Chapter 5 Stereochemistry at Tetrahedral Centers

Learning Objectives Enantiomers and the tetrahedral carbon The reason for handedness in molecules: Chirality Optical activity Pasteur’s discovery of enantiomers Sequence rules for specifying configuration Diastereomers and Meso compounds Racemic mixtures and the resolution of enantiomers A review of isomerism Chirality at nitrogen, phosphorus, and sulfur Prochirality Chirality in nature and chiral environments A surprise discovery.

Enantiomers and the Tetrahedral Carbon Enantiomers: Molecules that have a carbon with 4 different groups have a non-superimposable mirror image – enantiomer (opposite part or form). The molecule or object and its mirror image are called enantiomorphs (Greek opposite forms)

Figure 5.2 - Attempts at Superimposing the Mirror-Image Forms of Lactic Acid 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 A object and its mirror image are called enantiomorphs (Greek opposite forms)

Reason for Handedness: Chirality Chiral Molecules: Molecules that do not have a plane of symmetry and are not superimposable on their mirror image Achiral Molecules: Molecules with a plane of symmetry that is the same as its mirror image "chiral" comes from the Greek meaning "hand" and signifies that the molecules can have two forms differing from one another as the right hand does from the left.

Figure 5.3 - The Meaning of Symmetry Plane Hands, gloves are prime examples of chiral object. They have a “left” and a “right” version Symmetry Plane Not a Symmetry Plane The reason for handedness in molecules: Chirality

Chirality Center A point in a molecule where four different groups are attached to carbon Chiral center is the cause of chirality or optical activity Example: 5-bromodecane has four different groups that are bonded to C5 The reason for handedness in molecules: Chirality

Chirality Center Methylcyclohexane has a symmetry plane and therefore is an achiral molecule 2-Methylcyclohexanone does not have a symmetry plane and hence chiral molecule C2 is bonded to four different groups The reason for handedness in molecules: Chirality

Worked Example Which of the following molecules are chiral? a) b) Identify the chirality center in each a) b) The reason for handedness in molecules: Chirality

Worked Example Solution: All –CH3 and –CX3 carbons are not chirality centers All –CH2– and –CX2– carbons are not chirality centers All aromatic ring carbons are not chirality centers a) b) The reason for handedness in molecules: Chirality

Optical Activity Ordinary light consists of electromagnetic waves and oscillate in an infinite number of planes at right angles to its direction of travel. When light passes through a polarizer it has just one plane and is called plane polarized light Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active and the property is called optical activity. Optical activity is measured with polarimeter Optical activity

Polarimeter A polarimeter measures the rotation of plane-polarized light that has passed through a solution. The angle between the entrance and exit planes is the optical rotation. To have a basis for comparison, define specific rotation, []D for an optically active compound Specific rotation is that observed for 1 g/mL in solution in cell with a 1 dm path using light from sodium metal vapor (589 nm, Na D line) 1g per mL or 1 mL solution containing 1 g compound. If the wavelength of the light used is 589 nanometers (the sodium D line), the symbol “D” is used. The sign of the rotation (+ or −) is always given. Units: deg·mL·g−1·dm−1 simply degrees

Table 5.1 - Specific Rotation of Some Organic Molecules Levorotatory: Optically active substance that rotates the plane of polarization of plane-polarized light in counterclockwise direction Dextrorotatory: Optically active substance that rotates the plane of polarization of plane-polarized light in clockwise direction  If a chiral molecule is dextrorotary, its enantiomer (geometric mirror image) will be levorotary, and vice versa. In fact, the enantiomers will rotate plane polarized light the same number of degrees, but in opposite directions. Apart from direct measurement of the optical rotation of an actual sample,  it is not possible to determine whether a given chiral molecule will be levorotatory or dextrorotatory, directly from its absolute configuration. That is to say, both "R" and "S" stereocenters have the ability to be dextrorotatory or levorotatory. A dextrorotary compound is often prefixed "(+)-" or "d-". Likewise, a levorotary compound is often prefixed "(−)-" or "l-". The Rectus (R)- and Sinister (S)- prefixes are different from the preceding ones in that the labels R and S characterize the absolute configuration of a specific stereocenter, not a whole molecule. 

Worked Example A 1.50 g sample of coniine was dissolved in ethanol to make 10 mL solution and placed in a sample cell with a 5.00 cm pathlength The observed rotation at the sodium D line was 1.21° Calculate the specific rotation []D for coniine Solution: Given: l =5.00 cm = 0.500 dm;  = 1.21°; C = 1.50g /10ml =0.150 g/mL Optical activity

Worked Example Using the formula Optical activity

9.4 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

Sequence Rules for Specifying Configuration A general method applies to the configuration at each chiral center The configuration is specified by the relative positions of all the groups with respect to each other at the chiral center The groups are ranked and compared in an established priority sequence rules These rules are also called the Cahn–Ingold–Prelog (CIP) rules Configuration is the relative position of the atoms or groups on a chiral center. Configuration is the relative position of the atoms in a molecule that can be changed exclusively by cleaving and forming new chemical bonds.

Sequence Rules for Specifying Configuration Look at the four atoms directly attached to the chirality center, and rank them according to atomic number Atom with highest atomic number has highest ranking, and atom with lowest atomic number has lowest ranking Sequence rules for specifying configuration

Sequence Rules for Specifying Configuration If a decision cannot be reached by ranking the first atoms in the substituent, look at the second, third, or fourth atoms until the difference is found Sequence rules for specifying configuration

Sequence Rules for Specifying Configuration Multiple-bonded atoms are equivalent to the same number of single-bonded atoms An aldehyde has higher ranking than an alcohol. An aldehyde has higher ranking than an alcohol. A ketone has higher ranking than an aldehyde.

Sequence Rules for Specifying Configuration The atom with the highest atomic number is ranked1 and lowest 4 • With the lowest priority atom/group (4) pointing away, look at remaining 3 in a plane R configuration: if the curved arrow is drawn clockwise in ordering three atoms or groups 1-3 S configuration: if the curved arrow is drawn counterclockwise in ordering three atoms or groups 1-3 Absolute configuration: Exact 3-D structure of a chiral molecule

Worked Example Rank the following sets of substituents: Solution: a) –H, –OH, –CH2CH3, –CH2CH2OH b) –SH, –CH2SCH3, –CH3, –SSCH3 Solution: Using the sequence rules: a) –OH, –CH2CH2OH, –CH2CH3, –H b) –SSCH3, –SH, –CH2SCH3, –CH3 Sequence rules for specifying configuration Highest Lowest Highest Lowest

9.6 Diastereomers Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers (2R, 3R VS. 2S, 3S) In addition they can have stereoisomeric forms that are not mirror images, called diastereomers (2R, 3R VS. 2R, 3S or 2S, 3R) 2-amino-3-hydroxybutanoic acid (Threonine, an essential α-amino acid) 2-amino-3-hydroxybutanoic acid (Threonine, an essential α-amino acid). Epimers: Compounds in which two diastereomers differ at only one chirality center but are the same at all others

Worked Example How many chirality centers does morphine have? How many stereoisomers of morphine are possible in principle? Diastereomers

Worked Example Solution: Number of chirality centers = 5 Number of stereoisomers = 2n = 25 = 32 n = # of chiral centers Majority of the stereoisomers are too strained to exist Diastereomers

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 chiral achiral Tartaric acid occurs naturally in many plants, particularly grapes, bananas, and tamarinds. 180 degrees and superimpose.

Table 5.3 - Some Properties of the Stereoisomers of Tartaric Acid Enantiomers have same chemical and physical properties except optical rotation. Diastereomers have different properties.

Worked Example Does the following structure represent a meso compound? If so, indicate the symmetry plane Cis-3,4-dimethylcyclopentanol

Worked Example Solution: The molecule represents a meso compound The symmetry plane passes through the carbon bearing the –OH group and between the two ring carbons that are bonded to methyl groups What if it was trans-3,4-dimethylcyclopentanol?

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 The pure enantiomeric compounds need to be separated or resolved from the mixture (called a racemate) To separate components of a racemate we make a derivative of each with a chiral substance (resolving agent), the method called resolution This gives diastereomers that are separated by their differing solubility The resolving agent is then removed

A Review of Isomerism

Constitutional Isomers Compounds whose atoms are connected differently A review of isomerism

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

Worked Example What kinds of isomers are the following pairs? a) (S)-5-Chloro-2-hexene and chlorocyclohexane b) (2R,3R)-Dibromopentane and (2S,3R)-dibromopentane a) These two compounds are constitutional isomers (C6H11Cl) b) The two dibromopentane stereoisomers are diastereomers (2R,3R and 2S,3R) A review of isomerism

(2R,3R)-Dibromopentane and (2S,3R)-dibromopentane

Chirality at Nitrogen and Phosphorus N, P, and S are commonly found in organic compounds and can have chirality centers Trivalent nitrogen is tetrahedral and lone pair lowest ranked Does not form a chirality center since it rapidly flips Individual enantiomers cannot be isolated Rapid Inversion Chirality at nitrogen, phosphorus, and sulfur Trivalent: An atom that has three covalent bonds

Chirality at Nitrogen and Phosphorus May apply to phosphorus but it flips slowly Chirality at nitrogen, phosphorus, and sulfur

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

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 face (pronounced “ray”) if the three groups in priority sequence are clockwise, and si face (pronounced “sigh”) if they are counterclockwise. note that the designation of the resulting chiral center as S or R depends on the priority of the incoming group.

Prochiral Distinctions: Faces

Prochirality An sp3 carbon with two groups that are the same is a prochirality center 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 if the center becomes S, the group is pro-S Promoting the pro-R substituent to higher priority than the other identical substituent results in an R chirality center at the original sp3-hybridized atom, and analogously for the pro-S substituent.

Prochirality Biological reactions often involve prochiral compounds Determining the stereochemistry of reactions at prochirality centers helps in the study of mechanisms in biochemical reactions Example - Addition of water to fumarate Prochirality

Worked Example Identify the indicated faces of carbon atoms in the following molecules as Re or Si: Prochirality

Worked Example Solution: Draw the plane that includes the sp2 carbon and its substituents, and rank the substituents. The arrow that proceeds from group 1 to group 2 to group 3 is drawn If the direction of rotation is clockwise, the face is the re face. If rotation is counter-clockwise, the face is the si face Prochirality

Chirality in Nature and Chiral Environments Stereoisomers (enantiomers) are readily distinguished by chiral receptors in nature Pharmacological activity of some drugs depend on stereochemistry Of the two optical isomers of ibuprofen it is the S form which is the pharmacologically active component that has anti-inflammatory effect while the R form has no anti-inflammatory effect.

Summary Objects or molecules that are mirror images but not superimposable are said to be chiral Chiral compounds can exist as a pair of non-superimposable mirror-image stereoisomers called enantiomers Stereochemical configuration of a chirality center can be specified as either R or S by using Cahn–Ingold–Prelog rules Diastereomers have the same configuration in at least one center and opposite configurations at the others Epimers are diastereomers that differ in configuration at only one chirality center

Summary Meso compounds contain chirality centers but are achiral 50:50 mixtures of (+) and (-) enantiomers area called racemates If a molecule can be achiral to chiral in a single chemical step, it is said to be prochiral Prochiral sp2-hybridized atom has two faces, described as either Re or Si An sp3-hybridized atom is a prochirality center if, by changing one of its attached atoms results in a chirality center Atom whose replacement leads to an R chirality center is pro-R Atom whose replacement leads to an S chirality center is pro-S