Chapter 5

Stereochemistry:

Arrangement ofAtoms in Space;

Stereochemistry ofAddition Reactions

enantiomers9/06/07 update

IsomersIsomers - compounds with the same molecular formula but different structures

Stereoisomers different 3D structures cis-trans are one example

stereo isomers = isomers which differ only in their 3D structures; eg, cis & trans isomers, enantiomers and diastereomersenantiomers = non-superimposable (different) mirror images; majority of chemical and physical properties are identical

chiral = describes a molecule that is different from its mirror image; enantiomers are chiralachiral = describes a molecule that is the same as its mirror image

5.3 - Asymmetric CentersChiral molecules usually contain an asymmetric (chiral, stereo, stereogenic) centerAsymmetric center - tetrahedral atom bonded to four different groups - indicated with an asterisk (*)

achiral molecules have either one or both of the following plane of symmetry center of symmetry see next two slideschiral molecule (R)-lactic acid (no symmetry)achiral molecule water (plane of symmetry)

180samemirror

chiral center (stereo, stereogenic, asymmetric center) an atom attached to 4 different atoms or groups most chiral molecules contain chiral centers but a molecule can be chiral and not contain a chiral center

How about 2,3-hexadiene? chiral / achiralwhich??Alsomolecule with 2 or more chiral centers can beachiral

Best descriptions of the cyclohexanes shown arechiralachiralImpossible to describe

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5.6 - Drawing Enantiomers3D, prospective drawingsFisher projection (short-hand) *Horizontal bonds are out of paper toward viewer and*Vertical bonds are into the paper away from the viewer.=]

5.8 - Optical ActivityWhat properties are the same with chiral compoundsenantiomers? *Boiling point, melting point, solubility & cannot be easily separated (if at all)What properties are different with chiral compounds? *Interaction with plane-polarized light - light in which all the rays/waves oscillate in a single plane (normal light has ray oscillations in all directions)

How do we get plane-polarized light? Passing normal light through a polarizer

optical activity = a substance that rotates plane polarized light is chiral and said to be optically activeChiral compounds rotate ppl polarimeter = instrument used to measure the amount (in ) by which materials rotate plane-polarized light

Schematic diagram of a polarimeter

Specific rotation, [] = amount (degrees) that a substance rotates ppl expressed in a standard form It accounts for variables such as concentration (c) length (l) of the light path through the sample solution is the exptl (measured) rotation

Some molecules and specific rotations

The thalidomide story and tragedy..1959-62, prescribed as an analgesic for morning sicknessused extensively in Europe and Canada despite strong warnings that it not be given to pregnant women. FDA had not approved its use in U. S. at the time! By 1961, it was recognized as the cause for numerous birth defects (~7- 10,000 in 28 countries).Presently being evaluated for the treatment of AIDS CANCER LEPROSY ARTHRITIS

Pyrethin IIfound in chrysanthemum familynatural insecticide

Identify the stereogenic centers

Question: You have a solution of a molecule that is suspected to be chiral (should demonstrate optical activity) and find that the experimental rotation () is exactly 0. What could be done to demonstrate that the molecule actually is chiral? Highly improbable that the specific rotation of a chiral molecule would be exactly 0. What can you do?...Try a different polarimeterIncrease the sample concentrationCome back after lunch and try againAsk Raffaele or Rich for help

Absolute and relative configurations absolute configuration = the precise (true) 3D arrangement of atoms in a molecule

1951, first X-ray experiments were performed to allow the determination of the absolute configuration of a molecule

5.7 - Naming enantiomers - R,S system (Cahn-Ingold-Prelog)Enantiomers with one asymmetric center.one member has R configuration the other has S configuration. Visualize molecule in 3D and assign R/S priorities; 1->2->3 = R if clockwise, S = if counter clockwise

R/S notation = specifies absolute configuration of a chiral center; there is no correspondence between R and + or S and H ishiddenSee: http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem220a/absolute.pdf

Draw a 3D structure for (R)-2-methyl-1-butanol

Fischer projections = short hand for displaying molecules with stereogenic centers (sect 5.6)

*Horizontal bonds are out of paper toward viewer and vertical bonds are into the paper away from the viewer.

*90 rotation -> inverts the configuration (R -> S and vice versa). *Can be rotated 180 about an axis perpendicular to the paper without altering the configuration. *If the projection is rotated in a way that lifts some groups out of the paper, the absolute configuration will be reversed. See: http://www.chem.uic.edu/web1/OCOL-II/WIN/STEREO/F12.HTM

Note: Interchange two of the groups attached to a chiral center, the molecule mirror image. Odd number of interchanges the mirror image. Even number absolute configuration unchanged.How can you determine the absolute configuration from a Fischer projection??

Identify the absolute configurations of the followingEZRS

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A slightly expanded chart of isomersR & Ssame molecular formulas, different structures 2 or more chiral centers different 3D structure Notenantiomers

5.11 More than 1 Asymmetric Center

3-bromo-2-butanol - 2 asymmetric centers = 4 stereoisomers:A compound can have a maximum of 2n stereoisomers, where n = the number of asymmetric centersABCDEnantiomers = A/B and C/D.what are A/C, A/D, B/C, B/D?

Diastereomers = stereoisomers that are not enantiomers; have different chemical and physical properties

meso isomer = an achiral molecule with 2 or more chiral centers + an internal plane of symmetry; the molecule is achiral*Note* absolute configurations of the two chiral centers in meso-tartaric acid are opposite, R and S

Tartaric acid properties. 3 stereo isomers 4 crystal forms

Stereo-isomer Mp (oC)(gm/ml)H2O solubility(gm/100 ml)(+)168-170+121.760139(-)168-170-121.760139meso146-8 01.660125(+-) 206 0 1.788 20.6

pKa # 1pKa # 2(+) or (-)2.984.34meso3.234.82

*Chiral molecules with 2 stereogenic centers

*Achiral molecules with 2 stereogenic centers

Louis Pasteur, ~1860 crystallized racemic mixture of sodium ammonium tartrate mirror image crystals. racemic mixture = 1:1 mixture of enantiomers; has no optical activityCitric acid most common in fruits

Determine absolute configuration of citric acidSNeitherRWhich of the following are chiral?

5.10 - Enantiomeric excess (optical purity)Example[a] of (+)-alanine from fossil sample = + 4.25o [a] of pure (+)-alanine = + 8.5o

EE = optical purity (%) = {[a]observed / [a]pure}x100

SoEE = op = {4.25 / 8.5} x 100 = 50%

Interpretation50% of sample is pure (+), other 50% is racemic mixture(+)(+)(+)(-)Each square represents 25% of the sample50% is (+)50% is racemic = 25% (+) + 25% (-)total sample = 75% (+) and 25% (-)

5.16 - Separation of EnantiomersHow can enantiomers be separated?Fractional recrystallizationReaction to convert enantiomers to diastereomers for separation (disastereomers have different physical properties). (2) Separate diastereomers convert back to enantiomersChromatography - passage of a solution of enantiomers through a column packed with a chiral material - one enantiomer will have a greater affinity (like a right hand prefers a right glove) and travel slower through the column.Chiral probes - materials capable of distinguishing between enantiomers

..different solubilities..Separation of a racemic aminoalkyne by fractional crystallization

Why arent the [a]s exactly the same magnitudewhat should they be?

5.14 - Reactions involving chiral molecules (no change in chiral center, but R/S can change)

5.19 - Electrophilic Addition ReactionsReactions that form products with asymmetric centersachiral

Reactant has a chiral center & reaction makes a new oneRR

Product with two chiral centers********

Stereochemistry of H2 addition is syn.HDescribe the trans-productMeso Racemic mixtureAchiralMixture of diastereomers

Peroxyacid reaction syn-additionQuestion: What is/are the product/s of the reaction of cis-2-butene and a peroxyacid?

Describe the productRacemic mixtureMixture of disastereomersMesoNone of these apply

Hydroboration-Oxidationsyn, anti-Markovnikov hydrationConcerted reaction - bond-breaking/making processes occur in the same stepThe boron and hydride ion add to the two sp2 carbons at the same time - addition must be syn

Replacement of C-B bond with O-H

Hydroboration-Oxidation.syn-addition of HOH?Brominationanti-addition of Br-Br?

Is the product chiral?Yes, has 2 stereocentersNo, it is a meso compound There is no plane of symmetry, so yes it is chiral.

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5.21 - Biological MoleculesEnzymes are chiral reagents because their binding site is chiral

Receptors - protein that binds a particular moleculeAlso are chiral - allow selective binding of enantiomersExample - receptors in the nose are able to distinguish between 10,000 different smells - each enantiomer fits into a different receptor

The nose knows!

Many drug molecules are synthesized as racemates..either both molecules have comparable activity or one is inactive.R = bronchodilator (albuterol)S = antagonist19 of 20 essential amino acids are chiral.

Other stereogenic centers

Broccoli contains sulforaphane Increases the activity of certain enzymes capable of degrading toxic/carcinogenic compounds. Only (R)-stereoisomer is active and found in plants.

Figure: 05-01-31UN

Title: Fischer projections of enantiomers of 2-butanol.

Caption: Rank the groups in decreasing priority. If the lowest group is top or bottom, then it is already in a back position. If the lowest group is left or right, then the configuration is opposite from the way it looks. R is clockwise and S is counterclockwise.