Substitution Reactions of Alkyl Halides

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 ${\rm {C{-}X}}$ 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 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

S_N1 and S_N2 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 S_N2 reaction, there are two molecules involved in the rate-determining step—the substrate and the nucleophile. Therefore, S_N2 reactions are bimolecular. A bimolecular reaction is an elementary reaction that occurs between two reactants. An S_N1 reaction has only one molecule involved in the rate-determining step; therefore, S_N1 reactions are unimolecular. A unimolecular reaction is an elementary reaction with one reactant.

The overall mechanisms for S_N1 and S_N2 reactions are similar. However, an S_N2 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 S_N1 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 S_N2 reaction is that the nucleophile attacks the substrate, which causes the leaving group to leave. In an S_N1 reaction, the leaving group leaves on its own, followed by a nucleophilic attack.

For an S_N1 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 S_N2 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 S_N2 reaction is usually less substituted (methyl, primary, or secondary).

The size of the groups attached to or near the electrophilic carbon affects how the reaction proceeds. In an S_N2 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, S_N2 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 S_N2 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).

S_N1 reactions dominate when the electrophilic carbon is more substituted, while S_N2 reactions dominate when the electrophilic carbon is less substituted. For example, a primary alkyl halide is more apt to undergo an S_N2 reaction, whereas a tertiary alkyl halide is more apt to undergo an S_N1 reaction. S_N1 and S_N2 reactions each require similar conditions, so the enantiomeric product from the S_N2 reaction and the racemic products from the S_N1 reaction compete with each other. Since S_N1 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 S_N2 mechanism that leads to an inversion of stereochemistry at the electrophilic carbon. Tertiary electrophilic carbons proceed through an S_N1 mechanism, which leads to a racemic product.

Secondary carbons can proceed through an S_N1 or S_N2 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.