8.5: Nucleophilic Substitution - 2nd Order

The S_N2 reaction is nucleophilic substitution, 2^nd order. It is still a substitution reaction, but this time the rate-determining step involves two molecules. S_N2 reactivity is normally reserved for primary (or sometimes secondary) carbon atoms, which cannot form a stable carbocation. Instead, the formation of the \(σ_{C-Nuc}\) bond and the breaking of the \(σ_{C-LG}\) bond occur at the same time in what is known as a concerted mechanism. The reaction is 2^nd order because the rate of the reaction is dependent on the concentration of both the nucleophile AND the structure of the starting material.

rate = k [nucleophile][alkyl bromide]

What are the orbital interactions involved in an S_N2 reaction? For an S_N2 to occur, the nucleophile must be able to populate the \(σ^{*}_{C-X}\), where X is a good leaving group (pK_aH < 4). This means that the nucleophile must approach exactly 180° opposite of the direction of the leaving group, which is where the larger lobe of the \(σ^{*}_{C-X}\) lies. We call this backside attack. Since it is concerted, bond forming and bond breaking events occur simultaneously.

If we look at the potential energy diagram of an S_N2 reaction, we notice that it is quite different than an S_N1 reaction. There is no carbocation intermediate, but rather the rate-determining step involves a transition state that is pentacoordinate – both the nucleophile and electrophile are involved. This is why it’s 2^nd order.

S_N2 reactions have a very different stereochemical outcome than S_N1 reactions. An S_N2 reaction is stereospecific, which means that according to the mechanism, only one stereoisomer is possible. In the example above, the stereochemistry is inverted (inversion of configuration). This happens because of the concerted mechanism and the direction of \(σ^{*}\). Think of it like the sp³-carbon “flipping” like an umbrella in the wind.

Compare this result to the S_N1 reaction, where the stereochemical consequence is not inversion, but rather racemization:

Let’s think through the various factors that effect the S_N2 reaction.

1. Nucleophilicity – good nucleophiles are polarizable; much like their ability to delocalize charge over larger volumes, they also have better orbital overlap with empty \(σ^{*}\) orbitals. Good nucleophiles are often big and diffuse, and you will sometimes hear them describes as being soft (squishy like a pillow). Nucleophilicity does NOT correlate with basicity. Strong bases are tiny, point charges on electronegative atoms. Common nucleophiles are as follows:

Excellent	Good	Fair	Poor
CN^–, RS^–, I^–, RSH	RO^–, Br^–, N3^–, RNH2, NO2^–	Cl^–, CH3CO2^– (AcO^–), ROH	H^–, NH2^–

 

2. Leaving group ability – much like S_N1, the leaving group ability correlates with the pK_a of the conjugate acid, which must be less than 4.

3. Clear trajectory – the nucleophile must be able to attack the \(σ^{*}\). If this orbital is blocked by bulky groups, the reaction won’t occur. In fact, in some cases, the reaction will proceed by S_N1 instead. S_N2 reactions do not happen for tertiary carbons because the \(σ^{*}_{C-LG}\) is inaccessible because of the steric bulk of the tertiary center; an S_N1 reaction will occur instead.

4. Reaction conditions –solvents for S_N2 should be polar, aprotic (DMF, DMSO) because these solvents normally help to dissolve inorganic salts. Because there is no charged intermediate (carbocation), alcoholic solvents or other protic solvents will inhibit the reaction. This is because these solvents will aggregate/solvate the nucleophilic anions. Nonpolar solvents (THF, dioxane, MeCN, hexanes) can also be used.

 

Examples:

Biomedical Spotlight

Even though methyl iodide is a common reagent in organic chemistry, it is far too reactive in biological systems to be useful. In fact, it is so reactive that it will readily alkylate one's DNA, causing mutations that can cause disease. Methylation in biological systems is still an important biochemical pathway, but it is highly regulated (methyl groups can be added and removed by enzymes fairly easily). The source of the methyl group, however, is a small molecule known as S-adenosyl methionine (SAM). SAM is generated by the union of the amino acid methionine with the nucleobase adenine. Since methionine has a methylthioether functional group, it becomes electrophilic at carbon when activated by adenine (notice the positive charge on sulfur - this makes the methyl group highly electrophilic). As a result, S_N2-like mechanism can occur between nucleobases like cytosine. This reaction, whereby a methyl group is transferred to a substrate in S_N2 fashion, is catalyzed by a DNA methyl transferase and is the main source of methylation events in biological systems. But SAM is far less toxic to living organisms!