Reduction reaction: (content)

•Catalytic hydrogenations,
•Metal hydride reduction (LiAlH4, NaBH4,)
•Mechanism of Wolff-Kishner reduction,
and Clemmensen reduction,
• Meerwein-Pondoff-Varley reduction,
•Dissolving metals reduction with
mechanism.

1
ORGANIC SYNTHESIS
(FOURTH EDITION)

MICHAEL B. SMITH

Chapter 7

2
 Reduction
Some common reducing agents
Reducing agents Acts on:

Catalytic H2 / Pt, Pd or Ni C=C, CC

Hydrogenation

Hydroboration BH3 / THF C=C, CC

Dissolving Metal Nao / NH3 (liq.) C C

Lio / NH3 (liq.)
Metal Hydride NaBH4 / alcohol C=O
LiAlH4 / ether C=O

3
 alkyne

alkene

Hydroboration BH3 / THF C=C, CC 4

 Reducing Agents:

• There are three ways of introducing 2 Hs in a reduction.

1. The first method uses H2 gas. Catalytic hydrogenation
requires a metal catalyst (usually Pt, Pd or Ni) with H2.
2. A second method adds two protons and two electrons
to a substrate, and 2H+ + 2e- = H2
➢Reductions of this sort use alkali metals as a source
of electrons, and liquid ammonia as a source of
protons, Nao in NH3 (liq) or Lio in NH3 (liq).
➢These are called dissolving metal reductions.

5
 Reducing Agents:

3. The third way is to add hydride (H¯) and a proton (H+).

➢The most common hydride reducing agents contain
a hydrogen atom bonded to boron or aluminum.
Simple examples include sodium borohydride
(NaBH4) and lithium aluminum hydride (LiAlH4).
➢NaBH4 and LiAlH4 deliver H¯ to the substrate, and
then a proton is added from H2O or an alcohol.

6
1.Reduction of Alkenes: Catalytic Hydrogenation

• The addition of H2 occurs only in the presence of a metal

catalyst, and thus it is called catalytic hydrogenation.
• The catalyst consists of a metal, usually Pd, Pt, or Ni,
adsorbed onto a finely divided inert solid, such as charcoal.
• H2 adds in a syn fashion.

7
Reduction of Alkynes:

• There are three paths to add H2 to a triple bond:

8
Alkyne reduction to a Cis Alkene:

• Palladium metal is too reactive to allow hydrogenation of

an alkyne to stop after one equivalent of H2 adds.
• To stop at a cis alkene, a less active Pd catalyst is used,
Pd adsorbed onto CaCO3 with added lead(II) acetate and
quinoline. This is called Lindlar’s catalyst.
• Compared to Pd metal, the Lindlar catalyst is
deactivated
• With the Lindlar catalyst, one equivalent of H2 adds to an
alkyne to form the cis product. The cis alkene product is
unreactive to further reduction.

9
Alkyne reduction to a cis Alkene:

• Reduction of an alkyne to a cis alkene is a stereoselective

reaction, because only one stereoisomer is formed.
• Remember, one can also use hydroboration-acidification
instead of Lindlar’s catalyst to get a cis alkene.

10
Alkyne reduction to a Trans Alkene:

• In a dissolving metal reduction (such as Na in NH3), the

elements of H2 are added in an anti fashion to form a
trans alkene. Na has only one electron, so, electrons for
the reduction are added sequentially from 2 Na atoms.

11
• Dissolving metal reduction of a triple bond with Na in NH3 is
a stereoselective reaction because it forms a trans product
exclusively.
• Dissolving metal reductions always form the more stable
trans product preferentially.
• The trans alkene is formed because the vinyl carbanion
intermediate that is formed is more stable when the larger R
groups are further away from each other to avoid steric
interactions. Protonation of this anion leads to the more
stable trans adduct.

12
 Summary of Alkyne Reductions:

Three methods to reduce a triple bond

13
Reduction of Polar C—X  Bonds:

• Alkyl halides can be reduced to alkanes with LiAlH4.

• Epoxide rings can be opened with LiAlH4 to form alcohols.

Examples
of reduction of C – X
σ bonds with LiAIH4

14
 Dissolving metal reduction

Alkyne reduction to a Trans Alkene:

• In a dissolving metal reduction (such as Na in NH3), the
elements of H2 are added in an anti fashion to form a
trans alkene. Na has only one electron, so, electrons for
the reduction are added sequentially from 2 Na atoms.

15
• Dissolving metal reduction of a triple bond with Na in NH3 is
a stereoselective reaction because it forms a trans product
exclusively.
• Dissolving metal reductions always form the more stable
trans product preferentially.
• The trans alkene is formed because the vinyl carbanion
intermediate that is formed is more stable when the larger R
groups are further away from each other to avoid steric
interactions. Protonation of this anion leads to the more
stable trans adduct.

16
Mechanism:

Dissolving metal reduction

Vinyl anion Vinyl radical

17
P396

18
P396

19
Reduction Using Metal Hydrides P 310

20
21
Mechanism:

22
23
24
Selectivity in the Reduction of Monocyclic Molecules P 359

25
Selectivity in the Reduction of Monocyclic Molecules P 359

26
Path A

27
The stereoselectivity associated with substituted cyclohexanones can be
shown using the reaction of 4-tertbutylcyclohexan-1-one with LiAlH4 or
NaBH4, which gave the trans-alcohol [4-(tert-butyl)cyclohexan-1-ol]
as the major product (92% with LiAlH4 and 80% with NaBH4) via axial
attack (path a).
In general, axial approach to the carbonyl (path a) will lead to the major
product.

Note that the bulky tert-butyl group at C4 in 4-(tert-butyl)cyclohexan- 1-one

effectively locks the molecule into that chair conformation .

P 359
28
29
 Another prospect:
Generally, smaller reagents give more axial attack (path a)
and larger reagents give more equatorial attack (path b).

Large reducing agents, such as LiBH(Me2CHCHMe)3, are

hindered by the 1,3-axial interactions and therefore attack
equatorially. And gives more cis-product

Small reducing agents, such as NaBH4, preferentially

attack axially in order to avoid the eclipsing interactions,
because the 1,3-diaxial interaction for small molecules is
minimal.

30
Reduction of 4-tertbutylcyclohexan-1-one with LiAlH4 gave the trans-alcohol
[4-(tert-butyl)cyclohexan-1-ol] as the major product and Li s-Bu3BH yields cis alcohol

31
 Meerwein-Ponndorf-Verley reduction

The Meerwein-Ponndorf-Verley reduction is a classical reaction that uses

metals and it is the reverse of the Oppenauer oxidation discussed in
oxidation chap.

A ketone is treated with an aluminum alkoxide (e.g.,

triisopropoxyaluminum), in the presence of a hydrogen-donating solvent
(e.g., propan-2-ol). Heating at the reflux temperature of the solvent is
usually required to initiate transfer of the hydrogen to the ketone, reducing it
and generating acetone from propan-2-ol.

32
The major difference between reduction or oxidation is
the use of an alcohol solvent rather than a ketone
solvent (usually propan-2-ol rather than acetone).

33
 product
Ketone

solvent

34
Catalytic cycle of Meerwein–Ponndorf–Verley reduction
The MPV reduction is believed to go through a catalytic cycle involving a six-

member ring transition state as shown in Figure .

Starting with the aluminium alkoxide 1, a carbonyl oxygen is coordinated to

achieve the tetra coordinated aluminium intermediate 2. Between

intermediates 2 and 3 the hydride is transferred to the carbonyl from the

alkoxy ligand via a pericyclic mechanism. At this point the new carbonyl

dissociates and gives the tricoordinated aluminium species 4. Finally, an

alcohol from solution displaces the newly reduced carbonyl to regenerate the

catalyst 1.
35
 Other REDUCING AGENTS

Clemmensen Reduction
The Clemmensen Reduction allows the deoxygenation of aldehydes or ketones, to produce the
corresponding hydrocarbon.

The substrate must be stable to strong acid

36
Wolff-Kishner reduction

Mechanism

hydrazone

39
Contd..
Diimide anion

alkane

The Wolff-Kishner reduction :The mechanism begins with the attack of hydrazine of the
aldehyde or ketone for form an imine. Proton transfer steps then result in the formation
of a N=N bond. Deprotonation of the nitrogen and a rearrangement reaction result in the
formation of a diimide carbanion and the release of nitrogen gas. The carbanion then
picks up a proton from water to regenerate the base catalyst and provides the final
alkane product
40