10.7: Additions involving cyclic intermediates
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10.7.1. Reaction of alkenes with carbenes – cyclopropanation
The highly strained nature of cyclopropane compounds makes them very reactive and interesting synthetic targets. Additionally cyclopropanes are present in many biological compounds. One common method of cyclopropane synthesis is the reaction of carbenes with the double bond in alkenes or cycloalkenes. Methylene, H2C, is the simplest carbene, and in general carbenes have the formula R2C. Other species that will also react with alkenes to form cyclopropanes but do not follow the formula of carbenes are referred to as carbenoids.
Carbenes were once only thought of as short lived intermediates. The reactions of this section only deal with these short lived carbenes which are mostly prepared in situ, at the time of the main reaction. However, there do exist so called persistent carbenes, which are stabilized by a variety of methods often including aromatic rings or transition metals. In general a carbene is neutral and has six valence electrons, two of which are non bonding. These electrons can either occupy the same sp2 hybridized orbital to form a singlet carbene (with paired electrons), or two different sp2 orbitals to form a triplet carbene (with unpaired electrons), but we will focus exclusively on the more common singlet carbenes.
The reactivity of a singlet carbene is concerted and similar to that of electrophilic or nucleophilic addition. The highly reactive nature of carbenes leads to very fast reactions in which the rate determining step is generally carbene formation.
Preparation of methylene (:CH2)
The preparation of methylene starts with the yellow gas diazomethane, CH2N2. Diazomethane can be exposed to light, heat or copper to facilitate the loss of nitrogen gas and the formation of the simplest carbene methylene. The process is driven by the formation of the nitrogen gas which is a very stable molecule.
Carbene reaction with alkenes
A carbene such as methylene will react with an alkene which will break the double bond and result with a cyclopropane. The reaction will usually leave stereochemistry of the double bond unchanged. As stated before, carbenes are generally formed during the reaction; hence the starting material is diazomethane not methylene.
In the above case cis-2-butene is converted to cis-1,2-dimethylcyclopropane. Likewise, below the trans configuration is maintained.
In addition to the general carbene with formula R2C: there exist a number of other compounds that behave in much the same way as carbenes in the synthesis of cyclopropane derivatives. Halogenatedcarbenes such as dichlorocarbene, Cl2C:, are more stable than simple alkyl carbenes. Dichlorocarbene can be conveniently prepared from chloroform (CHCl3) with base in the presence of a phase transfer catalyst:
These halogenated carbenes form cyclopropanes in the same manner as methylene:
1. Knowing that cycloalkenes react much the same as regular alkenes what would be the expected structure of the product of cyclohexene and diazomethane facilitated by copper metal?
2. What would be the result of a reaction of diazomethane with trans-3-pentene in the presence of light?
3. What starting material could be used to form cis-1,2-diethylcyclopropane?
4. What would the following reaction yield?
1. The product will be a bicyclic ring, Bicyclo[4.1.0]heptane.
2. The stereochemistry will be retained making a cyclopropane with trans methyl and ethyl groups. Trans-1-ethyl-2-methylcyclopropane
3. The cis configuration will be maintained from reagent to product so we would want to start with cis-3-hexene. DIazomethane would be the carbene source, with methylene as the carbene.
4. The halogenated carbene will react the same as methylene yielding, cis-1,1-dichloro-2,3-dimethylcyclopropane.
- Vollhardt, K. Peter C. and Schore, Neil E. Organic Chemistry: Structure and Function. New York: Bleyer, Brennan, 2007.
- Abdel-Wahab, Aboel-Magd A. Ahmed, Saleh A. and Dürr, Heinz. “Carbene Formation by Extrusion of Nitrogen” in CRC Handbook of Organic Photochemistry and Photobiology. CRC Press, 2004.
- Karty, J. Organic Chemistry: Principles and Mechanisms, First Edition. W. W. Norton, 2014.
Chemtube3D: Stereoselective Cyclopropanation
10.7.2. Addition of halogens (Cl2 or Br2) to alkenes
Halogen molecules such as Cl2 and Br2 also add to alkene double bonds. Here we need not be concerned with orientation since the two ends of the adding molecule are identical, but the electrophilic addition mechanism helps us understand another characteristic of this reaction, its stereochemistry.
If bromine is added to cyclopentene, we might anticipate two products which differ in how the bromine atoms are geometrically related to each other. If the two bromines are on the same face of the ring, the compound is called cis. If they are on opposite faces, the compound is called trans. The experimental result is that only the trans product is formed.
One of the bromine atoms is acting as an electrophile. If we apply the usual mechanism, its first step it would go like this:
As we learned in our study of SN1 reactions, carbocations are attacked by nucleophiles on both faces. If a carbocation is present in this system, we’d expect to find both the cis and trans products.
This is not what happens when the experiment is done, so we conclude that the carbocation is not present, or it reacts immediately to form a new cation. Something is happening which prevents the nucleophilic bromide ion from attacking the face of the carbocation which already is attached to the first bromine. We understand that by envisioning that the electrophilic bromine atom attaches itself to both alkene carbon atoms. One bond is made using the electrons from the pi bond, and the other is made using an unshared electron pair from the bromine. This results in a new ring formed from the bromine and the two alkene carbon atoms. It is called a “bromonium” ion. Note that the mechanism for forming the three-membered ring has some parallels with cyclopropanation, described above.
Attack by the nucleophilic bromide ion on the bromine in this ring would only result in cyclopentene and bromine, so no reaction would occur. Attack by the bromide ion on the either of the alkene carbons would be like an SN2 reaction. The attacked carbon would invert, and the product would have the trans configuration. (Notice that there are two such products, which are enantiomers, so we get a racemic mixture.)
Khan Academy on alkene halogenation:
The simple addition of water to alkenes using H2SO4 and H2O is straightforward, but it can suffer from side reactions that reduce the yield, such as carbocation rearrangements. In such cases, one alternative us to use a more complex method, oxymercuration-demercuration, which nevertheless gives usually a cleaner reaction. It does, however, involve the use of toxic mercury reagents – in this case, mercury(II) acetate, written as Hg(OAc)2.
This reaction involves a mercury(II) compound acting as an electrophile, which is attacked by the alkene double bond to form a mercurinium ion bridge. A water molecule will then attack the more substituted carbon to open the mercurinium ion bridge, followed by proton transfer to a solvent water molecule.
The organomercury intermediate is then reduced by sodium borohydride – the mechanism for this final step is beyond the scope of our discussion here, but the H simply replaces the Hg group with retention of stereochemistry. The H that is introduced is shown explicitly.
Notice that overall, the oxymercuration – demercuration mechanism follows Markovnikov’s regioselectivity with the OH group attached to the more substituted carbon and the H attached to the less substituted carbon. The reaction is also stereoselective, in that the H and the OH are added exclusively anti to one another. The reaction is useful because strong acids are not required, and carbocation rearrangements are avoided because no discrete carbocation intermediate forms. However, it does require the use of highly toxic mercury compounds.
- Vollhardt, K. Peter C. Organic chemistry structure and function. New York: W.H. Freeman, 2007.
- Smith, Michael B., and Jerry March. March’s Advanced Organic Chemistry Reactions, Mechanisms, and Structure (March’s Advanced Organic Chemistry). New York: Wiley-Interscience, 2007 2007.
- Roderic P. Quirk , Robert E. Lea, Reductive demercuration of hex-5-enyl-1-mercuric bromide by metal hydrides. Rearrangement, isotope effects, and mechanism, J. Am. Chem. Soc., 1976, 98 (19), pp 5973–5978.
Some Practice Problems
What are the end products of these reactants?
The end product to these practice problems are pretty much very similar. First, you locate where the double bond is on the reactant side. Then, you look at what substituents are attached to each side of the double bond and add the OH group to the more substituent side and the hydrogen on the less substituent side.
In each case, predict the product(s) of these reactants of oxymercuration.
Propose the alkene that was the reactant for each of these products of oxymercuration.
- Wikipedia: Oxymercuration Reaction
- Carey 5th Ed Online: Oxymercuration-Demercuration
- Leah4Sci: Oxymercuration-Demercuration
10.7.4. Epoxide formation
Epoxide, also called oxiranes, are useful reagents that may be opened by further reaction to form anti vicinal diols. One way to synthesize epoxides is through the reaction of an alkene with a peroxycarboxylic acid such as MCPBA.
The peroxycarboxylic acid has an unusual property of having an electrophilic oxygen atom on the COOH group. The reaction is initiated by the electrophilic oxygen atom reacting with the nucleophilic carbon-carbon double bond. The mechanism involves a concerted reaction with a four-part, circular transition state. The result is that the originally electrophilic oxygen atom ends up in the epoxide ring and the C(O)OOH group becomes C(O)OH.
Peroxycarboxylic acids are generally unstable. One stable example is meta-chloroperoxybenzoic acid, shown in the mechanism below. Often abbreviated MCPBA, it is a stable crystalline solid that is popular for laboratory use. However, MCPBA can be explosive under some conditions.
Peroxycarboxylic acids are sometimes replaced in industrial applications by monoperphthalic acid, or the monoperoxyphthalate ion bound to magnesium, which gives magnesium monoperoxyphthalate (MMPP). In either case, a nonaqueous solvent such as dichloromethane, ether, acetone, or dioxane is used. This is because in an aqueous medium with any strong acid or base catalyst present, the epoxide ring is hydrolyzed to form a vicinal diol, a molecule with two OH groups on neighboring carbons. (For more explanation of how this reaction leads to vicinal diols, see below.) However, in a nonaqueous solvent, the hydrolysis is prevented and the epoxide ring can be isolated as the product. Reaction yields from this reaction are usually good. The reaction rate is affected by the nature of the alkene, with more nucleophilic double bonds resulting in faster reactions.
Since the transfer of oxygen is to the same side of the double bond, the resulting oxacyclopropane ring will have the same stereochemistry as the starting alkene. A good way to think of this is that the alkene is rotated so that some constituents are coming forward and some are behind. Then, the oxygen is inserted on top. (See the product of the above reaction.) One way the epoxide ring can be opened is by an acid catalyzed oxidation-hydrolysis. Oxidation-hydrolysis gives a vicinal diol, a molecule with OH groups on neighboring carbons. For this reaction, the dihydroxylation is anti since, due to steric hindrance, the ring is attacked from the side opposite the existing oxygen atom. Thus, if the starting alkene is trans, the resulting vicinal diol will have one S and one R stereocenter. But, if the starting alkene is cis, the resulting vicinal diol will have a racemic mixture of S, S and R, R enantiomers.
- Royals, E. 1954. Advanced Organic Chemistry. New York: Prentice Hall. 948 p.
- Streitwieser, A. and C. Heathcock. 1981. Introduction to Organic Chemistry. 2nd ed. New York: Macmillan Publishing Co. 1258 p.
- Vollhardt, K. and N. Schore. 2007. Organic Chemistry: Structure and Function. 5th ed. New York: W.H. Freeman and Company. 1254 p.
- Wheland, G. 1949. Advanced Organic Chemistry. 3rd ed. New York: John Wiley & Sons. 871 p.
1. Predict the product of the reaction of cis-2-hexene with MCPBA (meta-chloroperoxybenzoic acid)
a) in acetone solvent.
b) in an aqueous medium with acid or base catalyst present.
2. Predict the product of the reaction of trans-2-pentene with MMPP in CH2Cl2 solvent.
3. Predict the product of the reaction of trans-3-hexene with MCPBA in ether solvent.
4. Predict the reaction of propene with MCPBA.
a) in acetone solvent
b) after aqueous acidic work-up.
5. Predict the reaction of cis-2-butene in dichloromethane solvent.
1. a) Cis-2-methyl-3-propyloxacyclopropane
b) Racemic (2R,3R)-2,3-hexanediol and (2S,3S)-2,3-hexanediol
4. a) 1-ethyl-oxacyclopropane
b) Racemic (2S)-1,2-propandiol and (2R)-1,2-propanediol
- Carey 5th Ed Online: Epoxidation of Alkenes
- Leah4Sci: Alkene Epoxidation
- Chemtube3D: Oxidation of alkenes to form epoxides
- Rewrite of several sections from Libretexts, notably oxymercuration-demercuration. Authored by: Martin A. Walker. Provided by: SUNY Potsdam. License: CC BY-SA: Attribution-ShareAlike
- 11.3.5 Cyclopropanation of Alkenes. Authored by: Paul Tisher. Located at: https://chem.libretexts.org/LibreTexts/Purdue/Purdue%3A_Chem_26605%3A_Organic_Chemistry_II_(Lipton)/Chapter_11.__Addition_to_pi_Systems/11.3%3A_Concerted_Additions/11.3.5_Cyclopropanation_of_Alkenes. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike
- 27: Electrophilic Additions. Authored by: Kirk McMichael (Washington State University). Located at: https://chem.libretexts.org/Textbook_Maps/Organic_Chemistry/Book%3A_Organic_Chemistry_-_A_%22Carbonyl_Early%22_Approach_(McMichael)/27%3A_Electrophilic_Additions#Halogen_Addition. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike
- 22.214.171.124: Oxymercuration. Authored by: Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University) Lance Peery (UCD), Duyen Dao-Tran Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) Jim Clark (Chemguide.co.uk) Prof. Steven Farmer (Sonoma State University). Located at: https://chem.libretexts.org/LibreTexts/Purdue/Purdue%3A_Chem_26605%3A_Organic_Chemistry_II_(Lipton)/Chapter_11.__Addition_to_pi_Systems/11.1%3A_Electrophilic_Addition/11.1.2_Electrophilic_Addition_to_Alkenes/126.96.36.199%3A_Oxymercuration. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike
- 11.3.6 Epoxidation of Alkenes. Authored by: Kristen Perano . Located at: https://chem.libretexts.org/LibreTexts/Purdue/Purdue%3A_Chem_26605%3A_Organic_Chemistry_II_(Lipton)/Chapter_11.__Addition_to_pi_Systems/11.3%3A_Concerted_Additions/11.3.6_Epoxidation_of_Alkenes. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike
- 9:4 Hydroboration-Oxidation: A Stereospecific Anti-Markovnikov Hydration. Authored by: Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University) Prof. Steven Farmer (Sonoma State University) Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) Jim Clark (Chemguide.co.uk) William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry. Located at: https://chem.libretexts.org/LibreTexts/Winona_State_University/Klein_and_Straumanis_Guided/9%3A_Addition_Reactions_of_Alkenes/9%3A4_Hydroboration-Oxidation%3A_A_Stereospecific_Anti-Markovnikov_Hydration. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike