Central linking role of alcohols and carbonyls

Chapter 12
Alcohols from Carbonyl Compounds:
Oxidation-Reduction

carboxylic
acid

aldehyde

O
[O]

H2
C
R

OH

[O]

[H]

C
R

[H]

ketone

[O] and [H] are generic symbols for oxidation and reduction

Structure of Carbonyl Group

Carbonyl bond is highly polar

Substantial + charge on the carbon !

Dipole Moments (Debyes)

O

Carbonyl carbon = sp2 hybridized and trigonal planar

All three atoms attached to the carbonyl group lie in one plane

Water

1.85

Methanol

1.70

Acetone

2.88

__

2.88 D

C
H3C

CH3

Carbonyls react with nucleophiles

orbital of formaldehyde
The nucleophile adds to the + carbon
The electrons shift to the oxygen
The carbon becomes sp3 hybridized (tetrahedral!)
Several chapters in Organic II
For now, two nucleophiles that convert carbonyls to

alcohols:
z Hydride ions (H-)
z Carbanions (R-) second half of Ch. 12 (first topic Jan/08)

Organic Oxidations and Reductions

Carbonyl groups and alcohols can be interconverted

by oxidation and reduction reactions

Reduction: increasing the hydrogen content or decreasing

the oxygen content of an organic molecule

Alcohols can be oxidized to aldehydes; aldehydes

can be reduced to alcohols

Oxidation: increasing the oxygen content or decreasing the

hydrogen content of an organic molecule

Reduction by addition of two hydrogens

Three types of reductions: differing in how H2 is added.
1. Simplest reducing agent is molecular H2. Reductions using
H2 require a metal catalyst.
Used for alkenes or alkynes, less for carbonyl groups
2. Add two protons and two electrons to a substratethat is,
H2 = 2H+ + 2e-.
o Dissolving metal reductions use alkali metals as source
of electrons, and liquid ammonia as source of protons.

The Third Way

3. Add hydride (H) and then a proton (H+). (=H2)
The most common hydride reducing agents contain a
hydrogen atom bonded to boron or aluminum.
NaBH4 and LiAlH4 deliver H to the substrate, and then a
proton is added from H2O or an alcohol.

Used to convert alkynes to trans alkenes

Reductions of carbonyls to alcohols

Carboxylic acids can be reduced to primary alcohols

Several carbonyl compounds can be reduced to alcohols

A difficult reduction, requires the powerful reducing agent such as

lithium aluminum hydride (LiAlH4 also abbreviated LAH)

Aldehydes and ketones are reduced to 1o and 2o alcohols respectively

Esters are also reduced to primary alcohols
z LAH or high pressure hydrogenation can accomplish

this transformation

Aldehydes and ketones are reduced relatively easily; the mild

reducing agent sodium borohydride (NaBH4) is typically used

LAH or hydrogenation with a metal catalyst can also be used

Key step is reaction of hydride with carbonyl carbon

Stereochemistry of Carbonyl Reductions

Hydride converts a planar sp2 hybridized carbonyl carbon to a
tetrahedral sp3 hybridized carbon.

Carboxylic acids and esters are less reactive to reduction

than aldehydes and ketones and require the use of LAH

Lithium aluminium hydride is very reactive with water and must be

used in an anhydrous solvent such as ether

Sodium borohydride is considerably less reactive and can be

Conclusion: with achiral reducing agents, racemic mixture is produced

used in solvents such as water or an alcohol

Enantioselective Carbonyl Reductions

Biological reductions that occur in cells always proceed
with complete selectivity, forming a single enantiomer.
In cells, a common reducing agent is NADH.
NADH is a coenzymean organic molecule that can
function only in the presence of the enzyme.

Partial active site of alcohol

dehydrogenase with NADH

Enantioselective Carbonyl Reductions

The active site of the enzyme binds both the carbonyl
substrate and NADH, keeping them in close proximity.
NADH then donates H: in much the same way as a
hydride reducing agent.

Enantioselective Carbonyl Reductions

The reaction is completely enantioselective. Reduction
of pyruvic acid with NADH catalyzed by lactate
dehydrogenase affords solely the S enantiomer.
NADH reduces a variety of different carbonyl
compounds in biological systems. The configuration of
the product (R or S) depends on the enzyme used to
catalyze the process.

Oxidation of Alcohols
Primary alcohols can be oxidized to aldehydes or to carboxylic

acids
The oxidation is difficult to stop at the aldehyde stage and usually
proceeds on to the carboxylic acid

Oxidation of Primary Alcohols to Carboxylic Acids

Potassium permanganate (KMnO4) is a typical reagent used
for oxidation of a primary alcohol to a carboxylic acid

Oxidation of Alcohols
To stop at the aldehyde stage, use pyridinium chlorochromate (PCC)
z PCC is made from chromium trioxide under acidic conditions
z It is used in organic solvents such as methylene chloride (CH2Cl2)

Oxidation of Secondary Alcohols to Ketones

Oxidation of a secondary alcohol produces a ketone

z Many oxidizing agents can be used, including chromic acid

(H2CrO4), KMnO4, or Jones reagent (CrO3 in acetone)

The reaction is generally carried out in aqueous solution; purple of

MnO4- becomes the brown precipitate of MnO2

Example of oxidation mechanism

Mechanism of Chromate Oxidation

Step 2: An elimination reaction occurs by removal of a

hydrogen atom from the alcohol carbon and departure of
the chromium group with a pair of electrons.

z Step 1: A chromate ester is formed from the alcohol hydroxyl

Alcohol adds to chromate

Cr atom departs with pair of electrons originally on the alcohol oxygen

Hence organic compound is oxidized
and a water molecule departs

Why stopping oxidation of 1o ROH at aldehdye is difficult

Oxidation state of chromium is reduced from +6 to +4

Tertiary alcohols are not oxidized

Aldehydes form hydrates in water (an equilibrium)

z An aldehyde hydrate is a diol and can react by the same

mechanism to produce a carboxylic acid

Tertiary alcohols can form the chromate ester but cannot

eliminate because they have no hydrogen on the alcohol

carbon
z Tertiary alcohols are therefore not oxidized

Pyridinium chlorochromate (PCC) reactions are run in anhydrous

methylene chloride and the aldehyde cannot form a hydrate
z The oxidation of a primary alcohol therefore stops at the
aldehyde stage

Identification of the hydroxy group

z Spectroscopic Evidence for Alcohols
Alcohol O-H infrared stretching absorptions appear as strong,
broad peaks around 3200-3600 cm-1

z A Chemical Test for Primary and Secondary Alcohols

Chromium oxide in acid has a clear orange color which changes
to greenish opaque if an oxidizable alcohol is present

The Oxidation of Ethanol in the body

Ingested ethanol is oxidized in the liver first to CH3CHO
(acetaldehyde), and then to CH3COO (the acetate anion).
This oxidation is catalyzed by alcohol dehydrogenase.
If more ethanol is ingested than can be metabolized, the
concentration of acetaldehyde increases. Acetaldehyde, which is
toxic, is responsible for the feelings associated with a hangover.

Oxidation of 10 Alcohols - breathalyzers

Organometallic Compounds
Early breathalyzers were based on Cr6+ oxidations, as the redorange Cr6+ reagent is reduced to green Cr3+.

Carbon-metal bonds vary widely in character from mostly covalent

to mostly ionic depending on the metal

The greater the ionic character of the bond, the more reactive the
compound
+

Organopotassium compounds react explosively with water and burst into flame
when exposed to air

Individual blows into a tube containing K2Cr2O7, H2SO4.

The higher the concentration of CH3CH2OH in the breath, the
farther the green Cr3+ color extends down the sample tube.
This extent of the green color is then correlated with blood
alcohol levels.

 Preparation of Organolithium and Organo-

magnesium Compounds
z Organolithium Compounds

z Grignard Reagents
Grignard reagents are prepared by the reaction of organic halides
with magnesium turnings
+

Organolithium compounds can be prepared by reaction of an alkyl

halide with lithium metal in an ether solvent
+

An ether solvent is used because it forms a complex with the Grignard reagent
which stabilizes it

The order of reactivity of halides is R-I > R-Br > R-Cl (R-F is seldom used)

Reactions of Organolithium and Organo-

magnesium Compounds
z Reactions with Compounds Containing Acidic Hydrogen

Organolithium and Grignard reagents can be used to form

alkynides by acid-base reactions
+

Alkynylmagnesium halides and alkynyllithium reagents are useful nucleophiles

for C-C bond synthesis

Atoms
Organolithium and Grignard reagents behave as if they were
carbanions and they are therefore very strong bases
+

They react readily with hydrogen atoms attached to oxygen, nitrogen or sulfur, in
addition to other acidic hydrogens (water and alcohol solvents cannot be used)

z Reactions of Grignard Reagents with Oxiranes

(Epoxides)
Grignard reagents are very powerful nucleophiles and can react
with the + carbons of oxiranes
+
+
+

z Reaction of Grignard Reagents with Carbonyl

Compounds
Nucleophilic attack of Grignard reagents at carbonyl carbons is
the most important reaction of Grignard reagents
+

The reaction results in ring opening and formation of an alcohol product

Reaction occurs at the least-substituted ring carbon of the oxirane
The net result is carbon-carbon bond formation two carbons away from the
alcohol

Alcohols from Grignard Reagents

Aldehydes and ketones react with Grignard reagents to yield
different classes of alcohols depending on the starting carbonyl
compound

Reaction of Grignard reagents with aldehydes and ketones yields a new carboncarbon bond and an alcohol

Esters react with two molar equivalents of a Grignard reagent to

yield a tertiary alcohol
+
+

A ketone is formed by the first molar equivalent of Grignard reagent and this
immediately reacts with a second equivalent to produce the alcohol
The final product contains two identical groups at the alcohol carbon that are both
derived from the Grignard reagent

10

z Planning a Grignard Synthesis

Example : Synthesis of 3-phenyl-3-pentanol
+
+

The starting material may be a ketone or an ester

There are two routes that start with ketones (one is shown)

z Restrictions on the Use of Grignard Reagents

Grignard reagents are very powerful nucleophiles and bases
+

They react as if they were carbanions

Grignard reagents cannot be made from halides which contain

acidic groups or electrophilic sites elsewhere in the molecule

The substrate for reaction with the Grignard reagent cannot

contain any acidic hydrogen atoms
+
+

The acidic hydrogens will react first and will quench the Grignard reagent
Two equivalents of Grignard reagent could be used, so that the first equivalent is
consumed by the acid-base reaction while the second equivalent accomplishes
carbon-carbon bond formation

Solved Problem: Synthesize the following compound using an

alcohol of not more than 4 carbons as the only organic starting
material

z The Use of Lithium Reagents

Organolithium reagents react similarly to Grignard reagents
+

Organolithium reagents tend to be more reactive

z The Use of Sodium Alkynides

Sodium alkynides react with carbonyl compounds such as
aldehydes and ketones to form new carbon-carbon bonds

11

z Solved Problem
Synthesize the following compounds using reagents of 6 carbons
or less

Lithium Dialkylcuprates: The Corey-Posner,

Whitesides-House Synthesis
This is an alternative formation of carbon-carbon bonds which, in
effect, couples two alkyl halides

One of the halides is converted to a lithium dialkylcuprate by a

two step sequence
Treatment of the lithium dialkylcuprate with the other halide
results in coupling of the two organic groups

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