Nucleophilic Substitution Reactions

Written by tutor Raffi H.

This article assumes that the reader is reasonably familiar with the basic notions of structure, nomenclature and stereochemistry normally taught during the early stages of an Organic Chemistry course. In particular, the reader should be familiar with Organic Halides, as well as the concepts of Chirality, R,S-Configuration and Enantiomers.

Let’s first recall the definitions of Nucleophile and Electrophile:

Nucleophile: An electron-rich species. This will most often be an atom or molecule with 1 or more lone pairs of electrons that it can share (donate) to form a single bond. The Nucleophile can be neutral or negatively charged.

Examples of Nucleophiles are as follows:

OH     Cl     H2O     NH3

*Note: Lone pairs are often left off of the symbols for nucleophiles, as above, but they are there. When drawing curved arrows for mechanisms, you have the option of marking a lone pair, if you wish, but it is not required.

Electrophile: An electron-deficient species that acts as a target for a Nucleophile. This will most often be a molecule with one of its carbons attached to a more electronegative element, with the result that the carbon is carrying a partial positive charge.

This partially positive carbon is called the Electrophilic Carbon. It is this carbon that is attacked by the Nucleophile. For this article, the only electrophiles discussed will be Alkyl Halides.

Examples of Alkyl Halide Electrophiles :

The first is Bromomethane (common name: Methyl Bromide). The second is Bromoethane (Ethyl Bromide). The third is 2-Chlorobutane (sec-Butyl Chloride).

Nucleophilic Substitution Reactions

Nucleophilic Substitution Reactions are a group of reactions that involve the interaction of a Nucleophile with an Electrophile. The electron-rich nucleophile seekes out (attacks) the electron-deficient electrophile. Before the reaction takes place, the electrophile contains an atom or group called the Leaving Group, because it ultimately detaches from the electrophile. This atom or group is the electronegative species mentioned above and is attached to the Electrophilic Carbon. During the reaction this Leaving Group is replaced (substituted) by the Nucleophile. The General Reaction is as follows:

A is the Nucleophile and Q is the Leaving Group in this Image. This is a general image, and says nothing yet about mechanism. The arrangement of R groups is entirely irrelevant at this point. It simply represents the Substitution of a Nucleophile for the Leaving Group.

There are 2 types of Nucleophilic Substitution Reactions: SN1 & SN2, each having its own mechanism. The SN2 reaction is usually learned first. S stands for “Substitution”; N stands for “Nucleophilic”; and 1 or 2 refers to the reaction’s “Molecularity”: whether the RATE of the reaction depends on the concentration of 1 species (the Electrophile) or 2 species (Electrophile AND Nucleophile).

* Note: SN2 happens in 1 step, whereas SN1 happens in 2 steps. The 1 and the 2 do NOT refer to the number of steps in the mechanism, and it is here that many students confuse these two reactions. The 1 and the 2 refer to the reactions’ kinetics. That is, SN2 depends on the concentration of both Nuc. and Elect., whereas SN1 depends only on Elect. alone.

The SN2 Reaction

In an SN2 reaction a Nucleophile attacks the electrophilic carbon of the electrophile. The bond between nucleophile and carbon forms at the exact same time that the bond between carbon and Leaving Group breaks. In other words, Nuc-C bond formation and C-Leaving Group bond breakage happen simultaneously. In the transition state, the carbon is partially attached to both. Let’s look at the reaction:

Note how the Nucleophile engages in “backside attack”. That is, it approaches from the side opposite the Leaving Group, not the same side as the leaving group. Also pay particular attention to how the SN2 mechanism inverts the configuration at the electrophilic carbon – much like the popping inversion of an umbrella when it opens too far, or when a strong wind blows against the inside and inverts it. If the electrophilic carbon happens to be chiral, an SN2 reaction will invert the original configuration. That is, if the electrophile was originally S, then the product will now be exclusively R, and vice versa. Let’s look at an example:

In this image the Nucleophile is Green, and the Leaving Group Red. If we assign the electrophile an S configuration, starting with the Leaving Group and moving counterclockwise, then the product has the R configuration, starting with the Nucleophile and moving clockwise.

*Note: Assignments of R,S Configurations are based on the priority of the 4 groups attached to the chiral carbon. Most of the time the Nucleophile and the Leaving Group will have the same priority over the other groups. This will always result in Inversion of Configuration. Be aware, though that although the groups are always flipped in the SN2 mechanism, priority may cause the product to have the same R or S designation as the starting molecule. You will almost never see this.

Rate of SN2 Reactivity

For the SN2 reaction, Primary Alkyl Halides are more reactive than Secondary, which are, in turn, more reactive than Tertiary. Given the SN2 mechanism, it makes perfect sense that the greater the steric hindrance from larger groups as you go from primary to secondary to tertiary, the more difficult it becomes for the nucleophile to get close enough to the electrophilic carbon to react with it.

The SN1 Reaction

In an SN1 reaction, bond breakage and bond formation do NOT happen simultaneously. The leaving group departs first, taking the shared electron pair with it. This leaves a Carbocation, which is a species where the electrophilic carbon is completely deficient 2 electrons, so it carries a full +1 charge (Review the concept Formal Charge from General Chemistry, if necessary, if you are not sure why the charge is +1). At this point, the Nucleophile can attack this positive carbon center from either side, because the carbocation is a Triagonal Planar species. Therefore, if this carbon is Chiral, the product ends up being a Racemate (an equal mixture of Enantiomers), because Nucleophilic attack can happen at either face with equal probability. Of the two steps — Leaving Group departure and Nucleophilic attack — departure is the slow step, therefore the rate-limiting (rate-determining) step. This means that the concentration of Electrophile ALONE controls the rate of the reaction, hence the 1 in SN1. Let’s look at a few diagrams of this process:

Rates of Reactivity for SN1

For the SN1 reaction, Tertiary Alkyl Halides are more reactive than Secondary, which, in turn, are more reactive than Primary. The reason for this is the stability of the Carbocation formed upon departure of the Leaving group. Tertiary Carbocations are more stable than secondary carbocations, and secondary carbocations are more stable than primary.

The SN1 Reaction and Carbon Skeleton Rearrangement

The carbocations formed in SN1 reactions are susceptible to rearrangement. This means that Hydrogens or Methyl Groups might migrate to other parts of the carbocation in order to form a more stable carbocation. Examine the image below very carefully:

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