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3.1 Introduction to Stereochemistry
Stereochemistry
● Stereochemistry is the topic in organic chemistry that examines the three-dimensional structure of organic molecules ● Earlier, cis/trans isomers were studied (alkenes and cycloalkanes - due to the relative positioning of their substituents on the same (cis) or opposite(trans) side of the double bond or ring) ● Stereoisomers are molecules that have the same molecular formula and connectivity between the atoms but differ in the 3D arrangement of atoms or groups in space ● Stereoisomerism is often responsible for significant differences in the chemical and physical properties of organic compounds
3.2 Chirality and Enantiomers
Chirality and Enantiomers
● Chirality is the concept of “handedness” in an object ● Any object is either chiral or achiral ○ Chiral - possesses the property of handedness ○ Achiral - does not possess the property of handedness ● Ex: think about a pair of gloves and a pair of socks. The socks can be worn interchangeably on either foot - achiral. The gloves cannot be worn on the wrong hand - chiral.
● A simple test involves comparing the object and its mirror image for superimposability ● Superimposability is the ability to align (overlap) two objects so that every unique part of each is in direct alignment with the same unique part on the other
● Certain organic molecules can exist in a “left-handed” form or a “right-handed” form ● An organic compound that can exist as two different forms is a chiral molecule, and the two different forms are known as enantiomers ● Enantiomers are different compounds with the same molecular formula and atomic connectivity that are non-superimposable mirror images of each other
Chiral example:
● Lactic acid - a chiral molecule Non-superimposable = lactic acid is CHIRAL = Enantiomers (the original structure and its mirror images are referred to as enantiomers)
Achiral Example:
● 2-chloropropane
● At first glance, it may not be clear that the molecule is achiral. It is only through the application of the superimposability test that the molecule reveals its achiral nature.
● Molecules possess chirality due to the tetrahedral geometry of the stereocenter and the unique identity of the four atoms or groups oriented around it ● The direction of orientation (or “twist”) of these groups causes the handedness of the molecule that is recognized as the property of chirality ● Enantiomers have the same connectivity but different orientations (twist) of the four atoms or groups in 3D space
● The absence of a stereocenter is the reason why molecules like 2-chloropropane are achiral
● Identifying stereocenters in a molecule takes practice. ● In practice, it is helpful to quickly rule out carbon atoms that cannot be stereocenters (any CH2, CH3, or C involved in a multiple bond) because these carbons violate the necessary criteria for being a stereocenter ● The presence of a stereocenter in an organic structure is denoted using an asterisk to mark the stereogenic carbon
3.4 Biological Relevance of the Concept
of Chirality and Properties of
Enantiomers
● Stereochemistry has a particularly important relevance to the behavior of chiral molecules in biological systems, especially the human body
● The structure of ibuprofen, a chiral OTC analgesic. The stereocenter is indicated using an asterisk. ● Often, one of the enantiomers may be toxic or have other harmful effects ● Thalidomide - given to pregnant women in the late 1950’s and early 1960’s as a treatment for nausea ○ One of the enantiomeric forms was active as a therapeutic. It was not known that the other form caused severe birth defects (teratogenic)
● Many of the human senses are subject to the influence of chirality, in particular the sense of smell ● Carvone is a good example ● The two enantiomers are perceived as smelling differently is evidence that olfactory receptors in the human nose contain chiral groups, allowing them to respond more strongly to one enantiomer than the other
● An interesting note is that the physical properties of pairs of enantiomers are identical ● The percent composition of an unknown mixture of enantiomers can be determined using a device known as a polarimeter ● With polarimetry, the rotation of light by individual enantiomers is always equal but opposite ● Under carefully controlled and standardized conditions, the measurement of the optical activity of a pure single enantiomer of a compound gives a value known as the specific rotation. The specific rotation can be looked in reference tables and becomes a value that can be used like MP, BP, density to help identify which enantiomer of that compound is present.
● A counterclockwise rotation indicates a left-handed twist meaning that enantiomer is the “S” configuration ● Lastly, incorporate the S/R designation into the name of the compound
Let’s apply this to our example molecule of lactic acid:
(A) - original structure (B) - mirror image
Four dif groups around the stereo center - hydrogen, hydroxy, methyl, carboxylic acid
- Hydrogen (atomic # 1) = lowest priority; Hydroxyl group (OH) (O= atomic # 8)= highest priority To decide between priorities 2 and 3 it is a tie. In the methyl group, a carbon is attached directly to the stereocenter. In the carboxylic acid, a carbon is also attached directly to the stereocenter. Carbon = atomic # 6. To break a tie, follow the order of connectivity until you reach a point of difference. In the methyl group, carbon is attached to 3 hydrogens (lowest atomic number). In the carboxylic acid, carbon is attached to 3 oxygens (atomic number 6) so it wins the tie and is priority two.
Take the molecule (both enantiomers), and turn the structure so that the lowest priority substituent (the hydrogen) is oriented away from our eyesight:
Look for the direction of the twist or orientation of these groups around the stereocenter
If we start at the OH group (1), we would have to go clockwise, or to the right, to get to the second priority group, and again to get from the second priority group to get to the third priority group.
Once we’ve determined which structure corresponds to which enantiomer (R or S), we can take that designation and add it to the IUPAC systematic name for the molecule:
The Rules
● Simple rule for predicting the maximum number of individual stereoisomers possible for a molecule with multiple stereocenters. ● This rule states that a molecule with “n” stereocenters may exist as a maximum of 2^n individual stereoisomers. ● The rule confirms what was predicted based on different permutations of R/S at each individual stereocenter. ● The rule says, “maximum number”, as some structural feature of certain molecules will result in not all of the predicted number of individual stereoisomers existing. ● This rule is extremely helpful as the number of stereocenters in a molecule gets larger and larger.
Cholesterol
● Cholesterol possesses multiple stereocenters. ● What is the maximum number of stereoisomers that can exist for cholesterol?
● 8 stereocenters = 2^8 = 256 possible stereoisomers
2-bromo-3-chlorobutane
● Considering the first pair (stereoisomers 1 and 2), these molecules are related in that they are mirror images of each other. If one attempts to superimpose them on one another, it will be determined that they cannot.
● Stereoisomers three and four also form a pair of enantiomers. ● Thus far, it has been determined that 2-bromo-3-chlorobutane exists as two pairs of enantiomers (four total stereoisomers). ● This agrees with the extension to the above rule for determining the maximum number of individual stereoisomers possible, which says for the predicted maximum, there will be (2n/2) pairs of enantiomers.
● A curious question is to consider the relationship outside of the pairs. ● What is the relationship between stereoisomers one and three? What about one and four? How would we describe any pross-pairing, 1/3, 1/4, 2/3, 2/4? (diastereomeric) ● Examination of any of the cross-pairings reveals that they are not mirror images of one another.
● Diastereomers are stereoisomers that are not mirror images of one another.
Cis/Trans
● The relationship between cis/trans pairs of molecules is also diastereomeric.
If the stereoisomers of 1,2-dichloroethene are compared, the definition of diastereomers can be applied to these two molecules.
● While stereoisomers three and four are indeed mirror images of one another, if one is rotated by 180° in the plane of the paper, it becomes superimposable on the other (all the atoms and groups line up exactly on both molecules).
● The structure represented by either stereoisomer three or four is known as a meso compound. ● A meso compound is a molecule that contains stereocenters but is superimposable on its own mirror image. Due to this, meso compounds are achiral. ● The compound 2,3-dichlorobutane exists as three different stereoisomers: a pair of enantiomers and a meso compound.
3.8 Fischer Projection Formulae
Fischer Projections
A method for representing the structures of chiral molecules in 2D was developed by German Chemist Emir Fischer. To draw and understand Fischer projections correctly requires an understanding of an adherence to several conventions: ● The carbon representing the stereocenter is usually omitted and is represented instead by the crossing point of horizontal and vertical lines. ● Horizontal bonds are equivalent to “wedge bonds” (from wedge-and-dash notation). These bonds represent things that project towards the reader (out of the plane of the paper). ● Vertical lines are equivalent to “dash bonds” and represent things that project away from the reader (behind the plane of the paper).
● Take the R,R stereoisomer of 2-bromo-3-chlorobutane:
Fischer Projections: The Rules
When comparing the Fischer projections of two stereoisomers to determine relationships between them (notably in the superimposability test), certain rules must be followed as well: ● The only “allowed” move is a rotation of 180 degrees in the plane of the paper. ● No “flips” or rotations other than 180 degrees.
Thus, for the compound shown above, the name would be Z-1-bromo-2-chloro-2-floro-1-iodoethene.
In a similar fashion, the molecule shown below would be named as follows: E – 1-bromo-1-chloro-2-methyl-1-butene as the groups of higher priority are on opposite sides of the C=C.
