Stereochemistry at Tetrahedral Centers Chapter 5 Stereochemistry at Tetrahedral Centers Suggested Problems - 1-25,32-35,37-8,35,42-4,47,56-7

Isomers Compounds that have the same molecular formula but different structures. Isomers – compounds with the same molecular formula but different structures - fall into two classes. Constitutional isomers differ in the way their atoms are connected. They have the same molecular formula, but their atoms are connected differently. Stereoisomers differ in their way atoms are arranged in space. They have the same molecular formula and their atoms are connected to each other similarly, but their 3-dimensional structures are different. There are two kinds of stereoisomers: cis-trans isomers and isomers that contain asymmetric centers.

Constitutional Isomers Here are examples of constitutional isomers. Note the way their atoms are connected. The atoms in the isomers are attached in different ways – but their molecular formulas are the same. Ethanol and dimethyl ether, for example, both have the molecular formula C2H6O, but in one instance the oxygen is attached to only one carbon. In the other instance, the oxygen is connected to two carbons. Constitutional isomers differ in the way the atoms are connected.

Cis–Trans Isomers Cis–trans isomers result from restricted rotation. Cyclic structures restrict rotation. In cis-trans isomers, the atoms are connected similarly, but they are different in their arrangement in 3-dimensional space. This slide shows cis-trans isomers resulting from substituents being on the same or opposite sides of a ring. Note in the upper structures that the attachments appear identical – the difference is the bromide on the left jumps out of the plane toward you; the bromide on the right goes back behind the plane of the slide. Cis-Trans Isomers are also referred to as geometric isomers; they result from restricted rotation caused by a cyclic structure or a double bond. This slide shows some cyclic cis-trans isomers. Models show the two cyclobutanes are not the same compound. In the case of cyclic structures – Cis isomers have their substituents on the same side of the ring; trans isomers have their substituents on opposite sides of the ring. Cis: The substituents are on the same side of the ring. Trans: The substituents are on opposite sides of the ring.

Cis–Trans Isomers Double bonds restrict rotation. Compounds with double bonds can also have cis and trans isomers. Remember that double bonds are composed of a sigma () bond and a () bond. Rotation about the double bonds does not readily occur; it can only happen if the π bond breaks. Because of the higher energy barrier to rotation about a carbon-carbon double bond, a compound with a carbon-carbon double bond can exist in two distinct forms – the hydrogens bonded to the sp2 carbon can be on the same or on opposite sides of the double bond.  A compound with its two hydrogens on the same side of the double bond is referred to as a cis isomer. A compounds with its two hydrogens on the opposite side of the double bond is referred to as a trans isomer. Notice that the cis and trans isomers have the same molecular formula and the same bonds but have different configurations – they differ in the way their atoms are oriented in space. Cis: The hydrogens are on the same side of the double bond. Trans: The hydrogens are on opposite sides of the double bond.

Cis–Trans Isomers Cis and trans isomers can be separated from each other because they are different compounds with different physical properties. – eg. different boiling points and different dipole moments. Notice their different dipole moments. Unlike the cis isomers, the trans isomers have dipole moments of zero because the dipole moments of the individual bonds cancel. Cis–trans isomers have different physical properties.

Some Alkenes Do Not Have Cis–Trans Isomers If one of the sp2 carbons is attached to two identical substituents, then the compound cannot have cis and trans isomers. In these instances, ask yourself what is cis to what?  

Different Conformations Do not confuse the terms conformation and configuration. Conformations are different spatial arrangements of the same compound. They cannot be separated. Compounds with different conformations (conformers) cannot be separated.

Different Configurations Compounds with different configurations are different compounds. They can be separated. Bonds have to be broken to interconvert compounds with different configurations. Compounds with different configurations can be separated. Cis–trans isomers have different configurations.

Stereochemistry Some objects are not the same as their mirror images (technically, they have no plane of symmetry) A right-hand glove is different from a left-hand glove. The property is commonly called “handedness” Organic molecules (including many drugs) have handedness that results from substitution patterns on sp3 hybridized carbon

Chiral and Achiral Objects Chiral objects – not superimposable on their mirror image Achiral objects – superimposable on their mirror image An object with a right-handed or left-handed form is said to be chiral. You could never replace a severed left hand with a right one. At first glance, a left hand looks like a right hand, but they are not the same. A chiral object is different from the image it projects in a mirror. Could you lay the right ear on top of the image you see in the mirror?   Objects that are not chiral are said to be achiral. What’s the difference between the fork and its image in the mirror? Can you tell them apart? Which fork is different? Whether an object is “superimposable on its mirror image” is a key determinant as to whether it is chiral. Chiral objects are not superimposable on their mirror image. If a molecule is superimposable on its mirror image it is achiral.

Chiral Molecules Chiral molecules have an asymmetric center. An asymmetric center is an atom that is attached to four different groups. The usual cause of chirality in a molecule is an asymmetric center. An asymmetric center (also called a chiral center) is an atom bonded to four different groups. Look at the labeled carbon in 2-bromobutane – its four groups are CH3, H, Br, and CH2CH3. None of these are the same. 2-Bromobutane has an asymmetric center.

Compounds with an Asymmetric Center Here are four more examples of molecules with asymmetric centers. Note the four groups differ within each molecule. These molecules can exist in chiral forms. Asymmetric centers are also called chirality centers.

Enantiomers The two isomers are called enantiomers. A compound with one asymmetric center can exist as two stereoisomers. They are mirror images of each other. Here is 2-bromobutane again. Molecules that are nonsuperimposable mirror images of each other are called enantiomers. Each member of a pair of enantiomers is chiral.   A molecule that has a nonsuperimposable mirror image is achiral. Enantiomers have the same physical and chemical properties. The two isomers are called enantiomers. Enantiomers are different compounds: they can be separated. Enantiomers have the same physical and chemical properties.

Enantiomers are nonsuperimposable mirror images. Look at models of these two structures. Four different atoms are attached to the same carbon in each instance. But are the stereoisomers the same? They are not. The one on the left is not superimposable on its mirror image. They are enantiomers. Enantiomers are nonsuperimposable mirror images.

Chiral and Achiral Molecules This slide reiterates the difference between chiral and achiral molecules. Chiral molecules contain one or more asymmetric centers (where the four groups are different). Compounds with one asymmetric center can exist as two enantiomers. One enantiomer is not superimposable on its mirror image. Achiral compounds have superimposable mirror images. How many different groups are bonded to the principle carbon on the right? Note that two of the groups are the same. These are not stereoisomers of each other. They are not enantiomers. They are identical molecules. Chiral compounds have nonsuperimposable mirror images. Achiral compounds have superimposable mirror images (they are identical molecules).

Asymmetric Center versus Stereocenter An asymmetric center is called a stereocenter (or stereogenic center).   A stereocenter is an atom at which the interchange of two groups produces a stereoisomer. (This is how one enantiomer can be converted into another for visualization purposes – one needs merely to interchange two groups.) Stereocenters include: 1) asymmetric centers, where interchange of two groups produces an enantiomer. 2) the sp2 carbons or an alkene or the sp3 carbons of a cyclic compound, where the interchange of two groups converts a cis isomer to a trans isomer, or vice versa. Although all asymmetric centers are stereocenters, not all stereocenters are asymmetric centers. The double bond carbons above are not asymmetric centers. Asymmetric center: an atom attached to four different groups Stereocenter: an atom at which the interchange of two groups produces a stereoisomer

Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer Which of the following are enantiomers?

The Reason for Handedness: Chirality Molecules that are not superimposable with their mirror images are chiral (have handedness) A plane of symmetry divides an entire molecule into two pieces that are exact mirror images A molecule with a plane of symmetry is the same as its mirror image and is said to be achiral (See Figure 5.4 for examples)

Plane of Symmetry

Plane of Symmetry The plane has the same thing on both sides for the flask There is no mirror plane for a hand

Asymmetric (Chirality) Centers in Chiral Molecules Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different) In cyclic molecules, we compare by following in each direction in a ring

Plane of Symmetry Skip These two stereoisomers are both achiral They can be superimposed on their mirror images Note the plane of symmetry

Optical Activity Light restricted to pass through a plane is plane-polarized Plane-polarized light that passes through solutions of achiral compounds retains its original plane of polarization Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active

Plane-Polarized Light All physical properties of enantiomers are the same – boiling points, melting points, solubilities, etc…   One property that differs between enantiomers is the way they interact with plane-polarized light. Normal light consists of rays that oscillate in all directions. In plane- polarized light, all the rays in a beam of light oscillate in a single plane. Polarized sunglasses allow only light oscillating in a single direction to pass – in this manner they eliminate glare.

An Achiral Compound is Optically Inactive Shining polarized light through a sample tube containing an achiral compound does not result in any change to the plane of polarization of the light. The achiral compound is seen to be optically inactive. An achiral compound does not rotate the plane of polarization of plane-polarized light.

A Chiral Compound is Optically Active Molecules possessing a chiral center are capable of rotating the plane of polarization of plane-polarized light. When plane-polarized light passes through a solution of chiral molecules, the light emerges with its plane of polarization rotated in either a clockwise or a counterclockwise direction. Molecules possessing asymmetric centers of opposite configuration rotate the plane of polarized light in opposite directions. That is to say, if one enantiomer rotates the plane of polarized light in a clockwise direction, its enantiomer will rotate the plane of polarized light in a counterclockwise direction. Equally importantly, the enantiomers will not only rotate the plane of polarized light in opposite directions, but they will do so to the same extent (which can be measured in degrees with an instrument). A compound that rotates the plane of polarization of plane-polarized light is said to be optically active. Chiral compounds are optically active; achiral compounds are optically inactive.   If an optically active compound rotates the plane of polarization clockwise, the compound is said to be dextrorotatory and is indicated by the prefix (+). If an optically active compound rotates the plane of polarization counterclockwise, then it is said to be levorotatory and is indicated by the prefix (-). (Dextro and levo are latin prefixes meaning “to the right” and “to the left”. Sometimes lowercase d and l are used in place of (+) or (-).) A chiral compound rotates the plane of polarization of plane-polarized light.

Measurement of Optical Rotation A polarimeter measures the rotation of plane-polarized light that has passed through a solution The source passes through a polarizer and then is detected at a second polarizer The angle between the entrance and exit planes is the optical rotation.

A Polarimeter Rotation is measured in degrees, [] Clockwise rotation is called dextrorotatory = (+) Counterclockwise rotation is levorotatory = (-) The measurement of optical rotation is performed using a polarimeter. In a polarimeter, monochromatic light passes through a polarized lens and emerges as plane-polarized light, which then passes through a sample tube. If the tube is empty, the light emerges from it with its plane of polarization unchanged. The light then passes through an analyzer, which is a second polarized lens mounted on an eyepiece with a dial marked in degrees. The user looks through the eyepiece and rotates the analyzer until he or she sees total darkness. At this point the analyzer is at a right angle to the plane of polarized light. This analyzer setting corresponds to zero rotation because the plane of polarization was unchanged.   The sample to be measured is then placed in the sample tube. If it is optically active, it will rotate the plane of polarization. The user will have to rotate the analyzer until no light is once again coming through. The observed rotation (a), measured in degrees, clockwise or counterclockwise is recorded. The observed rotation depends on the number of optically active molecules that the light encounters in the sample, which in turn depends on the concentration of the sample and the length of the sample tube. The observed rotation is also dependent on temperature and the wavelength of the light source. The amount of rotation caused by an optically active compound will vary with the wavelength of light being used – the light source must be monochromatic (single-wavelength). Most polarimeters use the sodium D line (589 nM).

Specific Rotation To have a basis for comparison, we define specific rotation, []D for an optically active compound []D = observed rotation/(pathlength x concentration) = /(l x C) = degrees/(dm x g/mL) Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nm) The measurement of optical rotation is performed using a polarimeter. In a polarimeter, monochromatic light passes through a polarized lens and emerges as plane-polarized light, which then passes through a sample tube. If the tube is empty, the light emerges from it with its plane of polarization unchanged. The light then passes through an analyzer, which is a second polarized lens mounted on an eyepiece with a dial marked in degrees. The user looks through the eyepiece and rotates the analyzer until he or she sees total darkness. At this point the analyzer is at a right angle to the plane of polarized light. This analyzer setting corresponds to zero rotation because the plane of polarization was unchanged.   The sample to be measured is then placed in the sample tube. If it is optically active, it will rotate the plane of polarization. The user will have to rotate the analyzer until no light is once again coming through. The observed rotation (a), measured in degrees, clockwise or counterclockwise is recorded. The observed rotation depends on the number of optically active molecules that the light encounters in the sample, which in turn depends on the concentration of the sample and the length of the sample tube. The observed rotation is also dependent on temperature and the wavelength of the light source. The amount of rotation caused by an optically active compound will vary with the wavelength of light being used – the light source must be monochromatic (single-wavelength). Most polarimeters use the sodium D line (589 nM).

Specific Rotation and Molecules Characteristic property of a compound that is optically active – the compound must be chiral The specific rotation of the enantiomer is equal in magnitude but opposite in sign

Pasteur’s Discovery of Enantiomers Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms The optical rotations of equal concentrations of these forms have opposite optical rotations The solutions contain mirror image isomers, called enantiomers and they crystallized in mirror image shapes – such an event is rare

How to Draw Enantiomers Perspective formulas Fischer projections Enantiomers are drawn using either perspective formulas or Fischer projections.   Perspective formulas are drawn using solid and hatched wedges. A solid wedge represents a bond coming out of the plane of the screen toward you; a hatched wedge represents a bonding going back away from you. When you draw the first enantiomer, the four groups bonded to the asymmetric center can be placed around it in any order. The second enantiomer can be drawn by drawing the mirror image of the first enantiomer. A Fischer projection represents an asymmetric center as the point of intersection of two perpendicular lines. Horizontal lines project out of the plane of the paper; vertical lines project back behind the plane of the paper. Whether you are drawing perspective formulas or Fischer projections, interchanging two atoms or groups will produce the other enantiomer. Interchanging two atoms or groups a second time brings you back to the original molecule.

Sequence Rules for Specification of Configuration A general method applies to the configuration at each chirality center (instead of to the whole molecule) The configuration is specified by the relative positions of all the groups with respect to each other at the chirality center The groups are ranked in an established priority sequence and compared The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule

Sequence Rules (IUPAC) Look at the four atoms directly attached to the chirality center, and rank them according to atomic number. With the lowest priority group pointing away, look at remaining 3 groups in a plane Clockwise is designated R (from Latin word for “right”) Counterclockwise is designated S (from Latin word for “left”)

Sequence Rules (Continued) If a decision cannot be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms until difference is found

Sequence Rules (Continued) Multiple-bonded atoms are equivalent to the same number of single-bonded atoms

Naming Enantiomers Assign relative priorities to the four groups. Chemists use the letters R and S to designate enantiomers of differing configurations about a chiral center. (This is based on the Cahn-Ingold-Prelog convention.) For any pair of enantiomers with one asymmetric center, one member will have the R configuration and the other will have the S configuration. How is this system employed? First, the groups attached to the asymmetric center are ranked according to a certain set of priorities. The atomic numbers of the atoms directly attached to the asymmetric center determine the relative priorities. The higher the atomic number, the higher the priority. If there is a tie between two atoms, one considers the atoms to which the tied atoms are attached. Thus the ethyl group in the figure above has a higher priority than the methyl group. The carbon of the ethyl group directly attached to the chiral center is attached to H, H, and C (of the methyl group) whereas the carbon of the methyl group directly attached to the chiral center is attached to H, H, H. (In the figure above, bromine has the highest atomic number and the highest priority. Hydrogen has the lowest atomic number and the lowest priority. The ethyl and methyl group are prioritized as described above.) Assign relative priorities to the four groups.

Naming Enantiomers draw an arrow from 1 to 2 to 3 Second, place the group with the lowest priority to the back. In other words, in a perspective formula put it on the hatched wedge. Then draw an arrow from the group with the highest priority to the group with the next highest priority and so on from 1 to 2 to 3. If the arrow points in the clockwise direction, the asymmetric center is assigned an “R” (latin – rectus for right) configuration. If the arrow points in the counterclockwise direction, the asymmetric center is assigned an “S” (latin – sinister for left) configuration. Here is how these rules play out for 2-bromobutane. if the lowest priority group is on a hatched wedge, then clockwise = R and counterclockwise = S

Naming Enantiomers Note: If the group with the lowest priority is not on a hatched wedge to begin with, you can switch two groups placing the group with the lowest priority on the hatched wedge. Once the priorities have been fully assigned and the R or S configuration determined, remember to switch the configuration you determined to take into account that you switched two groups. If the lowest priority group is not on a hatched wedge, switch a pair so it is on a hatched wedge. Then, name the new compound.

Naming Enantiomers When using Fischer projections, remember that the groups at the top and the bottom project backward behind the plane of the paper and the groups to the sides project forward in front of the plane of the paper. Utilizing Fischer projections, the rules for naming are as follows: 1) Rank the groups bonded to the chiral center in order of priority.   2) Draw an arrow from the group with the highest priority (1) through the group with the next highest priority (2) to the group with the third highest priority (3). If the arrow points in a clockwise direction, the enantiomer has the R configuration, provided the group with the lowest priority (4) is on a vertical bond. If the arrow points in a counterclockwise direction, the enantiomer has the S configuration, provided the group with the lowest priority (4) is on a vertical bond.   if the lowest priority group is on a vertical bond, then clockwise = R and counterclockwise = S

Naming Enantiomers If the group with the lowest priority is on a horizontal bond, the answer derived from step 2 above will be the opposite of the correct answer. if the lowest priority group is on a horizontal bond, then counterclockwise = R and clockwise = S

R and S Versus (+) and (–) Some R enantiomers are (+) and some are (–). Some S enantiomers are (+) and some are (–). Do not confuse (+) and (-) with R and S. The former indicate the direction in which plane polarized light is rotated. The latter represent the arrangement of atoms about a chiral center. Some compounds with R configuration are (+) and some are (-). There is no correlation between (+) and (-) and R and S as indicated by this example.

If One Enantiomer Is (+), the Other Is (–) Each optically active compound has a characteristic specific rotation. A compound’s specific rotation is the rotation caused by a solution of 1.0 g of the compound per milliliter of solution in a 1.0 dm tube at a specified temperature and wavelength. The specific rotation [α] is given by the equation at the bottom of this slide.   T is the temperature in oC, λ is the wavelength, α is the observed rotation, l is the length of the tube in dm, and c is the concentration of the sample in grams/mL. If one enantiomer has a specific rotation of a certain value, the other enantiomer will have the same specific rotation but bearing the opposite sign.

Compounds with Two Asymmetric Centers maximum # of stereoisomers = 2n (n = # of asymmetric centers) The maximum number of stereoisomers a compound can have is given by 2n, where n is the number of asymmetric centers. Thus a compound with one asymmetric center can have two stereoisomers ( 21 enantiomers). A compound with two asymmetric centers can have four stereoisomers (22). 3-Chloro-2-butanol has two asymmetric centers. It can exist as four stereoisomers. Fischer projections of the four stereoisomers are shown here. The four stereoisomers of 3-chloro-2-butanol consist of two pairs or enantiomers. Notice that 1 is the mirror image of 2 and that 3 is the mirror image of 4. Thus 3-chloro-2-butanol can exist as two pairs of enantiomers. 1 and 2 are enantiomers. 3 and 4 are enantiomers.

Diastereomers 1 and 2 are enantiomers. 3 and 4 are enantiomers. The four stereoisomers of 3-chloro-2-butanol consisting of two pairs or enantiomers are shown again here. Notice that 1 is the enantiomer of 2 and that 3 is the enantiomer of 4. Again, 3-chloro-2-butanol can exist as two pairs of enantiomers. But there is more to this than the presence of simply two kinds of enantiomers. Compare compounds 1 and 3, 1 and 4, 2 and 3, and 2 and 4. Each of the compounds in these four groups are not identical and they are not mirror image stereoisomers of each other. Such stereoisomers are called diastereomers.   In a pair of diastereomers (with two asymmetric centers), the configuration of one of the asymmetric centers is the same, but the configuration of the other asymmetric center is different. Diastereomers are stereoisomers that are not enantiomers. Let’s determine the configurations of these eight chiral centers. For molecule 1, the configuration can be determined to be (S,R). For molecule 2, the configuration can be determined to be (R,S). These two molecules are enantiomers. Note that (S,R) and (R,S) are completely reversed. For molecule 3, the configuration can be determined to be (S,S). For molecule 3, the configuration can be determined to be (R,R). These two molecules are enantiomers. Note that (S,S) and (R,R) are completely reversed. But what about 1 and 3? Their configurations are (S,R) and (S,S). One of the asymmetric centers has the same configuration, but the other is different. Prove to yourself that the pairs 2,3; 1,4; and 2,4 share the same characteristic – namely that one center is the same but the other is different. 1 and 3, 2 and 3, 1 and 4, and 2 and 4 are diastereomers of each other. Whereas enantiomers have identical physical and chemical properties, diastereomers have different physical and chemical properties. In the case of Fischer projections for stereoisomers with two adjacent asymmetric centers, the enantiomers with the hydrogens on the same side of the carbon chain are called the erythro enantiomers. Those enantiomers with hydrogens on opposite sides of the carbon chain are called the threo enantiomers. Diastereomers are stereoisomers that are not enantiomers. 1 and 3 are diastereomers. 2 and 3 are diastereomers. 1 and 4 are diastereomers. 2 and 4 are diastereomers. Diastereomers have different physical and chemical properties.

Let’s Examine 2-amino-3-hydroxybutanoic acid

Two Asymmetric Centers, Four Stereoisomers Cyclic compounds with two asymmetric centers (four stereoisomers) can exist in cis and trans forms. Each of the four stereoisomers is chiral. Note the mirror image relationships of the two pairs of enantiomers. Each of the enantiomers on the left is diastereomeric with each of the enantiomers on the right and vice versa. The cis stereoisomers are a pair of enantiomers. The trans stereoisomers are a pair of enantiomers.

Identifying an Asymmetric Center An asymmetric center is attached to four different groups. It is important that the two carbons to which the ring substituent is bonded are different from each other. two asymmetric centers, four stereoisomers

No Asymmetric Centers There are only two stereoisomers: cis and trans. Note that in in the case of a 1,3-cyclobutane, two groups bonded to the carbon attached to the bromine are the same. This is not an asymmetric center. The same is true for carbon to which the methyl group is attached. Two groups bonded to this carbon are the same. It is also not an asymmetric center. This limits the number of stereoisomers to two – the two cis and trans geometric isomers. Both of these stereoisomers are achiral. There are only two stereoisomers: cis and trans.

No Asymmetric Centers There are only two stereoisomers: cis and trans. 1-Bromo-4-methylcyclohexane also has no asymmetric centers. Therefore, the compound has only two stereoisoers, the cis isomer and the trans isomer. Both stereoisomers are achiral. There are only two stereoisomers: cis and trans.

Meso Compounds Tartaric acid has two chirality centers and two diastereomeric forms One form is chiral and the other is achiral, but both have two chirality centers An achiral compound with chirality centers is called a meso compound – it may have a plane of symmetry The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral

Two Asymmetric Centers: Three Stereoisomers (a meso compound and a pair of enantiomers) Some compounds with two asymmetric centers have only three stereoisomers. Note the example in this slide. There are two asymmetric centers. Why are there not four stereoisomers? The answer lies in the fact that the mirror image isomer of 1 is identical to 1. Thus 1 is superimposable on its mirror image and, therefore, it is not chiral. Let’s determine the configurations of the two carbons. For 1 they are (S,R). For 2 they are (S,S). For 3 they are (R,R). If you rotate the mirror image of 1, you will see it is identical to 1. (One is allowed to rotate Fischer projections in the plane of the paper.)  

Superimposable Mirror Image A Meso Compound Has a Superimposable Mirror Image On the left is a perspective drawing of Compound 1 from the previous slide shown in a staggered erythro conformation. You can see that the mirror image is the same molecule. The Fischer projection of the same molecule on the right when rotated 180o also reveals the same molecule. Stereoisomer 1 (that shown here) on the previous slide is called a meso compound. Even though a meso compound has asymmetric centers, it is achiral because it is superimposable on its mirror image.    Meso compounds are optically inactive even though they have asymmetric centers.

A Meso Compound Has a Plane of Symmetry Notice that a plane of symmetry cuts a meso compound in half so that one half of the molecule is the mirror image of the other half. Consider this, if the top half of the molecule (S configuration) rotates light in a particular direction, the bottom half (R configuration) will rotate light in the opposite direction. Thus, they will cancel each other out.

A Meso Compound It is easy to recognize when a compound with two asymmetric centers has a stereoisomer that is a meso compound because the four atoms or groups bonded to one asymmetric center are identical to the four atoms or groups bonded to the other asymmetric center. For example, both of the asymmetric centers in the following compound are bonded to an H, OH, CH3, and CH(OH)CH3. A compound with the same four atoms or groups bonded to two different asymmetric centers will have three stereoisomers: one will be a meso compound, and the other two will be enantiomers. A compound with two asymmetric centers that have the same four groups bonded to each asymmetric center will have three stereoisomers: a meso compound and a pair of enantiomers.

A Meso Compound Meso compounds can also be found in cyclic structures. In the case of cyclic compounds, the cis isomer will be a meso compound and the trans isomer will be a pair of enantiomers. As a way to quickly look for meso compounds, look for a plane of symmetry in the molecule that cuts the molecule in half. The two meso compounds on the left have such a plane of symmetry. The pairs of enantiomers on the right do not. For cyclic compounds with the same substituent bonded to two asymmetric centers, cis = a meso compound and trans = a pair of enantiomers.

Naming Stereoisomers If a molecule has more than asymmetric center, the steps used to determine configuration must be applied separately to each center. You can see how this is done for each asymmetric carbon. It is important to remember to place the group with the lowest priority in the back. This is the case for the carbon on the left. For the carbon on the right, it is not. So two of the groups are switched placing the group with the lowest priority in the back. The configuration is then determined mentally (here “S”) and switched (back to “R”) to take into account that the groups were switched to permit the determination.

Naming Stereoisomers The same steps are employed with Fischer projections. Note that the group with lowest priority should be on the vertical. If it is on a horizontal, the initially determined configuration should be reversed.

Naming Stereoisomers The four stereoisomers of 3-bromobutan-2-ol are shown in perspective formulas and Fischer projections on this slide. Note how the letters S and R accompany the numbers in naming the molecules. Also notice that enantiomers have the opposite configuration at both asymmetric centers, whereas diastereomers have the same configuration at one stereocenter and the opposite configuration at the other stereocenter. Thus, compounds 1 and 2 are enantiomers as are 3 and 4. But 1 is a diastereomer to 3 and to 4. 2 is a diastereomer to 3 and to 4. Likewise, 3 is a diasteromer to 1 and to 2. And 4 is a diasteromer to 1 and to 2.  

Racemic Mixtures and The Resolution of Enantiomers A 50:50 mixture of two chiral compounds that are mirror images does not rotate light – called a racemic mixture (named for “racemic acid” that was the double salt of (+) and (-) tartaric acid) The pure compounds need to be separated or resolved from the mixture (called a racemate) To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent) This gives diastereomers that are separated by their differing solubility The resolving agent is then removed

Racemic Mixtures (Continued)

Racemic Mixtures (Continued)

Physical Properties of Stereoisomers The physical properties of enantiomers are the same. The physical properties of diastereomers are different. Here the meso compound is a diastereomer to each of the two enantiomers.

Separating Enantiomers Enantiomers cannot be separated by the usual separation techniques such as fractional distillation or crystallization because their identical boiling points and their solubilities cause them to distill or crystallize simultaneously.   Pasteur was the first to separate the enantiomers of tartaric acid (obtained from grapes) by separating different looking crystals. A mixture of equal amounts of both enantiomers is a racemic mixture. Separating those enantiomers is referred to as resolution of a racemic mixture. Enantiomers are now typically separated via chromatography using a column packed with a chiral material. The interaction of a chiral material with the two enantiomers in essence creates two separate diastereomeric interactions. separating by hand separating by chromatography

Physiological Properties of Enantiomers Biological systems are in essence “chiral”. Our bodies largely employ chiral compounds. Our bodies can therefore distinguish and react differently to separate enantiomers even though their individual physical properties are indistinguishable. Again, because our bodies are chiral they form different diastereomeric interactions with individual enantiomers. Thus, the two individual enantiomers of methamphetamine can have vastly different effects on the body. Enantiomers can have very different physiological properties.

Oranges and Lemons found in oranges found in lemons Limonene interacts with receptors in our nasal passages differently depending on the isomer. Which of the above exists in the R configuration. Hint: it is found in oranges. Go through the determination of configuration in this example. found in oranges found in lemons

Enantiomeric Excess Enantiomeric excess tells us how much of an excess of one enantiomer is in a mixture. A mixture of equal amounts of two enantiomers is called a racemic mixture or a racemate. Racemic mixtures are optically inactive because the individual enantiomer’s rotations cancel each other. A (+/-) symbol is used to specify a racemic mixture. Whether a particular sample of a compound exists as a single enantiomer, a racemic mixture, or an unequal mixture of enantiomers can be determined from it’s observed specific rotation.   If a sample of an enantiomerically pure compound has an observed specific rotation of X degrees, its enantiomer will have an observed specific rotation of –X degrees and a racemic mixture will have no observed specific rotation. If a sample of this compound is placed in the polarimeter and the measure of its specific rotation is determined to be less than X degrees (in either direction), the mixture is not optically pure. That is to say, one enantiomer is contaminated with a certain quantity of the other enantiomer. The enantiomeric excess (ee), also called the optical purity, tells us how much of an excess of one enantiomer is present in a given mixture. It is calculated form the observed specific rotation as illustrated by the equation in this slide. For example, if a sample of 2-bromobutane (specific rotation of pure enantiomer = 23.1) has an observed specific rotation of +9.2 then the enantiomeric excess can be calculated to be 40%. Enantiomeric excess = +9.2/+23.1 X 100% = 40% The excess of one of the enantiomers comprises 40% of the mixture. The other 60% comprises a racemic mixture. Thus the enantiomers are present in the amounts of 70% and 30%.

A Review of Isomerism The flowchart summarizes the types of isomers we have seen alkenes

Constitutional Isomers Different order of connections gives different carbon backbone and/or different functional groups

Stereoisomers Same connections, different spatial arrangement of atoms Enantiomers (nonsuperimposable mirror images) Diastereomers (all other stereoisomers) Includes cis, trans, configurational

Chirality at Nitrogen, Phosphorus, and Sulfur N, P, S commonly found in organic compounds, and can have chirality centers Trivalent nitrogen is tetrahedral Does not form a chirality center since it rapidly flips Individual enantiomers cannot be isolated

Chirality at Nitrogen, Phosphorus, and Sulfur (Continued) May also apply to phosphorus but it flips more slowly

Nitrogen and Phosphorus Can Be Asymmetric Centers Carbon is not the only molecule that can have an asymmetric center. Any atom that has four different groups or atoms attached to it is an asymmetric center. Nitrogen and phosphorus centers can be asymmetric centers.   If nitrogen and phosphorus contain four groups, chirality endures.

Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule Attack by hydride from the top “re” face produces (S)-2-butanol

Prochiral Distinctions: Faces An sp3 carbon with two groups that are the same is a prochirality center The two identical groups are distinguished by considering either and seeing if it were increased in priority in comparison with the other If the center becomes R the group is pro-R and pro-S if the center becomes S

Prochiral Distinctions in Nature Biological reactions often involve making distinctions between prochiral faces or groups Chiral entities (such as enzymes) can always make such a distinction Example: addition of water to fumarate

Chirality in Nature and Chiral Environments Stereoisomers are readily distinguished by chiral receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction

Let’s Work a Problem Erythronolide B is the biological precursor of erythromycin, a broad-spectrum antibiotic. How many chirality centers does erythronolide B have?

Answer The key to navigating this question is to apply the rules learned in this chapter on chirality and apply them to EVERY carbon atom in the ring system. When we examine under these terms we should come to the finding that there are 10 chiral carbons in Erythronolide B.