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8.2: Two mechanistic models for a nucleophilic substitution reaction

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8.2A: Associative nucleophilic substitution: the SN2 reaction

You may recall from chapter 6 that there are two mechanistic models for how a nucleophilic substitution reaction can proceed. In the first picture, the reaction takes place in a single step, and  bond-forming and bond-breaking occur simultaneously.

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This is called an 'associative', or 'SN2' mechanism.  In the term SN2,  S stands for 'substitution', the subscript N stands for 'nucleophilic', and the number  2 refers to the fact that this is a bimolecular reaction: the overall rate 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 pathway from reactants to products.

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If you look carefully at the progress of the SN2 reaction, you will realize something very important about the outcome. The nucleophile, being an electron-rich species, must attack the electrophilic carbon from the back side relative to the location of the leaving group.  Approach from the front side simply doesn't work: the leaving group  - which is also an electron-rich group - blocks the way. 

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The result of this backside attack is that the stereochemical configuration at the central carbon inverts as the reaction proceeds.  In a sense, the molecule is turned inside out. At the transition state, the electrophilic carbon and the three 'R' substituents all lie on the same plane.

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What this means is that SN2 reactions whether enzyme catalyzed or not, are inherently stereoselective: when the substitution takes place at a stereocenter, we can confidently predict the stereochemical configuration of the product.

 
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Exercise 8.2: Predict the structure of the product in this SN2 reaction.  Be sure to specify stereochemistry.

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Solution
 
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8.2B: Dissociative nucleophilic substitution: the SN1 reaction

A second model for a nucleophilic substitution reaction is called the 'dissociative', or 'SN1' mechanism: in this picture, the C-X bond breaks first, before the nucleophile approaches:

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This results in the formation of a carbocation: because the central carbon has only three bonds, it bears a formal charge of +1. Recall that a carbocation should be pictured as sp2 hybridized, with trigonal planar geometry.  Perpendicular to the plane formed by the three sp2 hybrid orbitals is an empty, unhybridized p orbital.

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In the second step of this two-step reaction, the nucleophile attacks the empty, 'electron hungry' p orbital of the carbocation to form a new bond and return the carbon to tetrahedral geometry.

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We saw that SN2 reactions result specifically in inversion of stereochemistry at the electrophilic carbon center.  What about the stereochemical outcome of SN1 reactions? In the model SN1 reaction shown above, the leaving group dissociates completely from the vicinity of the reaction before the nucleophile begins its attack.  Because the leaving group is no longer in the picture, the nucleophile is free to attack from either side of the planar, sp2-hybriduzed carbocation electrophile.  This means that about half the time the product has the same stereochemical configuration as the starting material (retention of configuration), and about half the time the stereochemistry has been inverted.  In other words, racemization has occurred at the carbon center. As an example, the tertiary alkyl bromide below would be expected to form a racemic mix of R and S alcohols after an SN1 reaction with water as the incoming nucleophile.

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Exercise 8.3: Draw the structure of the intermediate in the two-step nucleophilic substitution reaction above.
 

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While most nonenzymatic SN1 reactions are not stereoselective, we will see later that enzyme-catalyzed nucleophilic substitution reactions - whether SN1 or SN2 - almost always are stereoselective. The direct result of an enzymatic nucleophilic substitution reaction is more often than not inversion of configuration - this is  because the leaving group usually remains bound in the enzyme's active site long enough to block a nucleophilic attack from that side.  This does not mean, however, that enzymes can only catalyze substitution reactions with inversion of configuration: we will see in the next chapter (section 9.2) an example of an enzymatic nucleophilic substitution reaction in which the overall result is 100% retention of configuration.

In the SN1 reaction we see an example of a reaction intermediate, a very important concept in the study of organic reaction mechanisms that was first introduced in Chapter 6.  Recall that many important organic reactions do not occur in a single step; rather, they are the sum of two or more discreet bond-forming / bond-breaking steps, and involve transient intermediate species that go on to react very quickly. In the SN1 reaction, the carbocation species is a reaction intermediate. A potential energy diagram for an SN1 reaction shows that the carbocation intermediate can be visualized as a kind of valley in the path of the reaction, higher in energy than both the reactant and product but lower in energy than the two transition states.

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Exercise 8.4: Draw structures representing  TS1 and TS2 in the reaction above.  Use the solid/dash wedge convention to show three dimensions.

Solution

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Recall (section 6.2) that the first step of the reaction above, in which two charged species are formed from a neutral molecule, is much the slower of the two steps, and is therefore rate-determining.  This is illustrated by the energy diagram, where the activation energy for the first step is higher than that for the second step. Also recall that an SN1 reaction has first order kinetics, because the rate determining step involves one molecule splitting apart, not two molecules colliding.

 

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Exercise 8.5: Consider two nucleophilic substitutions that occur uncatalyzed in solution.  Assume that reaction A is SN2, and reaction B is SN1.  Predict, in each case, what would happen to the rate of the reaction if the concentration of the nucleophile were doubled, while all other conditions remained constant.

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Solution

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Many SN1 reactions are of a class that are referred to as solvolysis, where a solvent molecule participates in the reaction as a nucleophile. The SN1 reaction of allyl bromide in methanol is an example of what we would call methanolysis, while if water is the solvent the reaction would be called hydrolysis:

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Because water and alcohols are relatively weak nucleophiles, they are unlikely to react in an SN2 fashion.

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Exercise 8.6: Draw a complete curved-arrow mechanism for the methanolysis reaction above.

Solution

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8.2C: Nucleophilic substitutions occur at sp3-hybridized carbons

One more important point must be made before continuing: nucleophilic substitutions as a rule occur at sp3-hybridized carbons, and not where the leaving group is attached to an sp2-hybridized carbon:: 

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Bonds on sp2-hybridized carbons are inherently shorter and stronger than bonds on sp3-hybridized carbons (section 1.5C), meaning that it is harder to break the C-X bond in these substrates. SN2 reactions of this type are unlikely also because the (hypothetical) electrophilic carbon is protected from nucleophilic attack by electron density in the p bond.  SN1 reactions are highly unlikely, because the resulting carbocation intermediate, which would be sp-hybridized, would be very unstable (we’ll discuss the relative stability of carbocation intermediates in section 8.4B). 

Before we look at some real-life nucleophilic substitution reactions in the next chapter, we will spend some time in the remainder of this chapter focusing more closely on the three principal partners in the nucleophilic substitution reaction: the nucleophile, the electrophile, and the leaving group.

 

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