Difficulty: Intermediate | Prerequisites: Part 1 of these notes (Sections 4.1–4.4), comfort with sp3 geometry and optical activity
Once you can identify a chirality centre and understand that enantiomers exist, the next question is: how do you describe which enantiomer you are looking at? This section covers the naming conventions (R/S, +/–), the visual shorthand (Fischer projections), and the physical consequences of chirality (identical bulk properties, different biological behaviour). It also extends chirality beyond a single tetrahedral carbon to the chirality axis. If you are not yet comfortable identifying chirality centres and calculating enantiomeric excess, review Part 1 first.
The Cahn-Ingold-Prelog (CIP) system assigns R or S labels to chirality centres based on the atomic-number priority of substituents. Fischer projections are a 2D shorthand for representing 3D tetrahedral geometry. Enantiomers share bulk physical properties (melting point, boiling point, density) but differ in how they interact with other chiral objects, including biological receptors and polarised light. Chirality can also arise from restricted rotation around a bond axis (atropisomerism).
Absolute configuration
The actual 3D spatial arrangement of substituents at a chirality centre. In simple terms, this is the definitive answer to "which enantiomer is this?"
Relative configuration
How one chirality centre relates to another, determined by interconversion experiments rather than direct 3D analysis.
Cahn-Ingold-Prelog (CIP) system
The set of rules used to assign R or S labels to chirality centres, based on the atomic numbers of the attached substituents.
R configuration (rectus)
Assigned when the priority sequence of substituents (highest to lowest, with the lowest-priority group pointing away) traces a counterclockwise path.
S configuration (sinister)
Assigned when the priority sequence traces a clockwise path.
Fischer projection
A 2D representation of a tetrahedral centre. Vertical bonds point away from the viewer; horizontal bonds point toward the viewer.
Chiral recognition
The selective interaction of a chiral receptor or reagent with one enantiomer of a chiral compound. This is the molecular basis of why your nose can tell spearmint from caraway.
Chirality axis
An axis about which atoms or groups are arranged so that the spatial arrangement is not superimposable on its mirror image. Think of a left-handed screw vs. a right-handed screw.
Biaryls
Compounds with two aromatic rings joined by a single bond. When bulky substituents prevent free rotation, the two ring orientations become non-interconvertible.
Atropisomers (atopisomers)
Stereoisomers that differ by rotation about a single bond but exist independently because large substituents block that rotation.
The absolute configuration is the actual 3D arrangement of substituents at a chirality centre.
The relative configuration describes how one chirality centre relates to another and is determined by interconversion experiments (converting one compound into another without breaking bonds at the chirality centre).
Physical or virtual 3D models are invaluable here. Trying to do this purely on paper is much harder than it needs to be.
Higher atomic number takes precedence. Br (35) outranks F (9), which outranks H (1).
If two directly attached atoms are identical, compare the atoms attached to them and use atomic number to break the tie.
Work outward from the chirality centre. Compare all atoms attached to a particular atom at one level before going further down the chain.
Evaluate substituent atoms one by one, not as whole groups.
Multiply bonded atoms are "replicated." A double bond to oxygen is treated as if the carbon is bonded to two separate oxygen atoms (and the oxygen bonded to two separate carbons).
Chirality centres inside rings: trace both paths around the ring and compare priorities along each path.
Rank the four substituents from highest (1) to lowest (4) priority using the rules above.
Orient the molecule so that the lowest-priority group (4) points away from you (a dash bond in a wedge-dash drawing).
Trace the path from priority 1 → 2 → 3:
Counterclockwise = R (rectus)
Clockwise = S (sinister)
R/S and (+)/(–) are independent. There is no rule linking R to (+) or S to (–).
When both the configuration and the rotation are known, both are given: e.g. (R)-(–)-2-butanol, (S)-(+)-2-butanol.
Any combination of R, S, (+), and (–) is possible.
Vertical bonds point away from the viewer (into the page).
Horizontal bonds point toward the viewer (out of the page).
The lowest-priority element is usually placed on top.
A Fischer projection is a flat, cross-shaped drawing that encodes 3D information.
To determine R or S from a Fischer projection: orient it so that the lowest-priority group is at the top (pointing away), then read the remaining three groups and check clockwise vs. counterclockwise.
You can also convert a Fischer projection to a 3D wedge-dash structure and assign R/S from there.
Rotating a Fischer projection 180° in the plane of the page gives the same molecule.
Rotating 90° in the plane gives the enantiomer.
Swapping any two groups gives the enantiomer. Swapping two pairs returns the original.
Density, melting point, boiling point, refractive index, and solubility in achiral solvents are all the same for a pair of enantiomers.
Optical rotation: equal magnitude, opposite sign.
Interaction with other chiral molecules: enantiomers behave differently in chiral environments. This includes biological receptors, chiral catalysts, and chiral chromatography columns.
(R)-(–)-Carvone is the principal component of spearmint oil.
(S)-(+)-Carvone is the principal component of caraway seed oil.
Same molecular formula, same connectivity, same physical properties in achiral settings, but they smell completely different. The olfactory receptors in the nose are themselves chiral, so they distinguish between the two enantiomers.
(–)-Nicotine is much more toxic than (+)-nicotine.
(+)-Adrenaline is more active than (–)-adrenaline in constricting blood vessels.
(–)-Thyroxine regulates metabolism; (+)-thyroxine has no metabolic effect but was formerly used to lower cholesterol.
These differences arise because enzymes and receptors are chiral, and they interact selectively with one enantiomer.
Chirality does not require a single sp3 carbon with four different groups. It can also arise from a chirality axis: an axis around which substituents are arranged in a non-superimposable way.
Analogy: a left-handed screw and a right-handed screw are mirror images that cannot be superimposed.
Biaryls are compounds with two aromatic rings joined by a single bond (e.g. biphenyl, 1,1'-binaphthyl).
Although each ring is flat, the overall molecule is not. The rings twist relative to each other to reduce steric strain between nearby hydrogens.
Normally, rotation about the connecting bond is fast, so the two mirror-image forms interconvert rapidly and the compound is achiral overall.
When large substituents on the rings prevent free rotation, the two twisted forms become locked. Each form exists independently and does not convert to the other at room temperature.
These locked rotational isomers are called atropisomers.
Atropisomers are chiral and can be assigned R/S configurations using a modified CIP approach applied along the bond axis.
The carvone example (spearmint vs. caraway) is a vivid demonstration that chirality has real, perceptible consequences. Your nose is a chiral detector.
In drug development, the wrong enantiomer of a pharmaceutical can be inactive, toxic, or have entirely different effects. Regulatory agencies often require companies to characterise the activity of each enantiomer separately.
Students often assume R = (+) and S = (–). This is wrong. The R/S label is determined by the CIP priority rules and spatial arrangement. The (+)/(–) label is determined experimentally by polarimetry. They are independent.
Students sometimes rotate a Fischer projection 90° and assume they still have the same molecule. A 90° rotation gives the enantiomer; only 180° returns the original.
A common mistake when applying CIP rules is to compare entire substituent groups at once instead of working atom by atom, level by level outward from the chirality centre.
Students occasionally think all biaryls are chiral. Most are not, because free rotation around the connecting bond interconverts the mirror forms. Atropisomerism only arises when bulky groups block that rotation.
⚠️ CIP priority assignment is one of the highest-yield skills for exams. Practise until you can assign R/S to a drawn structure in under a minute.
⚠️ Fischer projection manipulation (what happens with 90° vs. 180° rotation, swapping groups) is a favourite source of exam questions.
⚠️ Know the distinction between absolute and relative configuration and be able to explain how interconversion experiments establish relative configuration.
⚠️ Be prepared to explain, with a specific example, why enantiomers can have different biological effects despite identical bulk physical properties.
True or false: R always corresponds to (+) rotation. (False. R/S and +/– are independent.)
In a Fischer projection, horizontal bonds point ______ the viewer. (Toward.)
True or false: Enantiomers have different melting points. (False. Bulk physical properties are identical.)
Fill in the blank: Compounds with two aromatic rings joined by a single bond are called ______. (Biaryls.)
True or false: Rotating a Fischer projection 90° gives you the same compound. (False. It gives the enantiomer.)
Q: In the CIP system, which takes higher priority: a –CH2OH group or a –CH2CH3 group? Explain your reasoning.
A: –CH2OH takes higher priority. Both groups start with carbon, so you move to the next atoms. The oxygen (atomic number 8) attached to the first carbon in –CH2OH outranks the carbon (atomic number 6) in –CH2CH3.
Q: You are given a Fischer projection with CH3 at the top, OH on the left, H on the right, and CH2CH3 at the bottom. Assign R or S.
A: Priority order: OH (1) > CH2CH3 (2) > CH3 (3) > H (4). H is on the right (horizontal, toward viewer), not pointing away. If you place H at the top (pointing away), the remaining groups trace counterclockwise: this is (R)-2-butanol.
Q: (R)-(–)-carvone smells like spearmint. What does (S)-(+)-carvone smell like?
A: Caraway. The two enantiomers interact differently with chiral olfactory receptors.
Q: What prevents biaryls from freely rotating and thus makes them chiral?
A: Large (bulky) substituents on the aromatic rings that physically block rotation about the connecting single bond, locking the molecule in one twisted conformation.
Q: How does a multiply bonded atom get treated in the CIP system?
A: It is replicated as a substituent. A double bond to oxygen means the carbon is treated as bonded to two oxygens, and the oxygen is treated as bonded to two carbons.
The CIP system and Fischer projections are tools you will use throughout organic chemistry, especially when discussing reaction stereochemistry (SN2 inversion, SN1 racemisation, addition reactions). Properties of enantiomers tie directly to biochemistry and pharmacology: drug design, enzyme specificity, and metabolic pathways all depend on chiral recognition. Atropisomerism connects to conformational analysis from Chapter 3 and has growing importance in modern drug design, where atropisomeric drug candidates are an active area of research.
Absolute configuration, relative configuration, Cahn-Ingold-Prelog, CIP rules, CIP priority, R and S notation, rectus, sinister, Fischer projection, wedge-dash drawing, priority rules, atomic number priority, multiply bonded atoms, replicated atoms, enantiomer properties, chiral recognition, carvone, spearmint, caraway, biological chirality, drug enantiomers, nicotine chirality, thyroxine, chirality axis, axial chirality, atropisomers, atropisomerism, biaryls, biphenyl, binaphthyl, hindered rotation, steric strain, OChem Chapter 4, organic chemistry stereochemistry, stereocentre naming