5.1 Overview of Isomerism and Stereoisomers

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    Constitutional Isomers and Stereoisomers

    constitutional isomers and stereoisomers

    Constitutional Isomers (a.k.a. Structural Isomers)

    Constitutional isomers, also known as structural isomers, have the same molecular formula (i.e. are isomers) but have a different 'bond connectivity.'  Below are a couple of examples.

    Constititutional Isomers Example 1
    Constititutional Isomers Example 2

    Stereoisomers

    Stereoisomers have the same 'bond connectivity' but a different 3D spatial arrangement of the atoms.  There are two types of stereoisomers, enantiomers and diastereomers.  Stereoisomers that are mirror images are termed enantiomers (often technically defined as nonsuperimposable mirror images).  Stereoisomers that are not mirror images are termed diastereomers (often technically defined as nonsuperimposable non-mirror images).

     

    Enantiomers, being reflections of each other, have the same physical characteristics: same melting point, same boiling point, same dipole moment etc.  This can make them difficult to separate.  Most separation techniques are based upon some difference in these physical characteristics between the compounds being separated.  Distillation works due to a difference in boiling point, and column chromatography works due to a difference in polarity, and neither can be used to separate a pair of enantiomers.  Diastereomers on the other hand usually have different physical characteristics and can often be separated by conventional means. 

     

    Stereoisomers are generally possible with two main molecular features:

    1. Cis/Trans isomers - These are possible for many alkenes and cycloalkanes.  Cis/Trans isomers are never mirror images and are therefore diastereomers.

    2. Stereoisomers having chiral centers - Most stereoisomers discussed in this chapter will fall into this category.

     

    Chiral centers are tetrahedral atoms (sp3 hybridized) that are bonded to 4 different groups.  In organic chemistry most chiral centers will be carbon atoms, but chiral centers could technically be any tetrahedral atom.  Chiral centers go by many names: chirality centers, stereogenic centers, asymmetric centers, and they are the most common example (but not the only example) of stereocenters.

     

    Stereoisomers having chiral centers may either be enantiomers or diastereomers depending upon the comparison.  Below are a couple of examples of stereoisomers.  You should notice that they all have the same bond connectivity and that this is also evident in their names; the only differences in the names of stereoisomers are stereochemical designations at the beginning of the names (cis vs trans and R vs S).  We'll learn how to assign R and S later in this chapter (5.2 Absolute Configurations: Assigning R and S) and a new designation for alkenes, E and Z, in a later lesson on naming alkenes (7.5 Nomenclature of Alkenes).

    Cis/Trans Isomers

    diastereomers 1
    diastereomers 2

    Isomers Having Chiral Centers

    enantiomers
    diastereomers 3

    Chiral vs Achiral

    Chiral molecules are those that have nonsuperimposable (non-identical) mirror images (i.e. enantiomers), whereas achiral molecules are those that are identical (superimposable) to their mirror images.  To rephrase this:

     

    The mirror image of a chiral molecule is its enantiomer.

     

    The mirror image of an achiral molecule is identical to the original molecule (achiral molecules do NOT have enantiomers).

     

    An example of a chiral and an achiral molecule are shown below:

    Chiral

    chiral molecule

    Achiral

    achiral molecule

    Both examples above are shown alongside their reflection across a mirror plane.  The chiral molecule is nonsuperimposable (non-identical) with its reflection which is its enantiomer.  Whereas the achiral molecule is superimposable (identical) with its reflection in every respect.

    The vast majority of chiral compounds have chiral centers, and therefore when trying to identify a molecule as chiral one should look for the presence of chiral centers.  Though rare, we will learn in a future lesson (5.6 Amine Inversion and Chiral Molecules without Chiral Centers) that there are a couple of molecules that are chiral even though they don't have chiral centers.  This is a relatively minor occurrence and many undergraduates are never even presented with these examples.

    More importantly, there are many compounds that have chiral centers and are still achiral.  I like to think of them as exceptions, and they get a special name: meso compounds.  We'll learn more about them later in this chapter (5.3 Molecules with Multiple Chiral Centers), but for now the definition will suffice: meso compounds are achiral compounds that have chiral centers.

    So when trying to identify a molecule as chiral, start by looking for chiral centers.  But it turns out there is a trick for identifying achiral molecules as well: any molecule with an internal mirror plane of symmetry (often termed a sigma plane) will be identical to its reflection and is achiral.  There are no exceptions either.  If a molecule has a sigma plane, it is achiral.  If we revisit methylcyclohexane which was identified as achiral above we can readily identify a sigma plane.

    achiral sigma plane

    However, a molecule only needs to have a sigma plane in any one of its rotational conformations to be achiral, and such a sigma plane may not be obvious.  In examining the molecule below on the left it may be difficult to recognize that it has a sigma plane.  Rotation around one of the C-C bonds makes it much easier to see. 

    achiral sigma plane 2

    The moral of the story is that it is not always straightforward to identify sigma planes.  Just because you can't find one don't immediately assume the molecule is chiral (though this is often true).  But if you do find a sigma plane the molecule is for sure achiral.  The example above is a meso compound fyi; it is achiral even though it has two chiral centers.

    Optical Activity

    There is another major difference between chiral and achiral molecules:  optical acitivity.  It turns out that chiral molecules rotate plane-polarized light and are termed optically active, whereas achiral molecules do not.

    Light, with its wavelike characteristics can have its 'wave' oriented in any plane.  This is exactly the case with unpolarized light which has light in all possible orientations.  But when it is passed through a polarizing filter all orientations except for largely one are blocked.  The light that passes through is largely of a single orientation (plus or minus a few degrees) and is said to be plane-polarized.  If plane-polarized light passes through a solution of an achiral compound it will leave the solution with the same orientation with which it entered.  But when plane-polarized light passes through a solution of a chiral compound it will leave the solution rotated relative to the orientation with which it entered.  The degree of rotation will be dependent upon the identity and concentration of the compound and upon the path length of the solution, but the direction it is rotated is intrinsic to the particular enantiomer.  We'll get more into the numbers regarding this later in the chapter (5.7 Optical Activity).

    Enantiomers always rotate plane-polarized light by the same degree (assuming equal concentrations and path lengths) but in opposite directions, and this can be used as an identifying characteristic for the two enantiomers.  The direction and degree of rotation is measured by a polarimeter.  The enantiomer that results in rotation to the right (clockwise) is termed the '+' or 'd' isomer (d is short for dextrarotatory).  The enantiomer that results in rotation to the left (counterclockwise) is termed the '-' or 'l' isomer (l is short for levorotatory).

    dextrorotatory and levorotatory

    +/- and d/l are referred to as relative configurations.  Whether we use the +/- or d/l convention it is worth noting that these configurations must be determined using a polarimeter; it is not possible to predict the direction of rotation by a simple inspection of the structure of the particular enantiomer.  But once you've identified the direction of rotation in one enantiomer, you know it will be the opposite direction for the other enantiomer.  In the next lesson we'll learn about the absolute configurations R and S (5.2 Absolute Configurations: Assigning R and S) which can be determined by a simple inspection of the structure of the particular enantiomer.

    We'll end this discussion with the introduction of one more term: a racemic mixture.  A racemic mixture is a 50/50 mixture of enantiomers.  As half the molecules in the mixture will rotate plane-polarized light in one direction and half in the opposite direction, plane-polarized light is not rotated on average, and therefore a racemic mixture is optically inactive.

    To summarize:

    • Chiral compounds are optically active.
    • Achiral compounds are optically inactive.
    • Racemic mixtures are optically inactive.

    Chirality

    A chiral molecule is one that is not identical to its mirror image, but it is often technically defined has having a nonsuperimposable mirror image which we identified in the last lesson as its enantiomer.  And molecules don't have the monopoly on chirality as many objects from our every day experience are chiral, most notably our hands.

    chiral hands

    Our hands are reflections of each other but are not identical.  That's why both right-handers and left-handers baseball gloves are produced.  They are made unique to the hand they'll be worn on depending upon whether the player is right-handed or left-handed.  In fact we often loosely distinguish between a pair of enantiomers by referring to one as the right-handed enantiomer and the other as the left-handed.

    But enantiomers are difficult to distinguish from one another as all of their physical properties (melting point, boiling point, dipole moment, etc.) are identical.  In fact it takes a chiral environment to distinguish between the right-handed and left-handed versions of a chiral compound.  (As baseball gloves are made specific to the right hand or left hand, they too are chiral.)  A great many drugs are chiral and often it is only one of the enantiomers that possesses the desired activity.

    The most infamous example of a chiral drug is thalidomide, a sedative that was often also prescribed to pregnant women in the 1950s to treat morning sickness.  It turns out it was the R-isomer that was responsible for these effects.  However, the drug was sold as a racemic mixture, and unfortunately the S-isomer acts as a teratogen causing birth defects.  What you should take away from this is that proteins themselves are chiral and are often found to bind one enantiomer more strongly than another as is the case with thalidomide.  Quite a bit of research regarding thalidomide has been performed and those interested can read more in a great article in Nature.

    Chiral Centers

    Now that we have a little idea as to the significance of chirality, the question becomes how do we recognize when a molecule is chiral?  The greatest indication of whether or not a molecule will be chiral is the presence of chiral centers.  Chiral centers are tetrahedral atoms (sp3 hybridized) that are bonded to 4 different groups.  In organic chemistry most chiral centers will be carbon atoms, but chiral centers could technically be any tetrahedral atom.  Chiral centers go by many names: chirality centers, stereogenic centers, asymmetric centers, and they are the most common example (but not the only example) of stereocenters.  While not all molecules having chiral centers will be chiral (i.e. meso compounds), the majority will, and there are very few examples of molecules that are chiral without having chiral centers.

     

    Let's start by looking at a molecule having just a single chiral center.  A molecule having just one chiral center is chiral, period.  It is only possible to have chiral centers and be achiral (i.e. to be a meso compound) for molecules that have more than one chiral center.

    chiral molecule

    The compound and its mirror image are not identical (i.e. are nonsuperimposable).  If we take and rotate the molecule on the right 180o out of the plane of the page you can see that the Cl and H are not in the same position.

    chiral molecule 2

    After rotating the second enantiomer we can see that the ethyl group (green) and methyl group (black) line up and are superimposable.  But the Cl and H are not superimposable.  The only difference between the molecule on the upper left and the molecule on the lower left is that the atoms bonded with the wedged and dashed bonds are switched.  In fact this is at the very heart of the term stereocenter.  A stereocenter is an atom where switching two groups results in a different stereoisomer.  And it is not limited to switching the wedged and dashed bond (though this is the most common); switching any two groups on a chiral center will get you the other version.

    This now gives us two ways to recognize when we have the reflected version of a chiral center:

    1. When it is simply drawn as a reflection.

    nonsuperimposable mirror images

    2. When two groups have traded places on a chiral center (groups attached with wedged and dashed bonds switched here)

    enantiomers stereocenter

    Both of these will be important in learning how to recognize the exact relationship between two molecules which we'll be addressing in a lesson later in this chapter (5.5 Isomeric Relationships Between Molecules).

    How to Identify Chiral Centers

    A common question on this exam for undergraduates is to indicate the number of chiral centers in a molecule (often a multiple choice question) or to identify all the chiral centers in a molecule (often by circling them).  Identifying chiral centers seems straightforward enough; just identify the tetrahedral atoms that are bonded to four different groups, right.  It really is that straightforward, but that doesn't mean it's always easy.  For larger molecules I recommend you take a systematic approach.  Let's identify all the chiral centers in the following molecule:

    how to identify chiral centers 1

    1. Chiral centers must be tetrahedral atoms (sp3 hybridized), so eliminate all atoms that are sp or sp2 hybridized from consideration.  There are 8 sp2 hybridized carbon atoms in this molecule and I've crossed them out below.

    how to identify chiral centers 2

    2. Chiral centers must be bonded to 4 different groups.  Any carbon bonded to two or more hydrogen atoms won't be bonded to four different groups and can be eliminated from consideration.  There are 6 such atoms crossed out below.

    how to identify chiral centers 3

    3. Chiral centers must be bonded to 4 different groups.  Any atom very obviously bonded to two (or more) identical groups won't be bonded to four different groups and can be eliminated from consideration.  There is 1 such atom crossed out below.  It is bonded to two methyl groups.

    how to identify chiral centers 4

    4. Examine the remaining atoms to see if they are indeed bonded to 4 different things.  At this point there are only three carbon atoms remaining to examine (the oxygen atom is sp3 hybridized but 2 of its 4 electron domains are lone pairs of electrons and it won't therefore have 4 different groups).

    how to identify chiral centers 5

    We'll examine the remaining atoms one at a time.

    how to identify chiral centers 6

    The carbon circled in blue in the above image is bonded to 3 carbon atoms and a hydrogen atom.  All three carbon atoms are unique (i.e. part of a distinct group) however, and the circled carbon atom is indeed a chiral center.  One of the carbon atoms it's bonded to is a methyl carbon and is easily seen as different than the other two carbon atoms.  The last two carbon atoms are both members of rings and are a little more difficult to distinguish.  Rather than worry about what they're attached to and following that until we find a difference, it's actually easier just to compare the entire side of the molecule each is on at once.  I've drawn a plane (blue dashed line) through the carbon under examination and between the two carbon atoms (in red) we're comparing.  The only way these two carbon atoms would be equivalent is if the entire part of the molecule left of the dashed line was exactly the same as the entire part of the molecule right of the dashed line, and it is easy to see that they are not.

    how to identify chiral centers 7

    The carbon circled in blue in the above image is bonded to 2 carbon atoms, an oxygen atom, and a hydrogen atom.  The two carbon atoms (in red) are unique, and the blue circled carbon atom is indeed a chiral center.  The two carbon atoms are easily identified as distinct as they differ in hybridization and one is part of a ring while the other isn't.  But once again I prefer to just compare the entire side of the molecule each is on at once.  I've drawn a plane (blue dashed line) through the carbon under examination and between the two carbon atoms (in red) we're comparing.  The parts of the molecules on either side of the dashed line are quite obviously different indicating again that these two carbon atoms are distinct.

    how to identify chiral centers 9

    The carbon circled in blue in the above image is bonded to 3 carbon atoms and a hydrogen atom.  All three carbon atoms are unique, and the circled carbon atom is indeed a chiral center.  One of the carbon atoms it's bonded to is a methyl carbon and is easily seen as different than the other two carbon atoms.  The remaining two carbon atoms it is bonded to can be distinguished as one is bonded to two hydrogen atoms and the other only one.  But once again I prefer to just compare the entire side of the molecule each is on at once.  I've drawn a plane (blue dashed line) through the carbon under examination and between the two carbon atoms (in red) we're comparing.  The parts of the molecules on either side of the dashed line are quite obviously different indicating again that these two carbon atoms are distinct.

    And there you have it; this molecule has 3 chiral centers (circled in blue in the image below).

    how to identify chiral centers ten

    Chiral Centers Besides Carbon?

    Chiral centers don't necessarily have to be carbon, but there are two reasons most of the examples you'll see in an organic chemistry course will be.

    1. This is organic chemistry, the chemistry of carbon.

    2. Carbon can make 4 bonds and most other atoms you're likely to find in organic molecules usually don't.  This limits the possible atoms that might be bonded to 4 different things.

    But one of the 4 different things an atom is bonded to doesn't actually have to involve another atom or a bond; 1 of the 4 things can be a lone pair of electrons.  We'll see something unusual with nitrogen for many amines at the end of this chapter (5.6 Amine Inversion and Chiral Molecules without Chiral Centers) so I'll ignore nitrogen for now, but check out the following ion in which sulfur is a chiral center.  The sulfur atom is bonded to the carbon of a methyl group, the carbon of an ethyl group, the carbon of a propyl group, and has a lone pair of electrons.

    sulfur chiral center

    Now that we know what a chiral center is and how to identify them, we'll learn how to assign absolute configurations, R and S, in the next lesson (5.2 Absolute Configurations: Assigning R and S).