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Stereochemistry

TABLE OF CONTENTS FOR THIS CHAPTER
1. Isomers:Definitions
2. Constitutional Isomers
3. Stereoisomers
4. Chirality
5. Symmetry Elements
6. Nomenclature for Enantiomers
7. Two Stereogenic Centers
8. Two Equivalent Stereogenic Centers
9. Comparative Properties of Enantiomers/Diastereoisomers
10. Optical Activity
11. Racemic Mixtures
12. Optical Purity
13. Resolution of Enantiomers
14. Kinetic Resolution
Isomers:Definitions
You are already familiar with the concept of isomers: different compounds which have the
same molecular formula. In this chapter we learn to make distinctions between various kinds of
isomers, especially the more subtle kind of isomers which we call stereoisomers.

Constitutional Isomers: Isomers which differ in "connectivity". The latter term means
that the difference is in the sequence in which atoms are attached to one another.
Examples of isomers pairs which are consitutional isomers are (1)butane and
methylpropane,i.e., isobutane, which are different in that butane has a sequence of four
carbon atoms in a row, but isobutane has a three carbon chain with a branch (2)dimethyl
ether and ethanol--the former has a C-O-C chain, while the latter has a C-C-O chain (3)

but in the case of 2-butanol there are two isomeric forms which can not be superimposed. and since the difference between diastereoisomers and enantiomers rests upon the concept of mirror image isomerism. Since we have previously considered constitutional isomerism. Cisand Trans-1. Enantiomers are mirror image isomers. They also don't have a cis or trans prefix. In a sample of butane. that is . they are diastereoisomers. we must now consider this latter phenomenon in greater detail. while the latter has a 5-membered ring. obviously. or they wouldn't both be called by the same name (2-butanol). then . They have a very specific. all of the molecules are identical because they can be superimposed upon one another in some conformation.  Stereoisomers: Isomers which have the same connectivity.4-dimethylcyclohexane are of the latter type. to indicate that they are diastereoisomers. This is the very most subtle way in which two chemical compounds can differ:In an overal sense. Thus all isomers are either constitutional or stereoisomers. Stereoisomers We have just seen that there are two major types of isomer.and trans-isomers in general are diastereoisomers. CHIRALITY . Mirror Image Isomerism To be isomers. The same is true of ethanol or propanol or 1-butanol. molecules must not be identical. They do not differ in connectivity. there are three types of isomers: (1)constitutional isomers (2)diastereoisomers and (3)enantiomers in order of increasing subtlety of difference. the same relationship which exists between an object and its mirror image.1-pentene and cyclopentane--the former has an acylic chain of 5 carbons.and trans-1. The test for "identicality" is one ofsuperimposability. They have the same connectivity but are not mirror images of each other. A key aspect of this difference. Stereoisomerism is a more subtle kind of isomerism in which the isomers differ only in their spatial arrangement. but now it is necessary to further notice that their are two sub-types of stereoisomers:  Enantiomers: Stereoisomers which are mirror images  Diastereoisomers: Stereoisomers which are not mirror images The examples of cis. as we all know.4-dimethylcyclohexane are a good example of a pair of stereoisomers. is that a mirror acts to interchange left and right hands. unique relationship to one another. not in their connectivity. Cis.

non-superimposable upon) its mirror image molecule or object is said to be chiral. This emphasizes the point that a molecule or object is guaranteed to be chiral only if it has a single stereogenic center. you can see that B slides over onto A with all corresponding groups superimposing perfectly. but one molecule is chiral and the other achiral. the very similar molecule 2-propanol is achiral and does not exist as an enantiomeric pair. In the illustration. Your can verify this by making models. This means it resembles a human hand in that the left and right hands are not superimposabile but can be readily distinguished (at least by some of us). viz. it must be chiral. but the ethyl group on B sits over the methyl group of A. 2-propanol has no stereogenic center and is achiral. having H. for example. The most common kind of stereogenic center is a carbon (or other atom) which has four different atoms or groups directly attached to it. We will learn how to name the two different enantiomers shortly.. Since it has just a single stereogenic center . especially complex molecules such as are found in biological systems. no methyl carbon atom or methylene carbon can be chiral since these groups automatically have at least two identical groups (H's) attached. If a molecule has a single stereogenic center it will necessarily be chiral. If it has more than one stereogenic center. but are mirror image isomers.methyl. the central C. is the use ofsymmetry elements.2-dimethylcyclobutane.We can. How can we predict whether a molecule is chiral or achiral?  One of the simple ways is to use the concept of a stereogenic center. and two methyl groups attached.e. Of course. a molecule or any object is said to be achiral if it is identical to (superimposable upon) its mirror image molecule or object. They both have two stereogenic centers. We will see a little later what happens when we have more than one stereogenic center. Many molecules are achiral. The two molecules have all the same kinds of bonds and are extremely similar.H. The examples shown below refer to cisand trans-1. especially useful when there is more than one stereogenic center. Many simple molecules are of this kind. The corresponding carbon atom of 2-propanol has an OH. The former of which is achiral and the latter chiral. On the other hand. the ring carbons which have the methyl and hydrogen groups attached.How can we anticipate when a molecule is chiral and therefore has an isomer (an enantiomer) or when it is achiral and has no enantiomer?  Consider 2-butanol. The illustration below (hopefully) shows that the mirror image of one 2-butanol isomer is nonsuperimposable upon the original molecule. By the same token.If the molecule or object has either a plane of symmetry or a center of symmetry it is achiral.  The second method. and the methyl group on B superimposes upon the ethyl group of A. You can see that the central carbon of 2-butanol (the one marked by an asterisk) is a stereogenic center. slide B over to A and superimpose the OH..  Although 2-butanol is a chiral molecule and therefore has two enantiomers.OH. which is an example of a chiral molecule. but you can also visualize trying to superimpose the two by sliding one structure over (mentally) on top of the other. it may be either . and its attached H of the B molecule over the corresponding gorups of the A molecule. A molecule or object which is not identical to(i. but many are chiral. and ethyl groups attached.

In the case illustrated. there are three isomers of 2. and 1-bromoethyl substituents.  Please note that the stereogenic center need not be carbon. so that where there is a methyl group on the right there is a H on the left. A center of symmetry will be encountered in any molecule which has two equivalent chiral centers (i. Again.another connects equivalent methyl groups. there is one enantiomeric pair plus this meso isomer.  What is the relationship between the cis and trans isomers of 1. having the same connectivity but obviously not being mirror images of each other. and that is the center of symmetry. but one other element of symmetry also guarantees an achiral molecule. and two enantiomeric trans isomers..bromine. . Note that in the cis isomer.  The plane of symmetry is relatively easy to find and is the most common one to look for. if there are four different groups attached to the nitrogen.chiral or achiral.e. To sum up. The two carbons of this molecule both have H. the two methyls are on the same side of the ring and are equidistant from the plane of symmtery which runs through the center of the ring perpendicular to the ring.3-dimethylcyclobutane.3-dimethylbutane (the so-called meso isomer).The meso isomer is just one of the three stereoisomers of this system. This is a point in the molecule for which any line drawn through the point will encounter identical components of the object at equal distances from the center of symmetry. both carbons have the same set of four distinct substituents) and in a conformation of such a molecule in which all identical groups are anti to one another.methyl. a single cis isomer. 2. One of the dotted lines shown connects the equivalent bromines on of the two carbons.2-dimethylcyclobutane??? They arediastereoisomers. It can be a quaternary nitrogen atom ( the nitrogen of an ammonium salt. the methyls are on opposite sides of the ring. and a third connects equivalent hydrogens (not shown). In the trans isomer. which is achiral. the center of symmetry is at the center point of the C2-C3 carbon-carbon bond.

Symmetry Elements Which Guarantee Achirality .

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What are the rules which govern which is which??  Priorities are assigned to each of the four different groups attached to a given stereogenic center (one through four.R. The convention which is used is called the (R. we will need to have nomenclature which distinguishes them from each other. (It should be understood that each stereogenic center has to be treated separately.) .S Nomenclature NAMING ENANTIOMERS Since two enantiomers are different compounds. one being the group of highest priority).S) system because one enantiomer is assinged as the R enantiomer and the other as the S enantiomer.

 In this kind of tie situation.  If this circular motion is clockwise. a vinyl group has priority over an isopropyl group. If it is counterclockwise. the carbon is considered to be bonded to two oxygens. F over O. the enantiomer is the R enantiomer. which we will call the beta atoms. while for the ethyl group the alpha atom is also carbon and the beta atoms are two H's and 1 carbon. the competition contines from alpha to beta to gamma to delta atoms until a tie-breaker is found. it is the S enantiomer. and the oxygen is considered to be bonded to two carbons. But the methyl and ethyl groups both are attached through carbon . priority assignments proceed outward to the next atoms. because of the double bond.  Draw a circular arrow from the group of first priority to the group of second priority. . H has the lowest priority. take the vinyl group. O over C. the alpha atom is carbon and the beta atoms are three H's. and H the fourth. in 2-butanol. Orient the molecule so that the group of priority four (lowest priority) points away from the observer.  Some additional conventions are necessary for handling multiple bonds and aromatic bonds. Each carbon of this double bond is considered to have two bonds to carbon. i.e. For this reason. and so on. In general. HOW TO ASSIGN GROUP PRIORITIES There is also a set of conventions (rules) which govern the setting of group priorities.S system of nomenclature. the example we considered previously. Oxygen gets the first priority.  Priority is based upon atomic number. This beta C of the ethyl group wins the priority competition because there is no beta atom on the methyl group which has an atomic number greater than 1 (all three beta atoms are H). In the case of a carbonyl group. so there is initially a tie for the second and third priorities. as shown in the illustration. and these are a little tricky to learn. Priority assignment is based upon the four atoms directly attached to the stereogenic center. For example.. and two C's.O. For the methyl group.(The directly attached atoms are the alpha atoms). As an example. the four atoms are H. which is a part of the R.

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with three stereogenic centers.3-dibromobutane. and a 1-bromoethyl substituent.RaSb. a Br. in 2.SaRb.Two Stereogenic Centers Non-Equivalent Stereogenic Centers  When a molecule has two stereogenic centers. the four stereoisomers can be designated as RaRb. each of them can be designated as R or S.  In general. Thus there are four possible stereoisomers. both stereogenic carbons have a H. there are eight possible stereoisomers. For example. If we designate one stereocenter as "a" and the other as "b" just for labelling purposes. The maximum of four stereoisomers is not . there will be a maximum of 2n stereoisomers. if there are n such stereogenic centers . For example. and SaSb These designations correspond to the cirucumstance theat stereocenter "a" can have the R or S configuration . Stereogenic centers are equivalent when all four substituents attached to the center are identical. a methyl.and stereocenter "b" can have either configuration. The maximum of 2noccurs when there are all non-equivalent stereocenters.

. This is because the 2R.  On the other hand. 2. It should be noted that the relationship between one enantiomeric pair and the other pair of enantiomers is that they are diastereoisomers. as we saw before. consisting of two pairs of enantiomers. including one achiral stereoisomer. since carbons 2 and 3 are equivalent.3R molecule.3S molecule is identical to the 2S.3-dibromopentane has two non-equivalent stereogenic centers and there are four stereoisomers.observed here. . In fact there are three stereoisomers.

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the mirror image inverts the configuration at each stereocenter).3S ( i. Since they have the same functional groups. e. In the case of two stereogenic centers (n = 2).g. the number of stereoisomers is less than the maximum of 2n. COMPARATIVE PROPERTIES OF ENANTIOMERS AND DIASTEREOISOMERS DIASTEREOISOMERS  Diastereoisomers are not mirror image isomers. which are not themselves chiral (handed.. We saw in an earlier diagram that this molecule has a point of symmetry in its most stable conformation. NMR and IR spectra. a pair of enantiomeers: these are the (2R. first of all .  There is also an achiral stereoisomer. since they have different solubilities. There is. however. i.  It should be noted carefully that the meso isomer is a diastereoisomer of the two enantiomers. A molecule which has stereocenters but is achiral is called ameso compound. solubility in typical achiral solvents.3-dibromobutane.. etc.. constitutional isomers) in that they have distinct chemical and physical properties.g. as we saw for 2. the two diastereoisomers will typically react at different rates.  Although their chemical properties(reactions) are similar. there are 3 stereoisomers. boiling and melting points. Note that the mirror image of 2R. they are usually rather similar to one another in their reactions and properties. meaning can distinguish left from right). but in fact is n + 1.3R is 2S. including both the qualitative reactions and the quantitative rates of reaction are identical when reacting with achiral chemical species.  Two diastereoisomers can usually be separated from one another by . . recrystallization.3S) isomers.TWO EQUIVALENT STEREOGENIC CENTERS  As noted above.. They are essentially like any other pair of isomers (e. they are not distinguished by any physical or chemical means which cannot distinguish mirror images.  Their chemical properties.e.e. when both stereogenic centers are equivalent.3R) and (2S. ENANTIOMERS  Since two enantiomers are mirror images of each other.  Therefore 2 enantiomers have exactly the same energy.

 One physical property which distinguishes 2 enantiomers is "optical activity". the rates of reaction of the 2 enantiomers will be different (more later). one physical property which can distinguish them is "optical activity" (see below). the measured rotation is divided by the concentration of the enantiomer and by the path length of the polarimeter cell to give a true measure of the inherent ability of the enantiomer to rotate the plane of polarized light.  Also.the line responsible for the yellow color of sodiumvapor lamps.e. that when 2 enantiome4s react with a pure single enantiomer of another chiral compound. in the counterclockwise direction). the other rotates it by -10. whether that person is using his left or right hand. This term refers to the property of chiral compounds (exclusively) of rotating the plane of planepolarized light to the right (clockwise) or to the left (counterclockwise). so then one of the original enantiomers will find a better energetic fit with the chiral compound than will the other. Note that in deriving the specific rotation. in using our right hand to shake hands with another person. and the path length in decimeters. Thus.  Since the exact amount of the rotation of the plane by a given enantiomer depends upon how much of that enentiomer the light encounters as it passes through the solution. OPTICAL ACTIVITY  Since enantiomers are "handed" or "chiral". then. when enantiomers react with another chiral compound. In general.  Chemically this occurs. however. Thus.5 degrees (i. This number is called the specific rotation. Both the original enantiomer and its reactant distinguish left from right .5 degrees clockwise (considered a positive rotation). . both chemical and physical properties of 2 enantiomers are exactly identical twoard achiral agents. we can easily tell.chemical or physical. but they rotate it in opposite senses. quantitatively. i. as noted above.  A positive (clockwise) rotation is sometimes called dextrorotation and a ngetaive rotation is sometimes called levorotation ..li>It is important to realize. they can be distinguished by other agents which are chiral. the sodium D line (529 nm).e.. The magnitude of the rotation also depends upon the wave length of the plane polarized light. the concentration is taken in grams per mL. so the a single wave length is usually used. if one enantiomer rotates the plane by 10.  The two enantiomers have exactly the same ability to rotate this plane. There is a better "fit" of the two right hands than there is of right hand to left hand.

it is easy to determine the purity of a sample containing both enantiomers in unequal amounts. For example. the composition of the mixture is 90% R and 10%S. Nevertheless. i.p. mathematically) arises in converted the ee (enantiomeric excess) into a specific composition given in terms of %R and %S.%S.if 1-butene is converted to 2-butanol by the addition of water catalyzed by acid.. This particular measure of optical purity is often called ENANTIOMERIC EXCESS( or ee) because it gives %R . However. and since there is nothing in the catalyst or solvent or reactant that is chiral. OPTICAL PURITY  If the specific rotation of a pure single enantiomer is known. special means are required for "resolution" of two enantiomers. Remember: ee represents not the % of one of the enantiomers. both enantiomers are formed in equal amounts(for a mechanistic explanation. SEPARATION OF ENANTIOMERS  The separation of 2 enantiomers present in a racemic mixture or any mixture of enantiomers.  Enantiomers are not readily separated by conventional means.RACEMIC MIXTURES  A racemic mixture is a 50:50 mixture of the 2 enantiomers of a chiral compound. m. for example. they are not problematic in many labaoratory organic syntheses. etc.'s.  Because the two enantiomers have equal and opposite specific rotations.  Whereas racemic mixtures are not particularly desirable. since they have the same solubilities. in the manufacture of drugs. usually only a single enantiomer is effective. racemic drugs are often used anyway because the other enaniomer is harmless. b. but the difference between the % of one pure enaniomer and the % of racemic mixture). a stereogenic center is created in a molecule where none previously existed. such as recrystallization or fractional distillation. Since both enantiomers have equal energy.'s. most naturally occurring compounds occur as a single enantiomer. cheaper) to synthesize. 80%. The %OPTICAL PURITY = specific rotation of the sample/specific rotation of the pure enantiomer. see later). a racemic mixture has a specific rotation of zero. . So. A small problem (admittedly very small. not as racemic mixtures. and racemic mixtrues are easier(read. Since the racemic mixture is 10%R and 10%S. it is optically inactive  In nature. is called resolution .p.e. this means that there is 80% of the R enantiomer plus 20% of the racemic mixture (not 20%S). The importance of racemic mixtures is that ordinary laboratory synthesis which generate a stereogenic center produce a racemic mixture. One simple way of doing this is as follows: If the enantiomeric excess of the R enantiomer is. so that it is desirable to synthesize only a single enaniomer.

. consider the generalized case shown in the illustration below. while enatiomers have the same solubilities and cannot be readily separated by simple recrystallization. This will form a compound with two chiral centers. and will give rise to 2 different diastereoisomers which can be separated from each other. One common strategy for resolution is often to take advantage of the circumstance that.  As an example. Following this separation the chiral resolving agent rcan be removed by through some chemical reaction to give the two separate enantiomers. The two enantiomers present in a racemic mixtrue can be reacted with a pure enantiomer of a chiral compound (called a resolving agent) which we have on hand (many occur in pure form in nature). diastereoisomers have different solubilites. The chiral resolving agentcan also be recovered for re-use.