Chemoselectivity

Reference:

Organic Chemistry, 2nd ed., by

Clayden, Greeves and Warren;
Chapter 23

• Reduction
• Oxidation
Oxidation
• Protection
Reduction
H H O O
H OH
R H R H R H R OH
H O O
NH 2
R H R R' R X
R = OR', NR' 2, Cl,...

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Part 1. Reduction

Part 1: Reduction
1.1 Reduction with metal hydrides
1.2 Catalytic hydrogenation
1.3 Dissolving metal reduction
1.4 Removal of functional group

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1.1 Reduction with Metal Hydrides

1.1 Reduction with metal hydrides

1.1.1 LiAlH4
1.1.2 Borohydride: NaBH4, LiBH4, Na(CN)BH3
1.1.3 Special reduction by BH3
1.1.4 Partial reduction to aldehydes

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1.1.1. LiAlH4: Strong Reducing Reagent = Poor Selectivity

Aldehydes/ketones/esters Amides are reduced to

are reduced to alcohol amines

LiAlH4 reduction of esters

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1.1.1. LiAlH4: Strong Reducing Reagent = Poor Selectivity

Aldehydes/ketones/esters Amides are reduced to

are reduced to alcohol amines

LiAlH4 reduction of amides

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1.1.2 Boronhydride is Milder: Better Selectivity
• NaBH4 only reduces aldehyde/ketone: chemoselectivity
• LiBH4 is stronger than NaBH4 but weaker than LiAlH4 : reduces
aldehyde/ketone and ester but not carboxylic acid/amide/nitrile:
chemoselectivity

• Na(CN)BH3 is milder than NaBH4: only reduces (protonated) imine

• Luche reduction: hard Lewis-acid metal promotes 1,2-addition

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1.1.3 Special: Reduction of COOH and Amide with BH3
Boron (BH3) reduces electron-rich carbonyl group – amide and carboxylate
(carboxylate and amide are least electrophilic towards metal hydrides)

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1.1.3 Special: Reduction of COOH and Amide with BH3
Boron (BH3) reduces electron-rich carbonyl group – amide and carboxylate
(carboxylate and amide are least electrophilic towards metal hydrides)

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1.1.4 Partial Reduction to Aldehydes
All previous reduction reduces carbon to +1 (R-OH/R-NH2).
How to reduce carbon to +2 (aldehyde)?
• Indirect method: fully reduction + partial oxidation

• Direct method: reduce by DIBAL (ester/amide/nitrile à aldehyde)

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1.1 Metal Hydride Reduction: A Summary

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1.2 Catalytic Hydrogenation

1.2 Catalytic Hydrogenation

1.2.1 Alkene
1.2.2 Alkyne and Arene
1.2.3 Acid Chloride (Rosenmund Reaction)
1.2.4 Nitro and Imine

1.2.5 Hydrogenolysis

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1.2.1 Catalytic Hydrogenation of Alkenes

Chemoselectivity: C=C vs C=O

(different polarity)

Stereoselectivity:
syn-addition

Reduction of α, β-unsaturated carbonyl, complementary with Luche reduction

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1.2.2 Catalytic Hydrogenation of Alkynes and Arenes
• Alkyne can be fully reduced to alkane à but not very useful
• Alkyne can also be partially reduced to alkene à very useful

Catalyst (Pd) is
poisoned by Pb

Stereoselectivity: cis-alkene from partial catalytic hydrogenation

trans-alkene from dissolving metal reduction (later)

• Arenes (aromatic ring, most common phenyl ring) can also be reduced
• Various temperature, pressure and catalyst (usually by trial-and-error)
is used for different selectivity

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1.2.3 Catalytic Hydrogenolysis of Acid Chloride to RCHO
Rosenmund reduction

BaSO4 has low surface area, hence lower the activity of Pd catalyst. Pd can be
further poisoned by quinoline to reduce its activity to avoid over-reduction.

Quinoline also neutralizes HCl generated from the reaction.

Compare with
the DIBAL
reduction of
ester to afford
aldehyde:

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1.2.4 Catalytic Hydrogenation of RNO2/Imine to Amines
Reduction of imine (C=N):

[Nitrile (C≡N)
can also be
reduced to
amine.]

Compare with reduction by Na(CN)BH3:

Reduction of RNO2:
Reduction also by Sn/HCl:

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1.2.5 Catalytic Hydrogenolysis

• Break C-X σ-bond (in benzylic amine/ether)

• C is an benzylic carbon
• X is a heteroatom, in particular O or N
• Attach a hydrogen each to this benzylic C and X
atom

• Useful to remove benzyl protecting group (later)

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1.2 Catalytic Hydrogenation/Hydrogenolysis: Summary

Relative
rather than
black-and-
white

Many cases
trial-and-error

Various T, p,
cat.

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1.3 Dissolving Metal Reduction

1.3 Dissolving Metal Reduction

1.3.1 Birch Reduction
1.3.2 Reduction of Alkynes

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1.3.1 Birch Reduction: Mechanism

unconjugated
diene product

If conjugated diene is needed à

simple isomerization by acid-catalyst:

kinetic
control

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1.3.1 Birch Reduction: Regioselectivity

• Electron-withdrawing groups promote ipso-para Birch reduction.

• Electron-donating groups promote ortho-meta Birch reduction.

Regioselectivity is controlled by stability of intermediate radical anion

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1.3.2 Dissolving Metal Reduction of Alkynes
Stereoselectivity: E-alkene

Selectivity is complementary to Lindlar’s catalyst:

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1.4 Removal of Functional Groups

1.4 Removal of Functional Group

1.4.1 Alcohols
1.4.2 Aldehydes and Ketones

alkenes and alkynes à reduced to alkanes

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1.4.1 Removal of Alcohol Functional Groups

Method 1: alcohol à alkene (by elimination) à alkane (by reduction)

Method 2: alcohol à tosylate à nucleophilic substitution

Other hydrides “H─” also work

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1.4.2 Removal of Carbonyl Functional Groups
• Mozingo reduction (via hydrogenolysis of thioacetal)

Neutral
condition
1.dithiol, BF3
2.RaNi (H2)
RaNi: Raney nickel – an reagent (stoichiometric amount) instead of a catalyst
Ni-Al alloy + NaOH à RaNi (H2 absorbed on Ni surface)
• Wolff-Kishner reduction (via elimination of N2 from hydrazone)
Basic condition
1.NH2NH2
2.OH-

• Clemmensen reduction
Acidic condition
1.Zn
2.Concentrated HCl
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Part 2. Oxidation

Part 2: Oxidation
2.1 “Complete” oxidation for carboxylic acid/ketone
2.2 Partial oxidation for aldehyde
2.3 Oxidation of aldehyde to carboxylic acid
2.4 Other types of oxidation (CM1121 Chapter 19)

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2.1 Complete Oxidation: Cr(VI)/Mn(VII)-Harsh/Unselective
2o alcohol is oxidized to ketone

1o alcohol is oxidized to carboxylic acid

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2.2 Partial Oxidation to Aldehyde: PCC, PDC and TPAP

v Aldehydes are very important

synthetic intermediates

What if only aldehyde is needed? The key is NO water!

Very often,
CH2Cl2 is
the solvent

regeneration
of oxidizer

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2.2 Partial Oxidation to Aldehyde: PCC, PDC and TPAP
§ Another mild oxidizing condition: Dess-Martin periodinane

§ Yet another mild oxidizing condition: Swern oxidation

gaseous by-products

b.p. of Me2S: 38 oC
(but very smelly L)
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2.3 Oxidation of Aldehydes to Carboxylic Acids
Pinnick reaction
Sodium chlorite (NaClO2): aldehydesàcarboxylic acid
[very mild condition, selective and also inexpensive]

J. Am. Chem. Soc. 1999, 121, 10004.

Of course, strong oxidizing reagent (e.g. KMnO4 and K2Cr2O7) also oxidizes
aldehyde, but at a risk of unwanted side-reactions.

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2.4 Other Types of Oxidation: Epoxidation (CM1121/2121)

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2.4 Ozonolysis and Oxidative Cleavage (CM1121)
§ Ozonolysis (mechanism is pericyclic reactions)

§ Oxidative cleavage

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2.4 Electrophilic Addition to Alkenes (CM1121)

Alkene is oxidized.

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2.4 Oxidation of Allylic Positions (Chapter 35)
§ Oxidize alkene by selenium dioxide to enone/enal, or allylic alcohol

If allylic alcohol is desired à oxidation conducted Conj. Carbonyl usually

in AcOH as solvent à allylic alcohol is trapped as formed (if allylic
allylic ester hence not further oxidized alcohol is not trapped)

Mechanism is by pericyclic
reactions (beyond CM2121
syllabus)

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2.4 Baeyer-Viliger Oxidation (Chapter 36)
• Baeyer-Villiger oxidation: ketone à ester
• Mechanism is via migration of carbon towards oxygen,
with a carboxylate leaving
• Acid catalyzed – both Brønsted acid and Lewis acid
• Also viewed as insertion of an oxygen atom between
C=O carbon and α-carbon
• If ketone is unsymmetrical, preference of insertion
follows: 3o>2o>benzyl/phenyl>1o>Me (but also
controlled by stereochemistry)

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2.4 Oxidation of Unfunctionalized Carbons
• Not often seen, but useful in industry (less steps and less cost)
• Oxidation product (with functional group) is usually more
reactive than the starting material (with no functional group).

Aromatic ring is stable

à not oxidized

J. Am. Chem. Soc. 2015, 137, 13776.

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