What makes the carbonyl carbon electrophilic? 1.RESONANCE: What would the resonance hybrid look like? 2.INDUCTION: The carbonyl carbon is bonded to a very electronegative oxygen. 3.STERICS: How does an sp 2 carbon compare to an sp 3 carbon in terms of the steric hindrance that an attacking nucleophile will feel? 20.4 Carbonyls as Electrophiles Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -1

20.4 Nucleophilic attack at carbonyl versus on sp 3 carbon Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -2

Consider the factors: resonance, induction, and sterics. Which should be more reactive as an electrophile, aldehydes or ketones? Why? Example comparison: 20.4 Carbonyls as Electrophiles Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -3

Why do some nucleophiles react with aldehydes and ketones and some not react? – Example nucleophilic attack: If the nucleophile is weak, or if the attacking nucleophile is a good leaving group (e.g., iodide ion), the reverse reaction will dominate. – Reverse reaction: 20.4 Nucleophilic Attack on a Carbonyl Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -4

Show the nucleophilic attack for some other nucleophiles. Nucleophiles to consider include OH –, CN –, H –, R –, H 2 O. 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? Why? 20.4 Nucleophilic Attack on a Carbonyl Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -5

Answer to the first example from previous slide: When the nucleophile attacks, is the resulting intermediate relatively stable or unstable? Why? The intermediate is relatively unstable because of the negative charge on oxygen. However, also notice that the nucleophile is similarly unstable. If a nucleophile is also a good leaving group, is it likely to react with a carbonyl? Why? In this case the nucleophile, hydroxide, is not normally considered a good leaving group. However, in the reverse reaction here it is leaving from an alkoxide intermediate that is similarly unstable. The reverse reaction dominates and no overall reaction is observed Nucleophilic Attack on a Carbonyl Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -6

If the nucleophile is strong and NOT a good leaving group, then an addition reaction is observed: Which of these nucleophiles do the above reaction? OH –, CN –, H –, R –, H 2 O Nucleophilic Attack on a Carbonyl – Nucleophilic Addition Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -7

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: – Adding an acid will help. HOW? Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics) Nucleophilic Attack on a Carbonyl Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -8

With a weak nucleophile, the presence of an acid will make the carbonyl more attractive to the nucleophile so an overall addition reaction is observed Nucleophilic Attack on a Carbonyl – Nucleophilic Addition Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 20 -9

Is water generally a strong or weak nucleophile? Show a generic mechanism for water attacking an aldehyde or ketone. Would the presence of an acid improve the reaction? 20.5 Water as a Nucleophile Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e

The products are called gem-diols or “hydrates” and are usually unable to be isolated. Why? How do the following factors affect the equilibria: entropy, induction, sterics? 20.5 Water as a Nucleophile Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e Acetone Formaldehyde Hexafluoroacetone

The addition of water to an aldehyde or ketone is catalyzed by acid 20.5 Water as a Nucleophile Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e

An alcohol acts as the nucleophile instead of water. Notice that the reaction is under equilibrium and that it is acid catalyzed. Analyze the complete mechanism (Mechanism 20.5) on the next slide. Analyze how the acid allows the reaction to proceed through lower energy intermediates Acetals – Formation Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e

20.5 Acetals – Formation Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e

How do entropy, induction, sterics, and Le Châtelier’s principle affect the equilibrium? 20.5 Acetals – Formation Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e and 6-membered cyclic acetals are generally product favored Product favored Reactant favored

Acetals can be attached and removed fairly easily. Example: Both the forward and reverse reactions are acid catalyzed. How does the presence of water affect which side the equilibrium will favor? 20.5 Acetals – Equilibrium Control Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e