Teaching Three-Dimensional Structural Chemistry ... - ACS Publications

In the Classroom

Teaching Three-Dimensional Structural Chemistry Using Crystal Structure Databases. 2. Teaching Units That Utilize an Interactive Web-Accessible Subset of the Cambridge Structural Database Gary M. Battle* and Frank H. Allen Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, United Kingdom *[email protected] Gregory M. Ferrence Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160

In Part 1 of this series (1), we noted the value of threedimensional (3D) crystal structure information to teachers and students of undergraduate chemistry programmes. The Cambridge Structural Database (CSD) (2) of half a million small organic and metal-organic structures was described, together with free Web access to a specially chosen and diverse subset of 500 structures chosen for their pedagogical value. We also noted that the full CSD system;the complete CSD plus software for search, structure visualization, and data analysis;is also available to teaching institutions. In Part 2 of this series, we illustrate the immediate educational benefits that can accrue through use of the teaching subset and its WebCSD interface, through a set of five examples. We discuss the pedagogical value of using experimentally measured 3D information on crystal and molecular structures. The full CSD System and its extended value in the teaching curriculum will then be discussed in Parts 3 and 4 of the series (3, 4). Overview of Teaching Units Each teaching unit discussed below is available in the form of an online tutorial accessible on the Cambridge Crystallographic Data Center (CCDC) Web site (5). The student is led through the tutorial via a series of panes that place the example into a chemical context and give the objectives of the tutorial. These introductory panes are then followed by a set of logical learning-step panes, and the tutorial ends with a summary of the key concepts that have been discovered. When specific structures are referred to in the tutorials, a hyperlink is provided that, when clicked, will automatically launch the WebCSD interface and display the structure or structures of interest. To facilitate integration with the users teaching materials and resources, a form is provided that, given a CSD structure reference code, or list of reference codes, will automatically generate a hyperlink that will display those structures in WebCSD. This hyperlink can then be incorporated into users' online teaching materials. In addition to working through the tutorial panes online, all tutorials may be printed from a pdf version. The five teaching units are summarized in Table 1. The main learning objectives are listed, and a brief description of the interactive activities required to complete the unit are given. The more detailed descriptions following illustrate the educational

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points being made in each unit, but they are not intended as a replacement for the tutorials themselves. Where appropriate, individual structures are referred to by their CSD reference codes (refcodes). Example 1. Aromaticity and the Planarity of Benzene The tutorial begins by noting the differences in reactivity of benzene compared to normal alkenes, for example, the ready addition of bromine across an alkene double bond compared to the Lewis acid-catalyzed formation of a monobromo derivative in the case of benzene. The student is then invited to open the structure of benzene (BENZEN02), to note its planar hexagonal shape, and to use the software to calculate and display the bond lengths and valence angles (Figure 1A). The bonds are all close to 1.38 Å, and the angles are all close to 120°, with any minor variations being due to experimental error in the crystal structure determination. It is noted that the benzene bond lengths fall between typical values for CdC double bonds (∼1.33 Å) and C(sp3)-C(sp2) single bonds (1.46 Å). The student is then asked to display the structure of cyclooctatetraene (ZZZSAE01, Figure 1B). Inspection of the structure shows that it is nonplanar with a tub-shaped conformation and has bond lengths are typical of alkenes (alternating between 1.33 and 1.46 Å, within experimental error) around the ring. The valence angles are all equal (at ∼127°), much larger than in benzene because of the increased ring size. It is noted that cyclooctatetraene undergoes a Br2 addition reaction typical of alkenes. Next, we consider what happens when cyclooctatetraene is treated with a powerful reducing agent. Thus, 1,3,5,7-tetramethylcyclooctatetraene (TMCOTT, Figure 2A) yields the dianion (TMOCKE, Figure 2B) on treatment with alkali metals. It is clear that TMOCKE is planar and investigation of the structure shows that it has bond lengths close to 1.40 Å and valence angles close to the 135° expected for a planar octagon. If we consider the number of π electrons, we discover that rings with 6 (BENZEN02) or 10 (TMOCKE) π electrons have symmetrical planar structures, whereas ZZZSAE01 and TMCOTT with 8 π electrons show alkenic behavior. The student is then asked to discover what happens when benzene is treated with powerful oxidizing or reducing agents. It is noted that strong oxidizing agents have no effect on benzene

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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 8 August 2010 10.1021/ed100257t Published on Web 06/09/2010

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Journal of Chemical Education

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In the Classroom Table 1. Topic, Learning Objectives, and Interactive Activities in each Teaching Unit Topic and Objectives

Interactive Activities

Unit 1: Aromaticity and the Planarity of Benzene

Visualize a series of benzene and cyclooctatetraene derivatives, measure and compare the carbon-carbon bond lengths and planarity of the structures; Relate structural characteristics to the number of π-electrons; Use findings to predict whether or not certain compounds are aromatic.

To investigate the structural requirements for aromaticity; To understand the stability of benzene in terms of its MO description; Apply Huckel's rule to predict whether certain compounds are aromatic. Unit 2: Ring Strain and Conformation

Calculate angle strain for a series of fully saturated planar carbocycles; Measure the actual angle strain in cyclohexane by analyzing structural data; Plot and compare calculated angle strain for planar rings with that measured in actual compounds; Visualize 3- to 6-membered carbocycles and account for the observed conformations.

Understand that angle strain can occur in cycloalkanes due to deviation from the ideal sp3 geometry and when neighboring bonds are forced to be eclipsed (Pitzer strain). Be able to account for the conformations of 3- to 6-membered carbocycles in terms of the strain present; Explain why cyclohexane is essentially strain free. Unit 3: Stereochemistry and Chirality

Compare two crystal structures of alanine and describe their relationship; Identify basic structural features that give rise to chirality; Describe the configuration of chiral centers in given molecules; Visualize and understand the relationship between structures of threonine, ephedrine, and tartaric acid; Examine further structures and recognize other features that can give rise to chirality, for example, quadrivalent and tervalent chiral atoms, restricted rotation and helicity.

To recognize a stereogenic (chiral) center in a molecule; To assign (R)- and (S)-configurations; To predict, identify and distinguish between enantiomers and diastereomers; To recognize a meso compound; To recognize other structural features that can give rise to chirality. Unit 4: VSEPR

Examine the structures of di-, tri-, and tetrachloromercury, determine the main factors that control the geometry adopted; Observe effects of lone pairs on geometry by examining XeF5-, water, and dibromodimethylselenium; Apply the VSEPR model to predict the geometry of given molecules; Compare predictions with crystal structures and comment on how closely the observed bond angles agree with the expected ideal values.

To investigate 3D molecular shape; To understand factors that determine the preferred 3D shape of specific molecules; To use the VSEPR model to predict 3D molecular shape.

Unit 5: Hapticity

Visualize given structures and investigate the different modes of metal-carbon bonding; Relate nomenclature to structural features; Examine a series of structures and identify the hapticity of the organometallic ligands.

To investigate the concept of hapticity and learn its nomenclature; To examine the structural perturbations of ligands as a function of their hapticity.

Figure 1. (A) Bond lengths and internal angles in benzene (BENZEN02) and (B) tub-shaped conformation of cyclooctatetraene (ZZZSAE01).

but that it is possible to oxidize some substituted benzenes, for example, hexakis(dimethylamino)benzene (GENFAG) oxidizes to a dication (GENFEK). Investigation shows that GENFEK has a boat conformation, and the bond lengths are far from equal. Similarly, it is possible to reduce hexakis(trimethylsilyl)benzene (KELVOM) to a dianion (KINFUI), which again has a boat conformation and unequal bond lengths. In terms of π electrons, a pattern is forming and the student is now invited to complete a table recording the number of π electrons and the ring conformation for each of the examples studied so far. A pane discussing the (different) MO descriptions of benzene and cyclooctatetraene then follows. Finally, Huckel's rule is derived from the table of π electron counts and the student is asked to use electron counting to predict the aromaticity (or not) of a variety of other compounds in the CSD teaching subset. These include tetra-t-butyl-cyclobutadiene (TBUCBD10), naphthalene (NAPHTA12), cyclohepta-1,3,5-triene (CHMOCO01), the cyclopentadienyl anion (NARGET), pyridine (PYRDNA01), 814


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Figure 2. (A) Puckered shape of 1,3,5,7-tetramethylcyclooctatetraene (TMCOTT) and (B) planar 1,3,5,7-tetramethylcyclooctatetraene dianion (TMOCKE).

and the (14)-, (16)-, and (18)-annulene compounds (FANNUL, ANNULE01, and ANULEN, respectively). The CSD structures can be used to check the correctness of the predictions. Example 2. Ring Strain and Conformation In 1885, von Baeyer proposed that if carbon prefers to have a tetrahedral geometry with bond angles of 109.5°, and assuming that all chemical rings would be planar, then rings of size other than 5 or 6 would be too strained to exist. However, we now know that rings can adopt a variety of nonplanar conformations, but von Beyer's hypothesis is a useful starting point for a discussion of ring strain. Following von Baeyer, the first pane asks the student to complete a table of the internal angles (θpred) that would be found in planar 3- to 8-membered rings and to assess the angle strain as the quantity (θpred - 109.5°). A simple plot (Figure 3) of ring size versus strain shows the largest strain is for

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r 2010 American Chemical Society and Division of Chemical Education, Inc.

In the Classroom

Figure 5. (A) L-(R)-alanine (LALNIN23) and (B) D-(S)-alanine (ALUCAL05) viewed along the C-H axis. Figure 3. Predicted (in planar rings) and experimentally observed (measured in CSD structures) angle strain in 3- to 8-membered rings. The angle strain is calculated as the quantities (θpred - 109.5°) and (θexp - 109.5°), respectively.

Figure 4. Octachlorocyclobutane (CLCBUT) shows that the cyclobutane ring can distort from planarity by folding about the ring diagonals to reduce Pitzer strain. The folding angle in CLCBUT can be measured as 26°.

3-membered rings, decreasing to almost zero for 5-membered rings, and then increasing again (but more slowly) for larger rings. Next, we look at what happens in actual compounds. The student is asked to examine five CSD structures (reference codes provided) that contain a cyclohexane ring by measuring all six internal angles in each ring, deriving the experimental average intra-ring angle (θexp) in each case, and then calculating the new angle strain as the quantity (θexp - 109.5). The procedure can be repeated for the other rings. These experimental values then form another column in the student's table of strain, and a modified distribution can be plotted as in Figure 3. The plot again shows the high strain in 3- and 4-membered rings, but the minimum strain is now at cyclohexane, and strain in 7- and 8-memberd rings is much reduced. The experiment then continues with a study of carbocyclic rings of sizes 3-6. For planar cyclopropane (QQQCIS01), the high ring strain is augmented by Pitzer strain because all of the H atoms are mutually eclipsed. Examination of the structure of cyclobutane (CLCBUT) shows that the ring can distort from planar by folding about the ring diagonals to reduce Pitzer strain (although this has little effect on intra-annular strain). The folding or puckering angle in CLCBUT can be measured as 26° using the CSD software (Figure 4). It is noted that, in oxetane (CIVXIO10), having one hetero-O atom reduces Pitzer strain, and the ring is closer to planarity. Although intra-annular angle strain in cyclopentane is low, the eclipsing effect introduces additional strain and this is compensated for by ring distortions. There are two maximally puckered cyclopentane conformations: the envelope (IHIPOE) and the half-chair (LISLOO). The extent of these distortions can be measured using the CSD by calculating torsion angles about the ring C-C bonds in each case. It is noted that the energy difference between the envelope and half-chair conformations is small, and in practice, cyclopentane adopts conformations between the two. At this point, the


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instructor may wish to extend the tutorial to cover the pseudorotation itinerary of 5-membered ring conformations, but this is not yet included in the published Web material. Cyclohexane normally adopts a chair conformation, as exemplified by CSD structure CYCHEX, and we know that this form is virtually free of strain (Figure 3). CYCHEX should be examined by the students to find an explanation, which should be confirmed by measuring the intra-ring angles (all close to 109.5°) and noting that all H atoms are now staggered and not eclipsed (or close to eclipsed) as in smaller rings. Students can also measure the distortion from planarity via the intra-ring torsion angles, which are (within experimental error) (55° around sequential ring C-C bonds. The tutorial concludes with a summary of the structural concepts that have been covered. Example 3. Stereochemistry and Chirality This tutorial introduces the importance of stereoisomerism and chirality in chemistry, particularly in biological systems and drug action. The value of experimental 3D structural information in illustrating basic concepts is reinforced. The student is first asked to compare two crystal structures of alanine: LALNIN23 and ALUCAL05, the natural L-(R)-alanine and the D-(S)-form, respectively. These two structures cannot be superimposed but are mirror images of each other. Various manipulations of the structures are described, including viewing each along the C-H bond (Figure 5) and comparing the results. From this, the tutorial develops rules for chirality perception by the student, and they are then asked to examine a number of structures and determine whether they contain a stereogenic center. Next, the concept of (R) and (S) enantiomers is introduced by defining the priority ordering of substituents at the chiral C atom in alanine, and students are asked to make (R) or (S) assignments for the CSD structures carvone (RERXIV, from spearmint oil), adrenaline (ADRENL), and ibuprofen (JEKNOC10). The tutorial then considers compounds having more than one stereogenic center, through an examination of threonine (LTHREO01, Figure 6), which has two such centers that can be identified as (2S,3R) in the CSD structure. The student is asked to determine which other stereoisomers can exist for threonine (four) and to determine their relationship as two pairs of mirror image (enantiomeric) structures: (2R,3R)-(2S,3S) and (2R,3S)-(2S,3R). The diasteromeric relationship between nonmirror image pairs is then introduced and exemplified via a study of the CSD structures for ephedrine (EPHEDR01) and pseudoephedrine (PSEPED01). Finally, the basic tutorial addresses the stereoisomers of tartaric acid (TARTAC, TARTAL04, and TARTAM) where the two stereogenic centers might be expected to generate four stereoisomers, paired up as for threonine above. In fact, we see


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In the Classroom

Figure 7. Planar XeF5- ion (present in CSD structure SOBWAH) maximizes the lone-pair repulsion so that they occupy the apexes of a pentagonal bipyramid. Figure 6. (A) (2S,3R)-threonine (LTHREO01) and (B) (2S,3R)-threonine (2D wedge-dot bonds representation).

only three stereoisomers: the mirror-image optically active forms (2S,3S) (TARTAC) and (2R,3R) (TARTAL04) and TARTAM, which is both (2R,3S) and (2S,3R) because the molecule has a mirror plane bisecting the central C-C bond so that no absolute distinction can be made between C2 and C3. Such compounds are not optically active (achiral) and are termed meso compounds. The basic chirality tutorial is followed by suggestions for more advanced exercises covering other kinds of molecules that can display chirality, for example, • Compounds with other quadrivalent atoms, for example, Si in CSD structures YONMET and YONMIX. • Compounds with tervalent chiral atoms, for example, pyramidal N in which the lone pair acts as the fourth substituent. The substituted aziridine compounds KIRCOD and KUBZOW are provided as examples for study. • Compounds that exhibit molecular chirality. Certain tetrasubstituted adamantanes, for example, 1-bromo-3-chloro-5-fluoro7-iodo-adamantane (XUKFIS) contains both (R) and (S) molecules in its crystal structure. • Chirality due to restricted rotation, where a tetra-ortho substituted biphenyl is provided as an example for study. NIYQUH consists of a single enantiomer, whereas NIYRAO contains both enantiomers in the crystal structure (a racemate). • Chirality due to helicity is exemplified by the hexahelicenes (HEXHEL, MEHXHE), which illustrate how clockwise and counterclockwise helices are not superimposable.

Example 4. VSEPR Method The basic shapes of molecules tend to be controlled by the number of electrons in the valence shell of the central atom. The valence-shell electron-pair repulsion (VSEPR) model facilitates the prediction of 3D molecular shapes. The tutorial begins by asking students to predict 3D structures for di-, tri-, and tetrachloromercury and to compare their predictions with CSD structures OKAJOZ (containing linear HgCl2), KUSMAM (trigonal planar HgCl3-), and KEYZUK (tetrahedral HgCl42-), with the shapes confirmed by measuring Cl-Hg-Cl angles. This is in agreement with the VSEPR model that predicts that preferred shapes will ensure that regions of enhanced electron density will take up positions as far apart as possible to generate a minimum-energy arrangement. A table is then provided of the ideal VSEPR geometries for compounds containing from 2-8 electron pairs. Using PF6- as an example, students are asked to determine the number of electron pairs present (6 pairs), predict the preferred 3D shape (octahedral), and confirm this by examining and measuring valence angles in CSD structure WINFAA. Several other CSD examples of 3-6 coordination are then provided to be studied in the same way. 816


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Figure 8. The “see-saw” shape of dibromodimethylselenium (RIZMIW), where the lone pair occupies an equatorial position in a trigonal bipyramid to minimize lone-pair-bonding-pair repulsions.

The tutorial then moves on to consider the effect of lone pairs, using the XeF5- ion (present in CSD structure SOBWAH, Figure 7), which shows the ion to be a planar fivecoordinate species. The tutorial explains the geometry in terms of maximizing the lone-pair repulsion so that they occupy the apices of a pentagonal bipyramid. The student is then asked to rationalize the “see-saw” shape of dibromodimethylselenium (RIZMIW, Figure 8), where the lone pair occupies an equatorial position in a trigonal bipyramid to minimize lone-pair-bonding-pair repulsions, and the 3D structure of the water molecule with an H-O-H angle less than the normal tetrahedral value. Water occurs commonly in CSD structures as a solvent, and MUSIMO01 is suggested as an example for this study. The tutorial concludes by suggesting a further dozen compounds for application of the VSEPR method, together with CSD structure codes for confirming the predictions. Example 5. Hapticity The tutorial is introduced by noting that certain ligands show multiple bonding modes to the central metal in organometallic compounds and this is denoted as the ligand hapticity (6). Beyond that, it is noted that the naming of organometallics is then similar to that of coordination compounds. The large proportion of metal-organic structures in the CSD (>52%) makes it an ideal resource for teaching in this area of chemistry. Many CSD structures, for example, VADRAU, IGODIR, TODDUL, OKUSES, and ALPHPD01, contain metal-carbon bonds and are true organometallics. Examination of OKUSES (Figure 9A) shows that the allyl ligand bonds to Mg through only one C atom, whereas in ALPHPD01 (Figure 9B), all three allyl C atoms bond to Pd. These “coordination numbers”, 1 in OKUSES and 3 in ALPHPD01, are the hapticity of the allyl group in each compound, denoted in compound name nomenclature using a Greek eta (η): OKUSES has an η1-allyl ligand and ALPHPD01 has an η3-allyl. This can be seen in the compound names assigned in the CSD to these compounds. It is noted that proper use of the η nomenclature in chemistry is not systematic, and hapticity must sometimes be inferred as η1 situations or the most common known hapticity for a particular ligand. A discussion of the Lewis and MO representations of the allyl ligand is then provided, and students are asked to examine


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In the Classroom

Figure 9. (A) Examination of OKUSES shows that the allyl ligand bonds to Mg through only one C atom, OKUSES has an η1-allyl ligand. (B) In ALPHPD01, all three allyl C-atoms bond to Pd, ALPHPD01 has an η3-allyl ligand.

Figure 10. The η5-cyclopentadienyl ligands in ferrocene (FERROCE27).

the allyl geometry in the two complexes. The student is then asked to examine a series of five further CSD structures and determine the hapticity of their acyclic ligands and to assign the correct η nomenclature, which can then be checked from the CSD compound name data. The tutorial then discusses cyclic ligands, with particular reference to the η5-cyclopentadienyl ligands in ferrocene (FERROCE27, Figure 10), and various manipulations and measurements on this structure are suggested. This section concludes by asking students to determine the hapticity of a number of other cyclic ligands up to η8. The final tutorial sections introduce the concepts of variable ligand hapticity, as shown by the cyclopentadienyl ligand in CACWOS, PEGJAM, and MULJIM, and the extension of the hapticity concept to deal with heterocyclic ring ligands, for example, the η5-2,3,4,5-tetramethylpyrrolyl ligand in EDEDUK. Use of the CSD is again valuable in permitting students to manipulate these structures, measure geometrical parameters, and check the assigned compound names. Pedagogical Value In Part 1 of this series (1), we noted the vital importance of crystal structure analysis in providing much of our knowledge of 3D structure at atomic and near atomic resolution. It is therefore unsurprising that depictions and discussions of crystal structures and the knowledge that they represent are to be found in most modern undergraduate texts in both organic and inorganic chemistry (7-10), where the citations are examples of many. This is especially true of inorganic chemistry, where the renaissance of the subject since the 1960s has been heavily dependent on crystal structure analysis to characterize the massive output of novel compounds over the last 50 years. The crystallographic databases have grown and matured over the same time scale and provide the ready ability for students to visualize and manipulate 3D structures, a facility that has been shown to enhance students'


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conceptual understanding and spatial abilities (11-13). Using these databases to examine the geometry of individual structures, and sets of related structures, is a natural extension of simple visualization that has already been exemplified and discussed in textbooks (9) and in this Journal (14-18). These latter references cover a broad spectrum of educational applications of the CSD, including inorganic, organic, and medicinal chemistry, and combined applications of the CSD and the Protein Data Bank (19) at the chemistry-biology interface. It has also been noted strongly that the use of “real” experimentally measured data is, in itself, of significant pedagogical value (20-22). In deriving the teaching modules described in this article, we wished to complement and extend currently available examples of CSD usage in a teaching environment. We have chosen examples that are core to any basic chemistry curriculum and that are often illustrated in texts by reference to crystal structure evidence. We are confident that these exercises are of sound pedagogical value. However, a formal assessment of the learning efficacy of these specific modules has yet to be carried out. Rather, our core purpose here has been threefold: (a) to illustrate how the CSD teaching subset can be used in teaching, (b) to encourage others to suggest additional structures for inclusion in the subset and to derive or suggest additional examples for inclusion in the teaching section of the CCDC Web site, and (c) to encourage others to comment on the developing set of CSD teaching examples so that we may publicize these comments via the Web site and provide a more authoritative discussion of pedagogical value in the near future. In Parts 3 and 4 of this series (3, 4), we will extend this discussion to example teaching applications of the complete CSD, which now contains more than 500,000 crystal structures and provides almost endless educational opportunities. Conclusions We have described a set of five teaching units that exemplify the use of experimentally measured 3D structures to teach a range of fundamental chemical concepts. The units utilize a 500structure subset of the Cambridge Structural Database (CSD) specially chosen for their value in a teaching environment. The units were designed with two goals in mind: first to give students the opportunity to use a Web-based environment to observe and interact with a diverse range of 3D structures and second to understand the benefits of using experimentally determined crystal structure data and appreciate its broad applicability across the chemistry curriculum. Acknowledgment The teaching database, a 500-structure subset of the Cambridge Structural Database (CSD), is based upon work supported by the United States National Science Foundation under Grant No. 0725294. Literature Cited


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