Ernest 1. Eliel University of Notre Dame Notre Dame, Indiana
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w h i n g Organic Stereochemistry
Organic chemistry may be divided into two aspects: the static (molecular architecture, ~hvsical mo~erties. and nomenclature) and the dvnamic - . . (reactivity and mechanism). I n both areas, stereochemical concepts are of prime importance. I n molecular architecture, corresponding to structure (which denotes the number and kind of a t o m in the molecule and the manner in which they are linked), there are the stereochemical concepts of configuration (denoting the arrangement of the atoms in threedimensional space) and conformation (the spatial arrangements possible by virtue of rotation about single bonds). Physical properties, such as dipole moments, ultraviolet, infrared, and nuclear magnetic resonance spectra, acid and base strength, etc., depend on stereochemistry as well as structure. Nomenclature has not only structural but also configurational aspects-now, embodied no longer in the old projectional D-L but in the new, truly three-dimensional R S system (1, 2). A knowledge of configuration (relative and absolute) as well as structure is required before we can consider the question of the architecture of a molecule settled-and rightly so, for molecules of identical structure hut differing configuration often have vastly different functions in the realm of natnre. Differences in reactivity may reflect differences in stereochemistry as much as differences in functionality. Many reactions are known which are "stereoselective" (2) meaning that of two possible stereoisomeric products, one is formed in considerable predominance over the other. Such stereoselectivity tends to be particularly marked in biological systems which often produce one stereoisomer to the total exclusion of the other, as for example in the hydration of fumaric acid in the presence of the enzyme fumarase which produces (-)-malie acid uncontaminated by the dextrorotatory isomer. Other reactions are "stereospecific" (2) meaning that of two stereoisomeric starting materials one gives a different product from the other (usually the two products are also stereoisomers). An extreme example, again from biochemistry, is one where only one stereoisomer enters into reaction and the other does not.. Thus fumarase Thia article is based upon a paper presented as a part of the Symposium an Three-Dimensional Chemistry beforc the Division of Chemical Education at the 144th Meeting of the American Chem~calSonety, Las Angeles, California, April, 1963. 'At the Univereity of Notre Dame, after teaching organic chemistry to the ohemistry and chemical engineering majors at the sophomore level for many years, it has now been shifted beak to the junior level with physical chemistry being taught in the sophomore year. It is believed that this will d o w us to use much more sophisticated thinking in terms of chemicd energetics and kinetics in the teaching of organic chemistry in general and stereochemistry in particular.
catalyzes the hydration of fumaric acid to (-)-malic acid hut it does not catalyze the hydration of maleic acid, the cis isomer of fumaric acid. One of the earliest discoveries in this area was made by Pasteur (3) more than 100 years ago who found that the mold Penicillium glaucum ferments the naturally occurring (+)-tartaric acid hut leaves the enantiomeric (-)-tartaric acid untouched. Besides these obviously significant biological implications of dynamic stereochemistry, it is also important in establishing and understanding reaction mechanisms. Conformational principles, especially, play an important role in this area. Teaching Stereochemistry
There are three levels at which, in the author's opinion, stereochemistry can and should be taught: the advanced, the elementary, and the preparatory. A thorough treatment is in order a t the advanced undergraduate or early graduate level, following a basic understanding of both organic and physical chemistry. The author has recently written a textbook (2) to help with this particular task. There are several ways in which the material can he presented. The conventional way-through a formal lecture course-will probably take two hours per week for a semester or three hours per week for a quarter. An alternate method might be to ask the students to read the textbook in 12-15 weekly doses and to devote one class period per week to answering questions on difficult points and to explaining highlights. This period might be one of three otherwise devoted to a course in reaction mechanisms or organic chemistry. Preferably such a reading-recitation arrangement should be supplemented with problem work. Of much greater scope than the advanced-level teaching of stereochemistry is the teaching of the subject a t the elementary organic (sophomore or junior) level.' Here the author has strong feelings as to the proper and improper way of handling the subject. He feels, quite uncompromisingly, that stereochemistry should be integrated with organic chemistry as a whole (starting with a model of methane and ending with DNA) and should not be taught as an appendage after most of organic chemistry has been dealt with in two dimensions. This strong feeling is based on personal learning experience, on the experience with a number of students who were taught the wrong way and never did grasp stereochemistry properly, and with more recent experience with students who not only assimilate stereochemical ideas early in the organic course with great fascination and enthusiasm but also emerge from the course with a real understanding of stereochemical concepts. It was a great disappointment, therefore, to find upon surveying the seven most popular organic Volume 41, Number 2, February 1964
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textbooks (as of March 1962, according to the Gimelli R e p ~ r t that ) ~ only three of them present the subject matter in a thoroughly satisfactory fashion and as many as two handle it in a manner which I would consider quite unsatisfactory. On the other hand; it is gratifying and probably in part indicative of the good sense of chemistry teachers, that the most popular text (used, as of March 1962 in 37% of the schools surveyed) has one of the best treatments. It is certainly to be hoped that future organic texts will have stereochemical concepts (optical and geometrical isomerism as well as conformational principles) presented early so that these concepts can then be illustrated and used appropriately over the entire area of the ~ u b j e c t . ~ Stereochemistry in the General Chemistry Course
The most controversial part of the thesis here presented is that of recommending the teaching of stereochemistry to freshmen. Since so much that was formerly taught a t a later stage has now filtered into the freshman course, some undergraduate teachers seem to have become apprehensive about further efforts in this direction. They are particularly hard t o convince when the subject matter deals with organic chemistry which is usually and perhaps necessarily taught in only quite cursory fashion a t the freshman level and thus does not appear to afford the required background for something as sophisticated as stereochemistry. Also, some freshman teachers are loath to add new subject matter to the curriculum because it obligates them to omit some other subject matter which they consider worthwhile. On the other side of the ledger, the current trend in freshman chemistry courses is to put greater emphasis on principles and to put less effort in a n encyclopedic treatment of inorganic chemistry. This makes for a more flexible course, and in the author's opinion, stereochemical principles are among those that deserve to be included. This is particularly true since, as will be demonstrated later, an extensive knowledge of organic chemistry is not required for an appreciation of stereochemical principles. In fact. stereochemistry is already touched on in a t least two freshman texts, although in so brief a fashion that one may have doubts as to whether the student is being either informed or stimulated. Of more significance in the teaching of stereochemistry to freshmen is the recent appearance of a small supplementary freshman text (4) by W. Herz "for beginning students of general science" in which, according t o the announcement of the book, "the concepts of conformational analysis and optical and geometrical isomerism, all of which are important to theunderstanding of biological phenomena, are discussed." The introduction of stereochemistry t o freshmen should be accomplished in two lectures in order not to consume excessive class time. The freshman lectures are definitely not designed to communicate a great z G ~S. P., ~ Private ~ ~communication ~ ~ , to the author from a committee =enart submitted March 25. 1962 to the Oreanio Suhcommittee of the Examinations Committee of the Division of Chemical Education, ACS. The author has examined two major organic texts which appeared in 1963. Unfortunately, stereochemistry is taken up early in only one of them, and even in t h t one it is not fully integrated in the fabric of the subject matter.
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amount of detailed information (this can be done later) but rather to generate interest by outlining the basic concepts and pointing out their importance. The avowed aim of my own freshman lecture is to put across to the student the idea of stereoselectivity and stereospecificity, i.e., to make him realize why a reaction may be stereoselective or stereospecific. I t is not difficult to motivate the student toward this study and get him to recognize its importance after he has been told that most of the major components of living matter are dissymmetric and are generated in that form in biochemical syntheses. (In contrast, the classical and more detailed and systematic approach a t the sophomore level puts the major stress on optical rotation. Without wishing to belittle the importance of optical rotation and especially of its recent progeny, optical rotatory dispersion (5)-which can, for example, be used to follow the denaturation of proteins and of DNA-it must be said that it is largely a diagnostic tool, and to spend too much time on the relationship between dissymmetry and rotation is apt to produce a ''so what?" attitude especially on the part of the intellectually more aggressive students.) The approach which the author chose for the presentation of stereochemical thinking-and which is neither particularly original nor claimed to be necessarily the best approach-begins with a very brief historical discussion of the nature of polarized light (Malus) including the showing of a schematic diagram of a polarimeter, and of the discovery of optically active suhstances by hragot and Biot. A second schematic diagram shows the effect of optically active substances on the plane of polarized light and serves to introduced the terms "angle of rotation," "dextrorotatory" and "levorotatory." The term "specific rotation" may also be introduced here by pointing out that rotation is proportional to the number of molecules encountered and that in order to obtain a quantity characteristic of a particular substance, one must divide by concentration and cell length. However, no great stress need be put on this term, in as much as it is not very important in the development of the major overall ideas. I t is next pointed out that some substances, such as quartz and urea, are optically active only in the solid state so that their optical activity is clearly a property of the crystal. However, other substances, such as turpentine, sugar, tartaric acid are active as solids, liquids, gases, or in solution so that there the activity is evidently a property of the molecule. Pasteur's suzeestion that o ~ t i c a activitv l is related to molecular dissymmetry is next introduced, the right and left hand being used as examples of dissymmetric, mirror-image objects. The term "enantiomer" is also introduced here. Yan't Hoff's picture of the tetrahedral carbon of type Cabcd (Fig. 1, top) as the focus of dissymmetry is now presented with a showing of pictures and models of enantiomeric molecules. The concept of configuration is touched on by saying that in any given instance, there is a real problem of determining which of the two arrangements of Cabcd corresponds to the d~xtrorotatoryand which to the levorotatory form. (This problem of configurational assignment may be likened to the structural problem of determining whether ClH60 is ethyl alcohol or diethyl ether-if the students know enough organic chemistry u-
a t this stage. Unfortunately, it seems beyond the scope of a freshman lecture to try to indicate a solution to the problem of configurational assignment.) Lactic acid is presented at this point as a simple molecule which has two enantiomers both of which occur naturally. To impress upon the student that optically active materials are widely distributed in nature, the rotation of a steroid (e.g., cholesterol), an alkaloid (e.g., quinine), a sugar (e.g., sucrose), a polypeptide or protein (e.g., oxytocin), and a nucleic acid (e.g., DNA) are presented next. (Only the names of the compounds and their specific rotations are shown assuming that the students' background in organic chemistry a t this stage is insufficient for them to appreciate the structural formulas.) At this point, the student begins to see the importance of enantiomerism in nature. One must now explain to him that the synthesis of dissymmetric substances does not ordinarily lead to optically active materials. The synthesis of Cabcd from Caabc (inactive) is presented in this context and is illustrated by the formation of or-bromopropionic acid by bromination of propionic acid. The student easily sees that both enantiomers are formed with equal ease and the concept of a racemic modification as an assembly of equal number of dextroand levorotatory molecules develops logically. It is next explained (and exemplified) that enantiomers are identical in all ordinary physical and chemical properties (except for sign of rotation) as well as in internal energy; again this may be rationalized through an analogy with an individual with perfectly shaped hands. (The relation between any two fingers of the right hand (say the thumb and the ring finger) is the same as the corresponding relation in the left hand-in fact, the terms "right" and "left" are meaningful only in the presence of some (external) orienting coordinate system.) Besides being indeed very similar, enantiomers are also equally reactive toward a symmetrical reagent. Again our analogy may be used: if the individual with perfectly shaped hands is also ambidextrous, he will be able to handle a symmetrical tool, such as a hammer, equally well with either hand. By now the student is curious how optically active molecules can originate a t all. His attention is therefore drawn to the fact that toward a dissymmetric "reagent," such as a glove, the two hands are not equal a t all. (A better analogy may be that of a right-and left-handed screw-when turned into a symmetrical wooden board, the two behave essentially the same, but toward an unsymmetrical right-handed nut, they behave very differently.) I n fact, one may write such mock reactions as
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+ right glove gloved hand (fast reaction) right hand + left glove no reection
right hand
This serves as an analogy for the high stereospecificity of certain chemical reactions. The lecture now enters its most difficultphase where the students find it hardest to keep up with the ideas. I t is therefore well to strengthen their interest with a few more examples of enantiomers which behave differently in a dissymmetric environment: that of asparagine where only one of the two enantiomers tastes sweet to man (who, because of all the proteins in his enzyme systems, is highly dissymmetric chemically
speaking); that of glutamic acid where one enantiomer but not the other is a well-known flavor-enhancing agent; and that of the antibiotic chloromycetin which, like many drugs, is effective only in one of its enantiomeric forms. The earlier-mentioned case of the fermentation of the natural (+) but not the unnatural (-)-tartaric acid by the enzyme systems of Penicillium glaucum may also he presented a t this stage.
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Figure 1.
The molecular basis of the right-hand-right-glove and right-hand-left-glove analogy may now be shown as indicated in Figure 1. The two enantiomers (+) and (-)-Cefgh react with a single enantiomer of Cabcd. The reactive spot of the molecules where interaction occurs is assumed to be a t c and f. It is clear that (-)-Cefgh must be turned upside down for the reaction to be written and that the two resulting molecules Cabcd, Cejgh, while stereoisomers, are no longer enantiomeric (mirror images). These molecules, it is explained are called diastereoisomers (nonenantiomeric stereoisomers) and differ in their physical and chemical properties and internal energy as much as other pairs of (structural) isomers might because the internal relationships in diastereoisomers, unlike those in enantiomers, are no longer the same. (As written in Figure 1, the product on the left has a close tog and remote from h, whereas in the molecule on the right, a is close to h and remote from g. If a and h can engage in intramolecular hydrogen bonding, for example, the second combination may well be the more stable one.) Kow (+)-and (-)tartaric acid and mesotartaric acid are presented as a set of stereoisomers containing both enantiomers and diastereoisomers and the difference in properties of the diastereoisorners is shown. (Some instructors may prefer to show only one enantiomer of active tartaric acid along with the meso form in order not to complicate the picture unnecessarily.) To drive home the difference in reactivity and properties of diastereoisomers, one may introduce yet another mechanical analogy: the difference of a right-hand-right-baseball glove and right-hand-left-baseball glove combination in compactness, feel, and possible reaction toward a flying baseball. The student may now begin to grasp the difference in reactivity between stereoisomers when both starting materials are dissymmetric. However, he does not yet have the basis to understand the asymmetric synthesis involved when active compounds arise from inactive precursors in biological systems. In order to make him understand this requires a consideration of transition state energetics and therefore some prior knowledge of energy profiles. Granted that knowledge, the underVolume 41, Number 2, February 1964
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lying principle can be illustrated by the example shown in Figure 2. The reduction of methyl isohexyl ketone (inactive) with (+)-2-butanol through a hydride transfer gives, in addition to inactive 2-hutanone, (+)-2methylisohexylcarbiuol in predominance over the (-)-isomer. Clearly the pair of starting materials as well as the pair of products are enantiomeric, not
(+I Figure 2.
diastereoisomeric and the preference thus seems at first sight surprising. The reason why there can yet be asymmetric synthesis is that in the transition state, both the asymmetry of the Pbutanol (A) and that of the incipient methylhexylcarbinol (B) are present and therefore there are two possible transition states, (+)-A,. .(f )-B and ( A . ( B , which are diastereoisomeric and therefore unequal in energy; the first happens to be preferred. The energetic situation is as diagramed in Figure 3.
Figure 3.
Here again a mechanical analogy may serve to drive home the point. The starting state in the analogy is a man with a pair of sunglasses with a speck of sand on the right lens. The man is symmetrical, the glasses are one of a pair of enantiomers (the other being a pair of sunglasses with a speck of sand on the left lens). The sand is now, accidentally, transferred from the glasses to the man. We now have the product: a man with a grain of sand in his right eye and a pair of clean sunglasses. The man now is one of a pair of enantiomers and the glasses are symmetrical. Nevertheless, the reaction is completely stereoselective: the grain of sand is only transferred to the right eye. not to the left eye. This is because the two possible transition states, one in which the sand is transferred from the right lens to the right eye, and the other in which it is transferred from the right lens to the left
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The process described in this analogy is, of course, much more highly stereoselective than the chemical reduction of 2-butanone shown in Figures 2 and 3. Its stereoselectivity corresponds more nearly to that of the earlier-mentioned biochemical processes in which, also. the differences in enerev between disstereaisomeric
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eye are diastereoisomeric; and in fact, the latter will be much higher in energy than the former, so to speak.' This is probably as far (or perhaps a little farther) than one can go in a freshman lecture. One may conclude the lecture by saying that while the principles of asymmetric synthesis, stereospecificity and stereoselectivity are now clear, the actual detailed mechanism remains to be elu~idated.~(In fact, much research is going on a t the present time on understanding the stereospecificity and stereoselectivity of enzymes. Other problems which have hut been referred to are the elucidation of configuration, the actual practical methods of obtaining optically active compounds and the origin of optical rotation in an asymmetric molecule. Some important topics, such as conformational analysis, have not been mentioned a t all. One of the ways of illustrating the scope of the lecture is by means of the quiz given following the presentation. The results showed quite a significant level of absorption of the material presented. They also pointed out certain shortcomings which will be avoided on future occasions. One, already mentioned, is that the lecture was too compressed. It should be extended over two hours. Another was that the material was presented too early in the course, following a treatment of the structure of organic compounds near the end of the fall semester. Better results could undoubtedly have been achieved had the lecture been given in the second semester-either near the beginning, follcwing an elementary treatment of the thermodynamics of chemical reaction and chemical kinetics, or near the end, as part of a series of specialized topics in organic chemistry. Despite this, the results were sufficiently promising to make us decide to repeat the experiment in the following academic year. The author hopes other freshman instructors will be encouraged to perform it also. Questions on Stereochemistry for Freshman Chemistry Students 1. What is meant by the statement, "An optically active substance is dextrorotatotory?" Would such behavior depend on the state of aggregation? Explain. 2. What are enantiomers? What is meant by the statement, "Enrtntiomers differ in configuration?" What is the source of enantiomerism a t the molecular level? 3. What is meant by "specific rotation?" If a substance shows a rotation of 5.00' when viewed in a 2-dm cell i n s solution of conoentrstion 0.1 g/ml, what is the specific rotation of the substance? (The dm or decimeter and the concentration in g/ml are the proper units for the expression of specific rotation.) 4. Suppose you have two beakers containing racemic tsrtario acid in aqueous solution. In beaker 1, half the tartaric acid is destroyed by chemical oxidation, e.g., by permanganate. In beaker 2, half the tartaric acid is destroyed by fermentation by the mold Paicillium glaueum. (a) What difference exists hetween the tartaric acid left over in beaker 1 and in beaker 2? (b) Explain, as best you can, the reason for this difference.
literature Cited (1) CRAM,D. J., AND HAMMOND, G. S., "Organic Chemistry," McGraw-Hill Book Co., Inc., New York, 1959, p. 144. (2) ELIEL, E. L., "Stereochemistry of Carbon Compounds," McGraw-Hill Book Co., Inc.. New York. 1962.. emeci. ally pp. 92,436. (3) PASTEUR, L., Compt. rend., 46,615 (1858). (4) HERE, W., "The Shape of Carbon Compounds," W. A. Benjamin, Inc., New York, 1963. (5) DJEEASS~ C., "Optical Rotatory Dispersion," McGraw-Hill Book Co., Inc., New York, 1960.
