4/18/2012 20.1 Ketones and Aldehydes – 20.1 Ketones and Aldehydes Relevant Examples • 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. 20 -1 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -2 Klein, Organic Chemistry 1e 20.2 Nomenclature of Aldehydes 20.2 Nomenclature of Aldehydes 1. Identify and name the parent chain: 1. Identify and name the parent chain: – For aldehydes, replace the e with an al. – Numbering the carbonyl group of the aldehyde takes priority – Example: over other groups. – Example: – Be sure that the parent chain includes the carbonyl carbon. – Example: Copyright 2012 John Wiley & Sons, Inc. 20 -3 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -4 Klein, Organic Chemistry 1e 20.2 Nomenclature of Aldehydes 20.2 Nomenclature of Ketones 1. Identify and name the parent chain. 1. Identify and name the parent chain: 2. Identify the name of the substituents (side groups) – For ketones, replace the e with an one. 3. Assign a locant (number) to each substituents. – Example: 4. Assemble the name alppyhabetically. • Name the following molecule. – The locant (number showing where the C=O is located) can be expressed before the parent name or before the suffix. – Example: Copyright 2012 John Wiley & Sons, Inc. 20 -5 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -6 Klein, Organic Chemistry 1e 1 4/18/2012 20.3 Preparing Aldehydes and 20.2 Nomenclature of Ketones Ketones 1. Identify and name the parent chain. 2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituents. 4. Assemble the name alppyhabetically. • Name the following molecule. • Practice with SKILLBUILDER 20.1 Copyright 2012 John Wiley & Sons, Inc. 20 -7 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -8 Klein, Organic Chemistry 1e 20.4 Carbonyls as Electrophiles 20.4 Carbonyls as Electrophiles • What makes the carbonyl carbon a good electrophile? What makes the carbonyl carbon a good electrophile? 1. RESONANCE: There is a minor but significant contributor that includes a formal 1+ charge on the carbonyl carbon. 2. INDUCTION: The carbonyl carbon is directly attached to a very electronegative oxygen atom. 3. STERICS: How does an sp2 carbon compare to an sp3? – What would the resonance hybrid look like for this carbonyl? Copyright 2012 John Wiley & Sons, Inc. 20 -9 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -10 Klein, Organic Chemistry 1e 20.4 Nucleophilic Attack on a 20.4 Carbonyls as Electrophiles Carbonyl • We want to analyze how nucleophiles attack carbonyls • Consider the factors: resonance, induction, and sterics. and why some nucleophile react and others don’t. • Which should be MORE REACTIVE as an electrophile, – Example attack: aldehydes or ketones? Explain WHY. • Example comparison: • If the nucleophile is weak, or if the attacking nucleophile is a good leaving group, the reverse reaction will dominate. – Reverse reaction: Copyright 2012 John Wiley & Sons, Inc. 20 -11 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -12 Klein, Organic Chemistry 1e 2 4/18/2012 20.4 Nucleophilic Attack on a 20.4 Nucleophilic Attack on a Carbonyl Carbonyl – Nucleophilic Addition • Show the nucleophilic attack for some other • If the nucleophile is strong enough to attack and NOT a nucleophiles. Nucleophiles to consider include OH–, good leaving group, then the full ADDITION will occur – – – CN , H , R , H2O. (Mechanism 20.1). • 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. • The intermediate carries a negative charge, so it will • Compare attack on a carbonyl with attack on an alkyl pick up a proton to become more stable. halide. Copyright 2012 John Wiley & Sons, Inc. 20 -13 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -14 Klein, Organic Chemistry 1e 20.4 Nucleophilic Attack on a 20.4 Nucleophilic Attack on a Carbonyl Carbonyl – Nucleophilic Addition • If the nucleophile is weak and reluctant to attack the • With a weak nucleophile, the presence of an acid will carbonyl, HOW could we improve its ability to attack? make the carbonyl more attractive to the nucleophile • We can make the carbonyl more electrophilic: so the full ADDITION can occur (Mechanism 20.2). – Adding an acid will help. HOW? • Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics). Copyright 2012 John Wiley & Sons, Inc. 20 -15 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -16 Klein, Organic Chemistry 1e 20.4 Nucleophilic Attack on a 20.5 Water as a Nucleophile Carbonyl – Nucleophilic Addition • Is there a reason why acid is not used with strong • Is water generally a strong or weak nucleophile? nucleophiles? • Show a generic mechanism for water attacking an aldehyde or ketone. • Predict whether the nucleophilic attack is product favored or reactant favored. WHY? • Would the presence of an acid improve the reaction? Copyright 2012 John Wiley & Sons, Inc. 20 -17 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -18 Klein, Organic Chemistry 1e 3 4/18/2012 20.5 Water as a Nucleophile 20.5 Water as a Nucleophile • If water were to attack the carbonyl, what likely mechanism steps would follow? Acetone • Will the overall process be fast or slow? Formaldehyde • Will the overall process be product or reactant favored? Hexafluoroacetone Copyright 2012 John Wiley & Sons, Inc. 20 -19 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -20 Klein, Organic Chemistry 1e 20.5 Water as a Nucleophile 20.5 Water as a Nucleophile • To avoid the unstable intermediate with two formal Acetone charges, the reaction can be catalyzed by a base (Mechanism 20.3). Formaldehyde Hexafluoroacetone • How do the following factors affect the equilibria: entropy, induction, sterics? Copyright 2012 John Wiley & Sons, Inc. 20 -21 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -22 Klein, Organic Chemistry 1e 20.5 Water as a Nucleophile 20.5 Water as a Nucleophile • The reaction can also be catalyzed by an acid (Mechanism 20.4). • How does the base increase the rate of reaction? Will it make the reaction more product‐favored? Copyright 2012 John Wiley & Sons, Inc. 20 -23 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -24 Klein, Organic Chemistry 1e 4 4/18/2012 20.5 Water as a Nucleophile 20.5 Acetals – Formation • 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) • How does the acid increase the rate of reaction? Will it on the next slide. make the reaction more product‐favored? • Analyze how the acid allows the reaction to proceed through lower energy intermediates. Copyright 2012 John Wiley & Sons, Inc. 20 -25 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -26 Klein, Organic Chemistry 1e 20.5 Acetals – Formation 20.5 Acetals – Formation • After the hemiacetal is protonated in Mechanism 20.5, the water leaving group leaves. Why is the water leaving group pushed out INTRAMOLECULARLY? Copyright 2012 John Wiley & Sons, Inc. 20 -27 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -28 Klein, Organic Chemistry 1e 20.5 Acetals – Formation 20.5 Acetals – Formation • You might imagine an INTERMOLECULAR collision that causes the water to leave. • Why is the INTERMOLECULAR step unlikely? 5 and 6-membered cyclic acetals are generally product favored • Practice with SKILLBUILDER 20.2. Copyright 2012 John Wiley & Sons, Inc. 20 -29 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -30 Klein, Organic Chemistry 1e 5 4/18/2012 20.5 Acetals – Formation 20.5 Acetals – Equilibrium Control • Acetals can be attached and removed fairly easily. • Example: • Both the forward and reverse reactions are acid catalyzed. 5 and 6-membered cyclic acetals are generally product favored • How does the presence of water affect which side the • How do entropy, induction, sterics, and equilibrium will favor? Le Châtelier’s principle affect the equilibrium? Copyright 2012 John Wiley & Sons, Inc. 20 -31 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -32 Klein, Organic Chemistry 1e 20.5 Acetals –Protecting Groups 20.5 Acetals –Protecting Groups • We can use an acetal to selectively protect an • Fill in necessary reagents or intermediates. aldehyde or ketone from reacting in the presence of other electrophiles. • Fill in necessary reagents or intermediates. Copyright 2012 John Wiley & Sons, Inc. 20 -33 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -34 Klein, Organic Chemistry 1e 20.6 Primary Amine Nucleophiles 20.6 Primary Amine Nucleophiles • As a nucleophile, are amines stronger or weaker than water? – If you want an amine to attack a carbonyl carbon, will a catalyst be necessary? • Will an acid (H+) or a base (OH‐) cataly st be most likely to work? WHY? • What will the product most likely look like? Keep in mind that entropy disfavors processes in which two molecules combine to form one. • Analyze the complete mechanism (Mechanism 20.6) on the next slide. Copyright 2012 John Wiley & Sons, Inc. 20 -35 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 20 -36 Klein, Organic Chemistry 1e 6 4/18/2012 20.6 Primary Amine Nucleophiles 20.6 Primary Amine Nucleophiles • The mechanism requires an acid catalyst.