- Stereochemistry questions
- Chiral drugs
- Structural (constitutional) isomers
- Chiral vs achiral
- Stereoisomers, enantiomers, and chirality centers
- Identifying chirality centers
- R,S system
- R,S system practice
- Optical activity
- Enantiomers and diastereomers
- Cis–trans isomerism
- E–Z system
- Conformations of ethane
- Conformational analysis of butane
What is chirality?
Chirality is derived from the Greek word χειρ (kheir) that stands for "hand". An object is said to be chiral if the object and its mirror image are non-superimposable, just like our right and left hand. Now you must be wondering what we mean by ‘non-superimposable’. When the mirror image of the object is placed over the original object and they do not overlap, as shown in the figure below, then the object and its image are said to be non-superimposable .
Illustration showing that our hands are not chiral, but a bottle is chiral.
Molecular chirality was discovered by Louis Pasteur back in 1848, when he successfully separated the two isomers of sodium ammonium tartarate. He observed that the two isomeric crystals were non-superimposable mirror images of each other, they had the same physical properties, but differed in their ability to rotate plane polarized light. This property was termed as optical activity.
In non-polarized light, electric and magnetic fields randomly orient in all planes. When the non-polarized light is made to pass through a polarizing filter, oscillations get oriented in only one particular direction, and is called plane polarized light.
As stated, chiral molecules are optically active, which implies that when a beam of plane-polarized light passes through a chiral molecule, it interacts with the molecule in such a way that the angle of the plane of oscillation rotates.
Illustration showing how a chiral sample can rotate plane-polarized light.
A pair of enantiomers always rotate plane-polarized light to an equal but opposite degree. Example: If a pure sample of (S)-carvone rotates plane-polarized light by +10°(clockwise), then a sample of (R)-carvone (in the exact same concentration and under the same experimental conditions) will rotate the plane polarized light by (–)10° (counterclockwise).
Most biological compounds are chiral.
Illustration showing biological compounds which are chiral, such as drugs, sugars, amino acids, DNA, and enzymes.
How to identify chiral carbon centers?
The rule of thumb is: chiral carbon centers are carbon atoms that are attached to four different substituents, that are placed at the corners of a tetrahedron. Chiral carbon atoms are also referred to as ‘stereogenic carbons’ or ‘asymmetrical carbon atoms’.
A chemical line diagram showing two compounds, compound 1 and compound 2. Compound 2 is the mirror image of compound 1. The chiral carbon is surrounded by four different groups represented as W, X, Y, and Z.
Compound 1 has a chiral carbon center, because it is attached to four different groups (W, X, Y and Z). Compound 2 is the mirror image of compound 1. As per our definition of chirality, compounds 1 and 2 should be non-superimposable. How do we confirm this? Let’s rotate compound 1 around one axis of rotation, and see if any of the products of rotation lead to compound 2. If not, then compound 1 is chiral. So let’s go ahead and sequentially rotate compound 1 about the C-X axis in a clockwise direction. The various products of rotation are shown below.
Illustration showing products of rotation of the groups around the chiral carbon.
So as you can see, none of the above structures is the same as the mirror image, compound 2. Thus we can be convinced that compound 1 is chiral.
Before we move on, let’s try to identify if the carbon atom in the following three compounds is a chiral center or not.
Enantiomers: (+) and (-) & ‘R’ and ‘S’ isomers
A chiral compound and its mirror image are referred to as “enantiomers”. So, we can define *enantiomers as being two stereoisomers that contain asymmetric carbon atoms, and are related to each other as non-superimposable mirror images. *
Enantiomers differ only in their optical activity i.e. the direction in which they rotate plane polarized light. If an enantiomer rotates polarized light to the right or in a clockwise direction, it is said to be the (+) or the dextrorotatory isomer. On the other hand, if the plane polarized light is rotated to the left or in a counter-clockwise direction, the stereoisomer is called as the (−) or the levorotatory isomer. Enantiomers have the same physical properties, except for the direction in which they rotate plane polarized light. Since these isomers exhibit different optical activity, they are sometimes also referred to as optical isomers.
Configuration of each chiral carbon of the two enantiomers is systematically assigned using the R/S system. This method of naming the enantiomers was developed by three chemists: R.S. Cahn, C. Ingold, and V. Prelog and is also often called the Cahn-Ingold-Prelog rules of naming enantiomers.
PS: There is no correlation between (+) and (-) , and the R & S stereochemical labels.. An ‘R’ stereoisomer can either be (+) or (-). Optical activity of R and S stereoisomers has to be measured experimentally with a polarimeter.
Assigning ‘R and S’ configuration to chiral centers: The Cahn-Ingold-Prelog rules
Before we get into the discussion of how to assign a configuration (R or S) to a chiral carbon enantiomer, let us be clear of how the spatial arrangement of the tetrahedral carbon, with respect to the plane of the molecule, is depicted on paper.
Illustration and description of the planes molecules occupy: W, X, Y, and Z.
Step 1: The four groups attached to the chiral carbon atom have to be arranged in the relative order of priority. The group with the highest atomic number is given the highest priority #1 and the group with the lowest atomic number is given the lowest priority i.e. #4. Let’s clarify this with an example.
Chemical line diagram showing a chiral carbon with bromine, chlorine, fluorine, and hydrogen attached to it. Each substituent is ranked 1-4 respective to its priority.
|Substituent||Atomic number||Priority number assigned|
Step 2: Make sure that the lowest priority group (#4) is pointing away from you i.e. it is attached to the hashed wedge in the 2D spatial arrangement.
Step 3: Now draw a curved arrow from the highest priority (#1) substituent to the second lowest priority (#3) substituent. If the arrow turns in a counterclockwise direction, the configuration at the stereocenter is labeled S ("Sinister" → Latin= "left"). If, however, the arrow turns clockwise, then the stereocenter is labeled R ("Rectus" → Latin= "right").
Illustration showing two compounds, 1a and 1b which are enantiomers.
As illustrated above, 1a is an ‘S’ isomer while 1b is the ‘R’ enantiomer.
How are we supposed to proceed if the lowest priority group is not pointing away from us? In such a case you will need to select any one of the two groups that are present in the plane of the molecule, rotate the molecule about that axis and step wise move the other three groups around until the lowest priority group (#4) is pointing away from you. Let’s understand this through the following example. Let’s sequentially rotate the molecule about the C-X bond in a clockwise direction until hydrogen points away from us.
Image showing sequentially rotate the molecule about the C-F bond in a clockwise direction until hydrogen points away you
Priority number is assigned to atoms that are attached directly to the stereogenic carbon, so what happens if there are two substituents with the same rank? In that case, simply proceed along the two substituent chains until you find a point of difference. Let’s again understand this through an example. Consider the following molecule
Image showing the 4 atoms attached directly to the chiral carbon (stereocenter) are chlorine (Cl) and 3 carbon atoms (C, C and C) respectively.
Here, the 4 atoms attached directly to the chiral carbon (stereocenter) are chlorine (Cl) and 3 carbon atoms (C, C and C) respectively. Clearly based on atomic numbers, Cl atom gets the highest priority (#1), but the other three atoms are tied (since they are all carbon atoms). So in such a case, we move along each substituent chain and see what atoms are directly attached to the three carbon atoms respectively
Image showing each carbon atom is directly attached to 3 other atoms (out of which two are hydrogens).
As you can notice, each carbon atom is directly attached to 3 other atoms (out of which two are hydrogens), so the deal breaker is the third atom (hydrogen vs carbon vs oxygen). Thus, we have been able to assign relative priorities to the four groups attached to the chiral carbon atom by moving along the substituent chains.
Image of the four groups attached to the chiral carbon atom
Chirality and drug development
The importance of chiral drugs in the drug development space cannot be understated. In pharmaceutical industries, 56% of the drugs currently in use are chiral molecules and 88% of the last ones are marketed as racemates (or racemic mixtures), consisting of an equimolar mixture of two enantiomers.
Although the enantiomers of chiral drugs have the same chemical connectivity of atoms; they exhibit marked differences in their pharmacology, toxicology, pharmacokinetics, metabolism etc. Therefore, when chiral drugs are synthesized, as much effort goes towards the rigorous separation of the two enantiomers. This ensures that only the biologically active enantiomer is present in the final drug preparation.
The enantiomers of a chiral drug differ in their interactions with enzymes, proteins, receptors and other chiral molecules too including chiral catalysts. These differences in interactions, in turn, lead to differences in the biological activities of the two enantiomers, such as their pharmacology, pharmacokinetics, metabolism, toxicity, immune response etc. *Surprisingly, biological systems can recognize the two enantiomers as two very different substances. *
But why do enantiomers have different biological activities?
Recognition of chiral drugs by specific drug receptors is explained by a three-point interaction of the drug with the receptor site, as proposed by Easson and Stedman. The difference between the interaction of the two enantiomers of a chiral drug with its receptor is illustrated below.
Easson-Stedman’s illustration of hypothetical interaction between the two enantiomers of a racemic drug with a receptor at the drug binding sites: The three substituents A, B, C of the active enantiomer (left) can interact with three binding sites a, b, c of a receptor by forming three contacts Aa, Bb and Cc, whereas the inactive enantiomer (right) cannot because the contact is insufficient.
In this case, one enantiomer is biologically active while the other enantiomer is not. The substituents of the active enantiomer drug labeled A, B, and C must interact with the corresponding regions of the binding site labeled a, b, and c of the receptor in order to have a proper alignment Aa, Bb, Cc. In this case, this fitting interaction produces an active biological effect. In contrast, the inactive enantiomer cannot bind in the same way with its receptor; thus, there is no active response. The attachment of an enantiomer to the chiral receptor is analogous to a hand fitting into a glove. Indeed, a right hand can only fit into a right hand glove. Similarly, only a particular enantiomer that has a complementary shape to the receptor site can fit into a receptor site. The other enantiomer will not fit, like a right hand will never fit into a left glove.
Some drugs are marketed solely as a pure single enantiomer (that is; the drug preparation has no contamination with the other enantiomer). Enantiomeric excess (ee) is a measurement of the degree of purity of any chiral sample. It reflects the degree to which a sample contains one enantiomer in excess over the other. A racemic mixture has an ee of 0% (both enantiomers are present in a 1:1 ratio), while a completely pure enantiomer has an ee of 100%. As an example, if a sample contains 70% of R isomer and 30% of S isomer, then it will have an enantiomeric excess of 40%. This can be rationalized as a mixture of 40% pure R with 60% (30% R and 30% S) of a racemic mixture.
Enantiomer ratio is extremely important because while one enantiomer is beneficial to the body, the other enantiomer can be highly toxic to the body. A well-known example of enantiomer related toxicity is the R- and S-enantiomers of thalidomide.
Chemical line drawing showing the difference between (S)-thalidomide and (R)-thalidomide.
The R-enantiomer is an effective sedative, which has a soothing effect that relieves anxiety and makes the patient drowsy; while, the S-enantiomer is known to cause teratogenic birth defects. A teratogenic fetus is one with deficient, redundant, misplaced or grossly misshapen parts. In fact, S-Thalidomide was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took the racemic mixture during pregnancy.
Few examples of chiral drugs, whose enantiomers vary drastically in their properties
- Human olfactory sensory organs are chiral, so the following pair of enantiomers smell very differently to us. R-isomer of carvone smells like spearmint leaves, while S-isomer of carvone smells like caraway seeds.
Chemical line diagram showing the difference between R-carvone (which smells like spearmint) and S-carvone (which smells like caraway seeds).
- In the case of the well-known painkiller, ibuprofen, the (S)-enantiomer has the desired pharmacological activity while the (R)-enantiomer is totally inactive.
Chemical line diagram showing the difference between (S)-ibuprofen and (R)-ibuprofen.
Hopefully now you have an appreciation of the concept of chirality. It’s amazing how two molecules that look so similar on paper can have strikingly different biological activities and thus strikingly different effects on the human body!
Want to join the conversation?
- The part that says "How are we supposed to proceed if the lowest priority group is not pointing away from us?" does not have the right image underneath it. The image that is used here is the one from the non-superimposable image (prior example).(15 votes)
- The non-superimposable chiral molecule is the one which rotates the plane polarized light right?(3 votes)
- Chiral molecules are optically active, meaning they rotate polarized light. The non-superimposable mirror images of a chiral molecule are called enantiomers. The interesting thing about enantiomers is that they rotate polarized light in the exact opposite way of each other, so if one enantiomer rotates it +25, the other will rotate it -25.(8 votes)
- what is the chiral center in carvone(2 votes)
- It's the C where the H is drawn sticking back.(4 votes)
- Hi i'm a bit confused over this sentence, "The importance of chiral drugs in the drug development space cannot be understated. In pharmaceutical industries, 56% of the drugs currently in use are chiral molecules and 88% of the last ones are marketed as racemates (or racemic mixtures), consisting of an equimolar mixture of two enantiomers."
What does "88% of the last ones are marketed as racemates" mean? The last ones??(2 votes)
- Does it mean to say 88% of THESE (the 56%) are marketed as racemates?(2 votes)
- It seems as though the image under "How are we supposed to proceed if the lowest priority group is not pointing away from us?" is repeated and the wrong example for the paragraph?(2 votes)
- Is vinorelbine drug chiral or achiral ?
and is there any specific stereochemistry in it structure?(2 votes)
- Can anyone elaborate on how to calculate Enantiomeric Excess? How does 70% R - 30% S translate to an ee of 40%?(1 vote)
- If the lowest priority is not pointing away from us, can we just continue as we would and at the end switch the configuration? I know that works most times i'm just not sure if it can always be used(1 vote)
- If enantiomers can 'rotate' plane polarised light, can plane polarised light rotate the enantiomers ?(1 vote)
- I don't think so. When plane polarised light passes through a chiral compound, the light gets rotated. It's not like the light rotates the compound. I'm not sure though, hope this helps<3(1 vote)
- Re: Thalidomide - this was my own mistake in failing to further check this, but I mentioned this about thalidomide in my seminar class and my prof (a chem prof) explained that R and S thalidomide rapidly convert in the body--it's one of maybe ten (very few) compounds that do that. There's no "safe" version. That said, even though it's a teratogen, it is receiving further research as a potential treatment for some cancers and leprosy. It is also poorly understood as a compound, as it has no effect in some animals like mice and apparently very different complications in rabbits (Derek B Lowe).
Also, virtually zero, if any, chiral compounds exist such that one is safe and one is toxic. Usually, one is either good or bad, and it's enantiomer is less effective or just inactive.(0 votes)