Frontiers of Crystallography: A Project-Based Research-Led

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Frontiers of Crystallography: A Project-Based Research-Led Learning Exercise Chick C. Wilson,*,# Andrew Parkin, and Lynne H. Thomas# School of Chemistry and WestCHEM Research School, University of Glasgow, Glasgow G12 8QQ, United Kingdom

bS Supporting Information ABSTRACT: A highly interactive research-led learning session for chemistry undergraduates is described, which aims to lead students to an awareness of the applications of crystallography technique through a mentored hands-on crystal structure solution and refinement session. The research-based environment is inherent throughout the 4.5 h program and is emphasized by several features in the learning experience. KEYWORDS: Upper-Division Undergraduate, Analytical Chemistry, Curriculum, Problem Solving/Decision Making, Crystals/Crystallography, Hydrogen Bonding, Molecular Properties/Structure, Undergraduate Research, X-Ray Crystallography

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rystallography is one of the core techniques in materials characterization and forms a part of most undergraduate chemistry degrees. It has relevance to many industrial areas, in particular, the pharmaceutical industry where full identification of the precise molecular configuration in the crystal structure is vital as the molecular configuration can have significant effects on the properties of the material of interest. In addition, crystallographic screening of solid forms constitutes a significant part of the premanufacturing process, allowing phase purity to be established. Other relevant areas in which crystallography is widely used include the food, pigments and dyes, and agrochemical industries. It forms a key investigative technique in any area where the solid state is important and is unrivalled in the level of information available in terms of defining chemical connectivity, molecular geometry and conformation, including intermolecular interactions. Diffraction techniques can be used as a characterization tool for synthetic chemists determining the precise chemical arrangement of the atoms in the materials that they have made, but also as a tool toward understanding the physical properties of materials in the solid state where the weaker intermolecular interactions can have a significant effect on a range of physical properties such as solubility, melting point, and mechanical strength. This has led to the development of high profile areas such as crystal engineering. The theory of diffraction, however, can often leave students mystified and undergraduate students can consequently lose the relevance of the material that they are studying. A more hands-on approach to such problems can help to demystify these areas. A “Frontiers of Crystallography” exercise has been introduced for upper-level undergraduate students in chemistry. This exercise is part of a series of themed “frontiers” afternoons comprising a supplementary course for undergraduate chemistry majors and is not assessed as part of the course-work.1 A vital component of the course is its relaxed, informal environment, Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.

which is encouraged by the Friday afternoon timing, room layout, attitude of the tutors, and the nonconventional course content. However, this exercise could also be employed in a physical or analytical chemistry laboratory course over two periods.

’ GOALS The aims of the exercise are not only to increase the understanding of crystallography by the undergraduate students, but also to provide the students with an opportunity to participate in the research process, undertaking an original research project over the course of two afternoon sessions, ideally resulting in the publication of this work in the form of a crystal structure report to a peer-reviewed journal. The learning process also allows the students to interact in an informal way with an active research group ranging from the professor in charge, to postdoctoral researchers (PDRAs) and Ph.D. students. ’ EXERCISE STRUCTURE The exercise requires 4.5 5 h, over two sessions, deliberately set 2 3 weeks apart (to allow for sample preparation), with a typical attendance of 20 30 students. Prior to the Frontiers of Crystallography exercise, the students should have had classroom exposure to the concepts of diffraction, structure solution and refinement, and crystallographic symmetry and space groups.2 Session 1

The first session, 1.5 h, has the broad aim of providing an introduction to crystallography and structural chemistry, relying on the students’ classroom knowledge of diffraction.3

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The introduction in session I discusses the importance of structural chemistry in one or more key science areas (for example hydrogen bonding or polymorphism). This allows not only a full contextual development of the course material, but also helps emphasize from the start the very strong researchdriver for the course. Moreover, the specific materials (or range of materials) chosen for study on the research component of the course are introduced in this context. Specifically, it is made clear that the materials to be studied fit into ongoing research programs (indeed they often form part of the project of a PDRA or Ph.D. student who will be involved in the hands-on research sessions). This relationship of the materials to be studied to local research interests is appropriate for a university or college with a strong research program and related crystallography facilities. However, this does not preclude undergraduate-only institutions from undertaking a similar exercise. For institutions without a strong research presence in crystallography, the Frontiers of Crystallography concept can still be a possibility. Various types of assistance are available to help establish such a course, including availability of the main organic crystal structure database, the charitably operated Cambridge Structural Database (CSD).4 The major national crystallographic associations, notably the American Crystallographic Association (ACA) and the British Crystallographic Association (BCA), have dedicated Educational Committees as a core part of their remit and operation, providing a professional central contact point from which to secure advice and relevant contacts. In terms of target materials, the identification of likely hydrogen-bonding patterns is an interesting exercise in its own right, covering core aspects of structural chemistry and could easily be carried out as an assignment prior to the Frontiers workshop, supported by access to structural information from the CSD. There are also many crystallographic groups who would be happy to share some of their more “routine” materials for potential inclusion in such courses. In many cases this assistance could also extend to providing the data for the exercise. The research emphasis is strengthened in this part of the introduction by holding a discussion session, sometimes modeled along the lines of a “Cafe Scientifique” open Q&A session.5 The more practical aspects of session 1 include a tour of the X-ray facilities used by structural chemistry researchers in the School of Chemistry, and on which the session 2 “hands-on” components are carried out. These tours are led by the course organizers or by PDRAs or senior research students from their groups. The tour emphasizes the research-level instruments to be used in the Frontiers exercise, and these will typically include a Bruker AXS Apex-II CCD-based diffractometer and a Rigaku R-axis/RAPID image plate diffractometer. Both instruments are state-of-the-art and utilized full-time on research projects in the School of Chemistry. The tour of facilities is augmented by observation of typical sample preparation procedures used to grow the crystals utilized in the Frontiers sessions. It is usually necessary to set up these crystallizations in advance, as material preparation can take several weeks to produce crystals of sufficient size and quality for the experiments to be carried out. Future plans include the possibility of making this session hands-on, if session 1 were to be extended. Feedback from students has indicated enthusiasm for this extension of the “hands-on” experience in sample preparation, which would have to be scheduled significantly in advance of the structure solution workshop. This is accessible in any wet chemistry laboratory as sample preparation, the growth of small

Figure 1. The hydrogen-bonded molecular complex that is the building block of a structure solved during a Frontiers of Crystallography exercise; 2-acetylpyridinium bromanilate.6

single crystals of organic materials, is usually based on simple slow solvent evaporation techniques. If such sample preparation is successful, then for those without access to “in-house” crystallography facilities, links with external crystallography groups or organizations could offer the opportunity of external data collection on samples for use in a Frontiers session. Throughout session 1 it is emphasized that the Frontiers exercise includes a real research component. As such, the possibility of “failure” is emphasized: good quality crystals may not be grown, there may be problems in obtaining data, and there may be problems in solving and refining the crystal structure. There is no attempt made to “pre-screen” the information provided to the students; at every stage the students see the data as the researcher would see it. It is stressed that those involved in tutoring also do not know the answer; though they have an idea of what might emerge, sometimes it does not work out and sometimes something completely different is found. For example, typically a molecular complex is chosen (hopefully produced by co-crystallization of two distinct components that might hydrogen bond to each other in the solid state). Sometimes this works and is regarded as a triumph of “crystal engineering” (an example of a structure solved during a Frontiers exercise is shown in Figure 1), whereas sometimes a complex is obtained with a totally different intermolecular bonding motif. Sometimes crystals of the individual components are obtained, sometimes new forms (polymorphs) of the individual components are produced, sometimes more than one form of the desired complex is produced, for example polymorphs, or different stoichiometric ratios, and sometimes crystals of such poor quality are obtained that they cannot be used. All of these are genuine exposures to the real research experience! Session 1 Outcomes

The anticipated outcomes from session 1 include (i) an awareness of why structural chemists do what they do and how they do it, which builds on a basic knowledge of crystallography and is applied in a research-led context; (ii) an introduction to research-level experimental techniques; (iii) initial exposure to the advanced equipment used for X-ray crystallography; and (iv) an increased interest in further study.7 A very high return rate for session 2 is anticipated and usually delivered. Session 2

Session 2, 3 h, is the practical hands-on data collection, structure solution, and refinement component of the Frontiers of Crystallography exercise. It is based on determining an unknown crystal structure, using samples prepared from crystallization 35

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experiments observed by the students in session 1. A team of 6 7 delivers the session, comprising academic faculty, PDRAs, and Ph.D. students from research groups related to the area of study; members of the team mentor individual small groups of undergraduate students, leading them through the process. The students typically work in groups of 4 5, analyzing the structure of a series of crystals for which full data sets have been collected by members of the research team prior to the session. In early workshops, a single structure was studied by all groups, but as a result of feedback from various sources (including participants), this has been modified to ensure, as far as possible, that each group has a data set from a distinct material. The full data sets typically take 6 12 h to collect and so are collected in preparation for the structure solution and refinement components undertaken in the practical session. If more than one target material appears to have crystallized, where possible, data sets are collected from each of these. In that case, it may be that one of the research investigations produces better results than another, depending on the system studied; again this is part of the research-driven learning experience for the students. Where single crystals are unable to be grown, powder X-ray diffraction is used to give characteristic fingerprint patterns of the materials obtained and these can be compared with one another and with patterns from the starting materials to assess whether a previously unknown material has been obtained. The session is split into two parts: (i) data collection and (ii) structure solution and refinement. In the first part, the students are taken through the process of how to assess the quality of candidate crystals for the diffraction experiment and how to select a suitable single crystal on which a full data collection could be attempted. The hands-on component of this makes use of optical and polarizing microscopes. Once the students have selected a crystal (of typical linear dimension 0.2 0.4 mm), it is mounted onto a fine glass fiber attached to a goniometer by manipulating the crystal, again under a microscope. This is then transferred to an X-ray diffractometer ready for data collection. A unit cell data collection is then carried out on the crystal, which involves collecting a series of frames of diffraction spots on the area detector; this typically takes around 30 min. The quality of the crystal can again be assessed by the quality of the diffraction spots observed; often the students discover that the crystal they have initially selected does not show good diffraction characteristics. Once good patterns are obtained, the computer software is then used to determine the unit cell parameters and these are compared with the known parameters obtained from the full data collection to identify whether this crystal is the same material. The students are then shown the steps involved in setting up a full data collection but without collecting data at this stage. The data analysis involves using the data already collected, to solve and refine the unknown crystal structure. This is carried out in small groups, each around a PC or a laptop with research-level software installed. To expedite the process in the 1.5 2 “live” hours available for this procedure, the structure solution and refinement is based on a template (see the Supporting Information). Each group is mentored by a Ph.D. student, with the course leaders adopting a purely advisory role, including asking relevant questions to ensure a degree of understanding of the procedures. It is stressed again throughout this process that no one knows the “correct” structure, so it is a full research-based experience. This is frequently manifested as different groups often take different paths though the process, depending on the practice

of the facilitator. It is also possible that some groups end up with a “better” solution than the others, even if tackling the same structure, which leads to discussion of the reasons why and of what could be done to ensure that both solutions represent the true situation (usually meaning that one or more groups are encouraged to revisit their conclusion). Once the structure has been successfully solved and refined, the students are led through the process of analyzing the structure, drawing out information that may be used in a scientific paper. This includes looking at the molecular conformation and also the three-dimensional crystal packing including any interactions such as hydrogen bonding. The template for analyzing and recording findings is shown in the Supporting Information. The students also make use of the Cambridge Structural Database4 to ensure that the structure that they have found is new and to see if there are any similar structures already reported in the literature. The findings of all the groups are pulled together at the end to help write the comment part of the paper or papers that are the additional potential outcome of the process. Additional assignments are set to augment this information. Session 2 Outcomes

The anticipated outcomes for session 2 include (i) use of advanced research-level instruments (diffractometers) and software; (ii) solution and refinement of a new, previously unknown, crystal structure; (iii) an exercise in making relevant observations on the structure that makes use of the information on related structures in the Cambridge Structural Database; (iv) interactions in a group and with a graduate student mentor, and (v) an awareness that in original research there is no “right” answer. This is emphasized by the different paths used for solution and refinement, and in some cases different final models that may or may not be equally valid. Sometimes the structures determined are not of great quality, possibly due to poor crystal quality and so forth; this is accepted as the outcome of the course—another example of research reality. If all works out, a short paper on any suitably high-quality structures determined will be written up for one of the crystallographic structure reporting journals such as Acta Crystallographica Section E or Zeitschrift fur Kristallografie: New Structures,6,8 with the potential inclusion as coauthors of those in the class who worked on the publishable new structure. In assessing initial outcomes, and with feedback from participants, the criteria for inclusion as an author on any resulting paper have been discussed, together with general discussions on publication. For similar exercises adopted elsewhere, this discussion is recommended as it covers a range of important educational and ethical issues. In the case of Frontiers of Crystallography, criteria based on additional research-related assignments that must be undertaken to “qualify” for coauthorship have evolved; these are focused on elements that will be included as background to the paper or to its discussion. Although these are only assessed informally, they are an important part of the process and ensure that genuine contributions are offered by all coauthors. Early engagement with editors is important, but it is clear that the “publication” outcome is likely to be most relevant for schools with crystallography research available or those who have been able to make a link with professional crystallography input through the routes outlined above. In general, editors are pleased to receive these papers and fully appreciate the reason for the oftenextensive author list. In some cases, the structures determined are of insufficient quality to warrant publication; again a reflection of the genuine 36

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research experience! In cases such as this, the research group will follow-up with efforts to obtain improved crystals and data sets and the undergraduate participants kept informed of progress on these.

undergraduate students who have participated with enthusiasm and 12 mentors whose expertise and engagement have helped make these sessions a success.

’ SUMMARY The Frontiers of Crystallography exercise is a research-led form of teaching that results in the exposure of students, in a relatively short and informal period, to a range of vital principles of the nature of research. These include awareness of the research process; experience of practical crystallography in a research environment; familiarity with modern structural chemistry techniques and research drivers; an ability to adapt to a problem with a genuinely unknown solution and “no right answer”; an experience of recording results and conclusions in a manner consistent with publication of original research; and hopefully, a published short paper. These research-led learning outcomes are generic and do not apply solely to the area of research explored, and this is emphasized to the students. It is rewarding that many of the students who participate in the exercise take up Ph.D. positions in the school and elsewhere, including a fair proportion in the research groups of the course organizers. It may be that participation in the Frontiers of Crystallography exercise helps fuel the enthusiasm of the participants for a research career.9 An important aspect of an exercise such as this, and one that is easily neglected, is the chance for the class to meet the “true persona” of the academic staff. Rather than someone standing at the front of the class, lecturing on what may be rather dry subject matter, in session 1 the students get to see the academic in their natural environment, talking about research in a relaxed and interactive way. For the majority of students, this is their first exposure to a research environment, and it can come as a surprise to find the staff so passionate about their work. The students are responsive to this environment, and after the usual ice breaking, they welcome the opportunity to “just ask anything” in this general area. This is particularly emphasized in the mini-Cafe Scientifique sessions. It is also illuminating for the students to ask questions to which the academics simply do not know the answer, stimulating further discussion.

’ REFERENCES (1) At the University of Glasgow in the United Kingdom, a Frontiers of Crystallography exercise has been introduced that is delivered to level3 MSci undergraduate students in chemistry (the MSci undergraduate curriculum at Glasgow is delivered over five years, with an industrial or international placement as year 4). The exercise is part of a series of themed “Frontiers” afternoons comprising a supplementary course for the students, and although formally compulsory, is not assessed as part of the course-work. The students attending the course are generally on one of the two major degree course streams (chemistry or chemistry with medicinal chemistry), or one of the three minor streams (chemistry with forensic studies, chemical physics, or chemistry with mathematics) within the chemistry course. (2) The curriculum at the University of Glasgow includes a level-3 course in diffraction, which introduces crystallographic symmetry and space groups. This is taken by all MSci chemists including those taking the medicinal chemistry major. Equipped with this, and an associated laboratory-based exercise on structure solution and refinement, the students are sufficiently prepared to contribute to the interactive Frontiers exercise. (3) At the University of Glasgow the diffraction course is offered in parallel with the Frontiers sessions. (4) Allen, F. H. Acta Crystallogr. 2002, B58, 380–388. (5) Cafe Scientifique. http://cafescientifique.org/ (accessed Oct 2011). (6) Thomas, L. H.; Boyle, B.; Clive, L. A.; Collins, A.; Currie, L. D.; Gogol, M.; Hastings, C.; Jones, A. O. F.; Kennedy, J. L.; Kerr, G. B.; Kidd, A.; Lawton, L. M.; Macintyre, S. J.; MacLean, N. M.; Martin, A. R. G.; McGonagle, K.; Melrose, S.; Rew, G. A.; Robinson, C. W.; Schmidtmann, M.; Turnbull, F. B.; Williams, L. G.; Wiseman, A. Y.; Wocial, M. H.; Wilson, C. C. Acta Crystallogr. 2009, E65, o1218. (7) At the University of Glasgow, this area can be selected as a topic for Level-3 essays or as a research project at Level-4. (8) Parkin, A.; Harte, S. M.; Carmichael, D.; Currie, S.; Drummond, L.; Haahr, A.; Haggerty, K.; Hunter, T.; Lamarque, A.; Lawton, L.; Martin, C.; Mathieson, J. E.; Mathieson, J. S.; McGlone, T.; McGregor, J.; McMillan, L.; Robertson, L.; Thatcher, R.; Vance, S.; Wilson, C. C. Acta Crystallogr. 2005, E61, o2280–o2282. Craig, G. A.; Thomas, L. H.; Adam, M. S.; Ballantyne, A.; Cairns, A.; Cairns, S. C.; Copeland, G.; Harris, C.; McCalmont, E.; McTaggart, R.; Martin, A. R. G.; Palmer, S.; Quail, J.; Saxby, H.; Sneddon, D. J.; Stewart, G.; Thomson, N.; Whyte, A.; Wilson, C. C.; Parkin, A. Acta Crystallogr. 2009, E65, o380. (9) Frontiers of Crystallography exercise has strong spin-offs into course assessment, in that several essay choices usually emerge from within the cohort attending the Frontiers course, supervised by one of the academic faculty involved.

’ ASSOCIATED CONTENT

bS

Supporting Information An example worksheet that is used as prompts to guide the student participants though the practical aspects of the Frontiers sessions. This material is available via the Internet at http://pubs. acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Present Addresses #

C.C.W. and L.H.T. are at Department of Chemistry, University of Bath, Bath BA2 7AY, U.K., where they are running an enhanced version of the Frontiers program.

’ ACKNOWLEDGMENT We thank all participants in these Frontiers exercises over the last five years at the University of Glasgow: around 120 37

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