1. 19.13 Nucleophilic Aromatic Substitution
Consider the reaction below in which the aromatic ring is attacked by a nucleophile
Is there a leaving group?
Copyright 2012 John Wiley & Sons, Inc.

2. 19.13 Nucleophilic Aromatic Substitution
Aromatic rings are generally electron-rich, which allows them to attack electrophiles (EAS)
To facilitate attack by a nucleophile:
A ring must be electron poor. WHY?
A ring must be substituted with a strong electron withdrawing group
There must be a good leaving group
The leaving group must be positioned ORTHO or PARA to the withdrawing group. WHY? We must investigate the mechanism – see next slide
Copyright 2012 John Wiley & Sons, Inc.

3. 19.13 Nucleophilic Aromatic Substitution
Draw all of the resonance contributors in the intermediate
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4. 19.13 Nucleophilic Aromatic Substitution
In the last step of the mechanism, the leaving group is pushed out as the ring re-aromatizes
Copyright 2012 John Wiley & Sons, Inc.

5. 19.13 Nucleophilic Aromatic Substitution
How would the stability of the transition state and intermediate differ for the following molecule?
Copyright 2012 John Wiley & Sons, Inc.

6. 19.13 Nucleophilic Aromatic Substitution
The excess hydroxide that is used to drive the reaction forward will deprotonate the phenol, so acid must be used after the NAS steps are complete
Practice with conceptual checkpoints 19.35
through 19.37
Copyright 2012 John Wiley & Sons, Inc.

7. 19.14 Elimination Addition
Without the presence of a strong electron withdrawing group, mild NAS conditions will not produce a product
Significantly harsher conditions are required
Copyright 2012 John Wiley & Sons, Inc.

8. 19.14 Elimination Addition
The reaction works even better when a stronger nucleophile is used
Why is NH2- a stronger nucleophile than OH-?
Copyright 2012 John Wiley & Sons, Inc.

9. 19.14 Elimination Addition
Consider the substitution reaction using toluene
The product regioselectivity cannot be explained using the NAS mechanism we discussed previously
Isotopic labeling can help to elucidate the mechanism – see next slide
Copyright 2012 John Wiley & Sons, Inc.

10. 19.14 Elimination Addition The C* is a 14C label
The NH2- first acts as a base rather than as a nucleophile
Copyright 2012 John Wiley & Sons, Inc.

11. 19.14 Elimination Addition
The benzyne intermediate is a short-lived unstable intermediate
Does a 6-membered ring allow for sp hybridized carbons?
The benzyne triple bond resembles more closely an sp2-sp2 overlap than it resembles a p-p overlap
Copyright 2012 John Wiley & Sons, Inc.

12. 19.14 Elimination Addition
A second molecule of NH2- acts as a nucleophile by attacking either side of the triple bond
Does NH2- act as a catalyst?
Copyright 2012 John Wiley & Sons, Inc.

13. 19.14 Elimination Addition
Further evidence for the existence of the benzyne intermediate can be seen when the benzyne is allowed to react with a diene via a Diels Alder reaction
Practice with conceptual checkpoint and 19.39
Copyright 2012 John Wiley & Sons, Inc.

14. 19.15 Identifying the Mechanism of an Aromatic Substitution Reaction
The flow chart below can be used to identify the proper substitution mechanism
Practice with SkillBuilder 19.7
Copyright 2012 John Wiley & Sons, Inc.

15. 20.1 Ketones and Aldehydes Common in biomolecules
Important in the synthesis of many pharmaceuticals
The basis upon which much of the remaining concepts in this course will build
The carbonyl group is common to both ketones and aldehydes
Copyright 2012 John Wiley & Sons, Inc.

16. 20.1 Relevant Examples
Identify the following as either an aldehyde or a ketone
vanilla flavor cinnamon flavor spearmint flavor almond flavor
Vaniillin Cinnamaldehyde (R)-Carvone Benzaldehyde
Shows relevant examples and gives students practice recognizing the structural difference between aldehydes and ketones
Steroids
Progesterone Testosterone
Copyright 2012 John Wiley & Sons, Inc.

17. 20.2 Nomenclature of Aldehydes
Identify and name the parent chain
For aldehydes, replace the e with an al
Example:
Be sure that the parent chain includes the carbonyl carbon
Copyright 2012 John Wiley & Sons, Inc.

18. 20.2 Nomenclature of Aldehydes
Identify and name the parent chain
Numbering the carbonyl group of the aldehyde takes priority over other groups
Example:
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19. 20.2 Nomenclature of Aldehydes
Identify and name the parent chain
Identify the name of the substituents (side groups)
Assign a locant (number) to each substituents
Assemble the name alphabetically
Example: Name the following molecule
Copyright 2012 John Wiley & Sons, Inc.

20. 20.2 Nomenclature of Ketones
Identify and name the parent chain
For ketones, replace the e with an one
Example:
The locant (number showing where the C=O is located) can be expressed before the parent name or before the suffix
Copyright 2012 John Wiley & Sons, Inc.

21. 20.2 Nomenclature of Ketones
Identify and name the parent chain
Identify the name of the substituents (side groups)
Assign a locant (number) to each substituents
Assemble the name alphabetically
Example: Name the following molecule
Practice with SkillBuilder 20.1
Copyright 2012 John Wiley & Sons, Inc.

22. 20.3 Preparing Aldehydes and Ketones
Some of the text from tables 20.1 and 20.2 could be removed so that the structures could be larger. Instructor could briefly explain these reactions.
Copyright 2012 John Wiley & Sons, Inc.

23. 20.4 Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile?
Resonance – there is a minor but significant contributor that includes a formal 1+ charge on the carbonyl carbon
What would the resonance hybrid look like for this carbonyl?
It helps to get a detailed understanding of what makes molecules reactive before looking at the specific reactions they undergo
Copyright 2012 John Wiley & Sons, Inc.

24. 20.4 Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile?
Induction – The carbonyl carbon is directly
attached to a very electronegative oxygen atom
Sterics - How does an sp2 carbon compare to an sp3?
Copyright 2012 John Wiley & Sons, Inc.

25. 20.4 Carbonyls as Electrophiles
Consider the factors: resonance, induction, and sterics
Which should be more reactive as an electrophile, aldehydes or ketones? Explain WHY!
Example comparison:
Instructor would explain how the sterics and induction of the R groups attached to the ketone makes the carbonyl less electrophilic
Copyright 2012 John Wiley & Sons, Inc.

26. 20.4 Nucleophilic attack on a Carbonyl
We want to analyze how nucleophiles attack carbonyls and why some nucleophile react and others don’t
If the nucleophile is weak, or if the attacking nucleophile is a good leaving group, the reverse reaction will dominate
Example attack:
Reverse reaction:
Copyright 2012 John Wiley & Sons, Inc.

27. 20.4 Nucleophilic attack on a Carbonyl
Show the nucleophilic attack for some other nucleophiles. Nucleophiles to consider include OH-, CN-, H-, R-, H2O
When the nucleophile attacks, is the resulting intermediate relatively stable or unstable? WHY?
If a nucleophile is also a good leaving group, is it likely to react with a carbonyl? Explain WHY!
Compare attack on a carbonyl with attack on an alkyl halide
Students should get a sense for how the properties of the nucleophile can affect whether the attack is likely to take place with emphasis on the quality of the nucleophile as a leaving group.
Copyright 2012 John Wiley & Sons, Inc.

28. 20.4 Nucleophilic addition
If the nucleophile is strong enough to attack and NOT a good leaving group, then the full addition will occur (mechanism 20.1)
The intermediate carries a negative charge, so it will pick up a proton to become more stable
Copyright 2012 John Wiley & Sons, Inc.

29. 20.4 Nucleophilic attack on a Carbonyl
If the nucleophile is weak and reluctant to attack the carbonyl, HOW could we improve its ability to attack?
We can make the carbonyl more electrophilic!
Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics)
Adding an acid will help. HOW?
It is nice to show how the addition of the acid makes the carbonyl more electrophilic by emphasizing the reasons that explained why it was electrophilic to begin with.
Copyright 2012 John Wiley & Sons, Inc.

30. 20.4 Nucleophilic addition
With a weak nucleophile, the presence of an acid will make the carbonyl more attractive to the nucleophile so the full addition can occur (mechanism 20.2)
After giving students a chance to think about it, the question at the bottom of the slide can be answered by the instructor: the acid would most likely protonate the nucleophile if the nucleophile were strong, which would decrease its ability to attack the carbonyl
Copyright 2012 John Wiley & Sons, Inc.

31. 20.4 Nucleophilic addition
Is there a reason why acid is not used with strong nucleophiles?
After giving students a chance to think about it, the question at the bottom of the slide can be answered by the instructor: the acid would most likely protonate the nucleophile if the nucleophile were strong, which would decrease its ability to attack the carbonyl
Copyright 2012 John Wiley & Sons, Inc.

32. Study Guide for Sections 19.13-19.15, 20.1-20.4
DAY 17, Terms to know:
Sections , nucleophilic aromatic substitution (NAS), benzyne, carbonyl, ketone, aldehyde
DAY 17, Specific outcomes and skills that may be tested on exam 3:
Sections ,
Be able to draw a complete mechanism, transition states, and predict products for any of the NAS reactions discussed
Given reactants and products, be able to give reagents necessary to achieve any of the NAS reactions we discussed
Be able to identify aldehyde and ketone functional groups
Be able to give IUPAC names for aldehydes and ketones
Given the name of a molecule, be able to draw its structure
Be able to rank aldehydes and ketones in terms of their strength as electrophiles using arguments based on sterics, resonance, and induction

33. Extra Practice Problems for Sections 19.13-19.15, 20.1-20.4
Complete these problems outside of class until you are confident you have learned the SKILLS in this section outlined on the study guide and we will review some of them next class period

34. Prep for Day 18 Must Watch videos: Other helpful videos:
(hydrates, acetals, hemiacetals, FLC)
(imines and enamines, FLC)
(Wolff Kishner, Organic chemistry tutor)
(imine hydrolysis, Osbourn)
Other helpful videos:
(acetals, Khan)
(acetals and more, UC-Irvine)
(imines and more, UC-Irvine) start at 7 minutes
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