Alkyl halides: Factors affecting SN2 versus SN1 reactions

FACTORS AFFECTING S_N2 VERSUS S_N1 REACTIONS

Key Notes

S_N1 versus S_N2

The nature of the nucleophile, the solvent, and the alkyl halide determine whether nucleophilic substitution takes place by the S_N1 or the S_N2 mecha-nism. With polar aprotic solvents, primary alkyl halides react faster than sec-ondary halides by the S_N2 mechanism, whereas tertiary alkyl halides hardly react at all. With polar protic solvents and nonbasic nucleophiles, tertiary alkyl halides react faster than secondary alkyl halides by the SN1 mechanism, and primary halides do not react. The reactivity of primary, secondary, and tertiary alkyl halides is controlled by electronic and steric factors.

Solvent

Polar, aprotic solvents are used for S_N2 reactions since they solvate cations but not anions. As a result, nucleophiles are ‘naked’ and more reactive. Protic  solvent  such  as  water  or  alcohol  are  used  in  S_N1  reactions  since they solvate and stabilize the intermediate carbocation. The nucleophile is also  solvated,  but  this  has  no  effect  on  the  reaction  rate  since  the  rate is dependent on the concentration of the alkyl halide.

Nucleophilicity

The rate of the S_N2 reaction increases with the nucleophilic strength of the incoming nucleophile. The rate of the S_N1 reaction is unaffected by the nature of the nucleophile.

Leaving group

The reaction rates of both the S_N1 and the S_N2 reaction is increased if the leaving group is a stable ion and a weak base. Iodide is a better leaving group than bromide and bromide is a better leaving group than chloride. Alkyl fluorides do not undergo nucleophilic substitution.

Alkyl halides – S_N2

Tertiary alkyl groups are less likely to react by the S_N2 mechanism than pri- mary or secondary alkyl halides since the presence of three alkyl groups linked to the reaction center lowers the electrophilicity of the alkyl halide by inductive  effects.  Tertiary  alkyl  halides  have  three  bulky  alkyl  groups attached to the reaction center which act as steric shields and hinder the approach of nucleophiles. Primary alkyl halides only have one alkyl group attached to this center and so access is easier.

Alkyl halides – S_N1

Formation of a planar carbocation in the first stage of the S_N1 mechanism is favored for tertiary alkyl halides since it relieves the steric strain in the crowded tetrahedral alkyl halide. The carbocation is also more accessible to an incoming nucleophile. The formation of the carbocation is helped by electronic factors involving the inductive and hyperconjugationeffects of the three neighboring alkyl groups. Such inductive and hyperconjugation effects are greater in carbocations formed from tertiary alkyl halides than from those formed from primary or secondary alkyl halides.

Determining the mechanism

Measuring how the reaction rate is affected by the concentration of the alkyl halide and the nucleophile determines whether a nucleophilic substitution is S_N2 or S_N1. Measuring the optical activity of products from the nucleo-philic substitution of asymmetric alkyl halides indicates the type of mecha-nism involved. A pure enantiomeric product indicates an S_N2 reaction. A partially or fully racemized product indicates an S_N1 reaction.

S_N1 versus S_N2

There are two different mechanisms involved in the nucleophilic substitution of alkyl  halides.  When  polar  aprotic  solvents  are  used,  the  S_N2  mechanism  is preferred. Primary alkyl halides react more quickly than secondary alkyl halides, with tertiary alkyl halides hardly reacting at all. Under protic solvent conditions with nonbasic nucleophiles (e.g. dissolving the alkyl halide in water or alcohol), the S_N1 mechanism is preferred and the order of reactivity is reversed. Tertiary alkyl halides are more reactive than secondary alkyl halides, and primary alkyl halides do not react at all.

There are several factors which determine whether substitution will be S_N1 or S_N2 and which also control the rate at which these reactions take place. These include the nature of the nucleophile and the type of solvent used. The reactivity of primary, secondary, and tertiary alkyl halides is controlled by electronic and steric factors.

Solvent

The S_N2 reaction works best in polar aprotic solvents (i.e. solvents with a high dipole moment, but with no O–H or N–H groups). These include solvents such as acetonitrile  (CH₃CN)  or  dimethylformamide  (DMF).  These  solvents  are  polar enough to dissolve the ionic reagents required for nucleophilic substitution, but they do so by solvating the metal cation rather than the anion. Anions are solvated by hydrogen bonding and since the solvent is incapable of hydrogen bonding, the anions remain unsolvated. Such ‘naked’ anions retain their nucleophilicity and react more strongly with electrophiles.

Polar, protic solvents such as water or alcohols can also dissolve ionic reagents but they solvate both the metal cation and the anion. As a result, the anion is ‘caged’ in by solvent molecules. This stabilizes the anion, makes it less nucleo- philic and makes it less likely to react by the S_N2 mechanism. As a result, the S_N1 mechanism becomes more important.

The S_N1 mechanism is particularly favored when the polar protic solvent is also a nonbasic nucleophile. Therefore, it is most likely to occur when an alkyl halide is dissolved in water or alcohol. Protic solvents are bad for the S_N2 mechanism since they solvate the nucleophile, but they are good for the S_N1 mechanism. This is because polar protic solvents can solvate and stabilize the carbocation interme- diate. If the carbocation is stabilized, the transition state leading to it will also be stabilized and this determines whether the S_N1 reaction is favored or not. Protic solvents will also solvate the nucleophile by hydrogen bonding, but unlike the S_N2 reaction, this does not affect the reaction rate since the rate of reaction is independent of the nucleophile.

Nonpolar solvents are of no use in either the S_N1 or the S_N2 reaction since they cannot dissolve the ionic reagents required for nucleophilic substitution.

Nucleophilicity

The relative nucleophilic strengths of incoming nucleophiles will affect the rate of the S_N2 reaction with stronger nucleophiles reacting faster. A charged nucleophile is stronger than the corresponding uncharged nucleophile (e.g. alkoxide ions are stronger nucleophiles than alcohols). Nucleophilicity is also related to base strength when the nucleophilic atom is the same (e.g. RO^- > HO^- > RCO₂^- > ROH^- > H₂O). In polar aprotic solvents, the order of nucleophilic strength for the halides is F^- > Cl^- > Br^- >I^- .

Since the rate of the S_N1 reaction is independent of the incoming nucleophile, the nucleophilicity of the incoming nucleophile is unimportant.

Leaving group

The nature of the leaving group is important to both the S_N1 and S_N2 reactions – the better the leaving group, the faster the reaction. In the transition states of both reactions, the leaving group has gained a partial negative charge and the better that can be stabilized, the more stable the transition state and the faster the reaction. Therefore, the best leaving groups are the ones which form the most stable anions. This is also related to basicity in the sense that the more stable the anion, the weaker the base. Iodide and bromide ions are stable ions and weak bases, and prove to be good leaving groups. The chloride ion is less stable, more basic and a poorer leaving group. The fluoride ion is a very poor leaving group and as a result alkyl fluorides do not undergo nucleophilic substitution. The need for a stable leaving group explains why alcohols, ethers, and amines do not undergo nucleophilic substitutions since they would involve the loss of a strong base (e.g. RO or R₂N^- ).

Alkyl halides – S_N2

There are two factors which affect the rate at which alkyl halides undergo the S_N2 reaction – electronic and steric. In order to illustrate why different alkyl halides react at different rates in the S_N2 reaction, we shall compare a primary, secondary, and tertiary alkyl halide (Fig. 1).

Alkyl groups have an inductive, electron-donating effect which tends to lower the electrophilicity of the neighboring carbon center. Lowering the electrophilic strength means that the reaction center will be less reactive to nucleophiles. There-fore, tertiary alkyl halides will be less likely to react with nucleophiles than primary alkyl halides, since the inductive effect of three alkyl groups is greater than one alkyl group.

Steric factors also play a role in making the S_N2 mechanism difficult for tertiary halides. An alkyl group is a bulky group compared to a hydrogen atom, and can therefore act like a shield against any incoming nucleophile (Fig. 2). A tertiary alkyl halide has three alkyl shields compared to the one alkyl shield of a primary alkyl halide. Therefore, a nucleophile is more likely to be deflected when it approaches a tertiary alkyl halide and fails to reach the electrophilic center.

Alkyl halides – S_N1

Steric and electronic factors also play a role in the rate of the S_N1 reaction. Since the steric bulk of three alkyl substituents makes it very difficult for a nucleophile to reach the electrophilic carbon center of tertiary alkyl halides, these structures undergo nucleophilic substitution by the S_N1 mechanism instead. In this mecha-nism, the steric problem is relieved because loss of the halide ion creates a planar carbocation where the alkyl groups are much further apart and where the carbon center is more accessible. Formation of the carbocation also relieves steric strain between the substituents.

Electronic factors also help in the formation of the carbocation since the positive charge can be stabilized by the inductive and hyperconjugative effects of the three alkyl groups.

Both the inductive and hyperconjugation effects are greater when there are three alkyl groups connected to the carbocation center than when there are only one or two. Therefore, tertiary alkyl halides are far more likely to produce a stable carbocation intermediate than primary or secondary alkyl halides. It is important to realize that the reaction rate is determined by how well the transition state of the rate determining step is stabilized. In a situation like this where a high energy intermediate is formed (i.e. the carbocation), the transition state leading to it will be closer in character to the intermediate than the starting material. Therefore, any factor which stabilizes the intermediate carbocation also stabilizes the transition state and consequently increases the reaction rate.

Determining the mechanism

It is generally fair to say that the nucleophilic substitution of primary alkyl halides will take place via the S_N2 mechanism, whereas nucleophilic substitution of ter-tiary alkyl halides will take place by the S_Nl mechanism. In general, secondary alkyl halides are more likely to react by the S_N2 mechanism, but it is not possible to predict this with certainty. The only way to find out for certain is to try out the reaction and see whether the reaction rate depends on the concentration of both reactants (S_N2) or whether it depends on the concentration of the alkyl halide alone (S_Nl).

If the alkyl halide is chiral the optical rotation of the product could be measured to see whether it is a pure enantiomer or not. If it is, the mechanism is S_N2. If not, it is S_N1.