*2Aldehydes - Ketones - Carboxylic Acids

1) Aldehydes & Ketones: Structure

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2) Aldehydes & Ketones: IUPAC naming

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3) Common Aldehydes & Ketones

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A) and B) Aldehyde & Ketone Prep: Alkyne Hydration (adding water)

9-BBN (exists as dimer) 9-Borabicyclo[3.3.1]nonane

Disiamylborane: (Sia)2B-H

Symmetrical

Symmetrical

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C) and D) Aldehyde & Ketone Prep: Oxidative Cleavage (of cis-diols)

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E) Aldehyde Prep: from Acid Halides

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F) Ketone Prep: from Acid Halides

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G) and H) Aldehyde and Ketone Prep: from Nitriles

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Lactones (Cyclic Esters) + Hydrides

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Reactions 1-6) Great Nucleophiles + Aldehyde or Ketone

DIBAL-H and LiAl(t-Butoxy)3-H are too weak.

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The Wittig Reaction: Overall Reaction + Mechanism 1979 Nobel Prize in Chemistry: Georg Wittig (Wittig Reaction) and H.C. Brown (Hydroboration)

R1 C O R2 aldehyde or ketone

+

+

Reaction of an aldehyde or ketone to form an alkene R4

R2

R4

C C

Ph3P C R3

Triphenylphosphonium Ylide (Wittig reagent) Great Nucleophile

R1

R3

alkene

+

Ph3P=O

Triphenylphosphine oxide (by-product)

Use the mechanism for “Great Nucleophiles.”

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The Wittig Reaction: Chemoselectivity • 

The Wittig reaction is highly selective for ketones and aldehydes

• 

Esters, Lactones (cyclic esters), Nitriles and Amides will not react AND are tolerated in the substrate.

• 

Acidic groups (alcohols, amines and carboxylic acids) are not tolerated.

O O

H

O

PPh3

+

O

O O

CHO

O +

O

O

Ph3P

O OCH3

OCH3

O

2

The Wittig Reaction: forming Hofmann Alkenes

Hofmann Alkene (least subst. alkene)

Zaitsev Alkene (most subst. alkene)

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The Wittig Reaction: Making the Ylide 1) A Wittig reagent (ylide) is prepared from the reaction of an alkyl halide with triphenylphosphine (Ph3P:) to give a phosphonium salt.

Ph3P

H3C Br

Ph3P CH3 Br

H3CLi THF

Ph3P CH2 ylide

Ph3P

CH2

phosphorane

Phosphonium salt

2) Any alkyl lithium (R-Li) can be used as a strong base 3) A phosphorane is a neutral resonance structure of the ylide.

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The Wittig Reaction: RetroSynthetic Analysis

Look at the “retrosynthetic arrow”

Two possible Wittig routes to an alkene “Disconnect” the alkene carbons to find the possible reactants. Disconnect this bond R2

R4

C C R3 R1

R2 C O R1

R2

R4 + Ph3P C

- OR R3

C PPh3 + O C R1

R4 R3

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Formaldehyde Hydrate (adding water) •  Heating Trioxane will release Formaldehyde, which is a gas at room temperature. •  Formaldehyde dissolved in water (40% aqeous solution) produces Formalin (a hydrate) H H

O

H C

O

heat

C C H O H H

O H

C

H

H2O H+ (cat.)

formaldehyde, b.p. -21°C trioxane, m.p. 62°C

HO OH H C H

formalin =>

Hydrates are 1,2—geminal diols, which are only stable when formed from small (with 1-3 carbons) aldehydes or ketones. Or if the substituent is an EWG

Chapter 18

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Acetal Formation: Poor Nucleophile Mechanism Get good at proton transfers

These rxn steps are ALL in equilibrium

H+ (catalytic)

R

O C

+ R'OH H

- R'OH

aldehyde

important

A catalytic amount of acid is needed to increase carbonyl reactivity.

OH H C OR' R

hemi-acetal

+ R'OH - R'OH

OR' H C OR' R

acetal (geminal-diether)

+ H2O

The mechanism for acetal/ketal formation is reversible

R

O C

+ R'OH R

ketone

- R'OH

OH R C OR' R

hemi-ketal

+ R'OH - R'OH

OR' R C OR' R

+ H2O

ketal (geminal-diether)

Dean-Stark Trap 2

Cyclic Acetal (and Ketals): Dioxolanes and dioxanes

R

O C

+ R

H+, - H2O HO

OH

1,3-diol

R

O C

H+, - H2O + R

HO

OH

1,2-diol

O R

H3O+

H3O+

O

O

R

R

O R

1,3-dioxane

1,3-dioxolane

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Acetals (and Ketals) as Protecting Groups Chemoselectivity Acetal (and Ketals) selectively form from aldehydes and ketone and NOT from other carbonyl compounds ( amides, esters or carboxylic acids)

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Imine (Shiff Base) Formation: Poor Nucleophile Mechanism These rxn steps are ALL in equilibrium

Get good at proton transfers

Use either an aldehyde or a ketone

carbinolamine

imine

H+ (catalytic)

important

A catalytic amount of acid is needed to increase carbonyl reactivity.

The mechanism for imine formation is reversible

H+ (cat.)

R

O C

H+ (cat.)

R'NH2 R

OH R C NHR' R

carbinolamine

- H2O R

N C

R' R

+ H 2O

Dean-Stark Trap 2

Aldehyde and Ketone Reactions with Primary and Secondary Amines

O C

R

1° amine:

R'NH2 R

R'

2° amine:

R

O C

ketone with α-protons

R

H H

R'

R R'

O C

N H

R

N H

R'

OH R C NHR' R

OH R C N R' R R' OH R' R C N H H R R'

- H2O R

- HO

- HO

_

_

N C

R'

Imine R

+ R' N C R R

R'

+ R' N R C R H H

Iminium ion

R'

-H

iminium ion

R'

+ R

N C

R' R

H

enamine

Aldehydes and Ketones do not react with tertiary amines (R3N) 3

Related to Imines: Oximes, Phenylhydrozones, and Semicarbazides O

C6H2NHNH2

H2NOH N

oxime

OH

N

N-C6H5

phenylhydrazone

H2NHNCONH2 O N

N H

NH2

semicarbazide

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Aldehyde and Ketone Reaction Summary with Amines

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1) Aldoxime Dehydration

2) Hydrogenation of Aldehydes and Ketones Alkenes are more easily hydrogenated (than carbonyl groups). So, we need a more reactive catalyst system •  Raney Nickel, finely divided Ni powder (or Nickel-Aluminum alloy) •  Leaching the alloy with base (NaOH) makes it porous and activates the surface with hydrogen gas. •  Widely used in industry: used to make hydrogenated vegetable oils; Raney Nickel is bought from W. R. Grace & Co.

O

OH Raney Ni

Chapter 18

H 2

3) Deoxygenation Reactions Reduction of C=O (of aldehyde or ketone) to CH2 Clemmensen Reduction if molecule is stable in hot acid. Wolff-Kishner reduction if molecule is stable in very strong base.

=>

Chapter 18

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3A) Clemmensen Reduction O C

CH2CH3

Zn(Hg)

CH2CH2CH3

HCl, H2O

O CH2

C

Zn(Hg) H

HCl, H2O

CH2

CH3

=> Chapter 18

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3B) Wolff-Kishner Reduction •  Form hydrazone, then heat with strong base like KOH or potassium t-butoxide. •  Use a high-boiling solvent: ethylene glycol, diethylene glycol, or DMSO. CH2

C H

H2N NH2

CH2

O

C H NNH2

KOH heat

CH2

CH3

=> Chapter 18

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We'll do reactions of amides later.

1) Carboxylic Acids: Polarity

Carboxylic acids •  are strongly polar compounds •  have two polar groups: hydroxyl (−OH) and carbonyl (C═O)

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2A) Carboxylic Acids: Hydrogen Bonding & BP & Water Solubility Hydrogen Bonding when one heteroatom uses its lone pair to pull (steal) a hydrogen atom from another heteroatom

Hydrogen Bonding is related to a molecule’s boiling point and water solubility 2

2B) Carboxylic Acids: Hydrogen Bonding & Water Solubility

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3) Carboxylic Acids: IUPAC naming

4

1

Substituents Affect Acidity

The magnitude of a substituent effect depends on its distance from the carboxyl group. 2

Rank the labeled protons Most acidic first / Least acidic last Ha

H

OHb OHc O

What are the approximate pKa values for each proton?

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1) Hydrolysis of Carboxylic Acid Derivatives: Acid Catalyzed

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2) Hydrolysis of Carboxylic Acid Derivatives: Hydroxide (base)

2

Lactones / Lactams (antibiotics)

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Penicillin •  β-lactam antibiotics (Penicillin) have ring strain. •  Bacterium have an enzyme (transpeptidase) that is responsible for repairing the cell wall •  The reaction between the enzyme and the β-lactam causes covalent modification of the enzyme (inactivating it and halting cell wall construction).

1) Carboxylic Acids: Deprotonation A nucleophile / base will first attack the most polar bond (O-H)

The hydroxide ion deprotonates the acid to form the carboxylate salt. Adding a strong acid, like HCl, regenerates the carboxylic acid.

Chapter 20

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2) Carboxylic Acids: Reduction with LiAlH4 or BH3

BH3•THF or diborane (B2H6) can chemoselectively reduce a carboxylic acid to an alcohol 2

3A) Carboxylic Acids: Reduction with Alkyl Lithium to Ketones

A general method of making ketones involves the reaction of a carboxylic acid with two equivalents of an organolithium reagent. Chapter 20

3

3B) Carboxylic Acids: Reduction with Alkyl Lithium (Mechanism) O R C OH

OH

OLi 2 R' Li

R C OLi

H3O+

R C OH

R'

R'

dianion

hydrate of ketone

O R C R'

+ H2O

ketone

•  A Great Nucleophile/Base will first attack the most polar bond (deprotonation of carboxylic acids) •  The second equivalent attacks the carbonyl. •  Hydrolysis forms the hydrate, which converts to the more stable ketone.

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4A) Carboxylic Acids: forming acid halides

5

4B) Carboxylic Acids: forming acid halides (Mechanism)

+ pyridine (you need something to soak-up the strong acid by-product) 6

4C) Carboxylic Acids: forming acid halides (Mechanism)

+ pyridine (you need something to soak-up the acid by-product) 7

5) Carboxylic Acids: forming Amides

•  The initial reaction of a carboxylic acid with an amine (deprotonation) gives an ammonium carboxylate salt. •  Heating this salt to well above 100° C drives off steam (dehydration) and forms an amide.

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