Incorporating Heterotopicity into Organic Chemistry Edwin Thall The University of Akron-Wayne College, Orwille, OH 44667 From its Greek roots "heteros" (different) and "topos" (place), heterotopicity is the study of the stereochemical non-equivalence of ligands and faces. While usually addressed in more advanced courses, inclusion of heterotopicity in an introductory organic chemistry course offers advantages. Students attain a better insight into stereochemistry, and for many non-chemistry majors, the sophomore-level course represents the last academic setting to investigate the subject. This paper reviews topological relationships (1-6)and suggests how to incorporate heterotopic concepts into the contemporary organic chemistry course. Topological Relationships Me Me The attachment of two similar groups to a tetrahedral 4 5 6 carbon creates a distinct structural feature. Just as the carbon in CWXYZ is a chiral center, the carbon of CWWXY Br \ /CI is a tetrahedral prochiral center-it has the capacity of atC taining chiral status. The environments of the two like II C groups in CWWXY are either identical (homotopic)or dis0 / \ tinct (heterotopic). The accompanying figure provides an H H organizational chart of topological relationships, that is, the characterization of ligands or faces based on position. Me To determine the topological relationship between two 7 8 9 ligands, we perform an 'imaginary replacement" test. For hydrogen ligands, the procedure is quite simple. Replace one hydrogen and then the other with deuterium, the next highest priority group. In circumstances when imaginary replacement leads to enantiomers or diastereomers, the liMe/ \H H Me gands are heterotopic. The highlighted hydrogens in chloroethane (1)are enantiotopic ligands because replacement 10 11 with deuterium gives rise to the enantiomers shown by 2 lighted hydrogens in (R)-l,2-dichloropropane (6) portray and 3. These ligands are designated pro-R (HE)and p r o 3 ligands. Imaginary replacement gives rise ( ~ ~ b r e p l a c i ffn n g with deuterium gives the ~ - ~ ~ n f i g u r ~diastereotopic to diastereomers. Also, diastereotopic ligands may be attion (2), and hence the descriptor. But keep in mind, no tached to different carbons within a molecule (71,or even correlation exists between the prochiral descriptor and the to carbons making double bonds (8). configuration of product. Replacement of Hn with fluorine A carbon to which a pair of enantiotopic or diastereoresults in the S-configuration (4). topic ligands are attached is called a prochiral center, be~ ~ ~ ligands ~ t need i not ~ be t attached ~ ~ toithe ~same cause replacement of one of its ligands would convert the carbon atom. In neso-2,3-dibromobutane (5), the highcarbon into a chiral center. Together, enantiotopic and dilighted hydrogens are bonded to different carbons, yet astereotopic ligands are classified as heterotopic, while liimaginary replacement leads to enantiomers, ~h~ highgands in identical environments are homotopic. For unrelated ligands, imaginary replacement Topological Relationships Between Ligands and Faces generates neither enantiomers, diastereomers, or identical structures. Heterotopicity can be extended to molecules possessing flat portions or faces. This type of stereochemical nonequivalence relies on dissimilar faces and features the trigonal prochiral center. For example, flipping formaldehyde (9) 180 ' Topological Equivalent Topological Non-equivalent reveals equivalent sides or homotopic faces. On (heterotopic;distinct mvironments) (homotopic;identical environments) the other hand, acetaldehyde (10,ll) possesses non-equivalent sides or heterotopic faces. The faces of the carbonyl group take on the role of ligand W in CWWXY. Here, the formation of a chiral center does not depend on ligand substitution, Enantiotopic Diastereotopic but rather on attack at one face or the other. To distinguish the faces of acetaldehyde, the Organizationalchart of topological relationships. three groups attached to the trigonal carbon are
% fi !
gc
1 +I-
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Journal of Chemical Education
ranked according to the rules of Cahn-Ingold-Prelog (7). The Re (rectus) face shown in 10 reflects a tri~onalprochiin ral center displaying a decreasing substituent the clockwise direction ( O > C H I > H I. For the Si (sinlscer) face (111, the priority decreases in a counterclockwise direction. Reactions 1and 2 illustrate the two types of heterotopic faces: enantiotopic and diastereotopic. For both reactions, hydrogen equally attaches to the Re and Si faces of the trigonal carbon. In the reduction of butanone (Reaction 11, (Re face attack) (Si faceattack)
butanone
(s)-2-butanol
( ~-2-butanol j
attachment of hydrogen to the Re face leads to (S)-2-butanol; attachment to the Si face gives the R-conf~guration. Because enantiomers are produced, butanone possesses enantiotopic faces. Next, note the reduction of (R)-3phenylbutanone (Reaction 2). The combined presence of a 0
(Refaceattack)
(Si face attack)
PH
P"
II & /"\ R Me CHPhMe
(2)
trigonal prochiral center and a chiral center represents the most common condition for diastereotopic faces. The formation of diastereomers characterizes the faces of (R)-3phenylbutanone as diastereotopic. The heterotopic faces displayed by alkenes contain either one or two trigonal prochiral carbons. Propene, possessing one center, requires a single descriptor to identify its faces as Re (12) and Si (13).However, if the face of a
31
double bond is Re a t both trigonal carbon atoms, then this is the Re, Re face; the faces ofE-2-pentene are Re, Re (14) and Si, Si (15). For faces displaying Re a t one and SI a t the other trigonal carbon atom, the prochiral center with the highest priority group(s) is specified first (8).For example, the faces of Z-2-pentene are Si, Re (16) and Re, Si (17). Incorporating Heterotopic Ligands At what juncture in the organic chemistry course should students first encounter heterotopicity? I introduce topological relationships of ligands along. with chirality, enantiomers, diastereomers, and meso compounds. .Holding models of dichloromethane, chloroethane, (R)-1,2-dichloropropane, and meso-2,3-dibromobutane,Luse imaginary replacement to demonstrate homotopic, enantiotopic, and diastereotopic hydrogen ligands. The initial presentation does not extend beyond characterizing simple topological relationships. The ensuing stereochemistry exam usually includes one problem to identify highlighted hydrogens similar to those shown in 1 S 2 1 . (Answers: enantiotopic, homotopic, diastereotopic, and unrelated.) Students often experience difficulty with the,steieochemistry of cyclic compounds, undoubtedly due, to rotational restrictions about single bonds of skeleton atoms. As a class exercise, the highlighted hydrogens of the dichl'orocyclopmpanes shown in 22-24 are identified as homotopic, enantiotopic, and diastereotopic. Then, I ask, 'How are 25/26, 27/28, and 29/30 related?" (Answers: identical;,enantiomers, and diastereomers.) An understanding of topo: logical relationships provides another tool for examining cyclic structures. An exam question may require students to analyze cis-1,4-dichlorocyclohexane(31) and charac-
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terize the topological relationships of HIM%, HI/H~,H a s , and H B 3 . (Answers: unrelated, homotopic, enantiotopic, and diastereoto~ic.) The base-assisted dehydrohalogenation of an alkyl halide favors elimination from the anti-periplanar mnforma. . tion. This type of reaction offers the opportunity to point out how removal of one heterotopic hydrogen ligand or the other can lead to distinct structures. For example, when (R)-2-bromobutane is subjected to dehydrohalogenation conditions, elimination of Hg produces Z-2-butene (Reaction 3). Conversely, elimination of Hs generates E-2butene.
A number of organic textbooks include subject matter related to heterotopic ligands in chapters dealing directly with nuclear magnetic resonance. The premise: enantiotopic and diastereotopic protons give rise to similar and distinct chemical shifts, respectively. Once students have mastered imaginary replacement, predicting the number of 'H-NMR signals becomes less complicated. I use the "Representing Isomeric Structure" (RIS) approach (9)to specify distinct 'H-NMR signals. Chloroethane (32) is allocated two arrows to represent the anticipated 'H-NMR signals, while 2-chlorobutane (33) is shown with five arrows-the diastereotopic protons give rise to distinct chemical shifts. The oxidation of primary alcohols offers another opportunity to demonstrate the distinct chemical behavior of heterotopic ligands. The enzyme catalyzed oxidation of ethanol into acetaldehyde has been the subject of much study since 1953 (10).The oxidized form of nicotinamide adenine dinucleotide (NADf) abstracts only the pro-R hydrogen of ethanol to form acetaldehyde (Reaction 4). When (R)-1-deuteroethanol (34) is subjected to the same conditions, it loses all of its deuterium to yield unlabeled acetaldehyde.
kinetics. The S N reaction ~ features the carbocation undergoing nucleophilic attack from both front and back. If some degree of racemization takes place, the trigonal carbocation possesses enantiotopic faces. Reaction 5 illustrates the S N displacement ~ of 2-bromobutane in water. According to the rules of Cahn-Ingold-Prelog, the faces of the secondary carbocation may be designated Re (35) and Si (36). Because Reaction 5 leads to racemization, the short-lived faces of the carbocation are enantiotopic.
When describing characteristics of the carbon-carbon double bond, I include homotopic and heterotopic faces. For selected alkene addition reactions, I construct models to demonstrate the consequences of attack at one face or the other. Consider the addition of hydrogen chloride to bromoethene. After the proton transfers to the unsaturated carbon in accordance with Markowikov's rule, the chloride ion equally attaches to the enantiotopic faces of the carbocation to form racemic 1-bromo-1-chloroethane. Reaction 6 illustrates how attack at the Re and Si faces give the S- and R-configurations, respectively. Emphasiz-
Y
r
(Ski-bromo- (Rkl-bromoI-chloroethane I-chloroethane ing reactions in this manner allows students to determine products based on the face attacked. Besides possessing the essential feature of faces, alkenes can undergo stereospecific reactions. Owing to reactants attaching to the same face of the carbon-carbon double bond, syn-additions are especially convenient for demonstrating how stereochemically different reactants give stereochemicallydifferent products. Examples of synadditions include hydroxylation with potassium permanC-C C-C-C-C ganate, epoxide formation with peroxy compounds, hydroH genation using Wilkinson's catalyst, cyclopropane OH formation with diazomethane, and hydroboration-oxidation in the synthesis of alcohols. 34 32 33 The syn-addition of KMn04 to Z and E-2-butene will Incorporating Heterotopic Faces serve as examples of stereospecific reactions. The homotopic faces of Z-2-butene form meso-2,3-butanediol (ReacI first refer to heterotopic faces in connection with nution 7),while the heterotopic faces of E-2-butene produce cleophilic substitution reactions that follow first-order racemic 2,3-butanediol (Reaction 8). On exams, I frequently require students to determine products based on the face attacked. For example, what forms when the Re, Re face of E-2-pentene is subjected to hydroxylation using KMn04?(See Reaction 9). OH The chemistry of aldehydes and ketones present another opportunity to incorporate stereethanol acetaldehyde ochem&al non-equivalerke. Hetero(Re face attack) (Si faceattack) topic faces derived from cnrbonvl comH H pounds closely resemble single descripH I I ( 5 ) tor alkenes such as 1-bromoetheneand ,C\-OH + ,--OH (SNI) ,C; propene. When carbonyl groups unBr Me Et Me Et dergo addition, they are susceptible to Me Et attack from both faces. Examples in2-bromobutane (R)-2-butan0' (S)-2-bu'an01 clude reduction with hydrogen, cyano-
'7'
I f
7'1
tt'tt
C-F-C-C
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Journal of Chemical Education
4
brornoethene
(Reface attack)(Si face attack1
Me
H
\ /
(Si. Re face attack) (Si, Re face attack H\ /Me H Me \ / -OH ~~n04_ + ?---OH /C\-OH C---OH H Me HI\Me
7
C
II
C
/
H Me Z-2-butene
(Re, Re faceattack)
(7)
(Si,Si faceattack)
/H
E-2-butene
(2R. 3R)-2, Wutanediol (25, 3s)-2, Wutanediol
fascinating, especially when they hear how one enantiomer may cure disease, suppress headaches, or smell good, while its mirror image may lead to a toxic substance, smell repugnant, or remaininert. For example, Eli Lilly & Company makes the sedative drug Darvon, and its mirror image, a cough medicine named Novrad, or Darvon spelled backwards. When describing amino acids and protein, I cite the method (11)developed for synthesizing several Gamino acids- proteins are prepared exclusively from L-amino acids. The procedure calls for a special catalyst based on a chiral rhodium complex. To synthesize L-alanine, 2-acetylaminopropenoic acid is hydrogenated with the catalyst and then hvdrolvzed. Reaction 11shows hvdroeen must a& ; the single tach to t h e ~ fice e to form L-alanine. ~ h does enantiomer orevail? Two exolanations are oossible: Either the catalystAdiscriminatesGetween the two faces, or both faces form a-com~lexeswith the catalyst. but one is more reactive than the'other.
(Re. Re face attack)
MY
fi
/"
KMnOl_
(Refa2 attack)
MYO?'H/H
.. (9)
1\
Me
L
H0& NHCOMe
H0& NHCOMe
Hz0
H+NH,
cod
L-alanine
2-acetylaminopropnoic acid (Re face attack)
(Si face attack) ('0)
acetaldehyde
(S)-acetaldehyde (R)-acetaldehydr cyanohydrin cyanohydrin
hydrin formation, and Grignard reagents. In the conversion of acetaldehyde to acetaldehyde cyanohydrin (Reaction 101,cyanide ion equally attacks Re and Si faces to produce the racemic modification. If the diastereotopic faces of (R)-3-phenylbutanone are allowed to undergo the same reaction, diastereomers are predicted. Asvmmetrlc Svnthesis Can certain reagents discriminate between the faces of a molecule? After ohserving a half-dozen addition reactions to heterotopic faces of al6enes and carbonyl compounds, students are ready to grasp the rudimentary principles of an asymmetric synthesis. Although asymmetric synthesis is not normallv included in the introductory organic chemistry course, some form of enhancement information may prove worthwhile. If a research or term paper is required, single enantiomer synthesis certainly would make an interesting topic. In the previous section, a n exercise called for predicting the product resulting from hydroxylation of the Re, Re face of&-2-oentene (Reaction 9). Realisticallv. inactive .. ooticallv . reagents cannot discriminate between heterotopic faces, and we exoect eaual attack to both faces of E-2-oentene. While mos't chekical techniques give rise to the'racemic mixture of some compound, a n asymmetric synthesis makes use of special chiral reagents to generate more of one enantiomer than the other. Students find the subject
.
Concluding Remarks Considering that the contemporary organic chemistry course already is bursting with more material than can be manageably conveyed, why bother to include topological relationships? Actually, the incorporation of heterotopic concepts does not entail entirely new concepts, but it does require more detail. Morrison and Boyd (12) write: Molecules are not two-dimensional formulas existing in a n imaginary flatland. They are three-dimensional objects, and they react in three-dmensionalspace. We cannot undrrstand molecules or the reactions they undergo unless we understand them in three dimensions. Five years have elapsed since I started to incorporate heteroto~icitvinto the so~homore-levelorganic chemistw course. M~ ciass sizes are relatively small, 12 to 18 st"dents, and I frequently construct molecular models to demonstrate the consequence of attack a t heterotopic ligands and faces. In large lecture halls where models may not prove practical, effective overhead displays are essential. However, in the small class environment, most students readily learn to recognize heterotopic faces and ligands, as well as to predict products resulting from attack a t specific prochiral centers. Literature Cited 1. Mislow, K; Rabin, M. 'Ibpiea Sfemhem. 1881.1.1. 2. Argmi, D.; Eliel, E. L. IbpieaSfrmhem.l888,4, 127. 3. Kagen, H. Organic Shhhemlafry; Wiley: New York. 1979. 4. Eliel, E. L.J. Chem. Edue. 1980.51.52. 5. Bassendale,A. T k ThirdDimmion in Orgonie Chemistry: Wiley: New York. 1994. 6. Morrison, R.T;Boyd. R.N. Orgnnic Chemistry, 6th ed.; RentieeHell, he.: Englewwd Cliffs, NJ, 1992,Chapter 32. 7. Cshn, R. S.:Ingold. C. K: Relog, V.A q a a Chem InL Ed. @*I.) 16% 5. 385. 9. Han8cn.K R.J. Am. Chem. Soe. lgGB,88,2731. 9. Thall. E.J. Chem. Educ. 1882.69.447. 10. Loewus,E A,: Westheher, E H.;Vennealand.B. J. Am. Chem. Soe. ISSS,75,5018. 11. hz&,M. D.;Bosnich, B.J A m . Chem. Soe. 1918, IW.5491. 12. Ref 6,p 367.
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