Name: sn2 backside attack and inversion
Uploaded: 2023-04-30T18:28:35.000Z
Duration: 2 min 27 s
Channel: JoVE

Kinetic studies of SN2 reactions show that both the nucleophile and the substrate participate in the rate-determining step. However, they do not precisely explain how the molecules arrange during the reaction. To derive the full mechanism of an SN2 reaction, consider the following theories.
Firstly, the substrate contains an electronegative halogen, which creates a polarized carbon-halide bond. This leads to an electrophilic center at the carbon attracting the nucleophile with its lone pair of electrons.
However, the presence of high electron density around the halide effectively blocks the frontside attack. Thus, the nucleophile approaches the electrophile from the side opposite to the leaving group leading to a backside attack.
As the nucleophile donates its lone pair to the electrophile, the leaving group pulls away with the electron pair bonded to the carbon. This results in a transition state where the bond formation between the nucleophile and substrate and the bond breakage between the substrate and leaving group occur simultaneously.
The transition state is highly unstable. To regain stability, the leaving group departs with the electron pair in a concerted manner leading to inversion of the substrate configuration.
Molecular orbital theory further supports the backside attack. The nucleophile&#8217;s lone pair of electrons occupies the highest molecular orbital, or HOMO. To form a bond, the HOMO needs to overlap with the lowest unoccupied molecular orbital, or LUMO, of the electrophile.
When a nucleophile approaches the electrophile from the same side as the leaving group, it faces a node, which results in the HOMO overlapping with the bonding and antibonding LUMO. Yet, no bond forms as the antibonding overlap cancels the bonding overlap.
In contrast, the backside approach of the nucleophile efficiently overlaps the HOMO with the LUMO of the electrophile leading to bond formation.
Thus, both theories support the SN2 reaction mechanism being concerted where the nucleophile attacks from the backside while simultaneously displacing the leaving group and causing an inversion of configuration.

sn2 reaction: mechanism

SN2 Reaction: Mechanism

The kinetic studies of SN2 reactions suggest an essential feature of its mechanism: it is a single-step process without intermediates. Here, both the nucleophile and the substrate participate in the rate-determining step.
The presence of the more electronegative halogen in the substrate creates a polarized carbon-halide bond. The halide pulls the electron cloud generating an electrophilic center at the carbon atom. Thus, the carbon atom carries a partial positive charge while the halide has a partial negative charge. The electrophilic carbon attracts the nucleophile with its lone pair of electrons.
However, the high electron density around the halide effectively blocks the same-side attack by the nucleophile. Thus, the nucleophile approaches the electrophile from the substrate's electron-poor side, leading to a back-sided attack. Therefore, the nucleophile donates its lone pair to the electrophilic carbon, 180&#176; away from the leaving group. 
As the halide departs from the electrophilic carbon, it moves away with the electron pair bonded to the carbon. This results in a transition state with a partially formed bond between the nucleophile and substrate and a partially broken bond between the substrate and leaving group.
With three solid and two partial bonds at the carbon, the transition state is highly unstable. Thus, the leaving group departs with the electron pair bonded to the carbon, leading to inversion of substrate configuration. (Figure 1)
<img alt="SN1 reaction mechanism, chemical equation diagram, illustrating carbocation formation and breakdown." src="/files/ftp_upload/11749/11749_PT_Figure%201.svg" style="text-align: center; height: 110px;" data-altupdatedat="1761830439000" data-alt="Figure1" />
Figure 1. SN2 mechanism
Further, the molecular orbital theory supports the backside attack as well. When the bonding orbital of the nucleophile, i.e., the highest occupied molecular orbital, or HOMO, approaches the lowest unoccupied molecular orbital, or LUMO, of the substrate from the same side as the leaving group, it faces a node canceling both the bonding and the anti-bonding overlap. In contrast, a backside attack by the nucleophile efficiently overlaps with the substrate's LUMO, resulting in bond formation.
Thus, the SN2 mechanism occurs in a single step, when the incoming nucleophile reacts with the substrate from a direction opposite the leaving group, which is displaced.
<h4>Suggested reading:</h4>
<ol>
	<li>Brown, W.H., &#38; Iverson, B.L., &#38; Anslyn, V.E., &#38; Foote S.C. (2014). Organic Chemistry. Mason, Ohio: Cengage Learning, 344-345.</li>
	<li>Solomons, G., &#38; Fryhle, C. &#38; Snyder, S. (2015). Organic Chemistry. New Jersey, NJ: Wiley, 246-248.</li>
	<li>Loudon, M., &#38; Parise, J. (2016). Organic Chemistry. New York, NY: Macmillan Publishers, 391-393.</li>
	<li>Klein, D. (2017). Organic Chemistry. New Jersey, NJ: Wiley, 277-278.</li>
	<li>Clayden, J., &#38; Greeves, N., &#38; Warren, S. (2012). Organic Chemistry. Oxford: Oxford University Press, 340-342.</li>
</ol>

The kinetic studies of SN2 reactions suggest an essential feature of its mechanism: it is a single-step process without intermediates. Here, both the ...

Education

JoVE Core

Organic Chemistry

Unit 1

Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

nucleophilic-substitution-and-elimination-reactions-of-alkyl-halides

KEY TERMS AND CONCEPTS

sn2 backside attack and inversion

SN2 reactions happen in one step and end with inversion of configuration. The nucleophile and the substrate both take part in the rate-determining step, and no intermediate forms.

The substrate contains a polarized carbon-halide bond. The more electronegative halogen pulls the electron cloud toward itself. That leaves the carbon atom electrophilic, or electron-poor, with a partial positive charge. The halide has a partial negative charge.

The electrophilic carbon attracts the nucleophile, which brings a lone pair of electrons. But the electron-rich halide blocks attack from the same side. For that reason, the nucleophile approaches from the opposite side of the leaving group. This is called a backside attack.

In the transition state, the nucleophile is partly bonded to the carbon while the carbon-halide bond is partly broken. The carbon has three solid bonds and two partial bonds, so this state is very unstable. As the halide leaves with the electron pair, the substrate flips and its configuration inverts.

Molecular orbital theory also supports this path. The nucleophile’s highest occupied molecular orbital, or HOMO, matches poorly with the substrate’s lowest unoccupied molecular orbital, or LUMO, from the same side because of a node. A backside attack gives better overlap and allows bond formation. So the SN2 mechanism is a single-step reaction in which the nucleophile attacks opposite the leaving group and displaces it.

SN2 Backside Attack and Inversion

alkyl halides

Alkyl Halides: Structure and Reactivity

Alkyl halides are halogen-substituted alkanes. In these compounds, one or more hydrogen atoms in an alkane is replaced by a halogen atom such as fluorine, chlorine, bromine, or iodine. The carbon bonded to the halogen is sp3-hybridized and has a tetrahedral shape. Not every carbon-halogen compound is an alkyl halide. If the halogen is attached to an sp2-hybridized carbon in a carbon-carbon double bond, the compound is a vinyl halide. If the halogen is attached to an sp2-hybridized carbon in an...

nucleophilic substitution reactions

SN1 and SN2 in Organic Substitution

Nucleophilic substitution reactions replace one group in a molecule with another. In these reactions, a nucleophile, which is a Lewis base, reacts with an electrophile, which is a Lewis acid. The nucleophile takes the place of a halogen atom bonded to carbon and releases a stable ion called the leaving group. This reaction pattern is closely related to Lewis acid-base chemistry. The electron-rich species acts as the nucleophile. The electron-deficient species acts as the electrophile. A key...

nucleophiles

Nucleophilic Strength in Substitution Reactions

Nucleophiles are electron-pair donors that take part in substitution reactions. The word comes from Greek and means nucleus-loving. Because they donate electrons, nucleophiles are also Lewis bases. Many nucleophiles are negatively charged species, such as hydroxide, chloride, and hydrosulfide. Neutral molecules can also act as nucleophiles when they have lone pairs of electrons. Examples include ammonia, amines, water, and alcohols. Some molecules without a lone pair can still behave as...

electrophiles

Electrophile Reactivity in Organic Reactions

Electrophile reactivity in organic reactions depends on how a species attracts electrons. Electrophiles are electron-poor and are key partners in nucleophilic substitution reactions. Their charge and orbital structure help explain why they react the way they do. Electrophiles can be positive or neutral species. A positive electrophile such as a proton reacts because it has a vacant, low-energy 1s orbital. Other positive electrophiles, such as carbocations, are reactive because they have an...

leaving groups

How Leaving Groups Affect Substitution

Leaving groups affect how nucleophilic substitution reactions happen. In this type of reaction, a nucleophile replaces a functional group on a substrate. The group that leaves is called the leaving group, and it departs when the bond breaks by heterolytic cleavage, taking both electrons with it. A good leaving group is usually a stable weak base. It can leave as an anion or as a neutral molecule. The easier it is for the leaving group to leave, the more it can influence the reaction rate. <br...

carbocations

Carbocation Structure and Stability

Carbocations are reactive carbon species formed during some nucleophilic substitution and elimination reactions. They are electron-deficient intermediates, with the central carbon holding only six electrons and three bonded atoms. Because they are short-lived and highly reactive, they play an important role in many organic reaction pathways. The central carbon in a carbocation is sp2 hybridized and has a trigonal planar shape. It also contains an empty p orbital that sits perpendicular to the...

sn2 reaction: kinetics

SN2 Rate Law and Reaction Mechanism

SN2 reaction kinetics links reaction rate to the concentration of reactants. In a chemical reaction, kinetic studies measure how fast reactants disappear or products appear under fixed conditions such as temperature, pressure, and solvent. These studies help chemists find the rate law, which can give clues about the species involved in the rate-determining step and the reaction mechanism. The rate of a reaction is found experimentally. Scientists withdraw small samples, called aliquots, at...

SN2 reactions happen in one step and end with inversion of configuration. The nucleophile and the substrate both take part in the rate-determining step, and no intermediate forms. The substrate contains a polarized carbon-halide bond. The more electronegative halogen pulls the electron cloud toward itself. That leaves the carbon atom electrophilic, or electron-poor, with a partial positive charge. The halide has a partial negative charge. The electrophilic carbon attracts the nucleophile,...

sn2 reaction: transition state

SN2 Reaction: Reactivity and Steric Effects

An SN2 reaction of an alkyl halide happens in one step. The nucleophile forms a bond with the electrophilic carbon while the halide leaves at the same time. No intermediate forms during this process. As the nucleophile approaches with its lone pairs, the leaving group moves away with the electron pair that was bonded to carbon. The transition state is shown with dotted partial bonds and square brackets. This state is very unstable, so it quickly changes into the more favored product state. <br...

sn2 reaction: stereochemistry

SN2 Inversion of Configuration

SN2 reactions cause inversion of configuration at the carbon being substituted. The nucleophile attacks from the back side, while the leaving group departs at the same time. This happens through a transition state, where the carbon changes from tetrahedral to trigonal bipyramidal and then back to tetrahedral. The change in shape helps explain the product stereochemistry. If the substrate is achiral at the alpha-carbon, the inversion is not seen. When the alpha-carbon is chiral, the reversal is...

sn1 reaction: kinetics

SN1 Reaction Rate and Unimolecular Step

SN1 reaction rate depends on the substrate, not the nucleophile. This pattern was identified by Sir Christopher Ingold and Edward D. Hughes while they studied nucleophilic substitution reactions of tertiary alkyl halides. A tertiary alkyl halide can still undergo substitution even when the nucleophile is weak. In their kinetic studies, the rate of product formation stayed the same when the nucleophile concentration changed, as long as the substrate concentration remained constant. That means...

sn1 reaction: mechanism

SN1 Reaction Steps and Carbocation Formation

The SN1 reaction follows a step-by-step pathway that begins with carbocation formation. In a polar protic solvent, a tertiary haloalkane can ionize so that only the substrate takes part in the rate-determining step, which is the slow step. First, the haloalkane undergoes heterolytic cleavage to form a carbocation intermediate and a halide ion. This bond break is highly endothermic and has a large activation energy. The polar protic solvent helps stabilize the ions by solvation, and that makes...

sn1 reaction: stereochemistry

SN1 Pathway and Product Chirality

SN1 reactions can change the chirality of a product because the reaction goes through a carbocation intermediate. First, the bond between the electrophilic carbon and the leaving group ionizes. Then the nucleophile attacks the carbocation. The carbocation formed in an SN1 reaction is sp2 hybridized and has a trigonal planar shape. Its three substituents lie in the same plane, which creates a plane of symmetry. That makes the carbocation achiral, so the nucleophile can approach from either side...

predicting products: sn1 vs. sn2

SN1 and SN2 Reaction Factors

Nucleophilic substitution of alkyl halides can follow an SN1 or SN2 pathway. In an SN2 reaction, the nucleophile attacks as the leaving group leaves at the same time. In an SN1 reaction, the substrate first splits to form a carbocation, which is a positively charged intermediate. The structure of the alkyl halide helps decide which mechanism is more likely. As alkyl substitution increases, steric hindrance also increases, which makes backside attack harder for SN2. More substituted alkyl...

elimination reactions

E2 vs E1 in Alkyl Halide Elimination

Elimination reactions of alkyl halides form alkenes by removing groups from adjacent carbons. A base can act on the substrate instead of causing substitution. It deprotonates the neighboring carbon, and the reaction creates at least one pi bond. The carbon bonded to the halogen is the alpha carbon, and the adjacent carbon is the beta carbon. These are also called beta elimination or 1,2-elimination reactions. Strong bases help drive this process. Common examples include hydroxides, alkoxides,...

e2 reaction: kinetics and mechanism

E2 Elimination: Rate, Base, and Solvent

E2 elimination is a concerted reaction of alkyl halides that forms an alkene. In this mechanism, the base removes a beta hydrogen as the halide leaves from the alpha carbon. The two bonds change at the same time, so the products are formed in one step. The rate-limiting transition state has partially broken carbon-hydrogen and carbon-halogen bonds. It also has a partially formed pi bond between the alpha and beta carbons. Because the beta hydrogen and the halide are eliminated together, the...

e2 reaction: stereochemistry and regiochemistry

e2-reaction-stereochemistry-and-regiochemistry

E2 Elimination: Major and Minor Products

E2 elimination reactions of alkyl halides can form one or more alkenes, and the product mix depends on regiochemistry and stereochemistry. Regiochemistry controls where the double bond appears. Stereochemistry controls the shape of the alkene that forms. When a substrate has two different beta hydrogens, a strong base can remove either one. That can give two regioisomeric alkenes. The more substituted alkene is the major product and is called the Zaitsev product. The less substituted alkene is...

e1 reaction: kinetics and mechanism

E1 Elimination: Carbocation Stability and Rates

E1 elimination depends on carbocation stability and reaction rate. It follows a two-step path. The first step is the rate-limiting loss of the leaving group. The second step is the abstraction of the beta hydrogen by a weak base. Experimental support for the E1 mechanism comes from kinetic studies and isotope studies. Kinetic studies show first-order kinetics, which means the rate depends only on substrate concentration. Isotope studies show that hydrogen is removed only in the second step. <br...

e1 reaction: stereochemistry and regiochemistry

e1-reaction-stereochemistry-and-regiochemistry

E1 Elimination: Zaitsev Product and Carbocation

E1 elimination often gives the most substituted alkene, called the Zaitsev product. In the example, water acts as a weak base and favors elimination over substitution, so two alkene products can form. The Zaitsev alkene is usually more stable than the Hofmann product because it has more alkyl groups attached to the double bond. The lower-energy pathway also helps explain why the Zaitsev product is favored. Its transition state has lower energy, so this product is both thermodynamically stable...

predicting products: substitution vs. elimination

predicting-products-substitution-vs-elimination

Choosing Products in Substitution and Elimination

Substitution and beta-elimination compete when a nucleophile reacts with an alkyl halide. The major product depends on the substrate, the nucleophile, the temperature, and the solvent. Because more than one pathway can happen at once, a reaction often gives a product mixture. The structure of the alkyl halide helps predict which mechanism is more likely. Methyl halides and 1° halides usually favor bimolecular reactions, especially SN2. SN1 and E1 are disfavored for 1° halides because the 1°...

key terms and concepts

Explore how SN2 reactions happen in one step, why nucleophiles attack from the backside, and how inversion of configuration forms in the transition state.

SN2 Backside Attack and Inversion | JoVE K12

organic chemistry

JoVE Core Organic Chemistry explains basic concepts of stereochemistry, reactions, and mechanisms using concise and easy-to-understand animated video lessons. Additionally, the scientist-in-action videos demonstrate the application of related concepts in classical and original research experiments performed in today's laboratories worldwide.

SN2 Backside Attack and Inversion

Description

Transcript

Tags