5. StereochemistryWhy this Chapter?Handedness is important in organic and biochemistry

Molecular handedness makes possible specific interactions between enzymes and substrates

*StereochemistrySome 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 handednessOrganic molecules (including many drugs) have handedness that results from substitution patterns on sp3 hybridized carbon

p. 2905.1 Enantiomers and the Tetrahedral Carbon In Muscle TissueIn Sour Milk

*EnantiomersEnantiomers 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

*Examples of EnantiomersMolecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image enantiomerBuild molecular models to see this

Carvones:S-(+)-carvoneCaraway(Dill)(Manderine Orange Peel)R-(-)-carvoneSpearmint

*5.2 ChiralityMolecules 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)

*ChiralityIf an object has a plane of symmetry it is necessarily the same as its mirror imageThe lack of a plane of symmetry is called handedness, chiralityHands, gloves are prime examples of chiral objectThey have a left and a right version

*Plane of SymmetryThere is no mirror plane for a handThe plane has the same thing on both sides for the flask

*Chirality CentersA point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality centerThere are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atomIf two groups are the same, then there is only one wayA chiral molecule usually has at least one chirality center

*Chirality Centers in Chiral MoleculesGroups 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. 293Examples:

p. 293

p. 294Learning Check:Label the chiral centers.

p. 294Solution:Label the chiral centers.*******How many possible stereoisomers? (2n) 2n = 21 = 2 2n = 23 = 8 2n = 23 = 8

Which of the following molecules possesses a plane of symmetry?A onlyB onlyC onlyA and CB and C

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

How many stereogenic centers are present in the following molecule?01247

*5.3 Optical ActivityLight restricted to pass through a plane is plane-polarizedPlane-polarized light that passes through solutions of achiral compounds remains in that planeSolutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically activePhenomenon discovered by Jean-Baptiste Biot in the early 19th century

* Optical ActivityLight passes through a plane polarizerPlane polarized light is rotated in solutions of optically active compoundsMeasured with polarimeterRotation, in degrees, is []Clockwise rotation is called dextrorotatoryAnti-clockwise is levorotatory

*Measurement of Optical RotationA polarimeter measures the rotation of plane-polarized that has passed through a solutionThe source passes through a polarizer and then is detected at a second polarizerThe angle between the entrance and exit planes is the optical rotation.

*Specific RotationTo 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.

*Specific Rotation and MoleculesCharacteristic 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

*5.4 Pasteurs Discovery of EnantiomersLouis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed formsThe optical rotations of equal concentrations of these forms have opposite optical rotationsThe solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes such an event is rare

*5.5 Sequence Rules for Specification of ConfigurationA 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 centerThe groups are ranked in an established priority sequence and comparedThe relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule

*Sequence Rules (IUPAC)Rule 1: Assign each group priority according to the CahnIngold-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 S (from Latin word for left sinister)

*Rule 2:If decision cant 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. 299Examples:

Fig. 9-8, p. 299Examples:

What are the absolute configurations of the chiral centers in the molecule shown below?1: R, 2: R1: R, 2: S1: S, 2: S1: S, 2: Rbecause of the ring structure, the compound does not have chiral centers

*5.6 DiastereomersMolecules 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

*Diastereomers

p. 304Epimers

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?12348

What is the relationship between the two compounds shown below?they are identicalthey are constitutional isomersthey are nonsuperimposable mirror images of each otherthey are different conformations of the same compoundthey have different atom connectivity

Which of the structures above are identical?A and C onlyB and D onlyA and D onlyB, C, and D onlyall are the same

*5.7 Meso CompoundsTartaric acid has two chirality centers and two diastereomeric formsOne form is chiral and the other is achiral, but both have two chirality centersAn achiral compound with chirality centers is called a meso compound it has a plane of symmetryThe two structures on the right in the figure are identical so the compound (2R, 3S) is achiral

Table 9-3, p. 306MesoEnantiomers

*5.8 Racemic Mixtures and The Resolution of EnantiomersA 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 acidThe 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 solubilityThe resolving agent is then removed

*Resolution of EnantiomersInseparable by normal extraction techniques due to identical chemical properties

*Resolution of EnantiomersSeparable by normal extraction techniques due to different chemical properties

*5.9 A Review of IsomerismThe flowchart summarizes the types of isomers we have seen

*Constitutional IsomersDifferent order of connections gives different carbon backbone and/or different functional groups

*StereoisomersSame connections, different spatial arrangement of atomsEnantiomers (nonsuperimposable mirror images)Diastereomers (all other stereoisomers)Includes cis, trans and configurational

*Stereochemistry of Reactions: Addition of H2O to AlkenesMany reactions can produce new chirality centers from compounds without themWhat is the stereochemistry of the chiral product?What relative amounts of stereoisomers form?Example addition of H2O to 1-butene

*Achiral Intermediate Gives Racemic ProductAddition via carbocationTop and bottom are equally accessible

*Stereochemistry of Reactions: Addition of H2O to a Chiral AlkeneWhat is the sterochemical result of the addition of H2O to a chiral alkene R-4-methyl-1-hexeneProduct has 2 chiral centers

Fig. 9-16, p. 313

*5.10 Chirality at Nitrogen, Phosphorus, and SulfurN, P, S commonly found in organic compounds, and can have chirality centersTrivalent nitrogen is tetrahedralDoes not form a chirality center since it rapidly flipsIndividual enantiomers cannot be isolated

*Also applies to phosphorus but it flips more slowly

p. 315

*5.11 ProchiralityA molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule

*Prochiral Distinctions: FacesPlanar faces that can become tetrahedral are different from the top or bottomA 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

*Prochiral distinctions, paired atoms or groupsAn sp3 carbon with two groups that are the same is a prochirality centerThe two identical groups are distinguished by considering either and seeing if it was increased in priority in comparison with the otherIf 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 or groupsChiral entities (such as enzymes) can always make such a distinctionExample: addition of water to fumarate

p. 317Examples

p. 317Learning Check:Identify the indicated Hs as Pro R or Pro S

p. 317Solution:Identify the indicated Hs as Pro R or Pro SPro S Pro R Pro R Pro S

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

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

p. 318Learning 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. 318Solution: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)-

*5.12 Chirality in Nature and Chiral EnvironmentsStereoisomers are readily distinguished by chiral receptors in natureProperties of drugs depend on stereochemistryThink of biological recognition as equivalent to 3-point interactionSee Figure 9-17

p. 318

p. 319

p. 321

p. 321

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

Important ConceptsRacemate A one to one mixture of enantiomers.Mirror Plane Chiral molecules cannot contain a mirror plane.Diastereomers Stereoisomers not related to each other as mirror images (ie. cis/trans).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.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 ConceptsAbsolute 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?If a solution shows optical activity, it must have a compound present whose mirror image is not superimposable on the compound itself.Molecules with plane of symmetry will show no optical activity.The angle of rotation of plane-polarized light depends on how many chiral molecules does the light interact with while passing through the sample.Enantiomers will always have opposite signs of optical rotation.The R enantiomers are dextrorotatory.

Which of the above molecules are achiral?A and CA and EB and CB and DD and E

How many stereoisomers exist for the molecule shown below?12348

How many meso dibromocyclopentanes, C5H8Br2, are there?01234

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?A and B are diastereomersA and B are not superimposableA and B are enantiomersA is meso and B is chiralA and B are E and Z isomers

How many stereoisomers exist for 5-methylhepta-2,3-diene? 12348

E-3-Hexene reacts with one equivalent of HBr. If there are no carbocation rearrangements, how many different isomeric products (including stereoisomers) will form?12 3 45

What is the relation between the following two compounds? diastereomers enatiomers identical constitutional isomers meso

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

Which of the following structures represents the lowest-energy form of (1S, 3S)-3-chloromethylcyclohexane?12345

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?A and B are diastereomersA and B are an exception to the rule and do not have the same properties. The sense of smell cannot be used to deduce anything about the stereochemistry of A and B.The receptors responsible for smell are chiralAs can be observed by looking into a mirror, our noses are chiral

How many prochirality centers does 1-butanol (CH3CH2CH2CH2OH) have?none1234

******Pass around models: Are they the same or different?Pass around spearmint & caraway oils: Are they the same or different?Explain receptors (G-protein) and how enantiomers fit (hand in glove)***********************Figure 9.8: Assignment of configuration to (a) (R)-()-lactic acid and (b) (S)-(+)-lactic acid.*Figure 9.8: Assignment of configuration to (a) (R)-()-lactic acid and (b) (S)-(+)-lactic acid.*******************Figure 9.16: Stereochemistry of the addition of H2O to the chiral alkene, (R)-4-methyl-1-hexene. A mixture of diastereomeric 2R,4R and 2S,4R products is formed in unequal amounts because reaction of the chiral carbocation intermediate is not equally likely from top and bottom. The product mixture is optically active.***********************************