Alkene Addition Pattern #2: The “Three-Membered Ring” Pathway

The “Three-Membered Ring” Pathway In Alkene Mechanisms: Halogenation, Oxymercuration, Halohydrin Formation, and Acidic Epoxide Opening

In the last post we walked through a proposal for how the bromination of alkenes works and showed that it adequately explains many of the experimental observations made for this reaction.

Namely, the reaction proceeds with anti addition of substituents across the alkene, and (where relevant) the reaction proceeds with “Markovnikov” regioselectivity. These observations are best explained through the intermediacy of a “bromonium ion”.

In this post we try to show that bromination is but one example of a whole family of reactions in introductory organic chemistry that pass through a positively charged three membered ring, including not just halogenation, but oxymercuration, halohydrin and haloether formation, and even addition to protonated epoxides.

Since all of these reactions follow the same pattern, if you learn any one of these mechanisms, you’ve essentially learned them all!

Table of Contents

1. Bromination of Alkenes: The Mechanism
2. Chlorination of Alkenes: Mechanism
3. Iodination of Alkenes: Mechanism
4. Chlorohydrin Formation: Mechanism
5. Haloether Formation: Mechanism
6. Chlorohydrin Formation With NBS: Mechanism
7. Oxymercuration Of Alkenes: Mechanism
8. Oxymercuration: The Reduction Step
9. A Non-Obvious Cousin Of Halonium Ions: Protonated Epoxides
10. Summary: The Key Pattern Of The “Three-Membered Ring Pathway”
11. Notes
12. (Advanced) References and Further Reading

1. Bromination of Alkenes: The Mechanism

This is just a review of what we saw in the previous post. Treating an alkene with Br₂ results in a vicinal dibromide with the two bromines oriented anti to each other. The key intermediate is a “bromonium ion”, which contains a positively charged 3-membered ring.

Taking bromination of alkenes as a starting point, we might ask: “do variants of this mechanism operate for other reactions of alkenes as well?”

The answer is yes!

2. Chlorination of Alkenes: The Mechanism

Take, for example, the chlorination  of alkenes. The products of this reaction has identical patterns of stereoselectivity and regioselectivity to those of bromination. Therefore we might surmise that they proceed through the same type of reaction intermediate! [This intermediate is called the “chloronium ion”]

3. Iodination of Alkenes: The Mechanism

This is also the case for iodination reactions, which proceed through the “iodonium ion”:

4. Chlorohydrin Formation: The Mechanism

This also applies to reactions where the intermediate chloronium ion is trapped with solvent (water in this case). After deprotonation of R–OH+ to give R–OH,  the product is referred to as a “chlorohydrin”.

Note that bromohydrin and iodohydrin formation work exactly the same way and if you merely replace “Cl” with either of those halogen atoms you’ll obtain the indicated product.

5. “Haloether” Formation: The Mechanism

As described in the last few posts, what’s notable about bromination is that by using a solvent which can act as a nucleophile, we can obtain products which incorporate that solvent. For example by using an alcohol as solvent, we obtain the following “chloroetherification” product. It likewise proceeds through the exact same mechanism described above.

Furthermore, these reaction pathways are not confined to the dihalogens Cl₂, Br₂, and I₂ [nor F₂, the Tiger of Chemistry, which is a very difficult beast to keep on its leash]. And a good thing too, since Cl₂ and Br₂ are to various extents vile and inconvenient to work with.

6. Chlorohydrin Formation Using N-Chloro Succinimide

A convenient source of “electrophilic” chlorine is the crystalline salt N-chlorosuccinimide (NCS), an innocuous appearing white crystalline solid. Alkenes react rapidly with NCS to form chloronium ions, which can then be intercepted to form a variety of useful products by analogy to those shown above. With the exception of this more convenient source of halogen, the reaction is otherwise the same. N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS) likewise find use.

Moving beyond the halogens, are there other reagents that form these cyclic intermediates? Why, yes indeed.

7. Oxymercuration: The Mechanism

When alkenes are treated with mercury (II) salts (such as mercuric acetate) in the presence of water or alcohols, we obtain products with the same pattern of stereochemistry and regiochemistry that we’re accustomed to seeing by now. What’s a likely intermediate here? A three-membered ring called the “mercurinium ion”.

8. Oxymercuration: The Reduction Step

Organomercury compounds find very little application in themselves, but can be used as intermediates in subsequent reactions. To replace mercury with hydrogen, sodium borohydride (NaBH₄) is added. In this case,  rather than being “anti” , the stereochemistry of this reaction ends up being a wash: treatment with NaBH₄ leads to cleavage of the C-Hg bond and formation of a free radical. The free radical can react from either face with hydrogen, leading to scrambling of the stereocenter.

To see a plausible mechanism, hover here or click this link.

How many other reactions go through this type of mechanism? There is actually a sizable list. For instance, there are electrophilic sources of sulfur and selenium that can likewise form three membered cationic rings just like those we’ve seen; we won’t go into those.

9. A Non-Obvious Cousin: Protonated Epoxides

One last example that is worth going into is one that might not immediately seem obvious: protonated epoxides.

Treatment of an epoxide with acid leads to a positively charged intermediate that resembles a bromonium ion. As you might guess, the nucleophile attacks the backside of the most substituted carbon and the resulting product has anti stereochemistry. Just as we’ve seen numerous times above.

10. Summary: The Key Pattern Of The “Three-Membered Ring Pathway”

Do some of the images in this post look repetitive? They should!

The lesson for this very long post from today is that one can group together a sizable number of different reactions by identifying their common mechanism. Just as there is a family of reactions that pass through the carbocation pathway, there is likewise a “family” of reactions that pass through a three-membered ring.  Instead of learning a dozen different mechanisms, we merely learn one – and merely change the actors to suit the occasion.

NEXT POST – Hydroboration of Alkenes

Notes

Note 1.  Besides the dihalides, there are also such things as mixed dihalides, such as iodine monochloride. We have all the tools at our disposal to answer how this reaction might proceed. What do you think the product is?

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(Advanced) References and Further Reading

This is a common mechanism for several reactions, including halogenation, halohydrin formation, and oxymercuration.

Halogenation:

1. The Halogenation of Ethylenes
   Irving Roberts and George E. Kimball
   Journal of the American Chemical Society 1937, 59 (5), 947-948
   DOI: 1021/ja01284a507
   One of the earliest descriptions in the literature of a three-membered bromonium ion, accounting for the anti stereochemistry of this reaction.
2. Stable carbonium ions. LXII. Halonium ion formation via neighboring halogen participation: ethylenehalonium, propylenehalonium, and 1,2-dimethylethylenehalonium ions
   George A. Olah, J. Martin Bollinger, and Jean Brinich
   Journal of the American Chemical Society 1968, 90 (10), 2587-2594
   DOI: 1021/ja01012a025
   This is an early paper on the characterization by NMR of halonium (3-membered chloronium, iodonium, and bromonium) ions by ionization of 1,2-dihaloethanes in superacid medium (SbF₅/SO₂).
3. Investigation of the Early Steps in Electrophilic Bromination through the Study of the Reaction with Sterically Encumbered Olefins
   R. S. Brown
   Accounts of Chemical Research 1997, 30 (3), 131-137
   DOI: 10.1021/ar960088e
   An account by R. S. Brown describing the research he carried out in interrogating bromonium ion intermediates by a variety of methods.Mercuration:
4. Mechanism of the oxymercuration of substituted cyclohexenes
   Daniel J. Pasto and John A. Gontarz
   Journal of the American Chemical Society 1971, 93 (25), 6902-6908
   DOI: 1021/ja00754a035
   This paper demonstrates that “the oxymercuration of substituted cyclohexenes proceeds via mercurinium ion intermediates which are formed in fast, reversible pre-rate-determining step equilibria”.
5. Organometallic chemistry. IV. Stable mercurinium ions
   George A. Olah and Paul R. Clifford
   Journal of the American Chemical Society 1973, 95 (18), 6067-6072
   DOI: 1021/ja00799a038
   The above paper by Nobel Laureate Prof. G. A. Olah demonstrates the existence and intermediacy of mercurinium ions in these reactions via the s and p routes using NMR spectroscopy.
6. Solvomercuration-demercuration. 11. Alkoxymercuration-demercuration of representative alkenes in alcohol solvents with the mercuric salts acetate, trifluoroacetate, nitrate, and methanesulfonate
   Herbert C. Brown, Joseph T. Kurek, Min Hon Rei, and Kerry L. Thompson
   The Journal of Organic Chemistry 1984, 49 (14), 2551-2557
   DOI: 1021/jo00188a007
   While Hg(OAc)₂ is the most commonly used reagent for this purpose, the trifluoroacetate, trifluoromethanesulfonate (triflate), or nitrate salts are more reactive and may be preferable for certain applications.
7. Mechanism of reduction of alkylmercuric halides by metal hydrides
   George M. Whitesides and Joseph San Filippo Jr.
   Journal of the American Chemical Society 1970, 92 (22), 6611-6624
   DOI: 1021/ja00725a039
   The reduction (demercuration) step is complex and involves free radicals. This paper by Prof. Whitesides (MIT, now at Harvard) studies the mechanism of this reduction, which is mentioned inside.