Free Radical Reactions
Last updated: September 15th, 2020 |
Allylic Bromination and Benzylic Bromination: What Is It, And How Does It Work?
In previous posts on radicals, we’ve seen how bromine can selectively react with tertiary C-H bonds (bond strength 93 kcal/mol) over secondary (96 kcal/mol) and primary (100 kcal/mol) C–H bonds.
If you recall that bond dissociation energies are a good guide for predicting radical stability, then you won’t be surprised to learn that “benzylic” and “allyllic” C–H bonds can also be brominated selectively. These C-H bonds are particularly weak because the radical formed through the homolytic breaking of C-H is stabilized by resonance.
Table of Contents
- Allylic and Benzylic Bromination: Examples
- Free Radicals Are Stabilized By Resonance
- The Mechanism of Benzylic Bromination With Br2 and Light/Heat
- Br2 Is Not An Appropriate Reagent For Allylic Bromination Since It Forms Vicinal Dibromides
- Using N-Bromo Succinimide (NBS) Ensures A Low Concentration Of Br2
- (Advanced) References and Further Reading
So what is allylic and benzylic halogenation, anyway? Here’s an example of each.
Take toluene and treat with either Br2 in the presence of light, as per this procedure, or N-Bromosuccinimide (NBS) in the presence of a radical initiator + heat (or light) and one of the benzylic C–H bonds is replaced with C–Br.
(Note that the “benzylic” position is the carbon attached to the benzene ring; the C-H bonds of the benzene ring itself are the “phenyl” C-H bonds).
Here’s an example of the allylic bromination of propene, this time using NBS and peroxides (or heat)
We’ve spent a considerable amount of time discussing the stability of free radicals, particularly that primary radicals are particularly unstable.
So what’s different in this case? And what’s this “NBS” stuff?
Recall that free radicals are stabilized by resonance, and bond dissociation energies (BDE’s) aka “bond strengths” measure homolytic bond cleavage.
So the methyl groups (above) aren’t ordinary methyl groups – the resulting radicals are greatly stabilized by resonance!
Therefore when we look at bond dissociation energies for benzylic and allylic C–H bonds it should not be surprising to find that these bond strengths are quite weak (89-90 kcal/mol for a primary allylic or benzylic radical) relative to tertiary C-H bonds (93 kcal/mol).
So how might allylic or benzylic bromination work?
For benzylic bromination, hopefully imagining the mechanism will be straightforward: after initiation (by heat or light), bromine radical then breaks the C-H bond (forming the benzylic radical) [propagation step #1] and the benzylic radical attacks Br2 to re-generate bromine radical [propagation step #2]. These two steps repeat until the concentration of Br2 runs low, whereupon radical chain termination will occur.
Let’s turn to allylic bromination. Do you see any reason why treating the molecule below with Br2 might lead to problems?
You might recall that alkenes react with Br2 to form vicinal dibromides, and that is in fact exactly what would occur if we were to just dump in 1 equivalent of Br2 with an alkene.
At issue here is the fact that we have 1 equivalent of Br2 swimming around, of which only a small proportion at any given time will exist as bromine radical [due to the initiation step].
How might we solve this problem and favour the radical substitution over the dibromination?
Imagine, if you will, we had a very low concentration of Br2. If the concentration of Br2 is kept low, not only will the rate of dibromination be lower, the relative concentration of bromine radical relative to Br2 will increase. Therefore, the rate of C-H abstraction relative to dibromination will increase, which will allow our allylic bromination product to be formed in a higher yield. *
Of course, this creates a new question: how do we generate a low, constant concentration of Br2?
As it turns out, there’s a way. If the bromonium ion source N-bromosuccinimide (NBS) is present with a trace amount of acid (HBr), HBr will react with NBS to give succinimide and Br2.**
Since one equivalent of HBr generates one equivalent of Br2, Br2 will be generated only after the completion of Propagation Step #1.*** This keeps the concentration of Br2 low and allows the free-radical reaction to out-compete the alkene addition reaction.
In all other respects the allylic bromination reaction is identical to the benzylic bromination reaction mechanism shown above. However in *some* situations there is an extra twist, which we will briefly discuss in the next post.
Next Post: Allylic Rearrangement
* If this explanation sounds somewhat unsatisfactory, you’re on to something. After all, doesn’t this decrease the concentration of Br• as well? One additional complication is that theoretical studies show strong evidence for a termolecular rate determining step in formation of the bromonium ion (that is, involvement by the alkene and two molecules of Br2). Decreasing the concentration of Br2 would therefore vastly decrease the rate of bromonium ion formation (and thus dibromination) relative to free radical halogenation.
** As it happens, NBS which has been left out for awhile will usually be contaminated with trace HBr (as well as Br2, which gives it a yellow or orange colour). For this reason if doing a radical reaction with NBS it’s common to avoid recrystallizing it before use, as it will remove the trace acid that jump starts the reaction in the first place.
*** As long as the initial concentration of HBr is low (i.e. it is used as a catalyst)
Allylic bromination with NBS is sometimes called the Wohl-Ziegler reaction.
- Die Synthese des Cantharidins.
Ziegler, K., Schenck, G., Krockow, E.W., Siebert, A., Wenz, A. and Weber, H. (1942),
Justus Liebigs Ann. Chem., 551: 1-79.
Ziegler’s report on using NBS for allylic bromination, from 1942.
- Brominations with N-Bromosuccinimide and Related Compounds. The Wohl-Ziegler Reaction.
Chemical Reviews 1948 43 (2), 271-317
An early but useful review of allylic bromination by Prof. Carl Djerassi (Stanford), who made many important contributions to steroid chemistry.
- Laws of Addition and Substitution in Atomic Reactions of Halogens
ADAM, J., GOSSELAIN, P. & GOLDFINGER, P. .
Nature 171, 704–705 (1953).
The “Goldfinger Mechanism” for allylic bromination, which proposed that NBS serves to provide a low concentration of Br2. Earlier proposed mechanisms involved the succinimidyl radical as the chain carrier, which is incorrect. It should be noted that addition of Br• to alkenes *does* occur to some extent, but the reaction is reversible, and if Br2 and HBr concentrations are kept low, any addition product will revert to the starting alkene.
- THE HIGH-TEMPERATURE CHLORINATION OF OLEFIN HYDROCARBONS
FREDERICK F. RUST and WILLIAM E. VAUGHAN
The Journal of Organic Chemistry 1940 05 (5), 472-503
An early, key observation. Rust and Vaughn found that addition of Cl2 to alkenes is favored at low temperatures, whereas at higher temperatures allylic substitution dominates.
- The Ratio of Substitution to Addition in the Reaction of Chlorine with Olefins in Dilute Carbon Tetrachloride Solution
T. D. Stewart, Kenneth Dod, and George Stenmark
Journal of the American Chemical Society 1937 59 (9), 1765-1766
An important piece of the puzzle to figuring out the mechanism for allylic halogenation, from 1937. Allylic substitution is favored over addition at lower concentrations of halogen (Cl2).
- Mechanisms of Benzylic Bromination
Glen A. Russell, Charles. DeBoer, and Kathleen M. Desmond
Journal of the American Chemical Society 1963 85 (3), 365-366
Benzylic bromination follows the same mechanism as allylic bromination, as this paper explains.NBS (N-Bromosuccinimide) is a convenient reagent for free-radical bromination, and the following papers are mechanistic studies involving NBS:
- The Mechanism of Benzylic Bromination with N-Bromosuccinimide
E. Pearson and J. C. Martin
Journal of the American Chemical Society 1963 85 (3), 354-355
These papers by Prof J. C. Martin (UIUC) were early in his career, before he did the work that he is most well-known for (studies on ‘hypervalent’ molecules, including the development of the ‘Dess-Martin Periodinane’).
- The Identity of the Chain-Carrying Species in Brominations with N-Bromosuccinimide: Selectivity of Substituted N-Bromosuccinimides toward Substituted Toluenes
E. Pearson and J. C. Martin
Journal of the American Chemical Society 1963 85 (20), 3142-3146
- N-bromosuccinimide. Mechanisms of allylic bromination and related reactions
H. Incremona and James Cullen Martin
Journal of the American Chemical Society 1970 92 (3), 627-634
- Radical Bromination of Cyclohexene in CCl4 by Bromine: Addition versus Substitution
W. McMillen and John B. Grutzner
The Journal of Organic Chemistry 1994 59 (16), 4516-4528
This paper describes careful kinetic studies that demonstrate that a low concentration of Br2 (such as that provided by impure NBS) will favor radical substitution over a polar addition reaction.
L. Greenwood, M. D. Kellert, and J. Sedlak
Org. Synth. Vol. 38, p.8 (1958).
A reliable procedure for allylic bromination with NBS in Organic Syntheses.
- o-XYLYLENE DIBROMIDE
Emily F. M. Stephenson
Org. Synth. Vol. 34, p.100 (1954)
A reliable procedure for benzylic bromination with Br2 in Organic Syntheses.
- The evolution of free radical chemistry at Chicago
Frank R. Mayo
Journal of Chemical Education 1986 63 (2), 97
For those interested in the history of science, this retrospective by Mayo tells the story of how he and Kharasch discovered the ‘peroxide effect’ and thereby a new area of organic chemistry.