Source: Baldwin, CHEM 2510, Ohio State University
Tags: synthetic utility, chlorination usefulness, bromination selectivity, stereochemistry, racemic mixture, enantiopure, diastereoselectivity, radical intermediate, sp2 planar radical, chiral centre, enantiomeric transition state, diastereomeric transition state, stereochemical outcome, CHEM 2510
Difficulty: Intermediate–Advanced Prerequisites: Radical halogenation mechanism and selectivity (Ch. 3.1–3.6), chirality, stereocentres, R/S configuration, enantiomers vs. diastereomers.
Knowing the mechanism and selectivity of radical halogenation is only half the story. You also need to know when these reactions are actually useful in synthesis and what happens to the stereochemistry of the product. Section 3.7 lays out practical guidelines for when chlorination or bromination gives you a clean, useful product and when it gives you a mess. Section 5.7 then asks the deeper question: if a new stereocentre is created during a radical reaction, do you get one stereoisomer or a mixture? The answer depends entirely on the geometry of the radical intermediate and whether a chiral centre already exists nearby. If you are not yet comfortable with chirality, enantiomers, and diastereomers, revisit those topics before reading on.
Chlorination is synthetically useful only when the substrate can produce just one monochlorinated product (high symmetry). Bromination is useful more broadly because of its high selectivity for the most substituted position. Stereochemically, a radical intermediate is sp2 and planar, so halogenation at that carbon destroys any existing stereocentre there, yielding a racemic product. If a nearby chiral centre survives the reaction, it can bias one face of attack, producing diastereoselectivity.
Racemic mixture (racemate)
A 50:50 mixture of two enantiomers. It shows zero optical rotation because the equal and opposite rotations cancel. Produced whenever a new stereocentre is created at an achiral (sp2, planar) intermediate with no nearby source of chirality. Think of it as: equal odds of attack from above and below a flat radical, so you get both mirror-image products in equal amounts.
Enantiopure
Describes a sample consisting of a single enantiomer. If the original stereocentre in a molecule is not disturbed during the reaction, the product at that position remains enantiopure. In simple terms, only one mirror-image form is present.
Stereoselective reaction
A reaction that produces one stereoisomer preferentially over others. Sub-types are enantioselective (favours one enantiomer) and diastereoselective (favours one diastereomer).
Enantiomeric transition state
Two transition states that are mirror images of each other and therefore equal in energy. Because they are equal in energy, they proceed at the same rate, giving a racemic mixture. This occurs when the radical intermediate is achiral.
Diastereomeric transition state
Two transition states that are not mirror images of each other and therefore differ in energy. The lower-energy pathway is favoured, so one diastereomer forms preferentially. This occurs when a surviving chiral centre near the radical makes the two faces of attack inequivalent.
When is chlorination useful?
Chlorination gives a useful product only when a single monochlorinated compound can form. This typically requires a molecule where all hydrogens are equivalent (e.g., cyclohexane, neopentane) or where only one type of C–H bond exists.
Example: chlorination of a symmetrical cycloalkane with only one type of hydrogen gives a single product in high yield.
If the substrate has multiple types of C–H bonds, chlorination produces a mixture that is often not synthetically useful because chlorine's selectivity is too low to give one product cleanly.
When is bromination useful?
Bromination is useful whenever you want halogenation at the most substituted position, because bromine is so selective that it reacts almost exclusively at 3° > 2° > 1°.
Bromination occurs only at the most substituted C that bears a hydrogen. If a molecule has one 3° C–H, bromination will target it almost exclusively.
This section tackles what happens to the three-dimensional arrangement of atoms when a radical reaction creates or destroys a stereocentre.
Core principle: The carbon radical intermediate is sp2-hybridised and planar. This has two major consequences:
If the radical forms at a carbon that was a stereocentre, the original stereochemistry at that carbon is destroyed (the planar radical is achiral at that position).
If the halogen then attacks the planar radical to create a new stereocentre, both faces of the radical are equally accessible (unless something nearby makes them different), giving a racemic mixture.
Starting material is achiral. The radical intermediate is achiral (sp2, planar).
Halogen can attack from the top face or bottom face with equal probability.
The two transition states are enantiomeric (mirror images, equal energy).
Result: racemic mixture, no optical activity.
Example: bromination of an achiral alkane that creates a new stereocentre gives a 50:50 mix of R and S products.
Consider a substrate with an existing stereocentre that undergoes chlorination. The stereochemical outcome depends on where the reaction occurs relative to that stereocentre.
Reaction at a carbon remote from the stereocentre (C1 or C4 products in the Baldwin example):
No new stereocentre is created at the site of halogenation.
The original chiral centre is undisturbed.
Product is enantiopure and optically active.
Reaction at the stereocentre itself (C2 product):
The radical forms at the chiral carbon, making it sp2 and planar.
The original stereochemistry is destroyed.
The radical intermediate is achiral at that position.
Halogen attacks from both faces equally.
Result: racemic mixture at that carbon.
Reaction at a carbon adjacent to the stereocentre (C3 product):
A new stereocentre is created, while the original one is preserved.
The surviving chiral centre makes the two faces of the radical inequivalent.
The two transition states are diastereomeric (not mirror images), so they differ in energy.
The lower-energy transition state is favoured.
Result: one diastereomer predominates (diastereoselectivity). In the Baldwin example, the C3 products form in a 75:25 ratio.
Because the products are diastereomers (not enantiomers), they have different physical properties and can be separated.
The radical carbon is sp2-hybridised, meaning it and its three substituents lie in one plane with the half-filled p orbital sticking out above and below. If there is nothing else in the molecule to distinguish "above" from "below," both faces are identical. Equal-energy transition states give equal rates, hence a 50:50 product mix.
To obtain enantioselectivity (preference for one enantiomer), you need a chiral source in the reaction. This can be a chiral catalyst that interacts with the transition state and makes one face of attack lower in energy than the other.
A chiral catalyst creates an energy difference between the two enantiomeric transition states, converting them into diastereomeric transition states (which are no longer equal in energy).
The degree of preference is measured as enantiomeric excess (ee).
Stereochemical decision tree for radical halogenation:
Is the radical intermediate achiral (no stereocentre anywhere in the molecule)? → Racemic mixture.
Is the radical formed at an existing stereocentre? → Stereocentre destroyed → racemic at that position.
Is the radical formed adjacent to an existing stereocentre (stereocentre preserved)? → Diastereomeric transition states → diastereoselective product.
Is the radical formed remote from any stereocentre? → Original stereocentre preserved → enantiopure product.
Stereocontrol in radical reactions matters in pharmaceutical synthesis, where the wrong enantiomer of a drug can be inactive or harmful. Chemists use chiral catalysts and chiral auxiliaries to bias radical reactions toward a single stereoisomer. The principle that a planar intermediate gives a racemic product is not limited to radicals; it also applies to sp2 carbocation intermediates in SN1 reactions and to enolate chemistry, so understanding it here pays dividends across organic chemistry.
Students often assume that if a product has a stereocentre, the reaction must be stereoselective. That is not the case. If the intermediate is achiral, you get a racemic mixture regardless of whether the product is chiral.
A common error is forgetting that the radical is planar (sp2). Students sometimes draw a tetrahedral radical and then wonder why the stereochemistry does not work out.
Some students confuse enantiomeric transition states with diastereomeric transition states. Enantiomeric TS's are equal in energy (racemic product). Diastereomeric TS's differ in energy (one product favoured).
Students sometimes think that all positions on a chiral molecule give enantiopure products. Only positions where the original stereocentre is untouched give enantiopure products. If the reaction occurs at the stereocentre, it is destroyed.
⚠️ Expect a problem where you are given a chiral starting material, asked to identify the site of halogenation, and then predict whether the product is enantiopure, racemic, or a diastereomeric mixture. Use the decision tree above.
⚠️ Be able to explain why a planar, sp2 radical intermediate leads to a racemic mixture in the absence of a nearby chiral influence.
⚠️ Know the difference between enantiomeric and diastereomeric transition states and be able to draw them.
⚠️ Understand that diastereomers have different physical properties and can be separated, while enantiomers cannot be separated by ordinary means.
⚠️ The concept of using a chiral catalyst to convert enantiomeric TS's into diastereomeric TS's is a recurring theme. Recognise it here and you will see it again in asymmetric synthesis topics.
True or false: A radical intermediate at a carbon that was previously a stereocentre retains the original configuration.
Fill in the blank: Two transition states that are mirror images of each other and equal in energy are called __________ transition states.
True or false: Bromination of an achiral substrate that creates a new stereocentre will give an enantiopure product.
Fill in the blank: Chlorination is synthetically useful only when the substrate can give a __________ monochlorinated product.
True or false: Diastereomers have different physical properties and can be separated by standard techniques.
Answers: 1. False (the radical is sp2 and planar, so the original configuration is lost). 2. Enantiomeric. 3. False (it gives a racemic mixture). 4. Single. 5. True.
Q: A student brominated an achiral alkane and obtained a product with a new stereocentre. The student measured zero optical rotation. Explain why.
A: The starting material was achiral and the radical intermediate was sp2 and planar (achiral). Both faces of the radical were equally accessible, so the R and S enantiomers formed in equal amounts, giving a racemic mixture with no net optical rotation.
Q: In the chlorination of (S)-2-bromobutane, the C2 product is racemic while the C1 product is enantiopure. Explain the difference.
A: At C2, the radical forms at the existing stereocentre, making it sp2 and planar. The original configuration is destroyed, and the halogen attacks both faces equally, giving a racemic product. At C1, the radical does not form at the stereocentre. The original chiral centre at C2 is preserved throughout, so the product retains its configuration and is enantiopure.
Q: The chlorination of (S)-2-bromobutane at C3 gives two diastereomeric products in a 75:25 ratio. Why is the mixture not 50:50?
A: A new stereocentre is created at C3 while the original stereocentre at C2 is maintained. The surviving chiral centre at C2 makes the two faces of the planar radical at C3 inequivalent. The two transition states are diastereomeric (different in energy), so the lower-energy pathway is favoured, giving unequal amounts of the two diastereomers.
Q: How could you convert a radical halogenation that gives a racemic mixture into one that gives predominantly one enantiomer?
A: Introduce a chiral source into the reaction, such as a chiral catalyst. The catalyst interacts with the transition state and makes one face of attack energetically more favourable than the other. This converts the enantiomeric transition states into diastereomeric ones, favouring the formation of one enantiomer and producing an enantiomeric excess.
The stereochemical principles here carry directly into SN1 reactions (Ch. 7), where a planar carbocation intermediate also gives racemic products from achiral substrates. Diastereoselectivity returns in addition reactions to alkenes (Ch. 8–9) and in aldol chemistry (later courses). The idea that a chiral catalyst can break the symmetry of enantiomeric transition states is the foundation of asymmetric catalysis, one of the most important areas in modern synthetic chemistry.
stereochemistry, stereoselective reaction, enantioselective, diastereoselective, racemic mixture, racemate, enantiopure, optically active, sp2 radical, planar intermediate, enantiomeric transition state, diastereomeric transition state, face of attack, top face, bottom face, chiral catalyst, enantiomeric excess, ee, radical halogenation stereochemistry, chlorination, bromination, synthetic utility, CHEM 2510, organic chemistry chapter 3, chapter 5