Conformers Consider 1,2-dibromoethane.
This molecule can rotate around its C-C single bond. The two
carbon-bromine bonds might at any moment be parallel, antiparallel,
perpendicular to each other, or anything in between. Such
configurations of a molecule are called conformers or conformational
isomers. Conformers easily interconvert into each other at room
temperature. When they get especially cold, they might not be able to
rotate so fast, but for room temperature purposes, we can think of them
as the same molecule. This is not true for constitututional
isomers, which are not connected in the same way. Another way to describe the situation above is by using what is
called a "Newman projection." This is a picture of what we would see if
we looked along the central carbon-carbon bond. The three conformers
above have the Newman projections shown below when we sight along the
C-C bond. Stereoisomers Sigma bonds have cylindrical symmetry about the
internuclear axis. Therefore, rotating about a single bond does not
affect the bond. This is not true for pi bonds, which have
C2 antisymmetry about the internuclear axis. Rotating around
a pi bond breaks the bond. Therefore, rotation around double bonds is
not possible. If we consider instead 1,2-dibromoethene, there are only two
possibilities for how the molecule can look, and those cannot
interconvert because doing so would break the pi bond between the carbons.
(At extremely high temperature, we might be able to get the bond to break
and then reform, but this is generally not true for room temperature
conditions.) We call these different configurations stereoisomers.
We cannot think of them as the same molecule because even though
the atoms are all connected the same way, they are distinctly different in
form and reactivity. We say the molecule is cis, or Z (for the German word "zusammen,"
meaning "together") if the bromines are on the same side and E (for the
German word "entgegen," meaning "opposite") if the bromines are on
opposite sides of the molecule. The case above is fairly clear cut. It is more difficult to
categorize the stereoisomers below as E or Z. To categorize this molecule, the first thing we do is "prioritize" the substituents in order of molecular weight. Using this system, Br is number 1, Cl is 2, F is 3, and H is 4. If substituents 1 and 2 are on the same side of the molecule, then the molecule is Z. If substituents 1 and 2 are on opposite sides of the molecule, then the molecule is E. In the figure above, the molecule on the left is E and the molecule on the right is Z. The priority of a substituent is clear when the substituent is a
uniatomic halogen--all you have to do is look at the molecular weight. If
the substituent is an alkyl chain, then we have to look along the chain
for the first point of difference and go by the molecular weight at that
point. We use the convention that multiple bonds count as single bonds to
that many atoms. Looking at the double bond in the middle of this molecule, we note
that F has the highest priority because it has the highest molecular
weight. The second highest priority is the vinyl group to its left,
because a carbon with a double bond counts as a carbon that is bonded to
two other carbon atoms. At the same point along the chain on the upper
right, the carbon is only bonded to one other carbon atom. Therefore, we
classify this molecule as Z, because the two highest priority groups are
on the same side of the atom. Enantiomers are another kind of stereoisomer. It is best to use
models to understand enantiomers. Take a carbon atom and attach to it
four different substituents. Then make another model in which two of
those substituents are flipped. The two molecules you have just made are
fundamentally different from one another. They are not the same molecule.
Another way to say this is that they are not super-imposable. Convince
yourself of this before you read any further. We say that the two molecules are non-superimposable mirror
images, or enantiomers, or sometimes we describe the situation
by saying that they are chiral. (You can see the mirror image
property by rotating the molecule on the right 180o
counterclockwise about an axis that comes out of the page as shown
below.) Just as we needed a way to classify the difference between E and Z
double bonds, we need a way to classify the difference between enantiomers
such as the ones shown above. We classify them by holding the molecule so
that its lowest priority substituent (same priority rules as above for E
and Z) is pointing into the page. If the substituents 1, 2, 3 are
circulating clockwise, then the molecule is "R". If they circulate
counterclockwise, then the molecule is "S." In the picture on the right
above, the lowest priority substituent (#4) is pointing back into the
page, and substituents 1, 2, 3 circulate counter-clockwise, so the
molecule is S. Its enantiomer on the left is R. The carbon in the
middle, which we are naming, is called the stereocenter. Why do we care about naming stereocenters in the first place? The
reason it's so important is that biological molecules are often chiral.
What's more, these molecules will only recognize and interact with
molecules that have a certain stereochemistry. So if a scientist makes a
drug with even one stereocenter of the wrong chirality, then there is a
high probability that the drug won't work. For example, look at the two
molecules below. They differ only in one carbon's connectivity.
Yet one of them is a deadly teratogen and the other is a useful sedative.
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This is one of the primary reason drugs are expensive. When scientists
synthesize drugs in the lab, what results is a mixture of diastereomers,
molecules with the same connectivity but different stereocenter
configurations.
The more chiral centers there are in the molecule, the more diastereomers
will result. In fact, for a molecule with n chiral centers, there are
2n diastereomers. Check this for a molecule with three
stereocenters. The possibilies are RRR, SSS, RSS, SRR, RSR, SRS, RRS,
SSR. Thus there are a total of 8 possibilities, or 2 It turns out that it is relatively easy to separate the molecules into groups as follows:
RRR and SSS These groups have molecules with exactly the opposite configuration at every carbon and each group is a pair of enantiomers. But now comes the hard part. It's very difficult to separate enantiomers. You will be separating enantiomers in the lab and if you don't agree with me now, you will after that! Up until about fifteen years ago, the FDA didn't enforce the current rule that drugs could only be sold in their enantiomerically effective form. Thalidomide came very close to being sold in the US in its teratogenic form. The sad story of the thalidomide babies born in Europe was one of the reasons that this rule was established. Note that vitamins, however, are not subjected to the same scrutiny as drugs.
Pure enantiomers have the property that they rotate plane polarized light. This is convienient for scientists, because it allows us to recognize pure enantiomers when we have them. We take a solution of the enantiomer and shine plane polarized light through it. Then we measure the rotation of that light when it comes out on the other side of the solution. The two enantiomers rotate plane polarized light in opposite directions by the same amount of degrees. This quarter, you will do an experiment in which you measure the rotation of plane polarized light by an enantiomer that you make. Hopefully, it will rotate. :) In any case, however, remember thatwhether a molecule is R or S has absolutely nothing to do with the direction in which it rotates plane polarized light. If you have equal amounts of both enantiomers (a racemic mixture, or racemate) then the two enantiomers will rotate light in opposite directions, cancelling each other out. If at the end of the lab your solution has no net rotation, then you probably didn't separate the enantiomers properly. More on this later. In case you hadn't made the connection yet, chirality in this context means the exact same thing that it meant back in section 1. There, we discussed it in very mathematical, group theoretical terms. We said that the defining property of chiral molecules was that they do not possess an improper rotation axis. Of course, the same must be true for the molecules above. A useful fact to remember is that an S1 axis is the same as a mirror plane and an S2 axis is the same as a center of inversion. If a molecule has either a mirror plane or a center of inversion, then it is not chiral. For molecules having more than one carbon, it is often useful to use Newman projections to determine whether or not the molecule is chiral. If any conformer of the molecule has a mirror plane or a center of inversion, then the molecule is not chiral. For example, consider 1,2-dichloro-1,2-dibromoethane. Looking at the Newman projection taken along the central C-C bond, we can see that the molecule possesses a center of inversion and therefore is not chiral, despite the fact that it has two stereocenters (where a stereocenter is a carbon with four different substituents attached). Such compounds are called meso compounds.
Diastereomers Molecules with more than one stereocenter have many different isomers. Say we have two stereocenters. Then the possible stereoisomers are RR, RS, SR, and SS. Only a pair of molecules with opposite chirality at both carbons can constitute an enantiomeric pair. RR and SS are an enantiomeric pair, as are RS and SR. However, RR and RS have a different relationship. They are called diastereomers. Diastereomers are molecules with opposite chirality at some of the carbons and the same chirality at other carbons. A molecule with 3 stereocenters has 8 stereoisomers: RRR, SSS, RRS, SSR, RSR, SRS, SRR, RSS. There are 4 pairs of enantiomers. Other combinations are diastereomers. In general, a molecule with n stereocenters has 2n stereoisomers. Enantiomers have exactly the same physical properties: melting points, boiling points, free energies, solubilities, etc. They differ only in their reactivity with other chiral molecules (such as the receptors in your nose; you might expect enantiomers to have different fragrances). On the other hand, diastereomers have different physical properties. In the lab, you will synthesize a racemic mixture of a chiral molecule. Separating the two enantiomers that you make will be the challenging part, because the fact that they have the same physical properties makes them difficult to pull apart. The trick that chemists use is to add another stereocenter to the molecule, thereby creating two diastereomers out of two enantiomers. Where you had a racemic solution of R and S, you now have a solution of two diastereomers: RR and RS. Then, after the diastereomers are separated based on their different physical properties (in this case, their different solubilities), the extra stereocenter is removed, and you're left with two different solutions of R and S. Neat, huh? This trick is used constantly in the laboratory synthesis of naturally occuring chiral molecules. *Reactions One last thing you need to know about stereochemistry is the kinds of reactions to expect. When you hydrogenate a double bond over a palladium catalyst (Pd/C), you get rid of all the double bonds. This may give rise to some chiral centers (in which case the molecule is called "prochiral", but the molecules are always created in a racemic mixture, because the double bond can picks up the hydrogens from top or bottom with equal liklihood. When you oxidize a molecule, you turn the hydroxy groups into ketones and the aldehydes into carboxylic acids. |
