18.4: Radical reactions in practice

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The three phases of radical chain reactions

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Because of their high reactivity, free radicals have the potential to be both extremely powerful chemical tools and extremely harmful contaminants. Much of the power of free radical species stems from the natural tendency of radical processes to occur in a chain reaction fashion. Radical chain reactions have three distinct phases: initiation, propagation, and termination.

The initiation phase describes the step that initially creates a radical species. In most cases, this is a homolytic cleavage event, and takes place very rarely due to the high energy barriers involved. Often the influence of heat, UV radiation, or a metal-containing catalyst is necessary to overcome the energy barrier.

Molecular chlorine and bromine will both undergo homolytic cleavage to form radicals when subjected to heat or light. Other functional groups which also tend to form radicals when exposed to heat or light are chlorofluorocarbons, peroxides, and the halogenated amide N-bromosuccinimide (NBS).

The propagation phase describes the ‘chain’ part of chain reactions. Once a reactive free radical is generated, it can react with stable molecules to form new free radicals. These new free radicals go on to generate yet more free radicals, and so on. Propagation steps often involve hydrogen abstraction or addition of the radical to double bonds.

Chain termination occurs when two free radical species react with each other to form a stable, non-radical adduct. Although this is a very thermodynamically downhill event, it is also very rare due to the low concentration of radical species and the small likelihood of two radicals colliding with one another. In other words, the Gibbs free energy barrier is very high for this reaction, mostly due to entropic rather than enthalpic considerations. The active sites of enzymes, of course, can evolve to overcome this entropic barrier by positioning two radical intermediates adjacent to one another.

Radical halogenation in the lab

The chlorination of an alkane provides a simple example of a free radical chain reaction. In the initiation phase, a chlorine molecule undergoes homolytic cleavage after absorbing energy from light:

The chlorine radical then abstracts a hydrogen, leading to an alkyl radical (step 2), which reacts with a second chlorine molecule (step 3) to form the chloroalkane product plus chlorine radical, which then returns to repeat step 2.

Likely chain termination steps are the condensation of two alkyl radical intermediates or condensation of an alkane radical with a chlorine radical.

Alkane halogenation reactions exhibit a degree of regiospecificity: if 2-methylbutane is subjected to a limiting amount of chlorine, for example, chlorination takes place fastest at the tertiary carbon.

This is because the tertiary radical intermediate is more stable than the secondary radical intermediate that results from abstraction of the proton on carbon #3, and of course both are more stable than a primary radical intermediate. Recall that the Hammond postulate (section 6.2, section 15.2B) tells us that a lower-energy intermediate implies a lower-energy transition state, and thus a faster reaction.

Unfortunately, chloroalkanes will readily undergo further chlorination resulting in polychlorinated products, so this is not generally a terribly useful reaction from a synthetic standpoint.

Alkanes can be brominated by a similar reaction. The regiochemical trends are the same as for chlorination, but significantly more pronounced (in other words, bromination is more regioselective). This is because hydrogen abstraction by bromine radical is much less exergonic than by chorine radical – and this in turn means that the transition state for abstraction by bromine resembles the resulting intermediate more closely than the transition state for abstraction by chlorine resembles its intermediate.

Another way of saying the same thing is that the bromination transition state has more ‘radical character’ than the chlorination transition state. Trends in radical stability thus have a greater influence on the speed of hydrogen abstraction.

The reaction proceeds through the radical chain mechanism. The radical chain mechanism is characterized by three steps: initiation, propagation and termination. Initiation requires an input of energy but after that the reaction is self-sustaining. The first propagation step uses up one of the products from initiation, and the second propagation step makes another one, thus the cycle can continue until indefinitely.

Step 1: Initiation

Initiation breaks the bond between the chlorine molecule (Cl₂). For this step to occur energy must be put in, this step is not energetically favorable. After this step, the reaction can occur continuously (as long as reactants provide) without input of more energy. It is important to note that this part of the mechanism cannot occur without some external energy input, through light or heat.

Step 2: Propagation

The next two steps in the mechanism are called propagation steps. In the first propagation step, a chlorine radical combines with a hydrogen on the methane. This gives hydrochloric acid (HCl, the inorganic product of this reaction) and the methyl radical. In the second propagation step more of the chlorine starting material (Cl₂) is used, one of the chlorine atoms becomes a radical and the other combines with the methyl radical.

The first propagation step is endothermic, meaning it takes in heat (requires 2 kcal/mol) and is not energetically favorable. In contrast the second propagation step is exothermic, releasing 27 kcal/mol. Since the second propagation step is so exothermic, it occurs very quickly. The second propagation step uses up a product from the first propagation step (the methyl radical) and following Le Chatelier’s principle, when the product of the first step is removed the equilibrium is shifted towards it’s products. This principle is what governs the unfavorable first propagation step’s occurance.

Step 3: Termination

In the termination steps, all the remaining radicals combine (in all possible manners) to form more product (CH₃Cl), more reactant (Cl₂) and even combinations of the two methyl radicals to form a side product of ethane (CH₃CH₃).

Problems with the chlorination of methane

The chlorination of methane does not necessarily stop after one chlorination. It may actually be very hard to get a monosubstituted chloromethane. Instead di-, tri- and even tetra-chloromethanes are formed. One way to avoid this problem is to use a much higher concentration of methane in comparison to chloride. This reduces the chance of a chlorine radical running into a chloromethane and starting the mechanism over again to form a dichloromethane. Through this method of controlling product ratios one is able to have a relative amount of control over the product.

Chlorination of other alkanes

When alkanes larger than ethane are halogenated, isomeric products are formed. Thus chlorination of propane gives both 1-chloropropane and 2-chloropropane as mono-chlorinated products. Four constitutionally isomeric dichlorinated products are possible, and five constitutional isomers exist for the trichlorinated propanes. Can you write structural formulas for the four dichlorinated isomers?

\[CH_3CH_2CH_3 + 2Cl_2 \rightarrow \text{Four} \; C_3H_6Cl_2 \; \text{isomers} + 2 HCl\]

The halogenation of propane discloses an interesting feature of these reactions. All the hydrogens in a complex alkane do not exhibit equal reactivity. For example, propane has eight hydrogens, six of them being structurally equivalent primary, and the other two being secondary. If all these hydrogen atoms were equally reactive, halogenation should give a 3:1 ratio of 1-halopropane to 2-halopropane mono-halogenated products, reflecting the primary/secondary numbers. This is not what we observe. Light-induced gas phase chlorination at 25 ºC gives 45% 1-chloropropane and 55% 2-chloropropane.

CH₃-CH₂-CH₃ + Cl₂ → 45% CH₃-CH₂-CH₂Cl + 55% CH₃-CHCl-CH₃

The results of bromination ( light-induced at 25 ºC ) are even more surprising, with 2-bromopropane accounting for 97% of the mono-bromo product.

CH₃-CH₂-CH₃ + Br₂ → 3% CH₃-CH₂-CH₂Br + 97% CH₃-CHBr-CH₃

These results suggest strongly that 2º-hydrogens are inherently more reactive than 1º-hydrogens, by a factor of about 3:1. Further experiments showed that 3º-hydrogens are even more reactive toward halogen atoms. Thus, light-induced chlorination of 2-methylpropane gave predominantly (65%) 2-chloro-2-methylpropane, the substitution product of the sole 3º-hydrogen, despite the presence of nine 1º-hydrogens in the molecule.

(CH₃)₃CH + Cl₂ → 65% (CH₃)₃CCl + 35% (CH₃)₂CHCH₂Cl

If you are uncertain about the terms primary (1º), secondary (2º) & tertiary (3º) Click Here.

It should be clear from a review of the two steps that make up the free radical chain reaction for halogenation that the first step (hydrogen abstraction) is the product determining step. Once a carbon radical is formed, subsequent bonding to a halogen atom (in the second step) can only occur at the radical site. Consequently, an understanding of the preference for substitution at 2º and 3º-carbon atoms must come from an analysis of this first step.

Radical Allylic Halogenation

Watch a video by Organic Chemistry Tutor on allylic halogenation:

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When halogens are in the presence of unsaturated molecules such as alkenes, the expected reaction is addition to the double bond carbons resulting in a vicinal dihalide (halogens on adjacent carbons). However, when the halogen concentration is low enough, alkenes containing allylic hydrogens undergo substitution at the allylic position rather than addition at the double bond. The product is an allylic halide (halogen on carbon next to double bond carbons), which is acquired through a radical chain mechanism.

Why substitution of allylic hydrogens?

As the table below shows, the dissociation energy for the allylic C-H bond is lower than the dissociation energies for the C-H bonds at the vinylic and alkylic positions. This is because the radical formed when the allylic hydrogen is removed is resonance-stabilized. Hence, given that the halogen concentration is low, substitution at the allylic position is favored over competing reactions. However, when the halogen concentration is high, addition at the double bond is favored because a polar reaction outcompetes the radical chain reaction.

Radical Allylic Bromination (Wohl-Ziegler Reaction)

Preparation of Bromine (low concentration)

NBS (N-bromosuccinimide) is the most commonly used reagent to produce low concentrations of bromine. When suspended in tetrachloride (CCl₄), NBS reacts with trace amounts of HBr to produce a low enough concentration of bromine to facilitate the allylic bromination reaction.