The term chiral, from the Greek work for 'hand', refers to anything which cannot be superimposed on its own mirror image. Certain organic molecules are chiral meaning that they are not superimposable on their mirror image. Chiral molecules contain one or more chiral centers, which are almost always tetrahedral (sp3-hybridized) carbons with four different substituents. Consider the molecule A below: a tetrahedral carbon, with four different substituents denoted by balls of four different colors.
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The mirror image of A, which we will call B, is drawn on the right side of the figure, and an imaginary mirror is in the middle. Notice that every point on A lines up through the mirror with the same point on B: in other words, if A looked in the mirror, it would see B looking back.
Now, if we flip compound A over and try to superimpose it point for point on compound B, we find that we cannot do it: if we superimpose any two colored balls, then the other two are misaligned.
A is not superimposable on its mirror image (B), thus by definition A is a chiral molecule. It follows that B also is not superimposable on its mirror image (A), and thus it is also a chiral molecule.
A and B are called stereoisomers or optical isomers: molecules with the same molecular formula and the same bonding arrangement, but a different arrangement of atoms in space. Enantiomers are pairs of stereoisomers which are mirror images of each other: thus, A and B are enantiomers. It should be self-evident that a chiral molecule will always have one (and only one) enantiomer: enantiomers come in pairs. Enantiomers have identical physical properties (melting point, boiling point, density, and so on). However, enantiomers do differ in how they interact with polarized light (we will learn more about this soon) and they may also interact in very different ways with other chiral molecules - proteins, for example. We will begin to explore this last idea in later in this chapter, and see many examples throughout the remainder of our study of biological organic chemistry.
Be aware - all of the following terms can be used to describe a chiral carbon.
chiral carbon = asymmetric carbon = optically active carbon = stereo carbon = stereo center = chiral center
Let's apply our chirality discussion to real molecules.
Consider 2-butanol, drawn in two dimensions below.
Carbon #2 is a chiral center: it is sp3-hybridized and tetrahedral (even though it is not drawn that way above), and the four substituents attached to is are different: a hydrogen (H) , a methyl (-CH3) group, an ethyl (-CH2CH3) group, and a hydroxyl (OH) group. If the bonding at C2 of 2-butanol is drawn in three dimensions and this structure called A. Then the mirror image of A can be drawn to form structure B.
When we try to superimpose A onto B, we find that we cannot do it. Because structure A and B are not superimposable on their mirror image they are both chiral molecules. Because A and B are different due only to the arrangement of atoms in space they are stereoisomers. Because A and B are mirror images of each other they are also enantiomers. When looking at simplified line structures is clear that there are two distinct ways of drawing 2-butanol which only differ in their spatial arrangement around a chiral carbon.
The 3D Structures of the Two Enantiomers of 2-Butanol
For comparison, 2-propanol, is an achiral molecule because is lacks a chiral carbon. Carbon #2 is bonded to two identical substituents (methyl groups), and so it is not a chiral carbon. Being achiral means that 2-propanol should be superimposable on its mirror image which is shown in the figure below. A more detailed explaination on why 2-propanol is achiral will be given in the next section.
2-propanol is achiral:
Molecules that are nonsuperimposable mirror images of each other are said to be chiral (pronounced “ky-ral,” from the Greek cheir, meaning “hand”). Examples of some familiar chiral objects are your hands. Your left and right hands are nonsuperimposable mirror images. (Try putting your right shoe on your left foot—it just doesn’t work.) An achiral object is one that can be superimposed on its mirror image, as shown by the superimposed flasks 25.7.1b in the figure below. 25.7.1b.
An an important questions is why is one chiral and the other not? The answer is that the flask has a plane of symmetry and your hand does not. A plane of symmetry is a plane or a line through an object which divides the object into two halves that are mirror images of each other. When looking at the flask, a line can be drawn down the middle which separates it into two mirror image halves. However, a similar line down the middle of a hand separates it into two non-mirror image halves. This idea can be used to predict chirality. If an object or molecule has a plane of symmetry it is achiral. If if lacks a plane of symmetry it is chiral.
Symmetry can be used to explain why a carbon bonded to four different substituents is chiral. When a carbon is bonded to fewer than four different substituents it will have a plane of symmetry making it achiral. A carbon atom that is bonded to four different substituents loses all symmetry, and is often referred to as an asymmetric carbon. The lack of a plane of symmetry makes the carbon chiral. The presence of a single chiral carbon atom sufficient to render the molecule chiral, and modern terminology refers to such groupings as chiral centers or stereo centers.
An example is shown in the bromochlorofluoromethane molecule shown in part (a) of the figure below. This carbon, is attached to four different substituents making it chiral. which is often designated by an asterisk in structural drawings. If the bromine atom is replaced by another chlorine to make dichlorofluoromethane, as shown in part (b) below, the molecule and its mirror image can now be superimposed by simple rotation. Thus the carbon is no longer a chiral center. Upon comparison, bromochlorofluoromethane lacks a plane of symmetry while dichlorofluoromethane has a plane of symmetry.
Identifying chiral carbons in a molecule is an important skill for organic chemists. The presence of a chiral carbon presents the possibility of a molecule having multiple stereoisomers. Most of the chiral centers we shall discuss in this chapter are asymmetric carbon atoms, but it should be recognized that other tetrahedral or pyramidal atoms may become chiral centers if appropriately substituted. Also, when more than one chiral center is present in a molecular structure, care must be taken to analyze their relationship before concluding that a specific molecular configuration is chiral or achiral. This aspect of stereoisomerism will be treated later. Because an carbon requires four different substituents to become asymmertric, it can be said, with few exceptions, that sp2 and sp hybridized carbons involved in multiple bonds are achiral. Also, any carbon with more than one hydrogen, such as a -CH3 or -CH2- group, are also achiral.
Looking for planes of symmetry in a molecule is useful, but often difficult in practice. It is difficult to illustrate on the two dimensional page, but you will see if you build models of these achiral molecules that, in each case, there is at least one plane of symmetry, where one side of the plane is the mirror image of the other. In most cases, the easiest way to decide whether a molecule is chiral or achiral is to look for one or more stereocenters - with a few rare exceptions, the general rule is that molecules with at least one stereocenter are chiral, and molecules with no stereocenters are achiral.
Determining if a carbon is bonded to four distinctly different substituents can often be difficult to ascertain. Remember even the slightest difference makes a substituent unique. Often these difference can be distant from the chiral carbon itself. Careful consideration and often the building of molecular models may be required. A good example is shown below. It may appear that the molecule is achiral, however, when looking at the groups directly attached to the possible chiral carbon, it is clear that they all different. The two alkyl groups are differ by a single -CH2- group which is enough to consider them different.
Predict if the following molecule would be chiral or achiral:
Achiral. When determining the chirality of a molecule, it best to start by locating any chiral carbons. An obvious candidate is the ring carbon attached to the methyl substituent. The question then becomes: does the ring as two different substituents making the substituted ring carbon chiral? With an uncertainty such as this, it is then helpful try to identify any planes of symmetry in the molecule. This molecule does have a plane of symmetry making the molecule achiral. The plane of symmetry would be easier see if the molecule were view from above. Typically, monosubstituted cycloalkanes have a similar plane of symmetry making them all achiral.
Determine if each of the following molecules are chiral or achiral. For chiral molecules indicate any chiral carbons.
Explanation
Structures F and G are achiral. The former has a plane of symmetry passing through the chlorine atom and bisecting the opposite carbon-carbon bond. The similar structure of compound E does not have such a symmetry plane, and the carbon bonded to the chlorine is a chiral center (the two ring segments connecting this carbon are not identical). Structure G is essentially flat. All the carbons except that of the methyl group are sp2 hybridized, and therefore trigonal-planar in configuration. Compounds C, D & H have more than one chiral center, and are also chiral.
In the ’s, a drug called thalidomide was widely prescribed in the Western Europe to alleviate morning sickness in pregnant women.
Thalidomide had previously been used in other countries as an antidepressant, and was believed to be safe and effective for both purposes. The drug was not approved for use in the U.S.A. It was not long, however, before doctors realized that something had gone horribly wrong: many babies born to women who had taken thalidomide during pregnancy suffered from severe birth defects.
Researchers later realized the problem lay in the fact that thalidomide was being provided as a mixture of two different isomeric forms.
One of the isomers is an effective medication, the other caused the side effects. Both isomeric forms have the same molecular formula and the same atom-to-atom connectivity, so they are not constitutional isomers. Where they differ is in the arrangement in three-dimensional space about one tetrahedral, sp3-hybridized carbon. These two forms of thalidomide are stereoisomers. If you make models of the two stereoisomers of thalidomide, you will see that they too are mirror images, and cannot be superimposed.
As a historical note, thalidomide was never approved for use in the United States. This was thanks in large part to the efforts of Dr. Frances Kelsey, a Food and Drug officer who, at peril to her career, blocked its approval due to her concerns about the lack of adequate safety studies, particularly with regard to the drug's ability to enter the bloodstream of a developing fetus. Unfortunately, though, at that time clinical trials for new drugs involved widespread and unregulated distribution to doctors and their patients across the country, so families in the U.S. were not spared from the damage caused.
Very recently a close derivative of thalidomide has become legal to prescribe again in the United States, with strict safety measures enforced, for the treatment of a form of blood cancer called multiple myeloma. In Brazil, thalidomide is used in the treatment of leprosy - but despite safety measures, children are still being born with thalidomide-related defects.
Label the molecules below as chiral or achiral, and locate all stereocenters.
1) For the following compounds, star (*) each chiral center, if any.
2) Explain why the following compound is chiral.
3) Determine which of the following objects is chiral.
a) A Glove.
b) A nail.
c) A pair of sunglasses.
d) The written word "Chiral".
4) Place an "*" by all of the chrial carbons in the following molecules.
a)
Erythrose, a four carbon sugar.
b) Isoflurane, an anestetic. Bright green = Chlorine, Pale green = Fluorine.
1)
2) Though the molecule does not contain a chiral carbon, it is chiral as it is non-superimposable on its mirror image due to its twisted nature (the twist comes from the structure of the double bonds needing to be at 90° angles to each other, preventing the molecule from being planar).
3)
a) Just as hands are chiral a glove must also be chiral.
b) A nail has a plane of symmetry which goes down the middle making it a achiral.
c) A pair of sunglasses has a plane of symmetry which goes through the nose making it achiral.
d) Most written words are chiral. Look one in a mirror to confirm this.
4
a)
b)
Circle all of the carbon stereocenters in the molecules below.
Circle all of the carbon stereocenters in the molecules below.
Here are some more examples of chiral molecules that exist as pairs of enantiomers. In each of these examples, there is a single stereocenter, indicated with an arrow. (Many molecules have more than one stereocenter, but we will get to that that a little later!)
Here are some examples of molecules that are achiral (not chiral). Notice that none of these molecules has a stereocenter.
It is difficult to illustrate on the two dimensional page, but you will see if you build models of these achiral molecules that, in each case, there is at least one plane of symmetry, where one side of the plane is the mirror image of the other. Chirality is tied conceptually to the idea of asymmetry, and any molecule that has a plane of symmetry cannot be chiral. When looking for a plane of symmetry, however, we must consider all possible conformations that a molecule could adopt. Even a very simple molecule like ethane, for example, is asymmetric in many of its countless potential conformations – but it has obvious symmetry in both the eclipsed and staggered conformations, and for this reason it is achiral.
Looking for planes of symmetry in a molecule is useful, but often difficult in practice. In most cases, the easiest way to decide whether a molecule is chiral or achiral is to look for one or more stereocenters - with a few rare exceptions (see section 3.7B), the general rule is that molecules with at least one stereocenter are chiral, and molecules with no stereocenters are achiral. Carbon stereocenters are also referred to quite frequently as chiral carbons.
When evaluating a molecule for chirality, it is important to recognize that the question of whether or not the dashed/solid wedge drawing convention is used is irrelevant. Chiral molecules are sometimes drawn without using wedges (although obviously this means that stereochemical information is being omitted). Conversely, wedges may be used on carbons that are not stereocenters – look, for example, at the drawings of glycine and citrate in the figure above. Just because you see dashed and solid wedges in a structure, do not automatically assume that you are looking at a stereocenter.
Other elements in addition to carbon can be stereocenters. The phosphorus center of phosphate ion and organic phosphate esters, for example, is tetrahedral, and thus is potentially a stereocenter.
We will see in chapter 10 how researchers, in order to investigate the stereochemistry of reactions at the phosphate center, incorporated sulfur and/or 17O and 18O isotopes of oxygen (the ‘normal’ isotope is 16O) to create chiral phosphate groups. Phosphate triesters are chiral if the three substituent groups are different.
Asymmetric quaternary ammonium groups are also chiral. Amines, however, are not chiral, because they rapidly invert, or turn ‘inside out’, at room temperature.
Label the molecules below as chiral or achiral, and circle all stereocenters.
a) fumarate (a citric acid cycle intermediate)
b) malate (a citric acid cycle intermediate)
b) malate (a citric acid cycle intermediate)
a) achiral (no stereocenters)
b) chiral
c) chiral
Label the molecules below as chiral or achiral, and circle all stereocenters.
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a) acetylsalicylic acid (aspirin)
b) acetaminophen (active ingredient in Tylenol)
c) thalidomide (drug that caused birth defects in pregnant mothers in the ’s)
a) achiral (no stereocenters)
b) achiral (no stereocenters)
c) chiral
Draw both enantiomers of the following chiral amino acids.
a) Cysteine
b) Proline
Draw both enantiomers of the following compounds from the given names.
a) 2-bromobutane
b) 2,3-dimethyl-3-pentanol
Which of the following body parts are chiral?
a) Hands b) Eyes c) Feet d) Ears
a) Hands- chiral since the mirror images cannot be superimposed (think of the example in the beginning of the section)
b) Eyes- achiral since mirror images that are superimposable
c) Feet- chiral since the mirror images cannot be superimposed (Does your right foot fit in your left shoe?)
d) Ears- chiral since the mirror images cannot be superimposed
Circle the chiral centers in the following compounds.
Identify the chiral centers in the following compounds.
All About Allenes, Chiral and Otherwise
Table of Contents
We’ve met alkenes before – right? Just in case you haven’t, let’s review the basics, because today’s post is going to depend on understanding a few of the most important concepts.
Alkenes contain both sigma [ σ] bonding formed through “head-on” orbital overlap [i.e. “single bonds”] and also pi [ π ] bonding where orbitals have “side-on” overlap [i.e. “multiple bonds”]
Alkenes like ethylene are flat [planar]. The p orbitals are at 90 degrees to this planar structure.
If you’ve ever used graphite lubricant, you might know it’s slippery because graphite is made up of layered sheets of flat, pi-bonded carbon, and the sheets have very little friction between each layer. Graphene is the same idea, only it’s a single layer.
Now let’s draw something weird. What do we get when we extend a second double bond directly adjacent to the first one?
Does this look strange to you? The first time you see this, you’ll probably think – yes! You might wonder – do these even exist? The answer is also – Yes! This moleule is called allene, and is part of a family of molecules called cumulenes, so named because the double bonds are cumulative (consecutive).
Now let’s ask: what might the bonding in this molecule look like? In other words, what does it look like in 3D?
You might think – simple! It’s flat, like an alkene!
It’s actually not quite that simple! The key is that central carbon – it has TWO π bonds.
You might recall that acetylene has two π bonds as well, at 90 degrees to each other.
The same is true for allene, except that it’s only the central carbon that is involved in two pi bonds.
Here’s what the orbitals of this molecule look like.
The hybridization of that central carbon? It’s sp, just like the carbons in acetylene. The end carbons are sp2
The line diagram of allene really does not do it justice.
So here I present a 3D “fly-by” of allene. Note how the two CH2 groups are “offset” with respect to each other by 90 degrees.
Allene is not flat! [those white balls – imagine they are hydrogen]
via GIPHY
Like so many things in organic chemistry, this simple fact leads to consequences that aren’t immediately apparent. Let’s pay attention to the mirror planes in this molecule. Note that there are two.
Recall that in order for a molecule to be chiral it must not be superimposable on its mirror image. If the molecule has a mirror plane (plane of symmetry) then it will be superimposable on its mirror image [and therefore achiral].
With two mirror planes this is definitely an achiral molecule.
Now let’s start playing around a bit. What happens if we replace one of the hydrogens by another group? In the drawing I’ve arbitrarily made this atom Cl but in practice it can be anything except H in this case.
Here’s a line drawing of the molecule and a picture of its orbitals.
Now here’s what it looks like in 3D. Notice that we’ve lost one of the mirror planes! But it still has one, so it’s still achiral.
via GIPHY
Now: what happens if we add a second group to the same carbon?
It’s still achiral! – in fact, we’ve gone back to having two mirror planes.
Now, finally, let’s change the position of that second group. Instead of making it so that there are two identical groups on the carbon, let’s change it so that there’s one on each carbon. Like this:
Here’s the 3D version.
via GIPHY
Now I ask: where are the mirror planes?
THERE ARE NONE! If there are no mirror planes —> then we are looking at a chiral molecule.
Wait. You might ask -what trickery is this? We have no chiral centres. Don’t we need something to have a chiral centre to be chiral?
Actually you are very familiar with a chiral object that has no chiral centre.
Have you ever screwed before?
No, no, no! I mean, screwed using a screwdriver. This is a chemistry blog. Don’t expect anything lascivious here.
See, most screw threads are, to use a familiar mnemonic, “righty tighty, lefty loosey.” You have to turn the screwdriver clockwise to screw it in, and counterclockwise to loosen. Screws are chiral!
[By the way the enantiomer of that common screw thread would be… “lefty tighty, righty loosey” – those types of threads exist BTW – especially in gas barbecues, so as to prevent people from trying to connect things to them such as garden hoses or other idiotic things].
Here’s a representative picture of two chiral screws. You can also imagine these as spiral staircases. Imagine walking up each staircase. On the staircase labelled “left- hand” below, your right arm would be on the inside as you ascend. On the “right-hand” staircase, your left arm would be on the inside as you ascend. [see Note 2]
Instead of having a chiral centre, screws have what we refer to as a “chiral axis“. Other common examples of things with chiral axes: spiral staircases, snail shells and DNA.
Our disubstituted allene has a chiral axis – just like a screw.
Screws are chiral – and chiral objects have enantiomers. And just as screws have enantiomers, so do chiral molecules with a chiral axis.
What would the enantiomer of the allene look like?
Here is an enantiomeric pair of allenes. Can you see now how they are not superimposable?
[In other words, an allene with a chiral axis vs. an allene without a chiral axis]
You might ask, is there some kind of short cut for recognizing a chiral allene? Sure.
Examine both “ends” of the allene. If either of those ends is attached to two identical substituents, it is achiral – because it will have a mirror plane.
If neither of the ends are attached to two identical substituents, then it is chiral.
Note 1. Bonus question: Would you expect this molecule to be chiral? Why or why not?
Note 2. Nerdy note about staircases, possibly a myth. This may or may not be true, but I recall reading a book in my childhood about castles where it was said that castles were built with staircases that forced someone ascending them [an attacker, presumably] to have their right (sword) hand on the inside and a descending defender to have their sword hand on the outside. The idea being that there is much more freedom of motion if your sword hand is on the outside because you have to swing it across your body.
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