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Alkyl Halides

Substitution Reactions of Alkyl Halides

Nucleophilic Substitution Reactions

Nucleophilic substitution reactions are reactions where a leaving group (a halide) is replaced with a functional group due to the presence of a nucleophilic reagent.

In organic chemistry, it is essential to know where electrons are located and how they move in a reaction. Some molecules are considered rich with electrons while other molecules are considered poor with electrons. A nucleophile is a molecule or ion rich in electrons that donates a pair of electrons that forms a covalent bond. Nucleophiles are attracted to positively charged areas. An electrophile is a molecule or ion that accepts electrons to form a covalent bond. Electrophiles are attracted to negatively charged areas.

Alkyl halides are the substrates (reactants) of an organic reaction known as the nucleophilic substitution reaction. Alkyl halides contain polar CX {\rm {C{-}X}} bonds. Polar bonds have a charge separation where the halogen (X) becomes partially negative and the carbon becomes partially positive. The polarization of the carbon-halogen bond makes the carbon attached to a halogen electrophilic. In general, because the nucleophile has electrons to donate, it bonds to (attacks) the electrophilic carbon bearing the halogen. The halide that was bonded to the carbon undergoes heterolytic cleavage, taking both electrons, and becomes a leaving group. A leaving group is a functional group that is able to leave a compound and usually forms a stable (weak) species.

Amongst the halogens, iodide is the largest, most polarizable conjugate base and makes the best leaving group. For halides, size is the main factor that determines leaving group ability. For halides, the order of leaving group (from best to worst) is iodide, bromide, chloride, and fluoride. Fluoride is such a small atom and its bond to carbon is so strong compared to the other halides that it does not function as a good leaving group.

Overall, the positively charged carbon center created by the carbon-halogen bond is an electrophile. Electrophiles are electron poor and therefore accept a pair of electrons to form a new covalent bond. When an alkyl halide, also known as the substrate or compound acted upon in a reaction, is in the presence of a nucleophile, the halogen leaves the substrate as the leaving group.

Nucleophilic Substitution Reaction of 2-bromopentane

In a nucleophilic substitution reaction, the alkyl halide, which contains an electrophilic carbon attached to a halide functioning as a leaving group, is the substrate of the reaction. The nucleophile will attack the electrophilic carbon, creating a new bond and kicking off the leaving group.
Nucleophilic substitution reactions are characterized by the following:
  • Substrate, which is a reactant molecule with an electrophilic carbon attached to a halogen
  • Leaving group, which is the halogen attached to the electrophilic carbon
  • Nucleophile, which is an electron-rich reagent that is usually an ionic compound
  • Solvent, which is the liquid that all the chemicals are dissolved in for the reaction to occur

SN1 and SN2 Reactions

SN2 reactions are bimolecular, while SN1 reactions are unimolecular. SN1 mechanisms are multistep mechanisms that include the formation of a carbocation intermediate. SN2 mechanisms are concerted mechanisms that have a nucleophilic attack and a loss of leaving group in the same step.

SN1 and SN2 reactions are two versions of nucleophilic substitution reactions. A substitution reaction is a chemical reaction in which one functional group (leaving group) is replaced with another functional group. For an SN2 reaction, there are two molecules involved in the rate-determining step—the substrate and the nucleophile. Therefore, SN2 reactions are bimolecular. A bimolecular reaction is an elementary reaction that occurs between two reactants. An SN1 reaction has only one molecule involved in the rate-determining step; therefore, SN1 reactions are unimolecular. A unimolecular reaction is an elementary reaction with one reactant.

The overall mechanisms for SN1 and SN2 reactions are similar. However, an SN2 reaction occurs in one concerted step, where the rate is dependent on the concentration of substrate and nucleophile. The one mechanistic step is a combination nucleophilic attack and the loss of leaving group step. An SN1 reaction is a multistep mechanism that usually begins with the leaving group leaving and the formation of a carbocation, which is the rate-determining step (RDS) of the mechanism followed by a nucleophilic attack step. Another way to think of the SN2 reaction is that the nucleophile attacks the substrate, which causes the leaving group to leave. In an SN1 reaction, the leaving group leaves on its own, followed by a nucleophilic attack.

For an SN1 reaction, the alkyl halide tends to be more substituted (tertiary or secondary halide). The halogen ion dissociates from the alkyl group first, and then the nucleophile bonds to the alkyl cation. An SN2 reaction mechanism occurs when the nucleophile attempts to bond with the carbon on the opposite side of the halogen ion. This results in a transition state with a weak, partial bond between the nucleophile and the carbon. The transition state also has a weakened, partial bond between the alkyl group and the halide ion. The halide is released, and the nucleophile completes the substitution reaction. The alkyl halide of an SN2 reaction is usually less substituted (methyl, primary, or secondary).

SN1 versus SN2 Reaction

The products of an SN2 reaction look very similar to the products of an SN1 reaction. However, the mechanism shows the different pathways to form the SN1 and SN2 products.

Substitution Reaction Outcomes

SN2 reactions involve inversion of the configuration of the carbon with a leaving group, while SN1 reactions involve racemization of the halide carbon. SN2 reactions predominate with methyl and primary alkyl halides. SN1 reactions predominate with tertiary alkyl halides. Secondary alkyl halides can undergo SN1 or SN2 reactions, depending on the solvent used.

The size of the groups attached to or near the electrophilic carbon affects how the reaction proceeds. In an SN2 reaction, the nucleophile has to approach directly opposite of the halide (referred to as backside attack). Larger groups block the electrophilic carbon from nucleophile attack from the back side. In general, SN2 reactions occur fastest for methyl and primary alkyl halides and slowest for tertiary alkyl halides.

Since the nucleophile approaches and attacks opposite of the leaving group, there is an inversion of configuration at the electrophilic carbon. An inversion is a change in orientation that occurs during SN2 reactions, when backside displacement of the halogen creates a new molecule with the opposite orientation of the original molecule. This results in an inversion of stereochemistry. An inversion of stereochemistry means the orientation of the nucleophile will be opposite that of the leaving group. If a leaving group were wedged (going up out of the plane), the nucleophile would be dashed (going down or below the plane).

SN1 reactions dominate when the electrophilic carbon is more substituted, while SN2 reactions dominate when the electrophilic carbon is less substituted. For example, a primary alkyl halide is more apt to undergo an SN2 reaction, whereas a tertiary alkyl halide is more apt to undergo an SN1 reaction. SN1 and SN2 reactions each require similar conditions, so the enantiomeric product from the SN2 reaction and the racemic products from the SN1 reaction compete with each other. Since SN1 mechanisms proceed through a carbocation, which is planar, the products are racemic. Racemic means a 1:1 mixture of enantiomers.

Methyl and primary electrophilic carbons (carbons attached to good leaving groups, such as alkyl halides) proceed through an SN2 mechanism that leads to an inversion of stereochemistry at the electrophilic carbon. Tertiary electrophilic carbons proceed through an SN1 mechanism, which leads to a racemic product.

Secondary carbons can proceed through an SN1 or SN2 mechanism, depending on other conditions, primarily the type of solvent used. The solvent is the substance that dissolves a material to form a solution. There are two main types of solvents—polar protic and polar aprotic solvents. A polar protic solvent is a solvent that contains a polar bond that exhibits hydrogen bonding. Examples of polar protic solvents include water, methanol, ethanol, ammonia, and many other alcohol and amine solvents. A polar aprotic solvent is a solvent that contains a polar bond but does not have hydrogen bonding. Examples of polar aprotic solvents include acetone, dimethyl sulfoxide (DMSO), dimethyl sulfide (DMS), dimethyl formamide (DMF), and similar solvents.

Stereochemistry of SN1 and SN2 Reactions

The products of SN2 reactions show inversion of stereochemistry. The products of SN1 reactions are racemic.

Comparing SN1 and SN2 Reactions

Conditions SN1 Reaction SN2 Reaction
Kinetics Unimolecular Bimolecular
Substrate 3° preferred
2° with polar protic solvents
1° does not occur
Methyl and 1° preferred
2° with polar aprotic solvents
3° does not occur
Stereochemistry Racemic Inversion of configuration
Solvent Polar protic Polar aprotic
Leaving group Required Required

SN1 reactions are fastest with tertiary leaving groups and form racemic products. SN2 reactions are fastest with methyl and primary leaving groups, and the products show inversion of configuration. Secondary leaving groups undergo SN1 or SN2 mechanisms, depending on conditions.