Interlude 1: Oxidations, Reductions & Other Functional Group Interconversions (FGI)

Chemistry 335 Supplemental Slides: Interlude 1 1

1. Definition of Oxidation and Reduction

For practical purposes in organic chemistry, oxidation and reduction are defined as follows:

Oxidation: • addition of oxygen to the substrate or • removal of hydrogen or • removal of one electron

Reduction: • addition of hydrogen to the substrate or • removal of oxygen or • addition of one electron

1. Definition of Oxidation and Reduction (cont’d)

Chemistry 335 Supplemental Slides: Interlude 1 2

Oxidation states in organic species are not always easy to assign, due to the covalent nature of bonding for organic molecules.

Instead of oxidation state, we define an oxidation number, using rules derived from Hendrickson, Cram, Hammond and Pine:

The contribution to each carbon is: – 1 for H 0 for C + 1 for electronegative elements

2. Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids

Chemistry 335 Supplemental Slides: Interlude 1 3

A. The most widely employed transition metal oxidants for alcohols are based on Cr(VI). Chromium trioxide = CrO3 Dichromate = Cr2O7

2-

Chromium trioxide will oxidize 2o alcohols to ketones. A specific cocktail of CrO3 and H2SO4 in acetone is called the Jones reagent, and is particularly effective for this transformation.

1o alcohols are (transiently) oxidized to aldehydes, but in the presence of water form the hydrate which can be further oxidized to the carboxylic acid.

2. Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids (cont’d)

Chemistry 335 Supplemental Slides: Interlude 1 4

The Jones reagent is (obviously!) very acidic and so cannot be used in the presence of acid-labile functional groups. In these instances, a modified reagent is employed.

Once again, 2o alcohols will be oxidized to ketones. 1o alcohols can be oxidized to aldehydes, provided that rigorously anhydrous conditions are employed. One disadvantage of the Collins reagent is that a large excess is often required in order to achieve good yields. This is particularly problematic given the toxicity and disposal issues surrounding Cr (VI) reagents.

2. Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids (cont’d)

Chemistry 335 Supplemental Slides: Interlude 1 5

Pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC) are also useful reagents for stopping at the aldehyde oxidation state. PCC is less acidic than the Jones reagent and PDC is even further reduced in acidity.

2. Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids (cont’d)

Chemistry 335 Supplemental Slides: Interlude 1 6

B. All these chromium reagents lead to a lot of toxic metal waste. And they’re also not always perfect at stopping at the aldehyde oxidation state. The Swern oxidation is often a much cleaner reaction… this is what REAL organic chemists use!

Non-acidic variants are also known. So what’s the mechanism? Back to the board!

To carry out a Swern reaction: • Combine dimethyl sulfoxide (DMSO) and oxalyl chloride at –78 °C. • Add your alcohol, in solvent. Mix for awhile. • Add triethyl amine, and warm to 0 °C. • Work up with water to remove the Et3NHCl. The other products are (smelly) gasses. • Behold! Nice clean aldehyde!

2. Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids (cont’d)

Chemistry 335 Supplemental Slides: Interlude 1 7

C. Selective oxidations.

notes: MnO2 is an insoluble brown powder: large excesses often required… … and Ag2O is kind of expensive!

3. A Brief (But Useful!) Survey of Other Important Oxidations

Chemistry 335 Supplemental Slides: Interlude 1 8

A. Allylic Oxidation B. Epoxidation*

C. Dihydroxylation* D. Ozonolysis

* asymmetric versions are well-known and very robust!

4. Reductions

Chemistry 335 Supplemental Slides: Interlude 1 9

Lots of functional groups can be reduced: alkenes, alkynes, C=O, C=N, and even alkyl halides.

4. Reductions

Chemistry 335 Supplemental Slides: Interlude 1 10

Broadly speaking, reductions can be grouped into 4 mechanistic classes:

A. Catalytic hydrogenation B. Nucleophilic reduction C. Electrophilic reduction D. Radical reduction

Notes: - often uses neutral, nonpolar substrates - usually gives syn addition if a heterogeneous catalyst is used - asymmetric hydrogenations with chiral metal complexes

Notes: - requires a polarized substrate, eg. - usually not stereospecific - asymmetric additions are sometimes possible (e.g. CBS cat.)

Notes: - good for reducing carboxylic acids; mechanism is via:

5. Catalytic Hydrogenation

Chemistry 335 Supplemental Slides: Interlude 1 11

Can be applied to alkenes, alkynes and imines (but not yet very useful for ketones).

Use of a heterogeneous catalyst (e.g. Pd on carbon) generally affords a syn addition of hydrogen. In other words the reaction is stereospecific.

5. Catalytic Hydrogenation

Chemistry 335 Supplemental Slides: Interlude 1 12

Can be applied to alkenes, alkynes and imines (but not yet very useful for ketones).

Use of a heterogeneous catalyst (e.g. Pd on carbon) generally affords a syn addition of hydrogen. In other words the reaction is stereospecific.

Relative to the size of a molecule, the heterogeneous catalyst is also huge. This means that the hydrogen will be delivered from the most accessible face of the molecule. In other words, the reaction is stereoselective.

5. Catalytic Hydrogenation

Chemistry 335 Supplemental Slides: Interlude 1 13

Catalytic hydrogenation can also be enantioselective, if a chiral metal complex is used (i.e. a metal with a chiral ligand). Lots of these are known.

Some Representative Chiral Ligands (of thousands...)

5. Catalytic Hydrogenation

Chemistry 335 Supplemental Slides: Interlude 1 14

This is super important industrially. Catalytic enantioselective hydrogenation accounts for over 50% of all asymmetric processes done in industry.

A couple of representative syntheses:

5. Catalytic Hydrogenation

Chemistry 335 Supplemental Slides: Interlude 1 15

Hydrogenation of alkynes will afford alkanes…

… unless a special poison is introduced into the catalyst!

In the Lindlar catalyst, the lead (and sometimes quinoline) poisons the palladium, allowing the skilled experimentalist to stop at the alkene. This is a particularly good way to generate cis double bonds. Note that the Wittig reaction also gives cis alkenes (usually), but most other olefinations give trans products. Therefore partial reduction from an alkyne can be a useful strategy!

6. Nucleophilic Reductions: Hydride Reagents

Chemistry 335 Supplemental Slides: Interlude 1 16

more reactive

more selective

• LiAlH4 and Red-Al will reduce almost anything: aldehydes, ketones, alcohols and esters (to provide the corresponding alcohols), nitriles (to 1o amines), and even – under forcing conditions – carboxylic acids! These reagents can even reduce alkyl tosylates!!

• DIBAL will reduce aldehydes and ketones as well, but in reactions with esters and nitriles, it is possible to stop at the corresponding aldehyde or imine (which hydrolyzes to aldehyde).

• NaBH4 will only reduce more reactive species: aldehydes, ketones, imines, etc.

• NaBH4 is compatible with water (and therefore other alcohols) whereas LiAlH4 (and to a lesser extent DIBAL) will catch fire if exposed to water!

*

*note: DIBAL is properly described as an electrophilic reducing agent but it’s convenient to discuss it here.

6. Nucleophilic Reductions: Hydride Reagents

Chemistry 335 Supplemental Slides: Interlude 1 17

Lithium or potassium trialkyl borohydrides are stronger reducing agents than NaBH4

The three electron-donating R groups make the borohydride more nucleophilic!

These also provide extra steric bulk that can be useful in providing selectivity in reactions.

all very powerful reducing agents!

6. Nucleophilic Reductions: Hydride Reagents

Chemistry 335 Supplemental Slides: Interlude 1 18

Another way to accomplish selective reduction of enones is to take advantage of electronics:

• Cerium is oxophilic and so binds to the oxygen of the enone. This activates the C=O toward direct nucleophilic attack.

• The presence of cerium almost always makes reagents “harder”, i.e. favours 1,2-addition over 1,4-addition.

• By contrast, the Cu–H bond in Stryker’s reagent constitutes a much “softer” nucleophile, and therefore favours 1,4-addition over 1,2-addition.

6. Nucleophilic Reductions: Hydride Reagents

Chemistry 335 Supplemental Slides: Interlude 1 19

Just as catalytic hydrogenation* provided a convenient means to control absolute stereochemistry (i.e. enantioselectivity) so too can hydride addition:

• Extremely useful reaction. Often gives ee’s in the 90 – 99% range, and good yields.

• Both enantiomers of CBS catalyst are commercially available (or make from proline).

• What’s the mechanism? See you in Chem 432…

*and epoxidation, and dihydroxylation...

7. Functional Group Interconversions: an Incomplete Summary

Chemistry 335 Supplemental Slides: Interlude 1 20

A. Aldehydes as Central Players in Organic Synthesis B. Alkenes as Central Players in Organic Synthesis

C. Alcohols and Alkyl Halides as Central Players in Organic Synthesis

7. Functional Group Interconversions:

Chemistry 335 Supplemental Slides: Interlude 1 21

A. Aldehydes in Organic Synthesis

7. Functional Group Interconversions:

Chemistry 335 Supplemental Slides: Interlude 1 22

B. Alkenes in Organic Synthesis

7. Functional Group Interconversions:

Chemistry 335 Supplemental Slides: Interlude 1 23

C. Alcohols and Alkyl Halides

7. Functional Group Interconversions: an Incomplete Summary

Chemistry 335 Supplemental Slides: Interlude 1 24

A. Aldehydes as Central Players in Organic Synthesis B. Alkenes as Central Players in Organic Synthesis

C. Alcohols and Alkyl Halides as Central Players in Organic Synthesis