1

1) Aldehydes & Ketones: Structure

2

2) Aldehydes & Ketones: IUPAC naming

3

3) Common Aldehydes & Ketones

1

A) and B) Aldehyde & Ketone Prep: Alkyne Hydration

Symmetrical Symmetrical

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

Disiamylborane: (Sia)2B-H

(adding water)

2

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

3

E) Aldehyde Prep: from Acid Halides

4

F) Ketone Prep: from Acid Halides

5

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

6

Lactones (Cyclic Esters) + Hydrides

1

Reactions 1-6) Great Nucleophiles + Aldehyde or Ketone

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

1

The Wittig Reaction: Overall Reaction + Mechanism

Reaction of an aldehyde or ketone to form an alkene 1979 Nobel Prize in Chemistry: Georg Wittig (Wittig Reaction) and H.C. Brown (Hydroboration)

R1C

R2O

R4CPh3PR3

+

+R3

CC

R2

R1

R4+ Ph3P=O

aldehyde or ketone

Triphenylphosphonium Ylide (Wittig reagent)

Great Nucleophile

alkene Triphenylphosphine oxide

Use the mechanism for “Great Nucleophiles.”

(by-product)

2

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.

HO

O

O

PPh3 O

O

O

O

CHO

+

+OCH3

Ph3PO O

O

OCH3

O

3

The Wittig Reaction: forming Hofmann Alkenes

Zaitsev Alkene Hofmann Alkene (most subst. alkene) (least subst. alkene)

4

The Wittig Reaction: Making the Ylide

Ph3P H3C Br Ph3P CH3

Br

Phosphonium salt

H3CLi

THFPh3P CH2 Ph3P CH2

ylide phosphorane

2) Any alkyl lithium (R-Li) can be used as a strong base

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

3) A phosphorane is a neutral resonance structure of the ylide.

5

The Wittig Reaction: RetroSynthetic Analysis

Two possible Wittig routes to an alkene

“Disconnect” the alkene carbons to find the possible reactants.

R3

CCR2

R1

R4

Disconnect this bond

CR2

R1

OR3

CR4

Ph3P+ CR2

R1

PPh3R3

CR4

O+- OR -

Look at the “retrosynthetic arrow”

Chapter 18 1

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)

O

COC

OC

H H

H

H

H

H

heatH C

O

HH2O H C

H

OHHO

trioxane, m.p. 62°C

formaldehyde, b.p. -21°C

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

H+ (cat.)

aldehyde hemi-acetal acetal (geminal-diether)

R HCO

OR'COH

RH

+ R'OH

- R'OH

+ R'OH

- R'OH OR'COR'

RH + H2O

important A catalytic amount of acid

is needed to increase carbonyl reactivity.

H+

Get good at proton transfers

(catalytic)

Acetal Formation: Poor Nucleophile Mechanism These rxn steps are ALL in equilibrium

2

The mechanism for acetal/ketal formation is reversible

Dean-Stark Trap

ketone hemi-ketal ketal (geminal-diether)

R RCO

OR'COH

RR

+ R'OH

- R'OH

+ R'OH

- R'OH OR'COR'

RR + H2O

3

Cyclic Acetal (and Ketals): Dioxolanes and dioxanes

R RCO

HO OH+ OOR R

H+, - H2O

H3O+

R RCO

HO+

R R

H+, - H2O

H3O+OH OO

1,3-dioxolane

1,3-dioxane

1,2-diol

1,3-diol

4

Acetals (and Ketals) as Protecting Groups

Acetal (and Ketals) selectively form from aldehydes and ketone and NOT from other carbonyl compounds

( amides, esters or carboxylic acids)

Chemoselectivity

important A catalytic amount of acid

is needed to increase carbonyl reactivity.

H+

Get good at proton transfers

(catalytic)

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

Use either an aldehyde or a ketone

carbinolamine

imine

2

The mechanism for imine formation is reversible

Dean-Stark Trap

R RCO

NHR'COH

RR

- H2O

R RCN R'R'NH2

carbinolamine

H+ (cat.) H+ (cat.)

+ H2O

3

Aldehyde and Ketone Reactions with Primary and Secondary Amines

R RCO

NHR'COH

RR

- H2O

R RCN R'R'NH2

1° amine: 2° amine:

Imine Iminium ion

R RCO

NCOH

RR

R' NH

R'R'

R' R RCN R'R' +

- HO _

iminium ion enamine

ketone with α-protons

RCO

NCOH

R - HOR' N

HR'

R'

R' RCN R'R' +

R

H H RHH R

H HRC

N R'R'

R

H

_- H +

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

4

Related to Imines: Oximes, Phenylhydrozones, and Semicarbazides

O

NN-C6H5

H2NOH

NOH

phenylhydrazoneoxime

C6H2NHNH2

N

H2NHNCONH2

NH

NH2

O

semicarbazide

5

Aldehyde and Ketone Reaction Summary with Amines

1) Aldoxime Dehydration

Chapter 18 2

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.

ORaney Ni

OH

H

2) Hydrogenation of Aldehydes and Ketones

Chapter 18 3

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 4

3A) Clemmensen Reduction

C

O

CH2CH3 Zn(Hg)

HCl, H2O

CH2CH2CH3

CH2 C

O

H HCl, H2O

Zn(Hg)CH2 CH3

=>

Chapter 18 5

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

O

H H2N NH2CH2 C

NNH2

H KOHheat

CH2 CH3

=>

RavenWeiss

We'll do reactions of amides later.

1

1) Carboxylic Acids: Polarity

Carboxylic acids •  are strongly polar compounds •  have two polar groups:

hydroxyl (−OH) and carbonyl (C═O)

2

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

3

2B) Carboxylic Acids: Hydrogen Bonding & Water Solubility

4

3) Carboxylic Acids: IUPAC naming

1

2

Substituents Affect Acidity

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

3

Rank the labeled protons Most acidic first / Least acidic last

OHc

O

H OHbHa

What are the approximate pKa values for each proton?

1

1) Hydrolysis of Carboxylic Acid Derivatives: Acid Catalyzed

2

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

1

Lactones / Lactams (antibiotics)

•  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).

Penicillin

Chapter 20 1

1) Carboxylic Acids: Deprotonation

The hydroxide ion deprotonates the acid to form the carboxylate salt.

Adding a strong acid, like HCl, regenerates the carboxylic acid.

A nucleophile / base will first attack the most polar bond (O-H)

2

2) Carboxylic Acids: Reduction with LiAlH4 or BH3

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

Chapter 20 3

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.

4

•  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.

R C

O

OH 2 R' Li

R C

OLi

OLiR'

H3O+R C

OH

OHR'

R C

OR' + H2O

dianion hydrate of ketone ketone

3B) Carboxylic Acids: Reduction with Alkyl Lithium (Mechanism)

5

4A) Carboxylic Acids: forming acid halides

6

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

+ pyridine (you need something to

soak-up the strong acid by-product)

7

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

+ pyridine (you need something to

soak-up the acid by-product)

8

•  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.

5) Carboxylic Acids: forming Amides