7.1 Introduction to Substitution Reactions • One group of atoms is replaced with another. – Generic example:
– Specific example:
7.1 Introduction to Substitution Reactions • Which side do you think will be favored in the dynamic equilibrium? WHY?
• Draw a reaction coordinate diagram that illustrates your equilibrium prediction.
• Label the nucleophile and the electrophile. Copyright 2012 John Wiley & Sons, Inc.
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7.1 Introduction to Substitution Reactions • During the substitution, one group ATTACKS and one group LEAVES. Can you label them in the reaction?
• A leaving group always takes a pair of electrons with it. • In the reaction below, fill in arrows to show the mechanism and label the leaving group. + O Copyright 2012 John Wiley & Sons, Inc.
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7.1 Introduction to Substitution Reactions Some leaving groups encourage a substitution better than others. A good leaving group must: 1. Create a positive charge to attract the nucleophile: The electronegative leaving group creates a partial charge on the site of attack to attract the negative charge of the nucleophile. 2. Be able to stabilize the electrons it leaves with:
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7.1 Introduction to Substitution Reactions Can you give some examples of groups of atoms that qualify as good leaving groups according to the two key criteria? 1. Create a positive charge to attract the nucleophile. 2. Be able to stabilize the electrons it leaves with.
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7.2 Alkyl Halides • Alkyl halides are compounds where a carbon group (alkyl) is bonded to a halide (F, Cl, Br, or I). • Recall from Section 4.2 the steps we use to name a molecule: 1. 2. 3. 4.
Identify and name the parent chain. Identify the name of the substituents (side groups). Assign a locant (number) to each substituent. Assemble the name alphabetically.
• The halide group is the key substituent we will name and locate. Copyright 2012 John Wiley & Sons, Inc.
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7.2 Alkyl Halides – Nomenclature • For each of these examples, convince yourself that they are numbered in the most appropriate way.
7.2 Alkyl Halides – Nomenclature • Some simple molecules are also recognized by their common names: – The alkyl group is named as the substituent, and the halide is treated as the parent name. – Methylene chloride is a commonly used organic solvent.
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7.2 Alkyl Halides – Nomenclature • Give reasonable names for the following molecules: Cl
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7.2 Alkyl Halides – Structure • Greek letters are often used to label the carbons of the alkyl group attached to the halide: – Substitutions occur at the alpha carbon. WHY?
Cl
• The amount of branching at the alpha carbon affects the reaction mechanism. There are three types of alkyl halides:
• Try more examples with CONCEPTUAL CHECKPOINT 7.1.
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R≠H
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7.2 Alkyl Halides – Structure • Alkyl halides are often toxic. Some are used as insecticides. For the insecticides below: – Label each halide as either primary, secondary, or tertiary. – For the circled atoms, label all of the alpha, beta, gamma, and delta carbons.
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7.2 Alkyl Halides – Structure • Halides appear in a wide variety of natural products and synthetic compounds. • The structure of the molecule determines its function, and functions include: – – – – –
Insecticides (DDT, etc.) Dyes (tyrian purple, etc.) Drugs (anticancer, antidepressants, antimicrobial, etc.) Food additives (Splenda, etc.) Many more
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7.3 Possible Mechanisms for Substitution Reactions
7.2 Alkyl Halides – Structure HOW does a molecule’s structure affect its function and properties?
• Recall from Chapter 6 the arrow pushing patterns for ionic processes:
1.
2. Copyright 2012 John Wiley & Sons, Inc.
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7.3 Possible Mechanisms for Substitution Reactions • Recall from Chapter 6 the arrow pushing patterns for ionic processes:
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7.3 Possible Mechanisms for Substitution Reactions • EVERY nucleophilic substitution reaction will involve nucleophilic attack and the loss of a leaving group.
3.
• The order in which these steps occur can vary. • The inclusion of a proton transfer or rearrangement can also vary.
4. Copyright 2012 John Wiley & Sons, Inc.
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7.3 Possible Mechanisms for Substitution Reactions
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7.4 SN2 – Mechanism
• Draw mechanisms for each possibility and critique their likelihood: 1. Nucleophilic attack first, then loss of leaving group
• How might you write a rate law for this reaction? 2. Loss of leaving group first, then nucleophilic attack
3. Both nucleophilic attack and loss of leaving group happen simultaneously
• What type of experiment could you run in the lab to test whether this mechanism is possible? • Test yourself with CONCEPTUAL CHECKPOINT 7.6.
• Practice arrow pushing with SKILLBUILDER 7.1. Copyright 2012 John Wiley & Sons, Inc.
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7.4 SN2 – Stereochemistry • What do the S, N, and 2 stand for in the SN2 name? • How might we use stereochemistry to support the SN2 mechanism for the following reaction?
7.4 SN2 – Backside Attack • The nucleophile attacks from the backside: – The backside is less hindered with electron density. – The nucleophile must approach the backside to allow proper orbital overlap that is necessary for bonding.
• Practice drawing SN2 reactions with SKILLBUILDER 7.2.
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7.4 SN2 – Backside Attack
7.4 SN2 – Kinetics
• Draw the transition state for the following reaction. Use extended dotted lines to represent bonds breaking and forming.
• Less sterically hindered electrophiles react more readily under SN2 conditions.
• Practice drawing transition states with SKILLBUILDER 7.3.
• To explain this trend, we must examine the reaction coordinate diagram.
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7.4 SN2 – Rationalizing Kinetic Data • How do we use the diagram to make a kinetic argument? • How do we use the diagram to make a thermodynamic argument?
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7.4 SN2 – Rationalizing Kinetic Data • Which reaction will have the fastest rate of reaction? H3C WHY? Nuc:
H3C
• 3° substrates react too slowly to measure. Copyright 2012 John Wiley & Sons, Inc.
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7.4 SN2 – Rationalizing Kinetic Data • An example to consider: neopentyl bromide: – Draw the structure of neopentyl bromide.
7.4 SN2 – Rationalizing Kinetic Data • If you memorize the rules, you will probably miss questions about exceptions to the rules. • It is better to understand the concepts than to memorize the rules.
– Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide? – Should neopentyl bromide react by an SN2 reaction relatively quickly or relatively slowly? WHY?
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7.5 SN1 – A Stepwise Mechanism
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7.5 SN1 – A Stepwise Mechanism • What do the S, N, and 1 stand for in the SN1 name?
• If kinetic experiments were performed to determine the rate law, you would find that:
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7.5 SN1 – Kinetics
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7.5 SN1 – Reaction Coordinate
• In a multistep mechanism, one step will be the slowest. • The slow step is the rate‐determining step (RDS). • Let’s consider a simple example. Which step determines how frequently the sand moves from the top of the hourglass to the bottom?
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7.5 SN1 – Reaction Coordinate • Which step is the RDS and WHY? • Why does the rate depend only on [electrophile] and NOT [nucleophile]?
7.5 SN1 vs. SN2 – Comparison • Consider the following generic SN2 reaction: – If [Nuc:‐] were tripled, how would the rate be affected? WHY?
• Consider the following generic SN1 reaction: – If [Nuc:‐] were tripled, how would the rate be affected? WHY?
• Practice with CONCEPTUAL CHECKPOINT 7.13. Copyright 2012 John Wiley & Sons, Inc.
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7.5 SN1 – Kinetics • The structure–rate relationship for SN1 reactions is the opposite of what it is for SN2 reactions.
• To explain this trend, we must examine the mechanism and the reaction coordinate diagram. Copyright 2012 John Wiley & Sons, Inc.
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7.5 SN1 – Rationalizing Kinetic Data
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7.5 SN1 – Rationalizing Kinetic Data • A carbocation forms during the mechanism.
• Recall that if a carbocation is more substituted with carbon groups, it should be more stable.
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7.5 SN1 – Rationalizing Kinetic Data
• To explain why the 3° substrate will have a faster rate, draw the relevant transition states and intermediates.
• HOW do carbon groups stabilize a carbocation? • Primary substrates react too slowly to measure. • Practice with SKILLBUILDER 7.4. Copyright 2012 John Wiley & Sons, Inc.
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7.5 SN1 – Stereochemistry • For the pure SN1 reaction below, predict the product(s). Pay close attention to stereochemistry.
7.5 SN1 – Stereochemistry • Consider the following reaction:
– What accounts for the 35%/65% product ratio? – Is the reaction reacting more by SN1 or SN2? – What happened to the Cl atom?
• Practice with SKILLBUILDER 7.5. Copyright 2012 John Wiley & Sons, Inc.
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7.5 SN – Summary
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7.6 Drawing the Complete Mechanism of an SN1 Reaction • In SN1, proton transfer steps often occur before the substitution process. – Why would a proton transfer sometimes be necessary before the substitution reaction? For example:
– If the OH is protonated first though:
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7.6 Drawing the Complete Mechanism of an SN1 Reaction • Would it also be helpful to protonate an OH group in an SN2 substitution?
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7.6 Drawing the Complete Mechanism of an SN1 Reaction • Let’s look at the complete mechanism.
• Practice with CONCEPTUAL CHECKPOINT 7.18. Copyright 2012 John Wiley & Sons, Inc.
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7.6 Drawing the Complete Mechanism of an SN1 Reaction • In SN1, proton transfer steps often occur after the substitution process. Examine the following example:
– The leaving group is good, but what about the nucleophile? – Draw a complete mechanism. Each step is an equilibrium. Which side will the equilibrium favor? – If the nucleophile were used as the solvent (a solvolysis reaction), would that shift the equilibrium one way or the other?
• Practice with CONCEPTUAL CHECKPOINT 7.19. Copyright 2012 John Wiley & Sons, Inc.
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7.6 Drawing the Complete Mechanism of an SN1 Reaction Summary of considerations to make: • Will proton transfers be necessary?
7.6 Drawing the Complete Mechanism of an SN1 Reaction • Rearrangements sometimes occur in SN1 reactions. For example:
– After the leaving group leaves, the resulting carbocation may rearrange. What type of rearrangements are likely? WHY? – Predict the product(s), and explain why the carbocation rearrangement is likely to occur before the nucleophile has a chance to attack.
• Check your work with CONCEPTUAL CHECKPOINT 7.20. Copyright 2012 John Wiley & Sons, Inc.
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7.6 Drawing the Complete Mechanism of an SN1 Reaction • Use the considerations from the previous slide to solve this problem:
– 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. Copyright 2012 John Wiley & Sons, Inc.
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7.7 Drawing the Complete Mechanism of an SN2 Reaction • Proton transfer steps occur often in SN2 reactions for the same reasons they occur in SN1 reactions.
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1. Predict the reagents necessary to complete this substitution. 2. Draw a complete mechanism. 3. Draw a complete reaction coordinate diagram including drawings for all transition states.
• Practice more with SKILLBUILDER 7.6. Copyright 2012 John Wiley & Sons, Inc.
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7.7 Drawing the Complete Mechanism of an SN2 Reaction • This reaction would be much slower without the proton transfers. WHY?
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7.7 Drawing the Complete Mechanism of an SN2 Reaction • Will this equilibrium probably favor reactants or products? WHY?
7.7 Drawing the Complete Mechanism of an SN2 Reaction • Another example of proton transfer in SN2:
– Will this equilibrium probably favor reactants or products? WHY? – Are carbocation rearrangements possible in SN2? Copyright 2012 John Wiley & Sons, Inc.
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• Practice with SKILLBUILDER 7.7. Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – Determining Which Mechanism Predominates
7.8 SN1 vs. SN2 – Carbocation Stability
• In our earlier discussions, we discussed two factors that determine whether a reaction will be SN1 or SN2:
• Before we can examine carbocation stability, let’s review some terminology:
1. Steric hindrance at the electrophilic site 2. The stability of the resulting carbocation
1. Vinyl
• There are two other important factors to consider: 3. The quality of the nucleophile 4. The solvent
2. Allyl
• Let’s learn some new terminology:
• Let’s examine factors 2, 3, and 4 in detail.
1. Benzyl 2. Aryl
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7.8 SN1 vs. SN2 – Carbocation Stability 2. The stability of the resulting carbocation: • If a relatively stable carbocation can form when the leaving group leaves, the mechanism may be SN1. • What factors affect the stability of carbocations?
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7.8 SN1 vs. SN2 – Carbocation Stability • The resonance for allylic and benzylic carbocations is illustrated below:
– INDUCTION—already discussed – RESONANCE—for example:
• Are allylic and benzylic halides more likely to undergo SN1 or SN2? Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – Carbocation Stability & Sterics • Consider whether vinyl and aryl halides are likely to undergo substitution:
7.8 SN1 vs. SN2 – The Nucleophile 3. The quality of the nucleophile: • What makes a nucleophile strong or weak? – Stability (induction, resonance, solvation) – Sterics
• Give some examples of strong nucleophiles and some examples of weak ones. • Can you make a steric argument? • Can you make a carbocation stability argument? • Practice with CONCEPTUAL CHECKPOINT 7.26. Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Leaving Group • What makes a leaving group good or bad? – Stability once it has left WITH a pair of electrons (induction, resonance, solvation)
• Will a strong nucleophile favor SN1 or SN2? WHY? • Practice with CONCEPTUAL CHECKPOINT 7.27. Klein, Organic Chemistry 1e
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7.8 SN1 vs. SN2 – The Leaving Group • The most commonly used leaving groups are halides and sulfonate ions.
• Give some examples of bad leaving groups and some examples of good ones (Figure 7.28 in the text). • If the leaving group is too bad, then the substitution can’t take place by either SN1 or SN2. For example: • What makes sulfonate ions such good leaving groups? • Practice with CONCEPTUAL CHECKPOINT 7.28. Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Solvent
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7.8 SN1 vs. SN2 – The Solvent δ+ δ4. The solvent ( ) surrounds each species in the mechanism, including the transition state:
δ+ δ-
4. The solvent: • The solvent surrounds each species in the mechanism including the transition state. How does that help to facilitate the reaction? See next slide. Copyright 2012 John Wiley & Sons, Inc.
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δ+ δ-
δδ+
δ+
δ-
δδ+
δ+ δ-
δδ+ δ+ δ-
δ- δ+
δ-
H
H
Nuc δ+ δ-
δδ+ δ-
LG R
δ+ δ-
δ+ δ-
• Consider how the energy diagram would be different with a polar versus a nonpolar solvent . Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Solvent • To specifically promote SN2, what role should the solvent play?
7.8 SN1 vs. SN2 – The Solvent • Will this reaction be SN1 or SN2?
– The solvent should facilitate the collision between the nucleophile and the electrophile. – Is it possible that the solvent could interfere with that key collision?
• What type of solvent would you choose to accomplish this role? Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Solvent Promoting SN2 • To promote an SN2, use a polar, aprotic solvent, such as DMSO or acetonitrile. • Polar aprotic solvents can stabilize the counterion of the nucleophile, leaving the nucleophile mostly naked and ready to attack the electrophile. Copyright 2012 John Wiley & Sons, Inc.
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Ready to attack!
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7.8 SN1 vs. SN2 – The Solvent Promoting SN1
• What do the highlighted red solvents have in common that makes them better than the others? Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Solvent Promoting SN2 • Because a polar, aprotic solvent will not effectively solvate the nucleophile, the nucleophile is less stable and starts with a high potential energy. • The activation energy will be lower and the reaction faster. Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – The Solvent Promoting SN1
• To promote an SN1 reaction, use a polar, protic solvent: • A polar, protic solvent will also stabilize the full and partial charges that form during the SN1 mechanism. • Practice with CONCEPTUAL CHECKPOINT 7.29.
• The protic solvent will hydrogen bond with the nucleophile, stabilizing it, while the leaving group leaves first. Copyright 2012 John Wiley & Sons, Inc.
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7.8 SN1 vs. SN2 – Solvent Effect on Halide Nucleophiles • 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?
7.9 Selecting Reagents to Accomplish Functional Group Transformation • How do we use what we’ve learned to set up successful reactions? – We must choose an appropriate substrate, nucleophile, leaving group, solvent, etc.
• If you are working with a 1° substrate, the reaction will be SN2, so what are the best conditions? – Nucleophile? – Leaving Group? – Solvent?
• Practice with SKILLBUILDER 7.8 Copyright 2012 John Wiley & Sons, Inc.
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7.9 Selecting Reagents to Accomplish Functional Group Transformation
7.9 Selecting Reagents to Accomplish Functional Group Transformation
• If you are working with a 3° substrate, the reaction will be SN1, so what are the best conditions?
• If you are working with a 2° substrate, the reaction could be SN1 or SN2, so what are the best conditions to get the stereochemistry you want, and WHY?
– Nucleophile? – Leaving Group? – Solvent?
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– Nucleophile? – Leaving Group? – Solvent?
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7.9 Selecting Reagents to Accomplish Functional Group Transformation • Some options and choices:
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7.9 Selecting Reagents to Accomplish Functional Group Transformation 1. Design a synthesis for the following molecule starting from (R)‐2‐chlorobutane.
1. Describe appropriate conditions for the following transformation.
• Copyright 2012 John Wiley & Sons, Inc.
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Practice with SKILLBUILDER 7.9. Copyright 2012 John Wiley & Sons, Inc.
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