C341 F2011 Chapter 7 NS - Indiana University …courses.chem.indiana.edu/.../C341F2011Chapter7NS.pdfC341/Fall 2011 Chapter 7: Nucleophilic Substitution Reactions Page 18 of 24 5. Synthesizing

C341/Fall 2011 Chapter 7: Nucleophilic Substitution Reactions

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Chapter 7 Outline: Nucleophilic Substitution Reactions 1. Alkyl Halides

2. The SN2 Mechanism


4. Determining which Mechanism Predominates

5. Practicing Problems – selecting reagents to accomplish desired outcomes

Of course I would want you to do ALL the problems at the end of the chapter, but your doing the following problems would be a good start:

7.37‐43, 7.48, 7.50‐56, 7.59‐62, 7.65, 7.67‐69

Why Might you Care about Nucleophilic Substitution?

Ethylene Oxide as a Sterilizing Agent for Medical Equipment


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Substitution Reactions:

Label the nucleophile and the electrophile. Which side do you think will be favored in the dynamic equilibrium? WHY?

Draw a reaction coordinate diagram that illustrates your equilibrium prediction.

In the reaction below, fill in arrows to show the mechanism and label the leaving group.

OO

+


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Nucleophilic Substitution Reactions

Three components are necessary for every substitution reaction: 1. R – an alkyl group containing an sp3 hybridized carbon involved in an C—X bond.

2. X – a leaving group; the LG must be able to accept/stabilize the electron density in the C—X bond (heterolytic bond cleavage).

What makes a good leaving group?

3. Nu – a nucleophile; the nucleophile must contain a lone pair or a pi bond, but it does not necessarily have to be negatively charged. (Charged nucleophiles react more easily than neutral ones.)


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1. Alkyl Halides

Which alkyl halide C—X bond will react fastest? Why?


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What is the rate law for this reaction?

What type of experiment could you run in the lab to test whether this mechanism is valid?

How might we use stereochemistry to support the SN2 mechanism for the following reaction?


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SN2 & Sterics

Less sterically‐hindered electrophiles react more readily under SN2 conditions. Sterics plays a part at the reactive carbon (α‐carbon), but also at the β‐carbon.

XNuc:

H

HH

XNuc:

H3C

HH3C


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Put the following reactants in order of ease of reacting via an SN2 reaction (1‐4; 1 = fastest, 4 = slowest)

a.

Br Br Br Br

b.

Br BrBrBr


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The SN1 Reaction

This is a two‐step reaction mechanism. What is the rate law? Which step is the RDS and WHY?


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SN1 Reactions & Substrate Reactivity


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SN1 Reactions & Stereochemistry

What accounts for the 35%/65% product ratio?

ClNaOH

OH OH

35% 65%

+


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SN1 vs. SN2 Overview

Summary of considerations to make:

• Will proton transfers be necessary?

– Look at the quality of the leaving group.

– Look at the stability of the final product.

• Will the mechanism be SN1 or SN2?

– Look at how crowded the electrophilic site is .

– Look at how stable the resulting carbocation would be.

• Are rearrangements likely?

– Look for ways to improve the stability of the carbocation.

• Will the product have inversion or racemization?

– SN1=racemization while SN2=inversion.


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1. Predict the reagents necessary to complete this substitution.

2. Draw a complete mechanism.

OHO O

racemic


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4. Determining Which Mechanism Predominates

A. Steric hindrance at the electrophilic site

B. The stability of the resulting carbocation

Alkyl

Allyl

Benzyl

C. The quality of the nucleophile

“Strong” or “weak” nucleophiles dictate different reactions Nucleophilicity increases down a column; why?

HS‐ > HO‐

I‐ > Br‐ > Cl‐ > F‐

Compare the SIZE of the nucleophile (molecule) as a whole:

O O O


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What are some general trends about Nu‐ you can make using the pKa table?

16

10

-9

51Acids CB


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D. The solvent

The solvent surrounds each species in the mechanism including the

transition state. How does that help to facilitate the reaction?

To specifically promote SN2, what role should the solvent play?

δ

δ

δ δδ

δ δ δ

δ

δ

δ

δ

δ

δ

δ δ

δ

δ δ

δ

δ δ

δ

δ

δ

δ

δδ


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What differentiates these solvents from each other?


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SN1 Reactions and Protic Solvents

Consider the nucleophiles F‐, Cl‐, Br‐, and I‐.

– In a polar, protic solvent, which should be most reactive? WHY?

– In a polar, aprotic solvent, which should be most reactive? WHY?

– Why does the size of the halide affect its ability to hydrogen bond?


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5. Synthesizing What You Want (Practicing Problems)

For the following reaction, indicate which reaction mechanism (i.e. write

SN1 and/or SN2 in the blank below) the following observations would

support.

A. the reaction rate increased when the [Nu] was increased

B. the reaction rate decreased when the [RX] was decreased

C. the reaction rate increased in the presence of a polar protic solvent

D. the reaction showed a rearranged product

E. the reaction showed more than one product

F. the reaction rate decreased when the LG was changed to Cl

G. the product was an ether


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Circle which of the following is a stronger nucleophile and provide a valid argument for your reasoning.

i. ii.

iii. iv.

v. vi. Circle which of the following is a better leaving group and provide a valid argument for your reasoning.

i. ii.

iii. iv.

NHNH


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Provide substitution mechanisms and major product(s) for the following reactions.


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Provide a viable step‐by‐step mechanism using mechanistic arrows to clearly demonstrate the following reaction outcome. Through what substitution mechanism MUST this reaction have proceeded?

NaOCH3

CH3OH

Br

OCH3

OCH3

+

How else could you have synthesized this product or obtained only one product?


Page 24 of 24

Design a synthesis for the following molecule starting from (R)‐2‐chlorobutane. Describe best conditions for the following transformation.

O

OH CN

C341 F2011 Chapter 7 NS - Indiana University …courses.chem.indiana.edu/.../C341F2011Chapter7NS.pdfC341/Fall 2011 Chapter 7: Nucleophilic Substitution Reactions Page 18 of 24 5. Synthesizing

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