5. Stereochemistry Why this Chapter? Handedness is important in organic and biochemistry Molecular handedness makes possible specific interactions between enzymes and substrates

2 Stereochemistry Some objects are not the same as their mirror images (technically, they have no plane of symmetry) ◦ A right-hand glove is different than a left-hand glove. The property is commonly called “handedness” Organic molecules (including many drugs) have handedness that results from substitution patterns on sp 3 hybridized carbon

p Enantiomers and the Tetrahedral Carbon In Muscle Tissue In Sour Milk

4 Enantiomers Enantiomers are molecules that are not the same as their mirror image They are the “same” if the positions of the atoms can coincide on a one-to-one basis (we test if they are superimposable, which is imaginary) This is illustrated by enantiomers of lactic acid

5 Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer Build molecular models to see this

Carvones: S-(+)-carvone Caraway (Dill) (Manderine Orange Peel) Caraway (Dill) (Manderine Orange Peel) R-(-)-carvone Spearmint

7 5.2 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 9.4 for examples)

8 Chirality If an object has a plane of symmetry it is necessarily the same as its mirror image The lack of a plane of symmetry is called “handedness”, chirality Hands, gloves are prime examples of chiral object ◦ They have a “left” and a “right” version

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

10 Chirality Centers A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom ◦ If two groups are the same, then there is only one way A chiral molecule usually has at least one chirality center

11 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

p. 293 Examples:

p. 294 Learning Check: Label the chiral centers.

p. 294 Solution: Label the chiral centers. * * * * * * * How many possible stereoisomers? (2 n ) 2 n = 2 1 = 2 2 n = 2 3 = 8

Which of the following molecules possesses a plane of symmetry? 1. A only 2. B only 3. C only 4. A and C 5. B and C

Which of the following statements about enantiomers is false? 1. They have identical melting points. 2. They have identical boiling points. 3. The magnitude of their specific rotations is identical. 4. They have identical densities. 5. They react at the same rate with optically active reagents.

How many stereogenic centers are present in the following molecule?

Optical Activity Light restricted to pass through a plane is plane- polarized Plane-polarized light that passes through solutions of achiral compounds remains in that plane Solutions of chiral compounds rotate plane- polarized light and the molecules are said to be optically active Phenomenon discovered by Jean-Baptiste Biot in the early 19 th century

20 Optical Activity Optical Activity Light passes through a plane polarizer Plane polarized light is rotated in solutions of optically active compounds Measured with polarimeter Rotation, in degrees, is [  ] Clockwise rotation is called dextrorotatory Anti-clockwise is levorotatory

21 Measurement of Optical Rotation A polarimeter measures the rotation of plane-polarized 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.

22 Specific Rotation To have a basis for comparison, define specific rotation, [  ] D for an optically active compound [  ] D = observed rotation (pathlength x concentration) =  = degrees (l x C) (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 specific rotation, [  ], of a sample is defined for each chiral molecule (the value is solvent dependent): Specific rotation is a physical constant for a substance as is melting point, boiling point, density, etc.

24 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 distinctly different shapes – such an event is rare

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

27 Sequence Rules (IUPAC) Rule 1: Assign each group priority according to the Cahn Ingold-Prelog scheme With the lowest priority group pointing away, look at remaining 3 groups in a plane Clockwise is designated R (from Latin for “right”) Counterclockwise is designated SCounterclockwise is designated S (from Latin word for “left” sinister)

28 Rule 2: If decision can’t be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms until difference is found Rule 3: Multiple-bonded atoms are equivalent to the same number of single-bonded atoms

Fig. 9-8, p. 299 Examples:

Examples:

What are the absolute configurations of the chiral centers in the molecule shown below? 1. 1: R, 2: R 2. 1: R, 2: S 3. 1: S, 2: S 4. 1: S, 2: R 5. because of the ring structure, the compound does not have chiral centers

Diastereomers Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers In addition they can have stereoisomeric forms that are not mirror images, called diastereomers

33 Diastereomers

p. 304 Epimers

Despite its name, ascorbic acid (vitamin C) is not a carboxylic acid, but rather has the structure shown below. How many stereoisomers of this compound are possible?

What is the relationship between the two compounds shown below? 1. they are identical 2. they are constitutional isomers 3. they are nonsuperimposable mirror images of each other 4. they are different conformations of the same compound 5. they have different atom connectivity

Which of the structures above are identical? 1. A and C only 2. B and D only 3. A and D only 4. B, C, and D only 5. all are the same

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 has a plane of symmetry The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral

Table 9-3, p. 306 MesoEnantiomers

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

41 Resolution of Enantiomers Inseparable by normal extraction techniques due to identical chemical properties

42 Resolution of Enantiomers Separable by normal extraction techniques due to different chemical properties

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

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

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

46 Stereochemistry of Reactions: Addition of H 2 O to Alkenes Many reactions can produce new chirality centers from compounds without them What is the stereochemistry of the chiral product? What relative amounts of stereoisomers form? Example addition of H 2 O to 1-butene

47 Achiral Intermediate Gives Racemic Product Addition via carbocation Top and bottom are equally accessible

48 Stereochemistry of Reactions: Addition of H 2 O to a Chiral Alkene What is the sterochemical result of the addition of H 2 O to a chiral alkene R-4- methyl-1-hexene Product has 2 chiral centers

Fig. 9-16, p. 313

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

51 Also applies to phosphorus but it flips more slowly

p. 315

Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule

54 Prochiral Distinctions: Faces Planar faces that can become tetrahedral are different from the top or bottom A center at the planar face at a carbon atom is designated re if the three groups in priority sequence are clockwise, and si if they are counterclockwise

55 Prochiral distinctions, paired atoms or groups An sp 3 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 was 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

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

p. 317 Examples

Learning Check: Identify the indicated H’s as Pro R or Pro S

p. 317 Solution: Identify the indicated H’s as Pro R or Pro S Pro SPro R Pro S

p. 318 Learning Check: Identify the indicated faces as Re or Si

p. 318 Solution: Identify the indicated faces as Re or Si Re Si

p. 318 Learning Check: Lactic acid in tired muscles results from reduction (addition of H) of pyruvate from the Re face. What is the stereochem of the product?

p. 318 Solution: Lactic acid in tired muscles results from reduction (addition of H) of pyruvate from the Re face. What is the stereochem of the product? (S)-

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 See Figure 9-17

p. 318

p. 319

p. 321

Important Concepts 1.Isomers - Same molecular formula – different compounds. Constitutional – Individual atoms are connected differently Stereoisomers – Same connectivity – different 3D arrangement. Mirror-Image Stereoisomers – Related as image – mirror image. 2.Chiral Molecule - Not superimposable on its mirror image. 3.Stereocenter – Carbon atom bearing 4 different substituents. 4.Enantiomers – Two stereoisomers, each a non- superimposable mirror images of the other.

Important Concepts 5.Racemate – A one to one mixture of enantiomers. 6.Mirror Plane – Chiral molecules cannot contain a mirror plane. 7.Diastereomers – Stereoisomers not related to each other as mirror images (ie. cis/trans). 8.Two Stereocenters In A Molecule – Create up to 4 stereoisomers: 2 diastereomerically related pairs of enantiomers. If the 2 stereocenters generate a mirror plane in the molecule, the molecule is known as a meso compound and is achiral. 9.Physical Properties of Stereoisomers – Most are the same except for the rotation of plane polarized light. One enantiometer rotates the plane of polarization to the right, the other to the left. This rotation is expressed as the specific rotation, [  ].

Important Concepts 10.Absolute Configuration - Determined by x-ray diffraction. Assignment of R or S, as determined by the Cahn, Ingold, and Prelog sequence rules. 11. Stereoselectivity - Preference for the formation of one stereoisomer when several are possible. 12. Resolution – Separation of enantiomers. Reaction with a pure enantiomer of a second chiral compound and separation of the diastereomers. Chiral chromatography.

Which statement about chirality and optical activity is false? 1. If a solution shows optical activity, it must have a compound present whose mirror image is not superimposable on the compound itself. 2. Molecules with plane of symmetry will show no optical activity. 3. The angle of rotation of plane- polarized light depends on how many chiral molecules does the light interact with while passing through the sample. 4. Enantiomers will always have opposite signs of optical rotation. 5. The R enantiomers are dextrorotatory.

Which of the above molecules are achiral? 1. A and C 2. A and E 3. B and C 4. B and D 5. D and E

How many stereoisomers exist for the molecule shown below?

How many meso dibromocyclopentanes, C 5 H 8 Br 2, are there?

An aqueous solution of A (one stereoisomer) and B (one stereoisomer) shows no optical activity. A and B are stereoisomers. Which statement cannot be true? 1. A and B are diastereomers 2. A and B are not superimposable 3. A and B are enantiomers 4. A is meso and B is chiral 5. A and B are E and Z isomers

How many stereoisomers exist for 5- methylhepta-2,3-diene?

E-3-Hexene reacts with one equivalent of HBr. If there are no carbocation rearrangements, how many different isomeric products (including stereoisomers) will form?

What is the relation between the following two compounds? 1. diastereomers 2. enatiomers 3. identical 4. constitutional isomers 5. meso

Which is the best accounting for the stereochemistry of the product formed by addition of HCl to (R)-4-chloro-1-pentene? 1. two enantiomers in equal amounts 2. two enantiomers in different amounts 3. two diastereomers in equal amounts 4. two diastereomers in different amounts 5. three stereoisomers, two of them in equal amounts

How many different meso compounds will be produced by the following reaction (assuming there are no carbocation rearrangements)?

Which of the following structures represents the lowest-energy form of (1S, 3S)-3-chloromethylcyclohexane?

Enantiomers have identical chemical and physical properties in achiral environments, while diastereomers have different properties in chiral and achiral surroundings. What can be deduced based on the observation that A smells like citrus fruits, while B has an odor of pine trees? 1. A and B are diastereomers 2. A and B are an exception to the rule and do not have the same properties. 3. The sense of smell cannot be used to deduce anything about the stereochemistry of A and B. 4. The receptors responsible for smell are chiral 5. As can be observed by looking into a mirror, our noses are chiral

How many prochirality centers does 1-butanol (CH 3 CH 2 CH 2 CH 2 OH) have? 1. none