Stereochemistry

STEREOCHEMISTRY

Intent and Purpose

Stereochemistry is the study of the static and dynamic aspects of the three-dimensional shapes of molecules. It has long provided a foundation for understanding structure and reactivity. At the same time, stereochemistry constitutes an intrinsically interesting research field in itsownright. Many chemists find this area of study fascinating due simply to the aesthetic beauty associated with chemical structures, and the intriguing ability to combine the fields of geometry, topology, and chemistry in the study of three-dimensional shapes. In addition, there are extremely important practical ramifications of stereochemistry. Nature is inherently chiral because the building blocks of life (_-amino acids, nucleotides, and sugars) are chiral and appear in nature in enantiomerically pure forms. Hence, any substances created by humankind to interact with or modify nature are interacting with a chiral environment. This is an important issue for bioorganic chemists, and a practical issue for pharmaceutical chemists. The Food and Drug Administration (FDA) now requires that drugs be produced in enantiomerically pure forms, or that rigoroustests be performed to ensure that both enantiomers are safe.

DRAWING STEREOCHEMICAL STRUCTURES

Structural diagrams which depict stereochemistry must be prepared with extra care to ensure there is no ambiguity.  The ability to proficiently draw and read such structures requires some practice with reference to 3D molecular models. Some simple "do's" and "don'ts" of the art of stereochemical drawing are illustrated below. 

In general, the molecules are presented in some kind of perspective drawing, based on the idea that the four substituents of a tetrahedral center can be divided into two pairs, laying in mutually perpendicular planes.  Most often the center and two of such substituents are shown in the plane of the drawing (i.e. the plane of the drawing surface) and their bonds are depicted as plain lines ( ). 

Bonds to the other two substituents are shown with different symbols.  Bonds to atoms above the plane of the drawing (coming out, toward the viewer) are shown with a bold wedge (  ), with the narrow end of the wedge starting at the stereogenic center.  As an alternative bald bar bonds (  ) are used.

Bonds to atoms below the plane (going in, away from the viewer) are shown with hash wedges (  ).  There are two separate conventions in use.  In the American usage the narrow edge points to the central atom, while in the European convention, the wide edge points to the central atom.  As an alternative, a bar of hash lines ( ) is used.  A broken line ( ) or an open wedge ( ) can also be found in some drawings, but their usage is discouraged

At this point you should know that a carbon has four bonds. You may be drawing a carbon with four single bonds that looks like this.

However, in reality, a carbon with four single bonds is not as planar (flat) as the picture implies. Instead the structure is more three-dimensional and looks like the picture  below:

Notice that the Bromine (Br) and the methyl group (CH3) are drawn with narrow solid lines. This means that these two substituents attached to the center carbon are planar (meaning flat against the page). Also notice that the hydrogen is drawn with a dotted line wedge which means that the hydrogen (H) is going into the plane of the paper. Finally, notice that the ethyl group (CH₂CH₃) is drawn with a solid wedge which means that it is coming out of the plane of the paper (towards you). From now on all carbons with four single bonds should be drawn with this stereochemistry.

A carbon with four single bonds has four different substituents attached to it. If the carbon has four different things attached to it, the carbon is called a stereogenic center or chiral center. Often these two terms are used interchangeably, however, we will be using the term stereogenic center for the rest of this section. Let's look at two molecules below to make sure that you understand.

 

   (A)                                   (B)

Notice that molecule (A) does not have any carbons with four different things attached to it (even the center carbon has two methyl groups attached to it). Therefore, it does not have a stereogenic center. However, let's look at molecule (B). Notice that the center carbon has four different things attached to it. It denotes a stereogenic center.

Once you are able to locate a stereogenic center it is important to note that a molecule with at least one stereogenic center on it is called an optically active molecule. This means that if you take the molecule and put it into a beaker and shine plane polarized light (just think of it like a flashlight) onto it, the light will not come straight out the other end.

A molecule without any stereogenic centers in it (not optically active):

Enantiomers

The next term that you are responsible for learning is enantiomers. The formal definition of enantiomers is as follows: Enantiomers are nonsuperimposable, mirror images. Most basic organic chemistry textbooks will give you this defintion. However, sometimes this definition becomes a bit confusing when you need to identify a pair of enantiomers on an exam. Therefore, I will give you a more informal definition to use.

Enantiomers: Two molecules, each having a stereogenic center with the same four things attached to the carbon, except that one molecule's stereogenic center is "R" and the other molecules stereogenic center is "S". Let's look at an example!

           (R)                                   (S)

Notice that both molecules have the same four things attached to the central carbon. Each carbon has a hydrogen on it, a chlorine, an ethyl group, and a methyl group. However, if you calculate the configuration of the stereogenic center you will see that one molecule is "R" and the other one is "S". Therefore, these two molecules are enantiomers.    

 A Racemic Mixture

The next term you are responsible for is a racemic mixture. The formal definition of a racemic mixture is a mixture of enantiomers in equal amounts. For example, let's look at the two molecules below.

                             

                 (R)                                    (S)

Notice that  we have 45 grams of each molecule which means that we have two enantiomers in equal amounts. Therefore, we have a racemic mixture.

The "R" molecule will cause the light in one direction and the "S" molecule will cause the light to bend in the other direction. Because the two molecules are present in equal amounts they will cancel one another out and the light will come out of the other side of the beaker straight (as seen above). Therefore, even though each molecule in a racemic mixture is optically active, the racemic mixture is not optically active and therefore will not bend the light.

Fischer Projection Formulas

The problem of drawing three-dimensional configurations on a two-dimensional surface, such as a piece of paper, has been a long-standing concern of chemists. The wedge and hatched line notations we have been using are effective, but can be troublesome when applied to compounds having many chiral centers. As part of his Nobel Prize-winning research on carbohydrates, the great German chemist Emil Fischer, devised a simple notation that is still widely used. In a Fischer projection drawing, the four bonds to a chiral carbon make a cross with the carbon atom at the intersection of the horizontal and vertical lines. The two horizontal bonds are directed toward the viewer (forward of the stereogenic carbon). The two vertical bonds are directed behind the central carbon (away from the viewer). Since this is not the usual way in which we have viewed such structures, the following diagram shows how a stereogenic carbon positioned in the common two-bonds-in-a-plane orientation ( x–C–y define the reference plane ) is rotated into the Fischer projection orientation (the far right formula). When writing Fischer projection formulas it is important to remember these conventions. Since the vertical bonds extend away from the viewer and the horizontal bonds toward the viewer, a Fischer structure may only be turned by 180º within the plane, thus maintaining this relationship. The structure must not be flipped over or rotated by 90º.

A model of the preceding diagram may be examined by .

In the above diagram, if x = CO₂H, y = CH₃, a = H & b = OH, the resulting formula describes (R)-(–)-lactic acid. The mirror-image formula, where x = CO₂H, y = CH₃, a = OH & b = H, would, of course, represent (S)-(+)-lactic acid.

Using the Fischer projection notation, the stereoisomers of 2-methylamino-1-phenylpropanol are drawn in the following manner. Note that it is customary to set the longest carbon chain as the vertical bond assembly.

The usefulness of this notation to Fischer, in his carbohydrate studies, is evident in the following diagram. There are eight stereoisomers of 2,3,4,5-tetrahydroxypentanal, a group of compounds referred to as the aldopentoses. Since there are three chiral centers in this constitution, we should expect a maximum of 2³ stereoisomers. These eight stereoisomers consist of four sets of enantiomers. If the configuration at C-4 is kept constant (R in the examples shown here), the four stereoisomers that result will be diastereomers. Fischer formulas for these isomers, which Fischer designated as the "D"-family, are shown in the diagram. Each of these compounds has an enantiomer, which is a member of the "L"-family so, as expected, there are eight stereoisomers in all. Determining whether a chiral carbon is R or S may seem difficult when using Fischer projections, but it is actually quite simple. If the lowest priority group (often a hydrogen) is on a vertical bond, the configuration is given directly from the relative positions of the three higher-ranked substituents. If the lowest priority group is on a horizontal bond, the positions of the remaining groups give the wrong answer (you are in looking at the configuration from the wrong side), so you simply reverse it.

 

The aldopentose structures drawn above are all diastereomers. A more selective term, epimer, is used to designate diastereomers that differ in configuration at only one chiral center. Thus, ribose and arabinose are epimers at C-2, and arabinose and lyxose are epimers at C-3. However, arabinose and xylose are not epimers, since their configurations differ at both C-2 and C-3.

Diastereomers

Diastereomers (sometimes called diastereoisomers) are stereoisomers that are not enantiomers. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter they are epimers. Each stereocenter gives rise to two different configurations and thus increases the number of stereoisomers by a factor of two.

Diastereomers differ from enantiomers in that the latter are pairs of stereoisomers that differ in all stereocenters and are therefore mirror images of one another. Enantiomers of a compound with more than one stereocenter are also diastereomers of the other stereoisomers of that compound that are not their mirror image. Diastereomers have different physical properties (unlike enantiomers) and different chemical reactivity.

Cis-trans isomerism and conformational isomerism are also forms of diastereomerism.

Diastereoselectivity is the preference for the formation of one or more than one diastereomer over the other in an organic reaction.

Erythro / threo

Two common prefixes used to distinguish diastereomers are threo and erythro (which correspond to the more intuitive syn and anti labels, respectively). When drawn in the Fischer projection the erythro isomer has two identical substituents on the same side and the threo isomer has them on opposite sides.When drawn as a zig-zag chain, the erythro isomer has two identical substituents on different sides of the plane (anti). The names are derived from the diastereomeric aldoses erythrose (a syrup) and threose (melting point 126 °C).

Another threo compound is threonine, one of the essential amino acids. The erythro diastereomer is called allo-threonine.

L-Threonine (2S,3R) and D-Threonine (2R,3S)

L-allo-Threonine (2S,3S) and D-allo-Threonine (2R,3R)

Achiral Diastereomers (meso-Compounds)

The chiral centers in the preceding examples have all been different, one from another. In the case of 2,3-dihydroxybutanedioic acid, known as tartaric acid, the two chiral centers have the same four substituents and are equivalent. As a result, two of the four possible stereoisomers of this compound are identical due to a plane of symmetry, so there are only three stereoisomeric tartaric acids. Two of these stereoisomers are enantiomers and the third is an achiral diastereomer, called a meso compound. Meso compounds are achiral (optically inactive) diastereomers of chiral stereoisomers. Investigations of isomeric tartaric acid salts, carried out by Louis Pasteur in the mid 19th century, were instrumental in elucidating some of the subtleties of stereochemistry.
Some physical properties of the isomers of tartaric acid are given in the following table.

(+)-tartaric acid:	[α]D = +13º	m.p. 172 ºC
(–)-tartaric acid:	[α]D = –13º	m.p. 172 ºC
meso-tartaric acid:	[α]D = 0º	m.p. 140 ºC

Fischer projection formulas provide a helpful view of the configurational relationships within the structures of these isomers. In the following illustration a mirror line is drawn between formulas that have a mirror-image relationship. In demonstrating the identity of the two meso-compound formulas, remember that a Fischer projection formula may be rotated 180º in the plane.