9. Stereochemistry

A Brief Review of Isomerism 1. Constitutional Isomers or Structural Isomers: Have the same molecular formula but different connectivities among the constituent atoms. Therefore the functional groups can be different 2. Stereoisomers: Have the same molecular formula, the same connectivities among the constituent atoms but different spatial arrangements of atoms Enantiomers: Pairs of stereoisomers that are non-superimposable mirror images of each other. b. Diastereomers: Stereoisomers that are not mirror images of each other i. Geometric Isomers: Cis-trans isomers; E-Z isomers ii. Configurational Diastereomers

Examples of Structural Isomers: Examples of Geometric Diastereomers:

Examples of Enantiomers & Configurational Diastereomers

Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer Enantiomers do not have a plane of symmetry McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Mirror-image Forms of Lactic Acid When H and OH substituents match up, COOH and CH3 don’t when COOH and CH3 coincide, H and OH don’t McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

The Reason for Enantiomerism : Chirality Molecules that are not superimposable with their mirror images are said to be chiral 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 The Flask has a plane of symmetry; It is achiral The Palm has no Plane of symmetry; it is Chiral McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 Chirality Centers A tetrahedral C in a molecule to which four different groups (or atoms) are attached is called a chirality center There are two nonsuperimposable ways that 4 different groups (or atoms) can be attached to one carbon atom A chiral molecule has at least one chirality center When a molecule has more than 1 chirality center, it may be overall achiral or chiral depending on whether it has a plane of symmetry or not. McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Chirality Centers in Chiral Molecules Groups are considered “different” if there is any structural variation In cyclic molecules, we compare by following in each direction in a ring McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 9.3 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 Biot in the early 19th century Enantiomers rotate plane polarized light by the same magnitude but in opposite directions. McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

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. McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 Specific Rotation To have a basis for comparison, 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 nanometers) See Table 9.1 for examples McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 7.00 mg sample dissolved in 1.00ml solvent and solution was placed in a cell with 2.00 cm pathlength, an observed rotation of +0.08 o was found. Calculate [ ]D for sample. Answer: C= 0.00700 g/1.00 mL = 0.00700 [ ]D = /(l x C) = degrees/(dm x g/mL) = 0.08/(0.200×0.00700) = 57.1 o McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Sequence Rules for Specification of Configuration The configuration at a chirality center specifies the relative positions of the 4 groups attached to that center with respect to each other. The 4 groups are ranked in priority from 1 to 4 using the Chan-Ingold-Prelog rules Depending on the relative positions one of two labels, R or S, is applied. With the lowest priority group (4) pointing away, the relative positions of the three other groups are compared. If 1  2  3 follows a clockwise path, the configuration is specified R If 1  2  3 follows an anti-clockwise path, the configuration is specified S McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

R-Configuration at Chirality Center Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn Note: If in the drawing the lowest priority group is not pointing away as required and the direction of the higher 3 is clockwise, then the configuration is S not R McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Examples of Applying Sequence Rules If lowest priority is back, clockwise is R and counterclockwise is S R = Rectus S = Sinister McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.6 Diastereomers In a molecule with multiple chiral centers, the mirror image is obtained when the positions of a pair of substituents is swapped FOR EVERY CHIRAL CENTER in the molecule 2R,3S 2S,3R 2R,3R 2S,3S 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 See Figure 9-10

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 9.7 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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.8 Molecules with More Than Two Chirality Centers Molecules can have very many chirality centers Each point has two possible permanent arrangements (R or S), generating two possible stereoisomers So the number of possible stereoisomers with n chirality centers is 2n Cholesterol has eight chirality centers McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

For example, we worked 1,2-dimethylcyclobutane in class. There are 2 chiral centers. Therefore the maximum number of stereoisomers (enantiomer & diasteromer) = 22 = 4. Trans-1,2-dimethylcyclobutane is chiral. There are 2 enantiomers of the trans-1,2-dimethylcyclobutane: (1R,2R)-1,2-dimethylcyclobutane & (1S,2S)-1,2-dimethylcyclobutane. Cis-1,2-dimethylcyclobutane is a meso compound & therefore achiral. The two possible mirror images, namely, (1R,2S)-1,2-dimethylcyclobutane & (1S,2R)-1,2-dimethylcyclobutane are identical. So if we have a formula with n chiral centers, of the maximum of 2n isomers, some may be identical if they achiral. You can only figure it what are meso or not meso by drawing the structures.

9.9 Physical Properties of Stereoisomers Enantiomeric molecules differ in the direction in which they rotate plane polarized but their other common physical properties are the same Diastereomers have a complete set of different common physical properties McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.10 Racemic Mixtures and Their Resolution A 50:50 mixture of two chiral compounds that are mirror images does not rotate light – called a racemic mixture or racemate The pure compounds need to be separated ot resolved from the mixture To separate components of a racemate, 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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.12 Stereochemistry of Reactions: Addition of HBr 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 HBr to 1-butene McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Achiral Intermediate Gives Racemic Product Addition via carbocation Top and bottom are equally accessible McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.13 Stereochemistry of Reactions: Addition of Br2 to Alkenes Stereospecific Forms racemic mixture Bromonium ion leads to trans addition McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Addition of Bromine to Trans 2-Butene Gives meso product (both are the same) McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 If your starting material is an achiral alkene (no chiral C’s present), then halogenation or hydrohalogenation will result in a racemic mixture of enantiomeric products. The net rotation due to a racemic mixture = 0 If your starting material is a chiral alkene, for example, with 1 chiral C, then the product will be a mixtures of diastereomers. This is illustrated on the next slide. The net rotation due to a mixture of diastereomers is not 0. McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

9.14 Stereochemistry of Reactions: Addition of HBr to a Chiral Alkene Gives diastereomers in unequal amounts. Facial approaches are different in energy McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003 9.17 Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

Prochiral distinctions, paired atoms or groups 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 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 McMurry Organic Chemistry 6th edition Ch 9 (c) 2003