Peggy Etter and Polymorphism: Highlights of an ... - ACS Publications

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Peggy Etter and Polymorphism: Highlights of an Enduring Scientific Legacy William H. Ojala Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01482 • Publication Date (Web): 22 Jan 2016 Downloaded from http://pubs.acs.org on January 25, 2016

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Crystal Growth & Design

Peggy Etter and Polymorphism: Highlights of an Enduring Scientific Legacy

William H. Ojala*, Department of Chemistry, University of St. Thomas, St. Paul, Minnesota 55105-1079

Abstract Margaret C. “Peggy” Etter in her brief but inspiring career made lasting contributions to the field of organic solid-state chemistry. Although her studies on hydrogen bonding may be those for which she is most clearly remembered, her studies on polymorphism, which can be traced to some of her earliest published work, are also a significant part of her scientific record. In this Perspectives article her polymorphism studies are summarized, and current work on these same polymorphic systems is described. The current and active interest in the polymorphs Peggy studied during her lifetime demonstrates that Peggy’s scientific legacy endures. Less easily traced but still discernible in this scientific record is evidence of the kind of scientist and person Peggy Etter was: energetic, vibrant, and unforgettable.

*William H. Ojala, Ph.D. Department of Chemistry University of St. Thomas 2115 Summit Avenue St. Paul, MN 55105-1079 Phone: (651)-962-5585 Fax: (651)-962-5209 e-mail: [email protected] 1 ACS Paragon Plus Environment


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Peggy Etter and Polymorphism: Highlights of an Enduring Scientific Legacy William H. Ojala*, Department of Chemistry, University of St. Thomas, St. Paul, Minnesota 55105-1079

Abstract Margaret C. “Peggy” Etter in her brief but inspiring career made lasting contributions to the field of organic solid-state chemistry. Although her studies on hydrogen bonding may be those for which she is most clearly remembered, her studies on polymorphism, which can be traced to some of her earliest published work, are also a significant part of her scientific record. In this Perspectives article her polymorphism studies are summarized, and current work on these same polymorphic systems is described. The current and active interest in the polymorphs Peggy studied during her lifetime demonstrates that Peggy’s scientific legacy endures. Less easily traced but still discernible in this scientific record is evidence of the kind of scientist and person Peggy Etter was: energetic, vibrant, and unforgettable.

2 ACS Paragon Plus Environment

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With time, even the most vivid memories can fade. In contributing this Perspectives essay to this special issue of Crystal Growth and Design, I hope to bring back memories of Margaret (Peggy) Etter and her contributions to solid-state organic chemistry to those of us who had the privilege of knowing her personally, and to introduce Peggy and her work, particularly in the area of polymorphism, to those who unfortunately can meet her only through her publications. A list of her papers is given in the special issue of Chemistry of Materials dedicated to her legacy in 1994 along with a biographical essay by Mark Hollingsworth and Mike Ward that beautifully describes her powerful influence both on the field of solid-state chemistry and in the lives of her many friends and colleagues.1 Peggy’s studies in the prediction and description of hydrogen bonding patterns in crystals are a well-known part of the scientific record, but perhaps less well known might be her studies of polymorphism in organic compounds. I hope that through this brief overview of her polymorphism work I can give readers of this Perspectives article a more complete appreciation of her contribution in this area so that it is not overlooked, especially in light of her more familiar H-bonding work. I hope I can also express to those readers who did not have the opportunity to meet Peggy why those of us who did meet her all those years ago still find her unforgettable as a person as well as a scientist. Peggy Etter and I were scientifically related in that we both had another unforgettable individual, Jack Gougoutas, as our Ph.D. research advisor during our graduate school years in the Chemistry Department of the University of Minnesota. Our stays in the Gougoutas laboratory did not overlap; Peggy completed her Ph.D. work in 1974, and I began mine in early 1978. Although (surprisingly, given the impact of her personality) I do not remember exactly when I met Peggy for the first time, it may have been at a Chemistry Department seminar in the early 1980s. As I was completing my thesis some years later, she as a new faculty member was



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moving into the former Gougoutas laboratory space in 90 Kolthoff Hall, where I was then working and writing. I will never forget how supportive and encouraging she was as I was completing my thesis; this was how I first became aware of one of her finest qualities as a mentor, her ability to bring out the best in those with whom she worked. As I happened to be present at the beginning of her academic career at the University, I also happened to be present at its close. During the last year of Peggy’s life (1991-1992), I worked in her laboratory with the Etter Research Group. At that point in my life I was struggling to obtain a teaching position and my academic future appeared uncertain, but Peggy helped me during the final stages of her own life by finding the funds to support my stay with her group as a postdoctoral research fellow. She suggested that I work on a project begun by her student Andrea Cicero investigating the polymorphism of anthranilic acid. Our work in her laboratory on this project ultimately resulted in a publication, “Polymorphism in anthranilic acid: A re-examination of the phase transitions,” which appeared in the Journal of the American Chemical Society in 1992.2 Although polymorphism was thus the subject of one of Peggy’s final publications, she actually published on the topic throughout her academic career, even at its beginning; the title of her Ph.D. thesis is, “Solid-State Chemistry and Crystallography of Two Polymorphs of 1Methoxy-1,2-Benziodoxolin-3-one.” Her subsequent publication record can be followed in detail by means of the helpful summary provided in the Chemistry of Materials issue devoted to her work and in which polymorphism is a recurring theme. At the beginning of my own research career, my interest in crystallography and solid-state organic chemistry was sparked by what I saw and read of the work that Jack, Peggy, and other previous workers in the Gougoutas research group, including Jon Clardy, Douglas Naae, Kuo Chang, and Leslie Lessinger, had done in investigating the solid-state rearrangements and reactions of hypervalent iodine compounds. As


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noted in her thesis title, Peggy’s publications in this area were centered on the reactivity of 1methoxy-1,2-benziodoxoline-3-one (I), particularly on its conversion by solid-state hydrolysis into o-iodosobenzoic acid (II) and its solid-state reduction by X-ray radiation into o-iodobenzoic acid (III) (Fig. 1). She described how different polymorphs in the benzoxiodole series could be

Fig. 1. Solid-state hydrolysis and X-ray decomposition of polymorphic I.

distinguished and inferences about their packing motifs drawn through the use of infrared spectroscopy.3 She examined the differing pathways with respect to twinning and topotaxy of the solid-state hydrolysis and photoreduction of two polymorphic forms of compound I.4 Current workers in the area of halogen bonding will find her discussions of close iodine-oxygen and iodine-halogen interactions and her identification of iodine-containing lattice planes as a factor in determining the course of these solid-state reactions to be of particular interest. These solid-state transformations could be followed at that time on Weissenberg and precession X-ray photographs, and Peggy and her predecessors in the Gougoutas group made extensive use of them. With the advent of automated detectors, film methods became obsolete. Subsequently, with the introduction of the CCD it is once again possible to obtain frame-by-frame views of the lattice very similar to those obtained by Peggy and her crystallographic contemporaries and to 5 ACS Paragon Plus Environment


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determine experimentally the three-dimensional relationship between parent and daughter lattices in a solid-state reaction or phase transition. The paper contributed to this special Etter commemorative issue of Crystal Growth and Design by Bruce Foxman and co-workers describing how to use the orientation matrix to examine solid-state reactions, phase transitions, and topotaxy is a timely and especially fitting re-introduction to this elegant aspect of solid-state chemistry.5 Polymorphism also figured in studies conducted by the Etter group on organic materials with potential non-linear optical properties. Molecules with large dipole moments such as pnitroaniline and its derivatives are of particular interest for NLO applications, but crystalline organic materials assuming centrosymmetric molecular packing arrangements cannot exhibit the necessary second-harmonic generation, and the crystal structure of p-nitroaniline itself is centrosymmetric. As part of a study of the formation of acentic hydrogen-bonded molecular aggregates in nitroaniline derivatives, the Etter group conducted an extensive search for new and non-centrosymmetrically packed polymorphs of p-nitroaniline by recrystallizing the compound from fifteen different solvents representing a wide range of solvent polarities. Although no new polymorphs of p-nitroaniline were obtained, six distinct crystal habits of this compound were.6 Also part of this work (with the collaboration of the research group of Stephen Byrn at Purdue University) was the analysis and structural comparison of two polymorphs of 1,3-bis(mnitrophenyl)urea, MNPU (Fig. 2), one of which, the α-form, crystallizes in space group P21/c


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Fig. 2. Polymorphs of 1,3-bis(m-nitrophenyl)urea, MNPU.

and is NLO inactive while the other, the β-form, crystallizes in space group C2 and is NLO active. The phenyl rings of the α-form are described as being slightly twisted with respect to each other in the solid state, but the phenyl rings of the β-form are described as being almost perpendicular to each other, a feature that the authors suggested might encourage the formation of a non-centrosymmetric packing arrangement.7 Current researchers will recognize this as a classic example of conformational polymorphism.8 This system has been of continuing interest; subsequent work has since identified a third anhydrous polymorph of MNPU as well as a solvated form.9 It has also been demonstrated that control over which of the three anhydrous polymorphs is obtained from the crystallization solution can be exerted by introducing suitably substituted gold-thiol self-assembled monolayers into it.10 The principal author of this latter study, Jennifer Swift, received the Margaret C. Etter Early Career Award from the American Crystallographic Association in 2005. A further example relevant to conformational polymorphism is described in a paper Peggy co-authored with Ruth Kress and Eileen Duesler of 3M and Ian Paul and David Curtin of the University of Illinois on the chiral and racemic polymorphs of binaphthyl. The transition from the low-temperature, racemic form to the hightemperature, chiral form was demonstrated in this case to occur not by way of a solid-to-solid transition but by way of a solid-gas-solid transition.11 7 ACS Paragon Plus Environment


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Not unexpectedly, hydrogen bonding is a common theme in Peggy’s polymorphism studies. Intramolecular hydrogen bonding in a metastable polymorph of dibenzoylmethane is described in one of her early publications as a member of the University of Minnesota Chemistry faculty; this work was the first in the literature in which the packing arrangements of two different polymorphs of a β-diketomethane compound could be compared.12 It had been reported previously that dibenzoylmethane could be obtained in four polymorphic forms, which were identified by melting point in the earlier literature as the “71°-form,” the “73°-form,” the “78°-form,” and the “81°-form.”13 The crystal structure of a stable Pbca polymorph obtained from carbon tetrachloride solution, from aqueous ethanol, and from cyclohexane/carbon tetrachloride solution had been published previously.14 Peggy and her co-workers obtained a metastable second Pbca polymorph by rapidly cooling a hot ethanol solution of dibenzoylmethane to 243 K and immediately removing the crystals from solution under a stream of dry nitrogen. By differential scanning calorimetry a melting point of 349-351 K (76-78°C, corresponding to the “78°-form”) was obtained for the stable Pbca form, while a melting point of 341-344 K (68-71°C, corresponding to the “71°-form”) or 349-351 K due to thermal transformation of the metastable form into the stable form, was obtained for the metastable Pbca form. A few years later the X-ray crystal structure of a third polymorph, obtained by slow evaporation from methanol and crystallizing in space group P21/c, was reported.15 Redeterminations of the stable Pbca polymorph as obtained from slow evaporation from methanol solution (reported melting point 350-351 K) and acetonitrile solution have appeared in the literature since,16 but the existence of the fourth polymorph of dibenzoylmethane has not yet been confirmed by a published crystal structure determination.


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Peggy’s interest in the role of H-bonding in associating molecules into predictable patterns is evident in her study of the solid-state cyclodehydration reaction that converts oacetamidobenzamide, which occurs in two polymorphic forms, into the one reported anhydrous form of 2-methylquinazo-4-one (compounds IVa/IVb and V in Fig. 3). The study elucidates the significance of the breaking of specific H-bond motifs,

Fig. 3. Thermal solid-state cyclodehydration of o-acetamidobenzamide (IV) into 2methylquinazol-4-one (V).

particularly the order in which they might be broken, with respect to the mechanism of the reaction.17 Here it is pointed out that just as cyclic H-bonded dimers may be formed preferentially when amides crystallize, these dimers may be the last among the possible Hbonding interactions to be disrupted in solid-state transformations. Consistent with Peggy’s interest in H-bonding trends is her observation that, in accord with the tendency she noted for carboxylic acids and amides to crystallize in packing arrangements maximizing the number of Hbond acceptor sites, the transformation of polymorph IVa into IVb leaves all its acceptor sites Hbonded even as an intramolecular H-bond between the amide carbonyl oxygen atom and the acetamide N-H hydrogen atom is broken. It is this difference between the polymorphs in intramolecular vs. intermolecular H-bonding that has since made o-acetamidobenzamide the



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subject of extensive computational studies relevant to crystal structure prediction.18 Its structure has been determined by neutron diffraction19 and its crystallization in the presence of additives20 and in a variety of solvated forms21 has been examined. A direct application of Peggy’s graph set methodology in examining H-bonding patterns is presented in her study of two polymorphs of 4’-nitrosalicylanilide (Fig. 4). The two polymorphs were found to differ in their molecular

Fig. 4. (a) 4’-nitrosalicylanilide, two polymorphic forms of which are described by Etter et al.22 (b) two possible H-bond patterns for salicylamide derivatives; intra N-H is observed in both polymorphs of 4’-nitrosalicylanilide.

packing patterns but not in their H-bond patterns. Here the possibility of competing H-bond patterns, intramolecular vs. intermolecular, in a series of salicylamide derivatives is explored, and in this paper twelve derivatives are assigned H-bond graph sets as part of the analysis of their H-bonding motifs. H-bonding and polymorphism are closely connected in this paper; it is proposed here that energy differences between competing H-bonding patterns can be compared on the basis of the number of polymorphic forms assumed, with those patterns that differ only slightly in energy presumably allowing formation of a greater number of polymorphs of the compound.22 Of the polymorphic systems Peggy examined, perhaps the two most spectacular are the wildly colorful, crystalline cyanine-oxonol dyes (Fig. 5) and the “jumping crystals” of


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Fig. 5. Polymorphic dye salt composed of 3,3’-dimethylthiacarbocyanine (DMTC) and 3,3’,5,5’-tetramethyltrimethine oxonol (TMO).

phenylazophenylpalladium hexafluoroacetylacetonate (VIa and VIb in Fig. 6). Combining the

Fig. 6. Polymorphs of phenylazophenylpalladium hexafluoroacetylacetonate “jumping crystals” identified by Etter and Siedle.27

tosylate salt of 3,3’dimethylthiacarbocyanine (DMTC) with the tetramethylammonium salt of 3,3’,5,5’-tetramethyltrimethine-oxonol (TMO) yields the cyanine-oxonol salt shown in Figure 5. Depending on the crystallization conditions and solvents used, fourteen forms of this salt could be obtained, although it had not yet been determined at that time whether some were solvates or may have contained the tosylate or tetramethylammonium ions as well as the DMTC and TMO moieties. Colors of these forms included gold, red, purple, green, and pink; morphologies 11 ACS Paragon Plus Environment


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included thick plates, narrow plates, needles, rhombohedra, fibrous threads, and trapezoids.23 Recognizing the sheer beauty and variety of these forms, Peggy and her colleague Ruth Kress Johnson examined their structures and transformations using optical microscopy as well as X-ray methods, a reminder of the usefulness of measuring and understanding external crystal morphology as well as internal crystal structure.24 A single-crystal spectroscopic study of the “gold” polymorph was subsequently undertaken by Craig Eckhardt and co-workers,25 and epitaxial growth studies using succinic acid substrates to preferentially produce a less thermodynamically favored form of one of these salts were more recently conducted by Mike Ward and Salvatore Bonafede.26 With her colleague Allen Siedle of 3M Central Research Laboratories, Peggy examined the conversion of the VIa polymorph of phenylazophenylpalladium hexafluoroacetylacetonate (yellow needles from hexane at

Peggy Etter and Polymorphism: Highlights of an ... - ACS Publications

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