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Cite This: Cryst. Growth Des. 2018, 18, 3704−3712 pubs.acs.org/crystal

Engineering Crystal Properties through Solid Solutions Matteo Lusi*

Department of Chemical Sciences and Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Ireland

ABSTRACT: The control of structures and properties in crystalline materials has many returns that justify the increasing efforts in this direction. Traditionally, crystal engineering focused on the rational design of single component molecular crystals or supramolecular compounds (i.e., ). More recently, reports on crystalline solid solutions have become common in crystal engineering research. Crystalline solid solutions are characterized by a structural disorder that enables the variation of stoichiometry in continuum. Often such variation corresponds to a variation of structural and physicochemical properties, and offers an opportunity for the materials’ fine-tuning. In some cases, though, new and unexpected properties emerge. As illustrated here, both behaviors make solid solutions particularly relevant to the scope of crystal engineering.

■ INTRODUCTION crystals whose “cells and symmetries are to a good extent controllable”. In his words, through such substitution “crystals In recent years, the number of publications that focus on some ‘ ’” 2 aspect of solid state chemistry has grown faster than, for with advantageous properties can be engineered . Later, Schmidt regarded the control of molecular packing as “a example, those focusing on more traditional synthetic ones ” 3 (Figure 1). problem of crystal engineering . Early attempts at crystal engineering exploited supra- molecular interactions4 to rationalize the features observed in known crystal structures and to design new ones.5,6 Even today the most successful strategy to engineer supramolecular crystals7 utilizes relatively weak interactions such as hydrogen and halogen bonds that drive the (self-)assembly8 of the chosen − chemical species.9 11 A similar approach is applied to metal complexes and coordination polymers in which organic and inorganic species are bonded by a stronger chemical (coordination) bond.10,12,13 Currently crystal engineering is identified as the branch of solid state chemistry that focuses on organic and “metal− organic” materials such as salts, molecular crystals, and − coordination polymers.14 18 Multicomponent Crystals. Supramolecular self-assembly Figure 1. Proportion of papers containing the keywords “synthesis” and “solid-state”, over the past century (from the Scifinder database). enables the utilization of molecules and ions as building blocks or tectons.19 In many cases, the supramolecular interactions 20 6,21 Such interest is fueled by the need for new materials for (synthons) and their motifs and patterns are so robust that technological applications, or better performing solid forms of the same supramolecular structures are produced consistently active pharmaceutical ingredients (API) and agrochemicals. by building blocks that present the appropriate functional groups. This approach allows for a rational modification of the Indeed, many physicochemical properties of a material depend 22 fi on its composition (chemical identity and stoichiometry) as whereby the degree of ne-tuning is determined by the difference in size and shape between well as its structure (polymorphs, defects, morphology, etc.). 23 Then, full control over composition and structure is required to equivalent building blocks. produce a material with optimal physical and chemical Such a supramolecular approach is particularly convenient properties for the intended application. The design, synthesis, whenappliedtomulticomponent crystals. In fact the modification, and characterization of crystal structures and their combination of more than one substance increases the potential properties fall within the scope of crystal engineering.1 for structural variability, which in single component crystals is Crystal Engineering. The first recorded use of “crystal engineering” is attributed to Pepinsky.2 He noted that in a Received: November 26, 2017 series of salts the substitution of the organic cation afforded Published: April 30, 2018

© 2018 American Chemical Society 3704 DOI: 10.1021/acs.cgd.7b01643 Cryst. Growth Des. 2018, 18, 3704−3712 Crystal Growth & Design Review limited to the phenomenon of polymorphism (Figure 2). Self- physical mixtures. In his seminal book,30 Kitaigorodskii used assembly has been successfully exploited to produce multi- “mixed crystals” to refer to molecular crystals in the broadest sense. In that case, the expression was also used for single component structures with Z′ > 1 or physical mixtures of polymorphs.36 Even recently, the term was used for common cocrystals,37 mixture of phases,38 and simple salts.39 Mixed crystal is sometimes also used for organic and coordination polymers, which are single macromolecules or blends rather than molecular crystals. Most often, though, the use of mixed crystal is limited to crystalline solid solutions of discrete molecules. More recently the expressions mixed cocrystal40 or solid solution41 have also been defined. These materials are cocrystals in which the structural function of a single conformer is ensured by two or more molecules that can be present in a variable ratio.42 Desiraju showed that solid solutions of three and four component cocrystals can be designed through crystal engineering.43,44 The term alloy, originally used only for metallic materials Figure 2. Example of structural relationship and variability possible for such as solid solutions, mixtures, and intermetallic and single component crystals (polymorphism), multicomponent crystal nonstoichiometric compounds,45,46 has also indicated both (discrete variations), and crystalline solid solutions/mixed crystals molecular47,48 crystals and coordination polymers.49,50 In this (continuous variation). case the qualifier organic51,52 is added to highlight the difference from the original acceptation. Within the field metallogranic 24 13 component crystals of neutral and charged species as well as frameworks, the expression multivariate MOFs has also been 25 multiple-phase composite solids. In these materials, which used to indicate solid solutions of porous coordination include metal complexes, salts, cocrystals, and, more recently, polymers.53 26 ionic cocrystals, multiple components cocrystallize in a In the future, this plethora of terms needs to be rationalized, stoichiometric ratio and behave as a supramolecular compound. and a homogeneous and a shared nomenclature needs to be 27 These compounds obey Dalton’s law of multiple proportion, defined for this class of materials. and, generally, in their crystals, each component occupies well- fi 28,29 de ned crystallographic positions. ■ SOLID SOLUTIONS IN CRYSTAL ENGINEERING Adifferent type of multicomponent material is represented by solid solutions.30,31 These phases are characterized by a Solid solutions of molecular and polymeric materials have been structural disorder,32 which is responsible for properties that are studied long before the concepts and strategies of crystal typical of liquid solutions. As with their liquid counterpart, the engineering were formalized.54,55 Most publications describe stoichiometry of solid solutions is not limited to a single the relationship between composition and structure. At the integral value but can be varied in continuum. Indeed, as for same time, there are numerous examples that demonstrate how liquid solution, solubility in the solid state does not need to be it is possible to fine-tune in continuum many properties such as complete but can be observed in a limited composition range. thermal and chemical stability, piezoelectricity, photochromism, Most importantly, the stoichiometry variation produces a , etc. (vide infra). Such a level of control is unmatched continuous variation of structural, thermal, and chemical in other areas of molecular and , and, properties (colligative), making these materials particularly as illustrated in the examples below represents a new possibility amenable to fine-tuning (Figure 2). Often solid solutions have for the rational design of structures as well as physicochemical properties that are between those of the pure components, but, properties for technological, pharmaceutical, and chemical in some cases, new properties arise. Either way, as illustrated in separation/storage applications. below, crystalline solid solutions represent an opportunity to Crystal Structures. Solid solutions are constantly inves- understand the structure property relationship. tigated to rationally modifying structures and to gain insight − into crystal packing principles.56 60 Vagard’s law states that in a ■ NOMENCLATURE: SOLID SOLUTIONS, MIXED solid solution a linear correlation exists between composition CRYSTALS, ETC. and unit cell dimensions.61,62 The relationship, originally Since its introduction in the 19th Century,33 the expression observed in metals and inorganic salts, also applies to molecular “solid solution” has been used in a variety of contexts to refer to crystals,63 zero dimensional metal complexes,47 and coordina- both crystalline and amorphous solids. Historically, probably tion polymers.64,65 In larger systems, deviations from strict due to the technical limitations that prevented accurate linearity are common.66 An accurate structure analysis of these structural characterization, the main criterion for the identi- crystals can reveal the causes of such deviation and help in fication of these phases has been their chemical composition understanding the structure−composition relationship. For (stoichiometry). In this sense the term has indicated any solid example in BiSX1−xYx (X, Y = Cl, Br, I) the anisotropic unit that did not obey Dalton’s law of multiple proportions.27 This cell variation is due to a rotation of the bismuth halide complex, included substitutional crystals and partially occupied host/ which is consequent of the progressive elongation of the guest systems,30 as well as interstitial and intercalated halogen−halogen interaction.67 In the organic acridine/ compounds.34 phenazine system, the increased H···H steric hindrance causes The expression mixed crystal35 has been used with multiple a similar molecular rotation that is responsible for the nonlinear meanings indicating crystalline solid solutions as well as relationship between volume and composition (Figure 3).68

3705 DOI: 10.1021/acs.cgd.7b01643 Cryst. Growth Des. 2018, 18, 3704−3712 Crystal Growth & Design Review

of the isomorphous barium and lead nitrates whereby the partial “segregation” of the cations causes a symmetry reduction from the centrosymmetric Pa3̅space group to the non- centrosymmetric R3.78 Technologically Relevant Properties. Solid solutions have been studied for almost a century to investigate the effect of chemical composition on optical, electrical, and photo- chemical properties.79 Diluted solid solutions of chlorophyll were found to alter yield and lifetime of the chlorophyll triplet state as well as the wavelength of maximum absorption.80 Similarly, organic crystals of α-naphthylphenylbiphenyl diamine (α-NPD) can be mixed with rubrene to produce white organic light-emitting diodes (OLED).81,82 Due to the low concen- Figure 3. Direct comparison of the crystal structures of acridine/ tration of the solute, these phases should perhaps be referred to phenazine solid solutions structures with 45 (blue), 68 (green), and as doped organic materials rather than solid solutions.83 75% (red) acridine composition; the short H···H contacts are highlighted in the red circle. Jones et al. have promoted photoreactivity in photostable benzylbenzylidenecyclopentanones by mixing chloro, bromo, 84 Structural changes can also occur in a discontinuous fashion. and methyl derivatives of the same moleucule. Oashi and co- A centrosymmetric racemic crystal will convert into a chiral one workers measured the photoreactivity of 3-chloro-, 3-bromo-, as soon as the enantiomeric enrichment begins, i.e., when the and 3-methylpyridine complexes and showed that the rate of first molecule is substituted in the racemate.58 At the same time reaction depends on the size of the cavity around the reactive such loss of symmetry is not always recognizable crystallo- group. Then they modify the cavity size by making solid solutions, which confirmed their theory and proved that the graphically. For example, the recently reported solid solution of 84,85 D- and L-malic acid could only be solved in the centrosymmetric rate of reaction could be tuned. A similar mechanism is C2/c space group despite simple geometrical considerations behind the improved water and light stability of Pigment Red that impose a chiral structure (Figure 4).69 For this reason the 170. Here denser, and hence more stable structures, are obtained through mixed crystals with bromo, chloro, fluoro, and methyl substituted analogues.86 Lahav and co-workers investigated and explained the origin of polarity and pyroelectricity in cinnamamide/thienylacryla- mide, and asparagine/aspartic acid systems.71,76,77,87 As discussed above, the reduction of crystal symmetry was attributed to a non-homogeneous distribution of the component within the mixed crystal. Hulliger et al. have discussed the polarity in solid solutions of polar 4-chloro-4′- nitrostilbene molecules and nonpolar 4,4′-dinitrostilbene.70 The photochromism of yellow, red, and blue diarylethenes Figure 4. Schematic representation of the racemic, solid solution, and can be tuned by preparing two- and three-component enantiopure crystals in the D-malic acid/L-malic acid system. crystalline solid solutions. The solid solutions enable access to intermediate color tones.88 In hydrogen bonded mixed salts effects of chiral (and polar) enrichment has been interpreted as of bipiridinium metal halide, color and light absorbance can be a “continuous loss of symmetry”, and it is observed in tuned by substitution of chloride and bromide ligands through − properties such as the intensity of the second harmonic.30,70 72 solid−gas reactions.65 Solid solutions of photochromic fulgide Other discontinuous transitions are observed between enables the modification of both absorption spectra and insulator/conductor or para-/ferromagnetic states.73 Here it mechanical properties of the crystalline product (Figure 5).89 must be stressed that the existence of different crystal forms as a Mixed organometallic crystals have been known for over 30 consequence of varied composition cannot be regarded as years. Ward prepared functionalized solid solutions of ferrocene polymorphism. In fact these phases would not lead to an and ruthenocene complexes and showed that the optical identical liquid or vapor state.74 On the other hand crystalline properties of the material follow the Beer’s law.90 Braga, solid solutions can exhibit polymorphism whereby a single Grepioni, and co-workers reported one of the first examples of chemical composition affords multiple crystal forms. In these the ferrocenium/cobaltocenium system that shows complete cases the stability of each can vary with composition.75 solubility.47 Those solid solutions enabled the fine-tuning of the In some instances, the structure of a mixed crystal differs polymorphic and transitions with a 20 °C range. from those of the parent components. For example, solid Pharmaceuticals. Arguably, the most detailed description solutions of the organic salts of tetracyano-p-quinodimethane of pharmaceutical solid solutions is related to the separation with tetraselenafulvalene and tetrathiafulvalene show enhanced and purification of enantiomers and racemic mixtures. In fact in electronic properties that are attributed to the disordering of such processes racemic solid solutions can be produced. This the molecular stacking.51 Lahav showed that chirality appeared large body of work includes the theoretical background needed upon inclusion of nonchiral of cinnamic acid molecules in to understand thermodynamic and kinetic behaviors of centrosymmetric cinnamamide structures.76,77 In that case the molecular solid solutions. The topic is frequently reviewed reduction of symmetry was explained by the occlusion of and will not be treated here.91,92 specific crystal faces as the crystal grows. In a similar way, Kahr The pharmaceutical industry has long investigated solid explained the long-known “double refraction” of mixed crystals solutions and eutectic mixtures with the idea of modifying the

3706 DOI: 10.1021/acs.cgd.7b01643 Cryst. Growth Des. 2018, 18, 3704−3712 Crystal Growth & Design Review

Figure 6. melting point of the three-component system of chloro-, bromo-, and methyl- para substituted benzyl alcohol. Reproduced from ref 59 with permission of The Royal Society of Chemistry.

the hardness of the crystals, which could be relevant in manufacturing processes.103 Recently, solid solutions have been prepared for pharma- ceutical cocrystals.40 Neutral APIs can be crystallized with two or more similar coformers that can substitute for one another in a variable ratio.60,69 Then, the use of mixed coformers can help increase structural and chemical variability as well as modify molecular solubility in the solid state. For instance, Zhang reported the phase diagrams of the ibuprofen enantiomers with Figure 5. Variation of absorbance measured for the peak in the visible 4,4′-bipyridine and suggested the potential use of that solid portion of the spectrum as a function of coloring and bleaching cycles solution for enantiomeric separation.104 in a series of fulgide compounds: (a) p-methyl- (1E), p-chloro- (2E), Nonstoichiometric hydrates are another type of solid and p-methyl-/p-chloro-fulgide (MIX-1E), (b) p-methyl- (1E), p- solutions that are sometimes encountered among pharmaceut- bromo (3E), and p-methyl-/p-bromo-fulgide (MIX-2E). Reprinted ical crystals. In LY297802 (Vedaclidine) tartrate the water with permission from ref 89. Copyright 2017 American Chemical content varies in continuum, from anhydrous to the hemi- Society. hydrate form, as a function of external humidity.105 Paroxetine HCl absorbs up to 0.8 equiv of water, and the absorption is associated with a continuous structure transformation in which dissolution rate and absorption of drugs.93 Goldberg et al. the unit cell volume increases from 915 Å3 for the anhydrous published a series of papers on mixed acetaminophen−urea,94 phase to 948 Å3 for the fully hydrated phase.106 In many cases, chloramphenicol−urea,95 and griseofulvin−succinic acid sys- though, nonstoichiometric hydrates are characterized by tems.96 They reported that the dissolution rate in solid channels that water can fill reversibly without structural solutions of these materials could increase up to seven times. changes. In crystals of sitafloxacin, the water content can − Similar results were reported for steroids in the mid-1970s,97 99 change between a di- and a sesquihydrate form without although early substitutional solid solutions of cholesterol had macroscopic structural changes.107 Manufacturing and storage been known for almost 50 years.100 of these crystals represent a serious technical challenge as any More recently, solid solutions of drug molecules are being variation of temperature and humidity can affect the product’s investigated to improve the thermal and mechanical response of composition, structure, and properties. the product, which are important for the materials manufactur- Inclusion Compounds. Inclusion compounds have been ing, tableting, and storage. Braga, Grepioni, and co-workers investigated for chemical separation. Typically a host material have reported binary and ternary solid solutions of chloro-, would preferentially absorb one compound from a mixture or a bromo-, and methyl- para substituted benzyl alchool.59,101 solution. For example, water and urea clathrates have been Their work shows that a variation of composition could raise studied for almost a hundred years for scientific curiosity, but the melting point of the product from 53 to 80 °C(Figure 6). also for molecular separation, sensing, and storage.34 In these The hydrogen bonded salt (±)-4-methylmethcathinone inclusion compounds, the simultaneous of hydrochloride undergoes an enantiotropic multiple guests (and solvents) is a common phenomenon upon cooling. Oswald and co-workers have reported that, in the that reduces the material selectivity.108 For example 9,99- solid solution (±)-4-methylmethcathinone HX (X = Cl or Br), (biphenyl-4,49-diyl)difluoren-9-ol crystallizes with both THF the polymorphic transition temperature could be altered by up and diethyl ether. Recrystallization from a mixture of those to 80 °C depending on the amount of bromide.102 Desiraju solvents produces a solid solution in which both solvents are observed that omeprazole crystallizes as a tautomeric solid included as guests (Figure 7).109 In the analogue 9,9′-(ethyne- solution. Then the relative tautomeric composition can be 1,2-diyl)bisIJfluoren-9-ol) host, selectivity toward butanol and controlled by varying the crystallization temperature and affects propanol guests varies with crystallization temperature.110 Petit

3707 DOI: 10.1021/acs.cgd.7b01643 Cryst. Growth Des. 2018, 18, 3704−3712 Crystal Growth & Design Review

Figure 7. 9,99-(Biphenyl-4,49-diyl)difluoren-9-ol forms a mixed clathrates with THF and diethyl ether in which the oxygen of the guest is hydrogen-bonded to the alcohol of the host. and co-workers describe the chiral discrimination of modified cyclodextrin toward the enantiomers of p-bromophenyletha- nol.111 In that case, the formation of a solid solution reduces the selectivity of the host toward the chiral guest. On the contrary, host structures with mixed molecular components can be readily prepared to rationally modify the properties of the material. For example, Cooper prepared a porous cocrystalline solid solution by mixing three organic cages in a 0.5:x:(0.5−x) composition. The stoichiometry affects the BET measured for the product.112 The Werner complexes ff ffi [MCl2(4-PhPy)4] (M = Ni, Co) show di erent a nity toward a mixture of xylenes absorbing the three isomers. In the mixed- metal solid solution, at 1:1 composition [Ni0.5Co0.5Cl2(4- ffi PhPy)4]theanity toward the para-xylene isomer is suppressed, and the selectivity toward the meta and ortho isomers is enhanced.113 Davis reported a steroidal organic alloy that produced channels whose cavity can be decorated with a variety of functional groups. In that polymeric solid solution the different substituents affected the size and polarity of the cavity.49 Solid Solutions of Coordination Polymers. In the past ′ 30 years, one-, two-, or three-dimensional coordination Figure 8. Room temperature structure of {[(4,4 -bipyridine)ZnCl2]}n ′ polymers have been a rewarding object of study for crystal (top) and {[(4,4 -bipyridine)CoCl2]}n (bottom). engineers.10 In many cases the robustness of the coordination bond enables the design of porous architectures, i.e., porous Remarkably the solid solutions exhibited up to 4 times better coordination polymers (PCP) and metal organic frameworks selectivity for CO over CO. − 2 (MOFs).114 117 As reported by Kitagawa and co-workers interdigitated 2-d Nassimbeni reported that, in a series of nonporous 1-d layer such as [{Zn(5-MeO-ip)(bpy)}]n coordination polymers of Ni and Cd thiocyanate, thermal (CID 5) and [{Zn(5-NO2-ip)(bpy)}]n (CID-6) with ip = stability could be varied within a 120 °C range depending on isophthalate and bpy = bipyridine undergo a phase trans- the ratio between Cd and Ni.64 In the 2-d {[(4,4′-bipyridine)- formation, from a nonporous to a porous structure, upon ZnCl2]}n polymer, the Zn atom is tetrahedrally coordinated at sorption of CO2. In the solid solution [{Zn(5-NO2-ip)1−x(5- room temperature and octahedrally coordinated at low MeO-ip)x(bpy)}]n the relative 5-NO2-ip/5-MeO-ip composi- temperature. The partial replacement of Zn with Co enforces tion affects the partial pressure at which the transformation the octahedral geometry at room temperature (Figure 8), occurs: “gate opening pressure” (Figure 9).121 In a more recent representing an example of how solid solutions can force a paper, the authors observed that in the same porous particular chemical connectivity/symmetry and contrast self- coordination polymer, the relative 5-NO2-ip/5-MeO-ip com- assembly.118 position affects the rotational frequency of the bipyridine Due to the fast expansion of the field, many solid solution of linkers.122 porous coordination polymers (PCPs) and metal organic Framework flexibility and sorption isotherms were also tuned frameworks (MOFs) are constantly reported. Feng showed that in a pillared-layer MOF obtained by mixing a number of mixing a variable amount of imidazole and 5-methylbenzimi- substituted 1,4-benzenedicarboxylate by Schwedler et al.123 Cui dazole in the synthesis of a porous tetrahedral imidazolate showed that chiral multivariate MOFs, with up to three framework (TIF), could serve to control connectivity and different metallosalen-based linkers, possess enhanced catalytic topology.119 Gao tuned the UV spectrum and magnetic activity compared to the physical mixture of the parent properties of a chiral porous coordination polymer by mixing compounds.124 a variable amount of Co and Ni metal centers with D- Due to the wide scientific interest around these materials, (+)-camphoric acid and 1,4-di(1-imidazolyl-methyl)-benzene dedicated reviews that summarize mixed components PCPs and ligands.120 Yaghi showed the degree of variability possible for MOFs are available.125,126 Here, it must be noted that as the these materials by mixing multiple ligands and included up to complexity of these structures increases, the presence of eight different functional groups in a single prototypal MOF.53 multiple components does not always result in solid solutions.

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line solid solutions represents a promising strategy that adds the fine-tuning of the latter to the structure variability typical of the former. Such level of control is hard to match in molecular chemistry. Ideally, the ultimate crystal engineer will assemble any molecules in the desired structure and will be able to control unit cell size and symmetry as well as any physicochemical properties. It is perhaps questionable whether real world applications require the degree of control enabled by solid solutions. Perhaps traditional supramolecular compounds (e.g., cocrystals) can produce enough variability for practical uses. However, the study of solid solutions answers an aesthetic demand that is implicit in each scientific activity.129,130 In this sense these materials certainly deserve some attention in crystal Figure 9. CO2 sorption isotherms recorded at 195 K for [{Zn(5-NO2- engineering. ip)(bpy)}]n (CID-5) [(5-MeO-ip)x(bpy)}]n (CID-6) and the solid solution [(5-MeO-ip)x(bpy)}]n (CID-5/6). Adapted with permission ■ AUTHOR INFORMATION of John Wiley & Sons, Inc. from ref 121. Copyright 2000 by John Wiley Sons, Inc. Corresponding Author *Address: AD1_028, University of Limerick, Castletroy, Co. Limerick, Ireland. E-mail: [email protected]. Different components can act as different structural elements being in a fixed stoichiometry, or they can form a composites in ORCID an epitaxial architecture: core−shell crystals127 and CORE- Matteo Lusi: 0000-0002-9067-7802 128 MOFS. Funding ■ SUMMARY AND PERSPECTIVE The author thanks the Science Foundation Ireland (SFI) for Grant 15/SIRG/3577. In the past six decades, the idea of crystal engineering has Notes evolved from a utopian dream to a concrete possibility. 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