Identifying Reaction Mechanisms

 

Why Bother?

Identifying the mechanism of a reaction requires careful analysis. It's work, so is the effort justified? Recognizing mechanisms allows us to understand many, apparently different, reactions, as one closely related reaction. For example, S_N2 reactions come in great variety, but they are all basically the same reaction. Recognizing this spares us learning them as many different reactions. The two reactions below (eqs. 1 & 2) may look unrelated, but they are both S_N2 reactions.

equation 1
equation 2

Moreover, recognition of the second as an S_N2 reaction immediately tells us that the modification below will fail because S_N2 substitution does not take place at aromatic carbons (eq. 3). In the end, knowing mechanisms saves time and effort.

equation 3 

Identifying the Mechanism

The steps below are one effective approach:

1. Analyze the structural change. If all that happens is a proton transfer or coordination of a Lewis acid-base pair, classify the reaction accordingly. If something more profound is happening, e.g. addition, elimination or substitution, use it as the basis for classification.
2. Take note of reagents and reaction conditions. If an electrophile is present, the reaction may be an electrophilic addition or substitution. If the reaction mixture is basic, base catalysis is reasonable but acid catalysis is not. At this point you should be able to form an hypothesis,
3. Use your knowledge of mechanistic characteristics to refine your hypothesis. For example, anti stereospecificity is characteristic of electrophilic addition and E2 elimination. Inversion of configuration is a characteristic of S_N2 displacement, and carbon skeleton rearrangement suggests a carbocation intermediate.
4. Write a detailed mechanism. Test your hypothesis from steps 1-3 by writing a mechanism. Use your knowledge of mechanisms in this step. For, example, you know that primary alkyl derivatives don't undergo substitution by the S_N1 mechanism. Your mechanism should be able to account for the reaction without unreasonable steps like the nucleophilic substitution at an aromatic carbon such as that in equation 3. (You may need to revise your hypothesis at this point.)

The S_N2 in equation 2 involves a substitution at the brominated carbon. (Bromine is displaced, and a new C-C bond is formed in its place.) The conditions are basic, so it's reasonable to propose that base removes a proton alpha to the two carbonyl groups to give an enolate nucleophile. Initial proton transfer is followed by S_N2 displacement to form the new C-C bond of the product. The S_N1 pathway cannot compete since the primary bromide cannot form a carbocation. Thus, this is an S_N2 reaction (eq. 4).

equation 4 

Reaction of bromine with cyclohexene gives trans-1,2-dibromocyclohexane (eq. 5). The structural change is addition. Bromine is an electrophile, a Br⁺ donor. Thus, this is likely an electrophilic addition. The adduct's trans configuration is the result of S_N2 ring opening of the intermediate bromonium ion with backside attack by a bromide nucleophile. But the reaction is not classified as S_N2 because overall it is an addition.

equation 5 

A final example. The overall structural change in equation 6 is elimination. (Water is lost, and a double bond is formed.)

equation 6 

The two logical mechanisms are the E1 and E2 pathways. You can easily eliminate the latter, because there is no strong base in this acidic solution to remove a β-proton. Also, hydroxide does not function as an E2 leaving group. This leaves the E1 mechanism. Acid to convert hydroxy into a leaving group by protonation is available. Writing the mechanism to test this hypothesis gives the reasonable pathway below (eq. 7).

equation 7 

The carbocation intermediate in this mechanism is teritary and benzylic, so it's very stable as carbocations go. This is a good low energy pathway.

Reverse Reactions

What do you do if you see a reaction that is the reverse of a familiar reaction? Simple, the principle of microscopic reversibility says that the detailed mechanisms of the forward and reverse reactions are identical. It's based on the logical idea that the lowest energy pathway for the forward reaction must also be the lowest energy pathway for the reverse reaction. Addition of HCN to carbonyl compounds (eq. 8) is reversible and proceeds via the same base-catalyzed nucleophilic addition to carbonyl mechanism in either direction.

equation 8