4: Radical Reactions

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 (think Pd(0) in a Stille or Suzuki reaction) 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.

Barton-McCombie Deoxygenation

Similar to the dehalogenation reaction above, radical reactions can be used to remove an alcohol from a molecule, thus deoxygenating (reducing) the compound. We need to use some unusual chemistry to make the deoxygenation possible, specifically we need to form a xanthate, a functional group similar to a carbonate that contains two sulfur atoms. One of the sulfurs is part of a thio carbonyl (C=S) which is very reactive toward radical reactions and readily reacts with tributyltin radical to form a Sn-S bond and a carbon radical. To form the xanthate, we react the alcohol with potassium hydride to generate a negatively charged oxygen nucleophile. This reacts with carbon disulfide (the sulfur equivalent of carbon dioxide) and then methyl iodide to generate the xanthate intermediate. Once the xanthate is formed, it can react with tributyltin radical to participate in our radical chain reaction. The first step generates a new S-Sn bond and a carbon radical that decomposes to yield a dithiocarbonate ester (a byproduct that must be removed after the reaction) and a new carbon radical. At this point, the molecule has been successfully deoxygenated and the final step with tributyltin hydride completes the reaction by forming a C-H bond and regenerating the chain propagating tin radical.

Barton Decarboxylation

You likely learned about polar decarboxylation reactions in Intro Orgo. These reactions enable the removal of a carboxylic acid in a 1,3-carbonyl acid functional group. The second carbonyl positioned beta to the carboxylic acid carbonyl is critical in the mechanism (either acidic or basic conditions). These polar reactions do not work when the other carbonyl is absent. Thus, a decorboxylation reaction that doesn't require the presence of a second carbonyl at a specific position is highly valuable for synthetic chemists. This example highlights the importance of the Barton decarboxylation, a radical decarboxylation that is similar to the deoxygenation reaction shown above. It relies on a different reagent than the deoxygenation, so a xanthate ester isn't formed, but the steps are very similar, including reaction of tributyltin radical with a thiocarbonyl. In the problem below, you can propose a mechanism for this interesting reaction.

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

Non-Chain Radical Combination Reactions

Some highly useful radical reactions involve the combination of two radicals to form an important new bond. (These look like a termination step in a radical chain mechanism.) These reactions have become increasingly relevant as new and more mild methods for Hydrogen Atom Transfer (HAT) reactions have recently been developed. We will explore some classic examples in this class of radical reactions which you can then apply to understand more contemporary transformations. The Hofmann-Loeffler-Freytag reaction enables remote functionalization of a haloamine that ultimately results in the formation of a new pyrrolidine ring (saturated 5-membered ring containing N). The reaction and mechanism are shown below. The first step in the reaction is the radical portion of the mechanism. (The chloroamine can be formed by treating the amine with t-butyl hypochlorite (tBuOCl).) Light promotes homolytic cleavage of the weak N-Cl bond to yield a Cl radical and an N radical. The next steps help explain the highly selective nature of this reaction. Bond rotation enables a HAT via a highly favored six-membered ring transition state that also transforms the reactive nitrogen radical into a more stable secondary carbon radical. The product of the first portion of the reaction forms via a radical combination reaction of the initially generated Cl radical with the newly formed C radical. This 1,4-chloroamine can undergo an intramolecular S_N2 reaction to yield the pyrrolidine product. A related example of a Hoffmann-Loeffler-Freytag reaction to yield a lactam is shown in the next problem.

Mechanism

A related reaction promoted by lead tetraacetate (Pb(OAc)₄) that proceeds via a key oxygen radical provides a synthetically useful method for the synthesis of tetrahydrofurans. As shown below, treatment of an alcohol with Pb(OAc)₄ yields a substituted tetrahydrofuran (THF). The mechanism does not have a radical combination step, instead relying on a Single Electron Transfer (SET) process between a carbon radical and lead to yield a carbocation. The mechanism begins with a substitution reaction on lead with the starting alcohol. The new O-Pb bond is weak and can homolytically cleave to yield Pb(III) and an oxygen radical. Like in the Hofmann-Loefflear-Freytag reaction, the oxygen radical does a Hydrogen Atom Transfer (HAT) step via a 6-membered ring transition state to yield a carbon radical that reacts with a formally positive Pb(II) via SET. Thus, the lead is reduced and the carbon is oxidized to a carbocation that readily reacts with the intramolecular alcohol to yield the desired THF.

Mechanism

Other useful radical combination reactions involve dimerization of carbonyl starting materials. The three most popular are the pinacol reaction, the McMurry reaction, and the acyloin reaction. These involve starting with ketones (pinacol and McMurry) or esters (acyloin) and adding a strong metal reducing agent like sodium, magnesium, or titanium to generate ketyl radicals that dimerize and ultimately produce diol (pinacol), alkene (McMurry), or keto alcohol (acyloin) products. Intermolecular examples of each are shown below. Intramolecular reactions are also possible and will occasionally show up in total synthesis papers.

Pinacol Reaction

Two equivalents of acetone react with magnesium metal via Single Electron Transfer (SET) to yield two radical anions (ketyl radical anions). These two anions react with cationic magnesium (+2) to yield the neutral diradical that undergoes a radical combination reaction to form a new carbon-carbon bond. The resulting 5-membered ring breaks down in the acidic workup to yield the diol product. In this case, the product is pinacol, the starting point for the pinacol rearrangement that we saw in Chapter 3.

McMurry Reaction

The McMurry reaction is nearly identical to the pinacol reaction except for the final step. The key difference is the use of titanium metal, generated in situ from titanium trichloride and lithium aluminum hydride. Titanium reacts with two ketones to yield two ketal radical anions that react with cationic titanium to yield a neutral diradical. The diradical participates in the radical combination reaction to yield a new 5-membered ring include a new C-C bond. At this point, the McMurry reaction diverges from the pinacol reaction. The titanocycle is not stable, instead it undergoes a deoxygenation reaction to yield an alkene product. Overall, the McMurry reaction acts like a reverse ozonolysis reaction by combining two ketones to yield an alkene.

Acyloin Reaction

The acyloin reaction begins just like the pinacol reaction with SET reactions to yield two radical anions. Dimerization (radical combination) yields the new carbon-carbon bond and an intermediate that looks like a double tetrahedral intermediate from the carbonyl addition section of Intro Orgo. Accordingly, ethoxide is a good leaving group which promotes formation of a 1,2-diketone. This compound is highly reactive toward reduction, so it will accept two more electrons from sodium to yield a diradical dianion. Radical combination generates a new pi bond. This diradical is stable and is quenched in the workup to produce a diol. Since this is an enol, it will tautomerize to yield the keto alcohol product.