Stereochemistry

Stereochemistry

chemistry in three dimensions

includes both structure and reactivity effects

Enantiomers

mirror-image stereoisomers

like left and right hands
(see page 172 in your text)

observed when a carbon atom has four different groups attached to it
CHXYZ or CX1X2X3X4

Enantiomer Examples






Chirality

property of having "handedness"
(different from its mirror image)

a molecule with any element of symmetry (e.g., a mirror plane) must be achiral

Stereogenic Centers

chiral centers or stereocenters

a molecule with a stereogenic center (e.g., CX1X2X3X4) will be chiral

a stereogenic center cannot be:
sp- or sp2-hybridized (must be sp3)
an atom with 2 identical substituents (e.g., any -CH2- group)

Identifying Chiral Molecules

achiral

chiral

Properties of Enantiomers

enantiomers have identical physical and chemical properties,
EXCEPT they

interact with another chiral molecule differently
(like trying on left- or right-handed gloves - left and right hands react differently)

rotate the plane of plane-polarized light by equal amounts but in opposite directions

Optical Activity

chiral compounds rotate the plane of plane-polarized light

rotation measured in degrees
clockwise (dextrorotatory or +) or
counterclockwise (levorotatory or -)

polarimeter - instrument for measuring optical activity

Specific Rotation

standard amount of optical rotation by 1 g/mL of compound
in a standard 1 decimeter (10 cm) cell

[a] = a / l C

where [a] is specific rotation
a = observed rotation in degrees
l = path length in dm
C = concentration in g/mL

Absolute Configuration

nomenclature method for designating the specific arrangement of groups about a stereogenic center

differentiates between enantiomers

uses the same sequence rules for establishing priority of groups as was used for E and Z

R and S Designations

assign priorities 1-4 (or a-d) to the four different groups on the stereogenic center

align the lowest priority group (4 or d) behind the stereogenic carbon

if the direction of a-b-c is clockwise, it is R

if a-b-c is counterclockwise, it is S

Right- and Left-Hand Views

textbook analogy - steering wheel

alternative analogy - your hands
assign priorities to your fingers in order of height
a = middle finger, b = pointer finger, c = thumb, d = wrist
R - this works for your right hand
S - this works for your left hand

Drawing 3-D Structures

practice with models

dotted-line & wedge

Fischer projections

Fischer Projections

a method for depicting stereochemistry at a series of chiral centers

arrange the chiral center so that:

• horizontal groups are forward
• vertical groups are oriented backward

Note that there are numerous ways to show a given chiral center

12 different Fischer projections represent (R)

12 different Fischer projections represent (S)

Multiple Stereogenic Centers

compounds with more than 2 stereocenters have more than 2 stereoisomers
e.g., 2-bromo-3-chlorobutane
(2R,3R) and (2S,3S) are enantiomers
(2R,3S) and (2S,3R) are enantiomers

in general, n stereocenters give 2^n stereoisomers

Diastereomers

stereoisomers that are not enantiomers
e.g., (2R,3R) and (2R,3S)
(not mirror images, but not the same either)

diastereomers may have different chemical and physical properties

Meso Compounds

compounds with stereogenic centers but which are not chiral
e.g., (2R,3S)-2,3-dibromobutane
(same as its mirror image)

Identifying Meso Compounds

mirror plane of symmetry

one stereocenter is the mirror image of the other

cis-1,2-disubstituted cycloalkanes are meso if the two substituents are identical

Cyclohexane Derivatives

chair interconversions affect conformation, but not configuration

trans-1,2-dichlorocyclohexane is (R,R) or (S,S)

cis-1,2-dichlorocyclohexane is (R,S)

one chair has the R stereocenter with axial Cl and S with equatorial

the other chair has R equatorial and S axial

the two chair forms are enantiomers but not isolatable

Configurations and Conformations of Disubstituted Cyclohexanes

substitution	cis	trans
1,2-X2	eq,ax <==> ax,eq (R,S) interconverting enantiomers	eq,eq <==> ax,ax (R,R) & (S,S) isolable enantiomers two conformations each
1,2-XY	eq,ax <==> ax,eq isolable enantiomers two conformations each	eq,eq <==> ax,ax isolable enantiomers two conformations each
1,3-X2	eq,eq <==> ax,ax (R,S) - meso compound two conformations	eq,ax <==> ax,eq isolable enantiomers two conformations each
1,3-XY	eq,eq <==> ax,ax isolable enantiomers two conformations each	eq,ax <==> ax,eq isolable enantiomers two conformations each
1,4-X2 no stereocenters	eq,ax <==> ax,eq equivalent conformations	eq,eq <==> ax,ax two conformations
1,4-XY no stereocenters	eq,ax <==> ax,eq two conformations	eq,eq <==> ax,ax two conformations

Racemic Mixtures

an equal mix of both enantiomers (also called a racemate)

a common form in the laboratory (but not in nature)

optical resolution - separating enantiomers from a mix (typically difficult)

Optical Purity / Enantiomeric Excess

unequal mixtures of enantiomers may occur

optical purity - compare actual rotation with what a pure enantiomer would give (in %)

enantiomeric excess - % excess of one pure enantiomer over the other

% optical purity = % enantiomeric excess

example - consider a mix of 75% (R) + 25% (S)

• optical rotation would be 50% (50% inactive racemic + 50% R)
• enantiomeric excess is also 50% (75% - 25%)

Optical Resolution

for acids or bases - formation of diastereomeric salts from a naturally ocurring acid or base

enzymatic resolution - preferential binding or reaction of just one enantiomer

Isomerism - Summary

isomers - same molecular formula (same collection of atoms used)

constitutional isomers -differ in the connections between atoms
different carbon skeletons
different functional groups
different locations of a functional group

Stereoisomers - Summary

stereoisomers - same connections but in different 3D arrangement

enantiomers - mirror-image stereoisomers

diastereomers - non-mirror-image stereoisomers:
cis-trans diastereomers
other diastereomers

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1.    What are we talking about?

The bottom line of this whole chapter is learning the difference between isomers.  There are two types of isomers, constitutional and stereoisomers.  Constitutional isomers are two compounds that have the same atoms present, but differ in their connectivity. 
ie:  

These compounds contain the same number of atoms, but the oxygen has been moved to form an ether instead of an alcohol.  Therefore, these compounds are constitutional isomers.

Stereoisomers also have the same atoms present, however the connectivity is the same.  This means the same number of hydrogens will be attached to each carbon and the same number of carbons will be attached to each carbon.  Picture this:

Now, these structures both appear to be the same, but careful observation will reveal that the amine groups attached are in the cis conformation on the left and the trans conformation on the right.  Therefore, the same atoms are present, but just in a different spatial arrangement. 

Not to beat this idea into your head, but here is another example of a stereoisomer, but this time we will use a hydrocarbon chain.

Notice that the chain on the left is in the cis conformation at the double bond and the chain on the right is trans.  This makes them stereoisomers.

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2.    I understand that chiral compounds are mirror images of each other that are not superposable, but how do I tell they are superposable?

The easiest way to tell if the mirror image is superimposable or not and superposable is to find the stereochemistry at the stereocenter. This entails you to find the stereocenter first and then label the groups attached to it in order of their priority. This means the atom with the highest atomic number will be labeled A and the next highest B. The next step is to rotate the molecule so the D group is facing away from you.
ie.

If the groups go from A to C clockwise, it is in the R configuration. If the groups are arranged counterclockwise, it is in the S configuration.

Practice a few

A                                                           B                                      C

 A has two stereocenters.  The top stereocenter is an R configuration and the bottom stereocenter is an S configuration.  For B the stereocenter is an S.  C does not have to be considered because there are two of the same groups attached, and is not chiral.

If the two compounds you are looking at are mirror images of each other, but the configuration at the stereocenter differs, they are not superposable.  Therefore they are chiral compounds.  If they are superposable, then they are achiral.    

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3.    How do I tell the difference between an Enantiomer and Diastereomer?

The easiest way to tell apart an enantiomer and a diastereomer is to look at whether or not the compounds are mirror images of each other. The best way to learn this is through practice. Here are a few examples, see if you can determine whether or not the compounds are enantiomers, the same, or diastereomers.

Hint: first determine if the compounds are mirror images of each other, and then find the individual stereochemistry around each chiral carbon.  Remember the hand rule or the clockwise/counterclockwise arrangement discussed in the previous section.

D

If you are having problems determining the configuration at each stereocenter, I suggest building a model. 

A is a pair of diastereomers, because the configuration is S, S in the first compound and R,S in the second compound.

B is a tricky one.  They are both in the trans configuration and there is a plane of symmetry.  Also, notice there is no carbon with four different groups.  Therefore, they are not enantiomers and there is no stereochemistry. 

C does not have a carbon with four different groups, so it does not have a stereocenter either. 

D is a pair of enatiomers. Notice they are mirror images of each other.

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4.    There is an R and there is an S, but I don’t know what to do with them.  Help!

If you have read the past few sections you know what the S and R designations are.    They tell what type of stereochemistry is found at the stereocenter.  Finding the stereochemistry at the stereocenters can help determine whether two compounds are enantiomers or diastereomers.  Also, R and S versions of the same compound will have different optical activity values. 

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5.    Quick Review of optical activity

Optical activity is the only physical property that differs from one enantiomer to the next.  Optical activity is measured when plane polarized light is passed through a compound.  When the light passes through the compound, it is bent either with positive rotation (dextrorotary) or with negative rotation (levorotary).  There is no correlation between positive or negative rotation with the S or R configuration.  S can be either dextrorotary or levorotary and the R enantiomer will be the opposite of the S.  The value given to optical activity is specific rotation.  The equation to figure out specific rotation can be found page 203 in your textbook. 

 

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6.    Okay, I’m getting this stereocenter thing, but somebody had to go and screw everything up and stick two stereocenters together.

When dealing with two or more stereocenters on the same compound, there are a lot of possibilities.  The first possibility is that the compounds are enantiomers of each other, the second that they are diastereomers, and finally that they can be meso compounds.  Diastereomers occur when the compounds have the same chemical formula, but are not mirror images of each other.
ie. 

 

Now look at these same atoms arranged differently to form an enatiomer.  These compounds are mirror images of each other.  However, they do have different stereochemistries, which makes them enantiomers.

 

You should also look at these next compounds and discover what makes them different from the above.

These compounds appear to be enatiomers, because they are mirror images of each other. They really are not. The middle two compounds are the meso compound, since they are the same. The outside two compounds are enatiomers of each other. Therefore, a meso compound is observed with stereoisomers where you would expect four different possible structures (two pairs of enantiomers), but there are only three stereoisomers.
 

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7.    Fischer Projections doesn’t mean a weekend out on the lake.  How do I interpret them?

Fischer projections are a quick way to show three dimensions without the hassle of having to draw 3-D.  They are very effective for those of us who lack artistic skills.  When you look at the diagram the horizontal lines represent atoms that are coming out at you.  The vertical lines mean they are going away from you.  Fischer projections can be rotated 180 degrees and still be the same compound.  However, if you flip it vertically or horizontally, it becomes the enantiomer. 

This Fischer projection has been flipped horizontally.  These two are enatiomers of each other.  The first projection has an S, R configuration.  The second projection has an R, S configuration.  

Now lets look at a vertically flipped diagram.

These compounds are enatiomers of each other.  

Finally, notice what happens when the diagrams are rotated 180 degrees in the plane of the paper.

 

The configuration at each stereocenter remains the same.

 

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8.    Cyclic Compounds

 

If you are anything like me, it is very hard for you to determine the stereochemistry in cyclic compounds the best way is just practice.   Hopefully, this area will help.  Do your best to determine the stereochemistry.

 

Analysis: