The three phases of radical chain reactions

The following video by Leah4Sci provides a good introduction to free radical reactions.

https://www.youtube.com/watch?v=Uz1_n9ZnksY

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.

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:

https://youtu.be/EUp2c5aO4dk

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.

 

Allylic Bromination Mechanism

Step 1: Initiation

Once the pre-initiation step involving NBS produces small quantities of Br₂, the bromine molecules are homolytically cleaved by light to produce bromine radicals.

Step 2: Propagation

One bromine radical produced by homolytic cleavage in the initiation step removes an allylic hydrogen of the alkene molecule. A radical intermediate is generated, which is stabilized by resonance. The stability provided by delocalization of the radical in the alkene intermediate is the reason that substitution at the allylic position is favored over competing reactions such as addition at the double bond.

The intermediate radical then reacts with a Br₂ molecule to generate the allylic bromide product and regenerate the bromine radical, which continues the radical chain mechanism. If the alkene reactant is asymmetric, two distinct product isomers are formed.

Step 3: Termination

The radical chain mechanism of allylic bromination can be terminated by any of the possible steps shown below.

Radical Allylic Chlorination

Like bromination, chlorination at the allylic position of an alkene is achieved when low concentrations of Cl₂ are present. The reaction is run at high temperatures to achieve the desired results.

Industrial Uses

Allylic chlorination has important practical applications in industry. Since chlorine is inexpensive, allylic chlorinations of alkenes have been used in the industrial production of valuable products. For example, 3-chloropropene, which is necessary for the synthesis of products such as epoxy resin, is acquired through radical allylic chlorination (shown below).

Useful polymers formed by radical chain reactions

Many household polymeric materials with which you are probably familiar are made with a radical chain reaction process. Polyethylene (PET), the plastic material used to make soft drink bottles and many other kinds of packaging, is produced by the radical polymerization of ethylene (ethene in IUPAC nomenclature). A radical initiator such as benzoyl peroxide undergoes homolytic cleavage when subjected to high temperatures.

In the propagation phase, the benzoyl radical (X• in the figure below) adds to the double bond of ethylene, generating a new organic radical.  Successive ethylene molecules add to the growing polymer, until termination occurs when two radicals happen to collide. In the figure below, the growing PET polymer is terminated by a benzoyl radical, but in an alternative termination step two growing PET radicals could condense.

Other small substituted alkene monomers polymerize in a similar fashion to form familiar polymer materials. Two examples are given below.

Destruction of the ozone layer by CFC radicals

The high reactivity of free radicals and the multiplicative nature of radical chain reactions can be useful in the synthesis of materials such as polyethylene plastic – but these same factors can also result in dangerous consequences. You are probably aware of the danger posed to the earth’s protective stratospheric ozone layer by the use of chlorofluorocarbons (CFCs) as refrigerants and propellants in aerosol spray cans.  Freon-11, or CFCl₃, is a typical CFC that was widely used until fairly recently.  It can take months or years for a CFC molecule to drift up into the stratosphere from the surface of the earth, and of course the concentration of CFCs at this altitude is very low.  Ozone, on the other hand, is continually being formed in the stratosphere.  Why all the concern, then, about destruction of the ozone layer – how could such a small amount of CFCs possibly do significant damage?  The problem lies in the fact that the process by which ozone is destroyed is a chain reaction, so that a single CFC molecule can initiate the destruction of many ozone molecules before a chain termination event occurs.

Harmful radical species in cells and natural antioxidants

While the high reactivity of the hydroxide radical is a beneficial trait in the atmosphere, it is a harmful trait when the same hydroxide radical is present in a living cell.  Hydroxide radical and other reactive oxygen species (ROS) such as superoxide (O₂^–) and peroxide (O₂ ^2-) are continuously produced as minor side-products in the reduction of O₂ to H₂O in respiration.

The ROS are highly reactive oxidizing agents, capable of inflicting damage to DNA, proteins, and the lipids of cell membranes – they are thought to play a major role in the natural aging process.  Hydroxide radical, for example, will initiate a radical chain reaction with the hydrocarbon part of an unsaturated  membrane lipid molecule that results in the formation of lipid hydroperoxide.

One important antioxidant that you are no doubt familiar with is ascorbic acid, or vitamin C.  It reacts with harmful radicals to produce the ascorbyl radical, which is significantly more stable than most other radical species due to resonance delocalization.  The end result of this first step is that a very reactive, potentially harmful radical (X•) has been ‘quenched’, and replaced by a much less reactive (and thus less harmful) ascorbyl radical.is thus potentially able to scavenge two harmful radical species.

Dehydroascorbate is subsequently either broken down and excreted, or else recycled (reduced) back to ascorbate.  This can happen either in a direct, enzyme-free reaction with glutathione, or through the action of a specific glutathione/NADH-dependant reductase enzyme.  You were invited to propose a likely mechanism for the enzyme-free reaction in problem 16.14.