Definitions o Stereochemistry refers to the 3-dimensional properties and reactions of molecules. o It has its own language and terms that need to be learned in order to fully communicate and understand the concepts. o Stereoisomers are compounds with the same connectivity, different arrangement in space.

A Brief Review of Isomerism The flowchart summarizes the types of isomers.

Constitutional Isomers (Structural) Different order of connections gives different carbon backbone and/or different functional groups

Stereoisomers (Configurational) Same connections, different spatial arrangement of atoms. –Enantiomers: (nonsuperimposable mirror images) –Diastereomers: (all other stereoisomers) Includes cis, trans isomers.

Constitutional Isomers vs Stereoisomers

Enantiomers – Mirror Images Molecules exist as three-dimensional objects. Some molecules are the same as their mirror image. Some molecules are different than their mirror image. –These are stereoisomers called enantiomers.

Enantiomers and the Tetrahedral Carbon Enantiomers are molecules that are not the same as their mirror image. This is illustrated by enantiomers of lactic acid.

Mirror-image Forms of Lactic Acid When H and OH substituents match up, COOH and CH 3 don’t when COOH and CH 3 coincide, H and OH don’t.

Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer.

Diastereomers Stereoisomers that are not mirror images. Geometric isomers (cis-trans). The cis isomer has two groups on the same side. The trans isomer has two groups on opposite sides.

Stereoisomers  Enantiomers …. pair of stereoisomers that are related to each other as non-super-imposable mirror image isomers  Meso compounds … stereoisomers that have more than one chiral center and are super-imposable on their mirror images  Diastereomers …. pair of stereoisomers containing more than one chiral center and are not mirror images of each other

Chirality Chiral: from the Greek, cheir, (hand). 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.

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.

For a molecule with 1 chiral center, 2 1 = 2 stereoisomers are possible. For a molecule with 2 chiral centers, a maximum of 2 2 = 4 stereoisomers are possible. For a molecule with n chiral centers, a maximum of 2 n stereoisomers are possible. Larger organic molecules can have two, three or even hundreds of stereogenic centers. Chirality Centers

2,3,4-trichlorohexane How many stereoisomers?

Two Chiral Centers 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. 2R,3S2S,3R 2R,3R 2S,3S

A meso compound is an achiral compound that contains tetrahedral stereogenic centers. All meso compounds contain a plane of symmetry. Compound C has two stereogenic centers but it contains a plane of symmetry, and is achiral; C is a meso compound. Meso Compounds

Since enantiomers are two different compounds, they need to be distinguished by name. This is done by adding the prefix R or S to the IUPAC name of the enantiomer. Naming enantiomers with the prefixes R or S is called the Cahn-Ingold-Prelog system. Labeling Stereogenic Centers with R or S * To designate enantiomers as R or S, priorities must be assigned to each group bonded to the stereogenic center, in order of decreasing atomic number. The atom of highest atomic number gets the highest priority (1).

R-Configuration at Chirality Center Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn.

In general, a molecule with no stereogenic centers will not be chiral. There are exceptions to this. With one stereogenic center, a molecule will always be chiral. With two or more stereogenic centers, a molecule may or may not be chiral, e.g. Meso compound (contains a plane of symmetry or a mirror plane) Achiral molecules contain a plane of symmetry but chiral molecules do not. A plane of symmetry is a mirror plane that cuts the molecule in half, so that one half of the molecule is a reflection of the other half. Chiral vs Achiral

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.

Plane-Polarized Light through an Achiral Compound

Plane-Polarized Light through a Chiral Compound

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.

The rotation of polarized light can be clockwise or anticlockwise. If the rotation is clockwise, the compound is called dextrorotatory. The rotation is labeled d or (+). If the rotation is counterclockwise, the compound is called levorotatory. The rotation is labeled l or (-). Two enantiomers rotate plane-polarized light to an equal extent but in opposite directions. Thus, if enantiomer A rotates polarized light +5 0, the same concentration of enantiomer B rotates it –5 0. No relationship exists between R and S prefixes and the (+) and (-) designations that indicate optical rotation. Optical Activity

Specific Rotations of some Common Organic Compounds Compound[  ] # * centers Penicillin V Sucrose Camphor MSG Cholesterol Morphine

Racemic Mixture An equimolar mixture of two enantiomers –because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero.

Polarimetry Use monochromatic light, usually sodium D Movable polarizing filter to measure angle Clockwise = dextrorotatory = d or (+) Counterclockwise = levorotatory = l or (-) Not related to (R) and (S)

Chirality in the Biological World Except for inorganic salts and a few low- molecular-weight organic substances, the molecules of living systems are chiral. Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system. Enzymes are Chiral and enhance Chirality: –chymotrypsin contains 251 chiral centers. –the maximum number of stereoisomers possible is

A schematic diagram of an enzyme surface capable of binding with (R)-enantiomer but not with (S)-enantiomer.

* Chiral centers are extremely important in biological processes and drug development. * Properties of drugs depend on stereochemistry. Biological Activity

Stereochemistry of Reactions: Addition of HBr to Alkenes Many reactions can produce new chirality centers from compounds without them.

إن الله وملائكتــه يصلــون على النبي يــأيــها الذيـن آمنوا صلــوا عليه وسلمـــوا تسليمـــا