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Nucleophilic Substitution Reaction

In this section, we will discuss the two major substitution reactions – SN1 and SN2 reactions. In nucleophilic substitution reactions involving alkyl halides as the substrate, a Lewis base (nucleophile) substitutes the halogen present in the alkyl halide. We will discuss nucleophilic reactions in which alkyl halides react with nucleophiles. A general representation can be done as follows:

image\26110 ch 20.png

The SN2 Reaction

SN2 stands for bimolecular nucleophilic substitution reaction. Consider the reaction between methyl iodide and sodium hydroxide.


image\Ch 20 sec E, g2.png


This reaction follows SN2 mechanism. Experimentally, it has been confirmed that the rate of this reaction depends on both the alkyl halide and the nucleophile (OH) involved. The reaction rate is written as follows:

Rate = k [CH3I] [OH ]

The Mechanism of SN2 Reaction

We will look at the mechanism involved in the reaction between methyl iodide and sodium hydroxide. The SN2 reaction proceeds via a five-coordinate transition state. This transition state has weak (the weak bonds are indicated by the dotted lines in the mechanism) carbon-iodine and carbon-oxygen bonds. Even though these two are weak bonds, the other three bonds involving the central carbon atom are complete bonds. As the leaving group detaches, there is an inversion of configuration (in chiral molecules) at the carbon where the leaving group was attached.

image\26118 ch 20.png

The mechanism of SN2 reaction

In SN2 reactions, the nucleophilic attack occurs opposite (backside attack) to the side where the leaving group is present. This type of nucleophilic approach is thermodynamically favored since the backside attack minimizes the electrostatic repulsions between the nucleophile and the leaving group involved. If substituents (especially bulky ones) are present on the carbon where the nucleophilic attack occurs, this can hinder the SN2 process. Hence, primary alkyl halides are the most reactive among alkyl halides with respect to SN2 reactions.
SN2 reactivity: Methyl > Primary > Secondary > Tertiary

image\Ch 20 p 277 g1.png

As mentioned earlier, the nucleophile and its concentration can influence the rate of SN2 reactions. So the rate is different for different nucleophiles. Nucleophilicity or the strength of a nucleophile depends on how efficiently it can make the leaving group leave from the alkyl halide or whatever the substrate is. Some generalizations can be made regarding nucleophiles. Along a period (in the periodic table), as basicity decreases, nucleophilicity decreases (e.g., F< RO< R2N< R2C). Along a group, as basicity decreases, nucleophilicity increases (e.g., F< Cl< Br< I).
Nucleophilicity can also be compared among species having the same nucleophilic atom. A negatively charged conjugate base of a neutral species (conjugate acid) is more nucleophilic than its corresponding neutral species. For example, HO is a better nucleophile than H2O.
A leaving group plays an important role in both substitution and elimination reactions. A good leaving group has a weak, polarized carbon-leaving group (C-X) bond. It should be stable on its own once it leaves the substrate, regardless of whether it stays as an ion or a neutral species. Sometimes solvation helps a leaving group to achieve this. Halides are good leaving groups. The order of leaving group ability is F < Cl < Br < I. In general, less basic the species is, the better the leaving group. Other good leaving groups include mesylate and tosylate

image\Ch 20 p 278 g1.png

The SN1 Reaction

SN1 stands for unimolecular nucleophilic substitution reaction. Let's consider a typical SN1 reaction.

image\Ch 20 Sn1 Reaction, g1.png

The rates of SN1 reactions depend only on the substrate (alkyl halide) concentration. The nucleophile does not influence the reaction rate of a typical SN1 reaction.

The reaction rate is represented as follows:

Rate = k [ (CH3)3CI ]

The Mechanism of SN1 Reaction

In this two-step reaction, the alkyl halide splits to form a carbocation intermediate and a halide ion. During the second step, the cation reacts with the nucleophile to form the final product. Since the carbocation formed is planar, the nucleophile can attack the electrophilic carbon from either side. Thus an SN1 reaction results in racemization.

image\Ch 20 fig 20-2.png

The mechanism of SN1 reaction

SN1 reactivity: Methyl < Primary < Secondary < Tertiary


SN2 reaction is favored when the alkyl halide involved is a primary or a secondary alkyl halide. SN1 reaction is favored when the alkyl halide involved is a tertiary or a secondary alkyl halide. In many cases, it is hard to predict the mode of reaction with secondary alkyl halides – it can either be SN1 or SN2, depending on certain other aspects such as the solvent used. The SN1 reaction being favored by tertiary halides is understandable, because of the carbocation intermediate that is formed during the SN1 process.
Polar solvents increase the rate of both types of substitution reactions. Polar solvents which have high dielectric constants can stabilize the transition state and this is highly useful in SN1 reactions. In SN2 reactions, the solvent effects are slightly different. Here what matters is whether the solvent is aprotic. Protic polar solvents such as water and carboxylic acids can undergo hydrogen bonding which in turn can interact with the nucleophile. This can decrease the rate of SN2 reactions. So it is better to use aprotic polar solvents when we are dealing with SN2 reactions. Dimethyl sulfoxide (DMSO) is a polar aprotic solvent.

image\Ch 20 Sn1 Reaction, g2.png

Quite often nucleophilic reactions compete with elimination reactions. Next, we will review elimination reactions.

Elimination reactions

There are two types of elimination reactions in general – E1 and E2 reactions. We will first consider an E2 reaction.

The E2 reaction

The E2 reaction mechanism can generally be represented as shown. In the mechanistic representation shown, B stands for the base and X stands for the halogen.

image\18203 ch 20.png

The mechanism of E2 reaction

The steps involved in an E2 reaction are the breaking of the carbon-hydrogen bond, the carbon double bond formation, and the breaking away of the carbon-halogen bond.
The rate of the E2 reaction is:     Rate = k [ RX ] [ base ]
So the reaction rate depends on both the substrate (RX) and the base involved.
In an elimination reaction, the major product formed is the most stable alkene. Usually, the most stable alkene is the most substituted alkene. The increased stability of more highly substituted alkenes can be attributed to electronic effect.

The E1 Reaction

Study the mechanism of E1 reaction.

image\Ch 20 fig 20-4.png

The mechanism of E1 reaction

In step (1), the alkyl halide forms (slow step) the carbocation and the halide ion. In step (2), the base abstracts the proton to form the product (alkene).


E1 reactivity: Methyl < Primary < Secondary < Tertiary

(Slowest)                                  (Fastest)


Substitution versus Elimination

Sometimes it is hard to predict the product of a reaction involving nucleophiles or bases. Why? Well, the reaction mechanisms are influenced by many factors. Different combination of factors result in different outcomes. Even though this is the case, let's boil down some of the factors that we can rely on for reasonably judging the outcome of reactions. We will consider some conditions that favor substitution over elimination, and vice versa. The two key factors that we look for are the type of substrate that is undergoing the reaction, and the extent of nucleophilicity or basicity of the anion involved in the reaction.
  1. Higher temperatures usually favor elimination over substitution. To be more precise, we can say that elimination is more favored than substitution reactions if the reaction occurs at a high temperature. The latter is more accurate because both types of reactions are favored by an increase in temperature, but elimination is more favored.
  2. Strong bases guide or dictate elimination over substitution in most cases. In general, E2 type of elimination is favored under such conditions.
  3. If there is less hindrance or less bulky substituents at the carbon where the leaving group is present, substitution (SN2) is favored over elimination (E2). Remember that in SN2 reactions, the transition intermediate is a species in which both the leaving group and the incoming nucleophile are attached to the carbon, where the substitution is taking place.
  4. Alkyl halides (tertiary), because of their bulky substituents, mostly prefer elimination rather than substitution provided that a strong base is present. Mild bases can make substitution to predominate even in tertiary alkyl halides. Can you think of a reason why tertiary alkyl halides prefer to undergo elimination? The reason is steric hindrance to the nucleophilic approach.

Note: We have been discussing a number of reactions, both substitution and elimination in terms of alkyl halides. This surely doesn't mean that only alkyl halides undergo these types of reactions.


Nucleophilic Substitution in Alkyl Halides - SN1 vs SN2 comparison

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