STUDY GUIDE FOR EXAM 2- ALDEHYDES AND KETONES

Oxidation of Alcohols to Carbonyl Compounds

The oxidation of alcohols to carbonyl compounds is the reverse of nucleophilic addition (below). Most oxidants accept the alcohol oxygen as a nucleophile followed by loss of the acidic hydrogen. The process is completed by an E2-like elimination of hydrogen from the proto-carbonyl carbon in concert with formation of the C=O -bond and reductive loss of the leaving group.

General Mechanism

Swern

Chromic Acid

Scope and Limitations

1. As a hydrogen atom is needed for the elimination step, 3o alcohols do not oxidize to carbonyl compounds.2. Normally 1o alcohols are converted to aldehydes and 2o alcohols to ketones.3. However, in the presence of water, aldehydes form hydrates that undergo more rapid oxidation than the

starting 1o alcohols. Thus with CrO3/H2SO4, Na2CrO7, K2CrO7, H2CrO4, 1o alcohols are converted to carboxylic acids.

4. This over-oxidation is avoided with the Swern oxidation or the use of PCC.

Nucleophilic Addition

Most of the reactions of aldehydes and ketones in these chapters are nucleophilic addition reactions. The oxygen in C=O polarizes the bond. Therefore, while electrophilic addition (electrophile first, followed by nucleophile) was favored for the comparatively non-polar, electron-rich alkene, carbonyls undergo nucleophilic addition (nucleophile first, followed by electrophile). Note how all the mechanisms begin exactly the same way:

General Mechanism

Hydride

LiAlH4 is similar

Carbanion

Grignard/Alkyllithium/Acetylide

Ylide

Wittig Reaction

The Wittig is unique in that the alkoxide oxygen in the tetrahedral intermediate attacks the phosphonium center forming an oxaphosphetane intermediate. Thus, the electrophile is not H+ as in the previous examples but the phosphonium center. The intermediate undergoes a reverse 2+2 process to form triphenylphosphine oxide and an alkene product to complete the process.

If the nucleophile is a weaker base than the alkoxide in the tetrahedral intermediate, an alternative mechanism is proposed. Here, the electrophile (usually H+) is added first to enhance the polarity of the C=O bond, and reduce the energy of the tetrahedral intermediate (transition state resembles this intermediate; stabilizing it will increase the rate). The reverse reaction rates are also enhanced, so the mechanisms feature equillibria.

Alcohol as Nucleophile – Acetal/Ketal Formation

1o Amine as Nucleophile – Imine Formation

2o Amine as Nucleophile – Enamine Formation

Cyanide as Nucleophile – Cyanohydrin Formation

Peracid as Nucleophile – Baeyer-Villager Oxidation

Developmental Problems

1. Complete the following ‘reactivity tree’ for a ketone:

2. Predict the products: a.

b.

c.

d.

e.

f.

g.

h.

i.

j.

O O

OH1) LAH, ether2) H2O

O

KCN

HCl / H2O

O

pH 5.5

NH

O Ph3PCHCH3

O

pH 5.5

NH2

Br

1) Ph3P2) n-BuLi3)

Ph

O

3. Predict the products – Part II: a.

b.

c.

d.

e.

f.

g.

h.

i.

j.

4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C7H6O2. Identify it!

5. How would you synthesize the following from cyclopentanone?a. b. c.

6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved. Propose a mechanism for the following transformation:

7. Hydrolyze the following derivatives back to the original aldehydes and ketones:a. b. c. d. e.

8. Difficult to start; however easy once you finish! Propose a synthesis for the following transformations:

9. Identify A, B, C and D:

10. Identify A-E:

11. Provide an efficient synthesis for the following:

a.

b.

c.

d.

e.

f.

g.

h.

i.

j.

from benzene and an epoxide as only sources of carbon

OH

O

from two primaryalkyl halides

O

EXA M PR EP ARA TIO N

Nomenclature: Aldehydes and Ketones

Syntheses: This is the first exam with targeted syntheses that you need to work out prior to the exam. You are free to work with your classmates as much as you want (except during the exam of course!). I will not post a key, nor provide you finished syntheses. If you want questions answered you must have made a reaonable attempt (in writing) at solving the synthesis on your own. During review sessions, any student that asks about the syntheses will be asked to go to the board to present what they have worked out so far. I will guide the class towards through any difficulties.

Enovid®: This common contraceptive contains the compound norethynodrel. Convert the precursor to this component using any reagents you require. (Hint: at some point you will need to use a protecting group!)

Tamoxifen®: This is a drug used in the treatment of breast cancer. Propose a synthesis of tamoxifen from the following 3’-hydroxybenzophenone, benzene and any carbon containing compounds of three carbons or less with any reagents you require.

Ibuprofen (Motrin®, Advil® Nuprin ®) Synthesize this common NSAID (non-steroidal anti-inflammatory drug) from benzene and any other reagents you wish.

Disparlure: This molecule is a sex attractant of the Porthetria dispar gypsy moth. Propose a synthesis of disparlure starting with any two aldehydes and/or ketones you wish as your sole sources of carbon atoms. Assume any Wittig reaction (hint) would give you exclusively the Z-isomer alkene as a product:

KE Y

1. Complete the following ‘reactivity tree’ for a ketone:

2. Predict the products:a.

b.

c.

d.

e.

f.

O O

OH1) LAH, ether2) H2O

O

KCN

HCl / H2O

O

pH 5.5

NH

g.

h.

i.

j.

3. Predict the products – Part II: a.

b.

c.

d.

e.

f.

O Ph3PCHCH3

O

pH 5.5

NH2

Br

1) Ph3P2) n-BuLi3)

Ph

O

g.

h.

i.

j.

4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C7H6O2. Identify it!

5. How would you synthesize the following from cyclopentanone?

6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved. Propose a mechanism for the following transformation:

7. Hydrolyze the following derivatives back to the original aldehydes and ketones:

8. Difficult to start; however easy once you finish! Propose a synthesis for the following transformations:

O

+ NH

O

+ NH2

a)

b)

O

+ OHc)

OH

d) OHHOO

e) OHHOO

+

9. Identify A, B, C and D:

10. Identify A-E:

11. Provide an efficient synthesis for the following:

a.

b.

c.

d.

e.

f.

g.

h.

i.

j.