20.1 Ketones and Aldehydes – Relevant Examples

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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

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:

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:

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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

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?

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:

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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.

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).

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?

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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

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?

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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.

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?

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

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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.

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

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20.6 Primary Amine Nucleophiles 20.6 Primary Amine Nucleophiles • The mechanism requires an acid catalyst. Note that the • Why does the reaction slow down below pH 4? optimal pH to achieve a fast reaction is around 4 or 5.

• Why does the reaction slow down when the pH is • Practice with SKILLBUILDER 20.3. greater than 5?

20.6 Primary Amine Nucleophiles vs. 20.7 Wolff‐Kishner Reduction Secondary Amine Nucleophiles • A proton transfer alleviates • Reduction of a carbonyl to an alkane: the +1 charge in both mechanisms. The difference occurs in the LAST step. – For 1° amines (Mechanism 20.6): the NITROGEN atom loses a proton directly. • Hydrazine attacks the carbonyl via Mechanism 20.6 to – For 2° amines (Mechanism 20.7): a neighboring CARBON atom form the hydrazone, which is structurally similar to an loses a proton. imine. • Practice with SKILLBUILDER • The second part of the mechanism is shown on the 20.4. next slide (Mechanism 20.8).

20.7 Wolff‐Kishner Reduction 20.7 Wolff‐Kishner Reduction

• In general, carbanions are unstable and reluctant to • What drives this reaction forward? form. • Is OH‐ a catalyst in the mechanism?

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20.8 Mechanism Strategies – 20.8 Mechanism Strategies • Note the many similarities between the acid catalyzed Sulfur Nucleophiles mechanisms we have discussed: • Under acidic conditions, thiols react nearly the same – Carbonyl is protonated first: as alcohols. Examples: • Makes the carbonyl more electrophilic • Avoids negative formal charge on the intermediate – Avoid high energy intermediate with two formal charges – Acid protonates leaving group so that it is stable and neutral upon leaving – Last step of mechanism involves a proton transfer forming a neutral product • Overall: under acidic conditions, reaction species should either be neutral or have a +1 formal charge.

20.8 Mechanism Strategies – 20.9 Hydrogen Nucleophiles Alternative to Wolff‐Kishner • Conditions to convert a ketone into an alkane: • We rarely see hydrogen acting as a nucleophile. WHY? What role does hydrogen normally play in mechanisms? • To be a nucleophile, hydrogen must have a pair of electrons. H:1‐ is calle d hdidhydride 1. A thioacetal is formed via an acid catalyzed nucleophilic addition mechanism. • Reagents that produce hydride ions include LiAlH4

2. Raney Ni transfers H2 molecules to the thioacetal converting (LAH) and NaBH4. Hydrides will react readily with it into an alkane. carbonyls. • Recall the Clemmenson (Section 19.6) reduction can also be used to promote this conversion.

20.9 Hydrogen Nucleophiles 20.10 Carbon Nucleophiles

• Carbon doesn’t often act as a nucleophile. WHY? What ROLE does carbon most often play in mechanisms? • Identify the nucleophile. • To be a nucleophile, carbon must have a pair of • Will the reaction be more effective under acidic or electrons it can use to attract an electrophile: under basic conditions? WHY? 1. A carbanion with a ‐1 charge and an available pair of electrons. However, carbanions are relatively unstable and • Show a complete mechanism (Mechanism 20.9). reluctant to form. • Analyze the reversibility (or irreversibility )of each step. 2. A carbon attached to a very low electronegativity • Describe necessary experimental conditions. atom such as a Grignard. Analyze the electrostatics of the Grignard reagent. Why are there two steps in the reaction?

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20.10 Grignard Example 20.10 Cyanohydrin O

H 1) BrMg O 3 equivalents • The cyanide ion can act as a nucleophile.

O 2) dilute HCl (aq) • Identify the nucleophile. • Will the reaction be more effective under acidic or under bbiasic conditions ? WHY? • Show a complete mechanism (Mechanism 20.10). Three equivalents of the Grignard are necessary. • Disadvantage: EXTREME toxicity and volatility of hydrogen cyanide. • Analyze the reversibility or irreversibility of each step. • Describe necessary experimental conditions. Why are there two steps in the reaction?

20.10 Cyanohydrin 20.10 Wittig Reaction

• Advantage: synthetic utility • Like the Grignard and the cyanohydrin, the Wittig reaction can be very synthetically useful. What do these three reactions have in common? • Example:

• Similar to the Grignard, one carbon is a nucleophile and the other is an electrophile. • Identify which is which.

20.10 Wittig Reaction – 20.10 Wittig Reaction – Wittig Reagent or Ylide Wittig Reagent or Ylide • The ylide carries a formal negative charge on a carbon.

• In gg,eneral, carbons are not good at stabilizing a negative charge. Are there any factors that allow the ylide to stabilize its formal negative charge? • Why is the charged resonance contributor the major contributor?

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20.10 Wittig Reaction – 20.10 Wittig Reaction Formation of an ylide • The Wittig mechanism (Mechanism 20.12): • To make an ylide, you start with an alkyl halide and triphenylphosphine. • Example:

• Which of the steps in the reaction is mostly likely the slowest? WHY? • The first step is a simple substitution. The second step • The formation of the especially stable is a proton transfer. triphenylphoshine oxide drives the equilibrium forward.

20.10 Wittig Reaction – 20.10 Wittig Reaction –Overall Formation of an Ylide • Is the base used in the second step strong or weak? • Overall, the Wittig reaction allows two molecular Why is such a base used? segments to be connected through a C=C. • Example:

– Describe the reagents and conditions necessary for the reaction to take place. – Give a mechanism. – Note how the colored segments are connected.

20.10 Wittig Reaction –Overall 20.11 Baeyer‐Villiger

• Overall, the Wittig reaction allows two molecular • An oxygen is inserted between a carbonyl carbon and segments to be connected through a C=C. neighboring group. • Mechanism 20.13 shows the movement of electrons. 1. retro

• Use a retrosynthetic analysis to determine a different set of reactants that could be used to make the target. • Practice with SKILLBUILDER 20.6.

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20.11 Baeyer‐Villiger 20.11 Baeyer‐Villiger Example

• Which step in the equilibrium is most likely the • If the carbonyl is asymmetrical, use the following chart slowest? WHY? to determine which group migrates most readily.

• Predict the product of the reaction, and give a complete mechanism.

• Note the last step is not reversible. WHY?

20.12 Synthetic Strategies 20.12 Synthetic Strategies

• Recall the questions we ask to aid our analysis‐ • Recall the questions we ask to aid our analysis 1. Is there a change in the carbon skeleton? 1. Is there a change in the carbon skeleton? 2. Is there a change in the functional group? 2. Is there a change in the functional group? • Changes to the • Changes to the carbon skeleton: carbon skeleton: C–C bond cleavage C–C bond formation • Name the reaction. • Name each reaction. • Practice with SKILLBUILDER 20.7.

20.13 Spectroscopic Analysis – 20.13 Spectroscopic Analysis – Infrared Spectroscopy NMR Spectroscopy • STRONG peak for the C=O stretch: • Protons neighboring a carbonyl are weakly deshielded by the oxygen.

typical carbonyl typical conjugated carbonyl • Aldehyde protons are strongly deshielded, usually appearing around 9 or 10 ppm. • Aldehydes also give WEAK peaks around – Why is the aldehyde proton shifted so far downfield? 2700–2800 cm‐1 for the C–H stretch. • In the 13C NMR, the carbonyl carbon generally appears around 200 ppm.

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20.13 Spectroscopic Analysis – NMR Spectroscopy • Predict 1H NMR shifts, splitting, and integration and 13C shifts for the following molecule.

O O H