The SN1 and SN2 reactions are two of the methods utilized in synthetic reactions in organic chemistry. They are convenient synthetic reactions that all organic chemists are sure to use them.
The SN1 and SN2 reactions are synthetic reactions, called nucleophilic substitution reactions, in which the substituents are swapped.
However, the reaction mechanism differs depending on the type of compound to be reacted with. In addition, the ease with which the synthetic reaction proceeds also differs. Without learning these reaction mechanisms, you will not be able to obtain your desired compounds. The solvent used in the synthesis is also important.
In this section, we will explain in an easy-to-understand manner how the synthetic reaction proceeds in terms of the reaction mechanism of SN1 and SN2 reactions, which can be said to be the basis of organic chemistry.
Table of Contents
- 1 A Material with High Electron Density Is a Nucleophile (Nu)
- 2 The Two-Step Reaction Is the SN1 Reaction
- 3 Three-Dimensional Inversion SN2 Reaction: Walden Inversion
- 4 Comparing the Difference Between the SN1 and SN2 Reactions
- 5 Differences in Stability Due to Solvent Effects
- 6 Distinguishing the Likelihood of Nucleophilic Substitution Reactions
A Material with High Electron Density Is a Nucleophile (Nu)
Before we can learn about nucleophilic substitution reactions, we must understand what a nucleophile (Nu) is in the first place. In a nucleophile (or nucleophilic reagent), they all have a high electron density. As a result, they try to make new bonds by attacking other compounds.
So, when does a high electron density increase and act as a nucleophile? A compound is more likely to be a nucleophilic reagent if it meets the following conditions.
- There is an unshared electron pair (lone pair).
- High electronegativity.
Atoms with a high degree of electronegativity are more likely to be electron-rich by attracting more electrons. In addition, the presence of an unshared electron pair makes it easier for lone pair not involved in the bond to attack other molecules.
These are widely known to function as nucleophiles. In addition, they tend to become nucleophilic reagents when they are negatively charged, such as anions.
Nucleophilic Substitution Reaction with the Presence of a Leaving Group (L)
Does the presence of a nucleophilic agent always cause a nucleophilic substitution reaction? Of course not. In addition to the presence of a nucleophile, there is another condition for a nucleophilic substitution reaction: the presence of a leaving group (L). The nucleophilic substitution reaction proceeds because of the presence of a leaving group.
Molecules (or atoms) that are easily stabilized by receiving electrons tend to become leaving groups. Typical leaving groups include halogens.
- Chlorine (Cl)
- Bromine (Br)
- Iodine (I)
These tend to be the leaving groups (L). The presence of the leaving groups allows the reaction to proceed as follows, for example.
It’s hard to understand with symbols like Nu and L. In an actual synthetic reaction, it looks like the following.
In this way, the leaving group and the nucleophilic reagent are replaced. This is why it is called a substitution reaction. Although halogens can function as nucleophiles, they are frequently used as leaving groups.
Although the reaction mechanisms are different, both SN1 and SN2 reactions involve leaving groups.
The Two-Step Reaction Is the SN1 Reaction
Now let’s see what the synthetic reaction actually looks like.
In the SN1 reaction, the start of the synthetic reaction is the separation of the leaving group. This results in the formation of a carbocation. In all SN1 reactions, the departure of the leaving group is the start.
You may wonder if the bond is covalently and strongly bonded, but it breaks off and leaves on its own. However, the leaving group will try to break the covalent bond and leave on its own.
Halogens, for example, are known for their high degree of electronegativity. As a result, they are divided into positive and negative charges within the molecule and are polarized. Because of the large charge bias, halogens are willing to move away from the molecule if the opportunity arises. So the leaving groups leave the molecule and carbocation is formed.
But the carbocation is an unstable intermediate, so the compound tries to maintain its molecular shape by re-capturing the separated halogen.
But what if there is a nucleophile in the same solution? In this case, the nucleophilic reagent attacks the carbocation at the moment the leaving group leaves the molecule.
The nucleophile attacks the carbocation faster than the carbocation tries to catch a leaving group (such as a halogen). As a result, the SN1 reaction occurs.
- The leaving group leaves and gives rise to a carbocation.
- The nucleophilic agent attacks the carbocation.
Because of the two reactions involved, the SN1 reaction is said to be a two-step reaction.
Stable Carbocation Causes an SN1 Reaction
The formation of the carbocation is a prerequisite for the SN1 reaction. Therefore, how easily the carbocation is formed plays a major role in the reaction rate. More precisely, the more stable the intermediate carbocation is, the faster the reaction rate is.
There is no doubt that the carbocation is an unstable intermediate. However, if the intermediate is not formed, the leaving group will not separate and produce an SN1 reaction. Therefore, the stability of the carbocation is very important as a factor in whether or not the SN1 reaction occurs.
The carbocation is stable in the following order.
The more alkyl chains that are attached to the carbocation, the more stable the intermediate is likely to be. In fact, it does not naturally give rise to a primary carbocation. On the other hand, a tertiary carbocation tends to be a stable structure.
The Rate of the SN1 Reaction Depends on a Single Molecule
Why is it called the SN1 reaction? This is because there is only one molecule in a nucleophilic substitution reaction that is involved in the reaction rate (rate-determining step). The rate-determining step (or rate-limiting step) is the part that determines the reaction rate. Since there is only one rate-determining step, we call it the “SN1 reaction” using the number 1.
What is the rate-determining step in the SN1 reaction? It is not the nucleophile that determines the reaction rate in the SN1. Rather, the rate-limiting step is the formation of the carbocation.
As soon as the carbocation is produced, the nucleophilic reagent attacks the carbocation. However, if no carbocation is produced, the SN1 reaction does not occur. No matter how highly nucleophilic the reagent (high electron density reagent) is, the reaction rate of the SN1 reaction does not change rate, because it is important that the carbocation is produced.
In the SN1 reaction, only the compounds to which leaving groups are attached are involved in the rate of the reaction. Nucleophiles do not play a role in the rate of the reaction.
The rate-determining step of the SN1 reaction may be illustrated using an energy diagram. The energy diagram is shown below.
The SN1 reaction requires the first and highest energy to be generated by the carbocation. The high energy state is called the transition state. A large amount of energy is required to reach the transition state.
On the other hand, when the nucleophile is attacking, the energy of the transition state is low. Therefore, once the initial reaction is underway, the rest of the chemical reaction proceeds automatically. For this reason, the first stage of the SN1 reaction is the rate-limiting step.
The probability of the SN1 reaction is as follows.
- Tertiary > Secondary > > > Primary > Methyl cation
We have already mentioned that the SN1 reaction does not occur with primary carbocations. This is simply because primary carbocations produce very little. On the other hand, the SN1 reaction proceeds at a slower rate with secondary carbocations. The reaction rate is faster in the case of tertiary carbocations.
As a reminder, the SN1 reaction proceeds exceptionally well with allyl cation and benzyl cation, even for primary carbocation.
In an allyl and benzyl cation, there is a double bond next to it. This allows resonance structures to be written and stabilizes the structure of the cation. This results in an SN1 reaction.
In Stereochemistry, the SN1 Reaction Results in Racemic Mixture
In the stereochemistry of the SN1 reaction, racemization occurs. In other words, if you have to consider stereochemistry, you should understand that two substances are created by racemic bodies.
After the carbocation is formed, the nucleophile can attack the chiral carbon atom from two directions, from above or below. The result is racemization.
Of course, if the substituents attached to the carbocation are the same, the stereochemistry is irrelevant because it is not a chiral carbon atom. Therefore, the racemic mixture is not formed. However, if the substituents attached to the chiral carbon are all different, a mirror image isomer will be produced.
Racemic isomers are important in stereochemistry. Understand that in the SN1 reaction, racemization causes the products to mix together.
Three-Dimensional Inversion SN2 Reaction: Walden Inversion
On the other hand, what does the SN2 reaction look like? Unlike the racemic SN1 reaction, the SN2 reaction reverses in three dimensions when it is attacked from the opposite side.
The SN2 reaction does not produce a carbocation. Instead, the nucleophile attacks from the opposite side, as shown below, and the transitional state is followed by the formation of a sterically inverted compound.
In this way, the nucleophilic reagent attacks in a way that replaces the leaving group.
When a carbocation is produced, as in the SN1 reaction, the nucleophile can attack from two directions: above and below. On the other hand, in the SN2 reaction, the nucleophile only attacks from the opposite direction and does not racemization. In this case, only one sterically inverted compound is produced.
The reaction in which the chiral center of the molecule changes is called Walden inversion. There are several organic chemical reactions that can cause Walden inversion, and the SN2 reaction is one of them.
Tertiary Alkyl Groups Don’t Cause Reactions Due to Steric Hindrance
The SN2 reaction is more likely to occur with methyl and primary alkyl groups. Secondary alkyl groups slow down the reaction rate and tertiary alkyl groups do not cause the SN2 reaction to occur.
In other words, let’s assume that the order of reactivity is the opposite of the SN1 reaction. Why does the SN2 reaction not occur with tertiary alkyl groups? This has to do with steric hindrance.
In tertiary alkyl groups, many substituents are attached to them. These substituents prevent the nucleophile from approaching the target carbon atom when it tries to attack it from the opposite side. As a result, the SN2 reaction does not occur.
For example, suppose that a nucleophilic substitution reaction is carried out for tert-butyl bromide. In this case, the SN2 reaction does not occur due to a steric hindrance. However, the SN2 reaction does occur with bromoethane.
If you write a structural formula like this, you can understand why a nucleophilic reagent cannot attack from the other side in a tertiary alkyl group. In organic chemistry, it is necessary to consider steric hindrances.
Note that although tert-butyl bromide does not cause the SN2 reaction, it does cause the SN1 reaction. This is as explained in the previous section.
-Cyclic Compounds Such as Cyclohexane Have Inferior Reactivity
For reference, it is known that the reactivity of the SN2 reaction is slower in cyclic compounds such as cyclohexane than in other compounds. What is the reason for this?
In cyclohexane, there is a known steric hindrance caused by hydrogen atoms. This is called 1,3-diaxial interaction. Hydrogen atoms in the 1 and 3 positions of cyclohexane cause steric hindrance in the axial.
In organic chemistry, differences in reaction rates can often be explained by steric hindrances.
Reactivity Varies Depending on the Type and Concentration of Nucleophilic Reagents and Leaving Groups
In the case of the SN2 reaction, the nucleophile is involved in the rate of the reaction; in the SN1 reaction, the nucleophile was not involved in the rate-limiting step. In the SN2 reaction, however, the nucleophile is involved in the rate of the reaction because it attacks from the opposite side.
The stronger the nucleophilicity (basicity) and the higher the concentration of the nucleophile, the more likely the SN2 reaction will occur. In other words, two factors are involved in the rate of the SN2 reaction. For this reason, the number 2 is used in the SN2 reaction.
Also, even with the same nucleophilic reagent, the more negatively charged a compound is, the stronger its nucleophilic properties will be. As mentioned above, the stronger the basicity, the stronger the nucleophilic property. The order of nucleophilicity is as follows.
- CH3O- > CH3OH
- C6H5NH2 > C6H5NH3+
This is easy to understand, because it is natural that the basicity becomes stronger with a negative charge. The energy diagram of the SN2 reaction is as follows.
When energy is added, a transition state is created. In this case, both the nucleophile and the reactive compound are involved in the reactivity.
Williamson Ether Synthesis Is an SN2 Reaction with Halogen Substitution
These synthetic reactions by SN2 reactions are also used in name reactions. In organic synthesis, there are many name reactions that utilize the name of the discoverer. One of these name reactions is the Williamson ether synthesis.
It is important to understand that Williamson ether synthesis is, in essence, a method of synthesizing ethers through the SN2 reaction. Therefore, the content is very simple if you understand what we have been talking about. The oxygen atom of the alcohol attacks the carbon atom to which the halogen is attached and the ether is synthesized by the SN2 reaction.
When performing ether synthesis, Williamson ether synthesis is frequently used.
However, the SN2 reaction is beneficial in all organic reactions, not just Williamson ether synthesis. In addition to alcohol, many types of molecules with other functional groups can be used to make many different types of molecules. They are as follows.
Nucleophilic substitution reactions can be used to synthesize a very large number of compounds. Let’s assume that all organic chemists use nucleophilic substitution reactions.
Comparing the Difference Between the SN1 and SN2 Reactions
Let’s try to sort out what the differences are when comparing these SN1 and SN2 reactions. They can be summarized as follows.
|SN1 reaction||SN2 reaction|
|Reaction rate||Reaction compounds||Nucleophiles and reaction compounds|
|Reaction||Single-molecule reactions||Double-molecule reactions|
|Number of reactions||Two-step reaction||One-step reaction|
Also, depending on the alkyl chain to which it is attached, such as tertiary or secondary, the reaction is either SN1 or SN2. This is shown below.
|SN1||Excellent||Good||No reaction||No reaction|
Depending on the substituents in the reaction compound, which reaction takes place will vary.
Leaving Groups (the Nature of the Halogen) Are Involved in the Reactivity
Incidentally, the SN1 and SN2 reactions have one thing in common in that the leaving groups are involved in the reactivity. The better the leaving group attached to the reactant compound, the easier the organic synthesis reaction occurs.
What kind of leaving group has the highest reactivity? The more easily the leaving group takes a stable state after leaving, the higher the leaving ability. The more stable the compound (conjugated base) after the release, the more likely it is that the leaving group will want to break the bond and move freely, so the higher the leaving capacity.
Specifically, what kind of molecule has a higher leaving capacity? In this regard, the higher the acidity of the substance produced by the leaving (the less basic it is), the better the leaving capacity.
The stronger the acidity of a substance, the more likely it is to exist as an ion in solution. Therefore, the more acidic the compound is, the more stable it will be after leaving. The acidity of halogens, in order, is as follows.
- HI (hydrogen iodide) > HBr (hydrogen bromide) > HCl (hydrogen chloride) > HF (hydrogen fluoride)
Therefore, the leaving capacity in the nucleophilic substitution reaction is in the following order.
- I (iodine) > Br (bromine) > Cl (chlorine) > F (fluorine).
When comparing iodine and fluorine, fluorine has a higher degree of electronegativity. Therefore, fluorine has a greater degree of polarization and seems to be the better leaving group. However, considering the stability after the leaving, iodine is superior because of its higher acidity.
Differences in Stability Due to Solvent Effects
In the nucleophilic substitution reaction, the reactivity varies depending on the solvent used. This is called the solvent effect. The solvent effect differs between the SN1 and SN2 reactions, so it is necessary to identify the solvent to be used.
The three main solvents used in organic synthesis are as follows
- Protic solvent
- Aprotic solvent
- Non-polar solvent
Let’s find out what each of the solvents is like.
-Polar Protic Solvents Strongly Stabilize Ions
Methanol (CH3OH), ethanol (CH3CH2OH), and acetic acid (CH3COOH) are known to be protic solvents. These molecules have strongly positively charged hydrogen atoms.
When a hydrogen atom binds to an atom with a high degree of electronegativity, such as an oxygen atom, the hydrogen atom becomes positively charged. As a result, they can form hydrogen bonds. The strongest type of polarization bond is the hydrogen bond.
Protic solvents are solvents that allow hydrogen bonding. In protic solvents, any ion with a positive or negative charge will be stable in solution.
A positively charged molecule will interact with a negatively charged solvent atom. A negatively charged molecule will interact with a positively charged hydrogen atom. As a result, the compound in solution will be stabilized.
For nucleophiles and leaving groups, acidity and basicity are important for reactivity. It is important to understand that these polar protic solvents strongly stabilize ions.
-Polar Aprotic Solvents Weakly Stabilizes Ions
In contrast, aprotic solvents exist. Because of the presence of oxygen and nitrogen atoms in the molecule, polar aprotic solvents are polarized. However, hydrogen atoms are not directly bonded to oxygen or nitrogen atoms, and therefore cannot make hydrogen bonds.
These compounds are polar aprotic solvents. The following are known aprotic solvents
- DMF (N,M-dimethylformamide)
- DMSO (dimethyl sulfoxide)
Although not hydrogen bonds, these molecules are polarized by oxygen and nitrogen atoms. As a result, they weakly stabilize the ions.
Therefore, consider that the use of aprotic solvents will stabilize the ions of the nucleophiles and leaving groups a bit.
-Non-polar Solvents Do Not Contribute to Stabilization
Non-polar solvents are molecules with only alkyl chains. Non-polar solvents include, for example, the following
These non-polarizing solvents are not polarized and therefore cannot stabilize either the cations (positive charge) or the anions (negative charge).
The Likelihood of SN1 and SN2 Reactions Varies with the Solvent
Because the properties of these solvents vary, the reactivity of the reaction depends on the solvent used. For a nucleophilic substitution reaction, consider the following.
- SN1 reaction: protic solvents are superior
- SN2 reaction: aprotic or non-polar solvents are superior
Why is there such a difference? Let’s start with the SN1 reaction.
The reactivity of the SN1 reaction depends solely on the reaction compound. The better the stability of the leaving group, the easier it is to produce carbocation and the higher the reaction rate. After the leaving groups are released, negative ions are produced. In order to stabilize these ions, the presence of a polarized solvent makes them more stable.
Also, the carbocation is positively charged, and the use of a polarized solvent stabilizes the cation. For this reason, the SN1 reaction can easily proceed in the following order
- Protic solvents > aprotic solvents > Non-polar solvents
In an energy diagram, it looks like the following.
The SN1 reaction is more likely to occur when polar protic solvents are used because the initial activation energy required to produce the intermediate is reduced.
-Solvent Effect in the SN2 Reaction
On the other hand, what about the solvent effect in SN2 reaction? In the SN2 reaction, the ion of the leaving group is stabilized, so protic solvents seem to be more reactive.
However, in the SN2 reaction, not only the compounds subjected to nucleophilic attack, but also the nucleophile plays an important role in the reaction rate. Therefore, the use of protic or aprotic polar solvents will stabilize the nucleophile. In other words, the ability of the nucleophile to attack the compound is weakened.
In the energy diagram, it looks like the following.
There is no significant difference in peak activation energy. On the other hand, the use of a polarized solvent stabilizes the nucleophile (ion). As a result, the more polarized a solvent is used, the more activation energy is required for the reaction.
Because more energy is required to enter the transition state, the SN2 reaction does not utilize protic solvents. Aprotic polar solvents or non-polar solvents are commonly used. Protic polar solvents make the SN2 reaction less likely to occur.
Distinguishing the Likelihood of Nucleophilic Substitution Reactions
One of the most important chemical reactions in organic synthesis is the nucleophilic substitution reaction. It is a convenient synthetic reaction that it can be said that all organic chemists use the SN1 and SN2 reactions. It is the mixing of a compound with a leaving group and a nucleophilic reagent that causes these reactions to occur.
There are two types of nucleophilic substitution reactions: SN1 and SN2 reactions. Although they are the same nucleophilic substitution reaction, the reactions may be more or less likely to occur under certain conditions. The following factors play a role in these reactions.
- The state of the reacting compound (tertiary, primary, etc.)
- Nucleophile to be used
- The bonded leaving groups
- Solvents used in synthetic reactions
Let’s distinguish between these and consider whether the SN1 or SN2 reaction will occur.
Furthermore, it is the nucleophilic substitution reaction that must be predicted in terms of reactivity and the compounds to be formed, taking even stereochemistry into account. It is important to understand these reaction mechanisms to synthesize organic compounds.