7.10: The SN2 Mechanism (2023)

the ace_norte2 mechanism

There are two mechanistic models of how an alkyl halide can undergo nucleophilic substitution. In the first picture, the reaction occurs in a single step, with bond formation and bond breaking occurring simultaneously. (In all figures in this section, 'X' indicates a halogen substituent.)

This is called 'S_norte2'mechanism. In terms_norte2, S stands for 'replacement', the subscript N stands for 'nucleophilic' and the number 2 refers to the fact that it is abimolecular reaction: the overall speed depends on a step in which two separate molecules (the nucleophile and the electrophile) collide. A potential energy diagram for this reaction shows the transition state (TS) as the highest point on the path from reactants to products.

If you look closely at the progress of S_norte2 reaction, you will notice something very important about the result. The nucleophile, being an electron-rich species, must attack the electrophilic carbon of thereversein relation to the location of the leaving group. The front approach simply doesn't work: the leaving group, which is also an electron-rich group, blocks the way.

The result of this back attack is that the stereochemical configuration at the central carboninvestas the reaction proceeds. In a sense, the molecule is backwards. In the transition state, the electrophilic carbon and the three 'R' substituents are all in the same plane.

What this means is that S_norte2 reactions, whether enzyme-catalyzed or not, are inherently stereoselective: when substitution occurs at a stereocenter, we can confidently predict the stereochemical configuration of the product. Below is an animation illustrating the principles we just learned, showing the S_norte2 reaction between hydroxide ion and methyl iodide. Note how retrograde attack on the hydroxide nucleophile results in inversion on the carbon tetrahedral electrophile.

Verbal description:

The reaction from the previous exercise can be explained using appropriate chemical terminology.

(R)-2-iodobutane is reacted with methanethiolate. One of the sulfur lone pairs attacks the C2 of iodobutane, forming a new bond. At the same time, the bond between C2 and iodine is broken, causing an iodide to form. The final product is (S)-2-methylsulfanylbutane.

We will be contrasting two types of nucleophilic substitution reactions. One type is calledunimolecular nucleophilic substitution (S_norte1), where the rate-determining step is unimolecular andbimolecular nucleophilic substitution (S_norte2), then the rate-determining step is bimolecular. We will begin our discussion with S._norte2 reactions and discuss S_norte1 reactionselsewhere.

Biomolecular nucleophilic substitution reactions and kinetics

In terms_norte2, the S stands for substitution, the N stands for nucleophile, and the number two stands for bimolecular, meaning that there are two molecules involved in the rate-determining step. The rate of bimolecular nucleophilic substitution reactions depends on the concentration of both the haloalkane and the nucleophile. To understand how the rate depends on the concentrations of both the haloalkane and the nucleophile, let's look at the following example. The hydroxide ion is the nucleophile and the methyl iodide is the haloalkane.

If we double the concentration of the haloalkane or the nucleophile, we can see that the reaction rate would occur twice as fast as the initial rate.

If we double the concentration of both the haloalkane and the nucleophile, we can see that the reaction rate would occur four times faster than the initial rate.

The bimolecular nucleophilic substitution reaction follows second-order kinetics; that is, the reaction rate depends on the concentration of two first-order reactants. In the case of bimolecular nucleophilic substitution, these two reagents are the haloalkane and the nucleophile. For further clarification on reaction kinetics, the following links may help in understanding rate laws, rate constants, and second-order kinetics:

• Setting a reaction rate
• Rate laws and rate constants
• The determination of the rate law
• second order reactions

Combined bimolecular nucleophilic substitution reactions

bimolecular nucleophilic substitution (SN₂) the reactions areconcerted, which means they areone step process. This means that the process by which the nucleophile attacks and the leaving group leaves is simultaneous. Therefore, the formation of bonds between the nucleophile and the electrophilic carbon occurs at the same time as the breaking of the bond between the electrophilic carbon and the halogen.

The potential energy diagram for an SN₂reaction is shown below. After nucleophilic attack, a single transition state is formed. A transition state, unlike a reaction intermediate, is a very short-lived species that cannot be isolated or observed directly. Again, this is a concerted one-step process with only one state transition occurring.

Sterically hindered substrates will reduce S_norte2 reaction rate

Now that we have discussed the effects that the leaving group, the nucleophile, and the solvent have on biomolecular nucleophilic substitution (S_norte2) reactions, it's time to turn our attention to how the substrate affects the reaction. Although the substrate, in the case of nucleophilic substitution of haloalkanes, is considered the entire molecule circled below, we will pay special attention to the alkyl portion of the substrate. In other words, what interests us most is the electrophilic center that carries the leaving group.

in the sectionKinetics of nucleophilic substitution reactions, we learn that the SN₂the transition state is too crowded. Remember that there are a total of five groups around the electrophilic center, the nucleophile, the leaving group, and three substituents.

If each of the three substituents in this transition state were small hydrogen atoms, as illustrated in the first example below, there would be little steric repulsion between the incoming nucleophile and the electrophilic center, increasing the ease with which the nucleophilic substitution reaction can take place. . Remember, for the SN₂For the reaction to occur, the nucleophile must be able to attack the electrophilic center, resulting in the expulsion of the leaving group. However, if one of the hydrogens were replaced by an R group, such as a methyl or ethyl group, there would be an increase in steric repulsion with the incoming nucleophile. If two of the hydrogens were replaced by R groups, there would be an even greater increase in steric repulsion with the incoming nucleophile.

How does steric hindrance affect the rate at which an SN₂will the reaction occur? As each hydrogen is replaced by an R group, the rate of the reaction slows down significantly. This is because the addition of one or two R groups protects the back of the electrophilic carbon, preventing nucleophilic attack.

The diagram below illustrates this concept, showing that electrophilic carbons bonded to three hydrogen atoms result in faster nucleophilic substitution reactions, compared to primary and secondary haloalkanes, which result in nucleophilic substitution reactions occurring at faster, slower, or much faster rates. slower, respectively. Note that a tertiary haloalkane, one with three R groups attached, does not undergo any nucleophilic substitution reactions. The addition of a third R group to this molecule creates a completely blocked carbon.

Substitutes on neighboring carbons Slow nucleophilic substitution reactions

We learned earlier that the addition of R groups to the electrophilic carbon results in nucleophilic substitution reactions that occur at a slower rate. What happens if R groups are added to neighboring carbons? It turns out that adding substitutes on neighboring carbons also slows down nucleophilic substitution reactions.

In the example below, 2-methyl-1-bromopropane differs from 1-bromopropane in that it has a methyl group attached to the carbon next to the electrophilic carbon. The addition of this methyl group results in a significant decrease in the rate of a nucleophilic substitution reaction.

If R groups were added to carbons further away from the electrophilic carbon, we would still see a decrease in the reaction rate. However, branching to carbons further away from the electrophilic carbon would have much less of an effect.

frontal attacks vs. rear

A biomolecular nucleophilic substitution (S_norte2) The reaction is a type of nucleophilic substitution in which a lone pair of electrons in a nucleophile attacks an electron-deficient electrophilic center and binds to it, resulting in the ejection of a leaving group. It is possible for the nucleophile to attack the electrophilic center in two ways.

• Frontal Attack:In a frontal attack, the nucleophile attacks the electrophilic center on the same side as the leaving group. When a frontal attack occurs, the stereochemistry of the product remains the same; that is, we have configuration retention.
• back attack:In a rear attack, the nucleophile attacks the electrophilic center on the opposite side of the leaving group. When a rear attack occurs, the stereochemistry of the product does not remain the same. There is configuration inversion.

The following diagram illustrates these two types of nucleophilic attacks, where the frontal attack results in configuration retention; that is, the product has the same configuration as the substrate. Back attack results in configuration inversion, where the configuration of the product is opposite to that of the substrate.

Experimental Observation: InyouS_norte2Eraactions proceed with nucleophilic attacks on the rear

Experimental observation shows that all S_norte2 reactions proceed with inversion of configuration; that is, the nucleophile will always attack from the rear along S_norte2 reactions. To think about why this might be true, remember that the nucleophile has a lone pair of electrons to share with the electrophilic core, and the leaving group will take a lone pair with it as it leaves. Since like charges repel each other, the nucleophile will always proceed via a reverse displacement mechanism.

S_norte2 reactions are stereospecific

the ace_norte2 reaction is stereospecific. A stereospecific reaction is one in which different stereoisomers react to give different stereoisomers of the product. For example, if the substrate is an R enantiomer, a forward nucleophilic attack results in configuration retention and R enantiomer formation. A rearward nucleophilic attack results in configuration reversal and R enantiomer formation.

On the other hand, if the substrate is an S enantiomer, a forward nucleophilic attack results in configuration retention and formation of the S enantiomer. A subsequent nucleophilic attack results in configurational inversion and formation of the R enantiomer.

In conclusion, s._norte2 reactions starting with the R-enantiomer as the substrate will form the S-enantiomer as the product. Those that start with the S enantiomer as the substrate will form the R enantiomer as the product. This concept also applies to substrates that arecisand substrates thattrans. If hecisconfiguration is the substrate, the resulting product will betrans. Conversely, if thetransconfiguration is the substrate, the resulting product will becis.

Collaborators

• Professor Steven Farmer (sonoma state university)

• William Reusch, Professor Emeritus (state of michigan u.),Organic Chemistry Virtual Text Book

  (Video) Ch7 3 SN2 Overview

• Organic Chemistry with Biological Emphasisbytim soderberg(University of Minnesota, Morris)

• jim clark (chemguide.es)

Juan D. Robertoymarjorie c Village(1977)Basic Principles of Organic Chemistry, Second Edition.WA Benjamin, Inc., Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions: "Permission is granted for individual, educational, research, non-commercial reproduction, distribution, display and performance of this work in any format."