case, the formation of the more stable form has hampered the obtention of the 3D structure being superseded by the new layered *sql*-Hg(Im)2. These examples demonstrate the dormant resemblance of metal–organic materials with such well known phenomenon in organic compounds. Another important subject are phthalocyanines, being copper phthalocyanine the model compound. They revolutionized color printing offering a better economic remedy but facing polymorphic troubles since their discovery. Subtle alterations of their crystal packing which is based on π···π interactions, acutely influences the absorption properties with the consequent color change from blue to red [119]. *Intergrowth polymorphism* and *intergrowth supramolecular isomerism* in coordination polymers has also been promoted by flexible linkers and several examples have been reported hitherto mainly with d10 metal ions [120]. This ability to present different properties available in a single crystal open new possibilities for materials design.

*Polymorphism and Supramolecular Isomerism: The Impasse of Coordination Polymers DOI: http://dx.doi.org/10.5772/intechopen.96930*
