5.4 Carbon-Carbon Bond Forming Radical Reactions

Objectives  

After completing this section, you should be able to:

1. Understand radical reactions involved in carbon-carbon bond formation
2. Draw mechanisms incorporating radicals to explain reaction outcomes
3. Plan syntheses using radical reactions

Key Terms  

Make certain that you can define, and use in context, the key terms below.

• Radical initiation
• AIBN
• Radical propagation
• Bu₃SnH
• Radical termination

Study Notes  

Don't forget that all mechanisms in this chapter involve the movement of single electrons (radicals!), so we will use single-headed arrows in our mechanisms.

Content  

Initiation and Propagation Steps

Before getting into the actual radical reactions, we first need to comment on two key reagents: AIBN (AzobisIsoButyroNitrile) and Bu₃SnH (tributyltin hydride). We will use AIBN as our radical initiator and Bu₃SnH as the precursor for our chain propagating radical, tributyltin radical. Upon heating, AIBN cleaves to form nitrogen gas and two radicals that react with Bu₃SnH to yield two tributyltin radicals, as shown below. Tributyltin is our chain propagating radical, so these two radicals can each start a radical chain process (the propagation steps) resulting in the production of our desired molecule. Please remember a few key points about initiation and propagation steps: 1) We only need a small amount of the initiator to begin the chain process. Generally, 1 mol% of AIBN (0.01 equivalents) is sufficient to generate enough tributyltin radicals for the propagation steps. Although not a true catalyst, you can think about AIBN like the catalyst that must be present to make the chain reaction possible. 2) The chain propagating radical, tributyltin radical, must be a reactant in your first propagation step and a product in your last propagation step. Tributyltin radical looks a bit like a catalyst but it is different in a key way. Tributyltin hydride is consumed in the reaction and must be present in a stoichiometric amount (at least 1.0 equivalents) or the chain will be broken before all of the starting material reacts. Don't forget, the propagation steps are the only productive steps in a chain reaction. This is where your product is formed. 3) Termination steps break the chain and are undesired. In radical chain reactions, combining two radicals to form a new bond is never a productive reaction. Your product will never come from a termination step. These molecules are undesired byproducts and their formation must be very limited for the radical chain reaction to be synthetically useful.

Dehalogenation Reactions

Tributyltin hydride is a useful reagent for the dehalogenation (reduction) of alkyl halides. This illustrates a radical chain mechanism using tributyltin as the chain propagating radical. (As always, AIBN and tributyltin hydride combine in the initiation steps shown above to produce tributyltin radical.) Once the tributyltin radical is formed, it reacts to form a new Sn-Br bond by cleaving the C-Br bond to generate a carbon radical. This forms tributyltin bromide, a byproduct that must be removed after the reaction, and the new carbon radical that is part of our chain process. The carbon radical reacts with tributyltin hydride (remember, we have a very small amount of AIBN, just enough to start the process, and at least 1 equivalent of Bu₃SnH to react completely with the alkyl bromide starting material) to form the new C-H bond in the product and another molecule of tributyltin radical that can participate in another cycle of the chain process.

 

Carbon-Carbon Bond Forming Reactions

Radical chain reactions mediated by Bu₃SnH can also promote the formation of carbon-carbon bonds. These are among the most important radical reactions in synthetic chemistry since they provide us with another option in our toolbox of methods to make critical molecular connections. Key components in these reactions are a carbon-halogen bond that can react with the chain propagating tributyltin radical to generate a carbon radical that combines with an alkene or alkyne to form the new carbon-carbon bond. These reactions occur both inter- and intramolecularly with the latter being favored for higher yields and better regioselectivity. Radical reactions are kinetically controlled so they provide a very useful strategy for the synthesis of 5-membered rings. This is even true for most instances when selecting between the formation of 5- versus 6-membered rings in intramolecular cyclization reactions. (The smaller ring forms faster and, thus, is favored.) In intermolecular reactions, it is often helpful to have an electron poor alkene or alkyne as the radical partner to help favor regioselectivity with the (generally) more substituted radical formed in the first step. An example reaction and mechanism are shown below for a standard intermolecular carbon-carbon bond forming reaction. An intramolecular example is shown in the following problem.

Mechanism

Exercise \(\PageIndex{1}\)

For the following intramolecular C-C bond forming reaction, predict the product and propose a mechanism for its formation.

Answer

Like in our intermolecular example above, the tributyltin radical attacks the carbon-halogen bond to yield a carbon radical. This new radical participates in an intramolecular C-C bond forming reaction to form a 5-membered ring radical that reacts in the final step to form the product and regenerate the chain propagating radical. Note, because of ring strain, we won't form the 4-membered ring resulting from addition to the other side of the alkene.

Exercise \(\PageIndex{2}\)

Predict the product of the following reaction.

Answer

This problem highlights that radicals can easily form on sp² carbons and is a reminder that bond rotation is always important to consider. The key intermediate forms and reacts to yield the new 6-membered ring which forms faster than the 7-membered ring alternative.

Exercise \(\PageIndex{3}\)

One of the most powerful examples of the utility of carbon-carbon bond forming radical reactions in synthesis is Curran's synthesis of hirsutene published in 1985. The reaction below is the final step in the synthesis. Propose the structure of hirsutene and a mechanism for its formation.

Answer

DOI - https://doi.org/10.1021/ja00291a077

This follows the pattern we observed previously. The tin radical reacts with the iodide to form a carbon radical that reacts with the alkene to form a new 5-membered ring. The resulting tertiary radical reacts with the alkyne to form the third 5-membered ring in hirsutene. Note that the stereochemistry in the starting material determines the stereochemistry in the product. The alkyl chain coming out forms a new bond from above the initial 5-membered ring. The alkyl chain going back forms a new bond from beneath the initial 5-membered ring.

 

 

Contributors  

• Prof. Kevin Shea (Smith College)