STEREOCHEMISTRY

Stereochemistry

The different types of isomers. Stereochemistry focuses on stereoisomers

Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules.

Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "three-dimensionality".

The study of stereochemical problems spans the entire range of organic, inorganic, biological, physical and supramolecular chemistries. Stereochemistry includes methods for determining and describing these relationships; the effect on the physical or biological properties these relationships impart upon the molecules in question, and the manner in which these relationships influence the reactivity of the molecules in question (dynamic stereochemistry).

History and significance

Louis Pasteur could rightly be described as the first stereochemist, having observed in 1849 that salts of tartaric acid collected from wine production vessels could rotate plane polarized light, but that salts from other sources did not. This property, the only physical property in which the two types of tartrate salts differed, is due to optical isomerism. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon.

Cahn-Ingold-Prelog priority rules are part of a system for describing a molecule's stereochemistry. They rank the atoms around a stereocenter in a standard way, allowing the relative position of these atoms in the molecule to be described unambiguously. A Fischer projection is a simplified way to depict the stereochemistry around a stereocenter.

Thalidomide example

An oft cited example of the importance of stereochemistry relates to the thalidomide disaster. Thalidomide is a drug, first prepared in 1957 in Germany, prescribed for treating morning sickness in pregnant women. The drug was discovered to be teratogenic, causing serious genetic damage to early embryonic growth and development, leading to limb deformation in babies. Some of the several proposed mechanisms of teratogenecity involve a different biological function for the (R)- and the (S)-thalidomide enantiomers. In the human body however, thalidomide undergoes racemization: even if only one of the two enantiomers is administered as a drug, the other enantiomer is produced as a result of metabolism. Accordingly, it is incorrect to state that one of the stereoisomer is safe while the other is teratogenic. Thalidomide is currently used for the treatment of other diseases, notably cancer and leprosy. Strict regulations and controls have been enabled to avoid its use by pregnant women and prevent developmental deformations. This disaster was a driving force behind requiring strict testing of drugs before making them available to the public.

Definitions

syn/anti peri/clinal

Many definitions that describe a specific conformation (IUPAC Gold Book) exist:

• a torsion angle of ±60° is called gauche
• a torsion angle between 0° and ± 90° is called syn (s)
• a torsion angle between ± 90° and 180° is called anti (a)
• a torsion angle between 30° and 150° or between –30° and –150° is called clinal
• a torsion angle between 0° and 30° or 150° and 180° is called periplanar (p)
• a torsion angle between 0° to 30° is called synperiplanar or syn- or cis-conformation (sp)
• a torsion angle between 30° to 90° and –30° to –90° is called synclinal or gauche or skew (sc)
• a torsion angle between 90° to 150°, and –90° to –150° is called anticlinal (ac)
• a torsion angle between ± 150° to 180° is called antiperiplanar or anti or trans (ap).

Torsional strain results from resistance to twisting about a bond.

Stereochemistry

Challenge: explain enantiomers to someone who is not a chemist!

Properties:

Enantiomers:

Same chemical and physical properties in achiral environments.

A mixture of these cannot be separated by normal GC or HPLC techniques

Different chemical and physical properties in chiral environments.

A mixture of these can (theoretically) be separated by chiral GC or HPLC techniques

Diastereomers:

Different physical/chemical properties in chiral/achiral environments.

Naproxen An Over-the -Counter Chiral Auxillary

Brinkman, J. A., Sowa, J. R., Jr. In Catalysis of Organic Reactions, Herkes, F. E., Ed., Marcel Dekker: New York, 1998, p. 543 - 549.

Stereogenic center (stereocenter) - a point in a molecule bearing groups such that an interchange of any two groups will produce a stereoisomer.

Number of possible stereoisomers = 2ⁿ , n = # of stereocenters.

For Crixivan determine # possible stereoisomers?

Relative vs. Absolute Configurations

Relative configuration - 3-D structure is not known but it is known that one structure is the mirror image of the other.

(+) or d - dextrorotatory - cpd that rotates light to the right.

(-) or l - levorotatory - cpd that rotates light to the left.

(�) - racemic mixture - 1:1 mixture of (+) and (-) cpds, zero rotation.

Enantiomeric excess:

Absolute configuration - 3-D structure is known.

R, S Nomenclature

(-)-alanine

1.   Prioritize - assign a priority to the groups around the stereocenter

a.   increasing atomic mass of the atom attached to stereocenter

b.   in case of a tie move to the next atom

1.   Place - place the lowest priority group in the back.

2.   Connect a ® b® c

Always draw the arrow on paper as you mind can easily reverse itself!

Shortcut: if lowest priority group is unambiguously in the front then reverse assignment.

Examples:

Try these:

Draw the structure of (S)-penicillamine (used for treatment of arthritis):

How many stereocenters are present; label each stereo center as R/S:

Reading Fischer Projections

Groups along the horizontal plane are facing forward. Groups along the vertical plane are facing back.

Haworth Projections - good for cyclic compounds.

E/Z Nomenclature - It's E/Z!

1. Split double bond in half.

2.   Prioritize - assign a priority to the groups attached to each carbon (same rules as R/S)

3.   E - entgegen (opposite) - highest priority groups are on the opposite sides.

Z - zusammen (together) - highest priority groups are on the same side.

Stereochemical Reactions

Inversion of Configuration

S_N2 reactions are an excellent example of reactions that go with inversion of configuration.

Retention of Configuration

Tosylation

Derivativization Reactions

Racemization

Epimerization - a form of racemization

May occur with enolizable carbons:

Examples

 

Separation of Enantiomers

A) Pasteur's Method

A.  Resolution

B.   Resolution-Racemization

Asymmetric Synthesis

A.  Diastereoselective synthesis:

• uses a chiral auxillary to induce chirality in a prochiral substrate.
• products are diastereomers in which one forms in greater amounts than the other.

Example:

A.  Enantioselective synthesis:

• uses a chiral catalyst or stoichiometric reagent with a prochiral substrate.
• Selectivity occurs through diastereomeric transition states.

Example:

A.  Kinetic Resolution

• Racemic mixture reacts with a pure chiral catalyst or enzyme. One enantiomer of the racemic mixture reacts faster than the other.