REDUCTIONS

Marino Petrini
Advanced Organic Chemistry
Chemistry and Advanced Chemical
Methodologies

REDUCTION OF MULTIPLE C-C BONDS

CATALYTIC HYDROGENATION
Metals employed: Pt, Pd, Rh, Ru, Ni.
MECHANISM: since this process occurs under heterogeneous conditions,
a surface process is likewise
 CATALYTIC HYDROGENATION: MAIN FEATURES

The reaction is SYN STEREOSELECTIVE

Addition is favored on the LESS HINDERED side of the molecule.

CH3 H2 CH3 CH3

+
Pt
CH3 CH3 CH3
85 : 15

CH3 CH3 CH3

H2
+
CH2 Pt CH3 CH3

70 : 30

POLAR GROUPS (OH, NH2 etc.) having a coordinating effect on the metal surface
direct the hydrogen uptake on the same side respect to their position

H2 H
+
Ni H
HO HO HO
95 : 5

HOMOGENEOUS CATALYSIS
Complexation of the metal with organic ligands makes the organometallic molecule soluble in
organic solvents. It is therefore possible to exploit an homogeneous catalysis in the reduction.

Wilkinson catalyst: (Ph3P)3RhCl

Mechanism:
 Homogeneous catalysis usually provides a higher selectivity:

Me Me
Me Me
(Ph3P)3RhCl

H2

O O

Py
[(R3P)Ir(COD)]

H2
H3CO H3CO

Using CHIRAL LIGANDS on metal makes possible to realize an

ENANTIOSELECTIVE reduction

Ph2P
O PPh2 PPh2 PPh2
O PPh2 PPh2 N
O Ph

(-)(R,R) DIOP (R) BINAPHOS BZPPM

Mechanism:

Diastereomeric
intermediates

Ks >> KR
EXPERIMENTAL CONDITIONS

Solvents: MeOH, C6H6, THF.

Pressure: low pressure high enantioselectivity

Additives: Et3N, basic compound allow a decrease in the process pressure.

Best results are recorded with substrates bearing a polar function amenable of
coordination with the metal.

CO2H
Ph
R OH HN CH3 CO2H
R
O

CO2H (-) DIOPRh CO2H

Ph Ph
H
HN CH3 HN CH3
H2
O O

(R) 90% ee

Ease of reduction of different functional groups towards catalytic hydrogenation

Substrates are listed in order of decreasing reactivity

SUBSTRATE PRODUCT

RCOCl RCHO Very easy

RNO2 RNH2
RC CR RHC CHR
RCHO RCH2OH
RCH=CHR RCH2CH2R
RCOR RCHOHR
ArCH2OR ArCH3 + ROH
RC N RCH2NH2

RCOOR’ RCH2OH + R’OH Difficult

RCONHR’ RCH2NHR’ Difficult

Very difficult

RCOO- Inert
Functional Product Catalyst Typical Reaction Functional Product Catalyst Typical Reaction
Group Conditions Group Conditions

NR2 T = 50-100°C,
Fast at room C R Pd, Ni 1-4 atm
CH2R
temperature (r.t.) H
C C C C Pd, Pt, Ni, and 1 atm except r.t., 1 atm. Additives
Ru, Rh for very (Pb, quinoline)
H H substituted or for partially
hindered alkenes
RCOCl RCHO Pd deactivating the
catalyst
Low H2 pressure
and r.t. Additives Harsh conditions
(Pb, quinoline) RCOOH RCH2OH Pd, Ni, Ru
C C C C
H H Pd for partially
deactivating the T = 200°C, high
catalyst RCOOR RCH2OH Cu-Cr, Ni pressure

Moderate H2 T = 50-100°C, high

Rh, Pt pressure (5-10 pressure, NH3 is
atm). T=50-100°C RC N RCH2NH2 Ni, Rh added to increase
the yield
High pressure
Ni, Pd (100-200 atm). Harsh conditions
RCONH2 RCH2NH2 Cu-Cr
T = 100-200°C

Low rate at r.t. r.t. , 1-4 atm

OH RNO2 RNH2 Pd, Ni, Pt
O Pt, Ru and 1-4 atm.
R C R R C R Acid catalysis
H R2C=NR R2CHNHR Pd, Pt
r.t. 4-100 atm

High pressure
Cu-Cr, Ni T = 50-100°C
Reactivity:
R-Cl I>Br>Cl>F. Bases
O
R-Br R-H Pd favor the reduction
C R
R-I for R=alkyl
CH2R
r.t., 1-4 atm, Acid
o Pd catalysis for H OH Slow at r.t. 1-4 atm,
OR ketones O acid catalysis
C R C C C C
H Pt, Pd

PARTIAL REDUCTION OF ALKYNES:

LINDLAR catalyst: 1% Pd on CaCO3 + Pb(CH3COO)2

STEREOSELECTIVE reduction : alkene Z (CIS):

Alkenes E (TRANS) may be obtained by monoelectronic reduction using

alkali metals (Li, Na, Ca) in liquid NH3

Terminal alkynes may be selectively reduced in the presence of internal alkynes and viceversa.
 REDUCTION OF C=O GROUPS
CATALYTIC HYDROGENATON
ALDEHYDES are the most easily reductable carbonyl systems under catalytic hydrogenation.
a,b-Unsaturated aldehydes can be selectively reduced depending upon the nature of the netal
catalyst employed.

H2, Os
OH

H H2, Pd O

O H

H2, Ni
OH

KETONES require hard conditions which can be partially softened under acid catalysis:

H2, Pt
O OH
AcOH
CH3 CH3

CARBOXYLIC ACIDS may be reduced only under harsh conditions.

REDUCTION WITH COMPLEX METAL HYDRIDES

Aldehydes and ketones rapidly react with complex hydrides such as LiAlH4.
Li+ is able to provide the needed electrophilic catalysis coordinating the carbonyl oxygen.
Release of the first H- is very fast but the rate of reduction progressively decreases for
the other hydrides.

LiAlH4 must be used in ethereal solvents just like reactive organometallic reagents since
it reatcs violently with water and quickly with alcohols. Reaction of LiAlH4 with 3 equivalents
of t-BuOH was formerly used to obtain tris-t-butoxy aluminiumhydride, a selective reducing
agent now replaced by other hydrides such as DIBAL-H and Red-Al (vide infra).
NaBH4 is less reactive than LiAlH4. In this instance the electrophilic catalysis
is provided by polar protic solvents (usually alcohols) since Na+ is unable to effectively
promote the nucleophilic addition:

R O H
O
OH
H3B H
ROBH3 + C H
H3C H3C CH3
CH3

As a matter of fact, LiBH4 is more reactive than NaBH4 (Li+ is more effective than Na+):

The same effect can be obtained by adding to NaBH4 LiCl or Lewis acids such as AlCl3

BH3 is also able to reduce ketones to the corresponding alcohols but with a different
mechanism than that of complex hydrides: (LiAlH4, NaBH4, etc.):

Boron and aluminum hydrides provide a direct electrophilic catalysis with the
trivalent atom via a Lewis acid-base interaction with the carbonyl oxygen.
This enhances the electrophilicity of the sp2 carbon.
 REDUCTION OF CARBOXYLIC ACID DERIVATIVES
TO ALDEHYDES

O
H H OH
O Al O
O O O
O
Na Red-Al
THPO R
THPO R
toluene -70°C

O Red-Al O

MeO OCH3 MeO H

N

N
CH3

The most popular reducing agent for this purpose is DIBAL-H (i-Bu2AlH)

H
O Al O
OEt DIBAL-H H
O Ph toluene, -60°C O Ph

The selectivity displayed by these reagents is due to the formation of a mixed acetal
intermediate which is un reactive under stoichiometric conditions ( 1 eq. reductant).
The free carbonyl function is regenerated upon acidic hydrolysis during work-up
operations

DIBAL-H converts nitriles into the corresponding N-Al imines which once again
can be cleaved to the parent carbonyls upon acidic hydrolysis
 REDUCTION OF IMINES AND IMINIUM IONS
Imines are poorly electrophilic and react sluggishly with usual complex hydrides.
Brønsted catalysis (pH 4 to 6) can be used but it is not compatible with common hydride reagents.
Sodiun cyanoborohydride NaBH3CN is less reactive than NaBH4 (CN is electron-withdrawing)
and reacts at pH » 4-6 with the obtained iminium ions:

Reduction of oximes requires lower pH values because of the minor basicity of

the nitrogen atom

Reactivity of complex hydrides used in reduction reactions

REDUCTION PRODUCTS

HYDRIDES Iminium Acyl Aldehydes Ketones Esters Amides Carboxylic

ions halides acids salts

LiAlH4 Amine Alcohol Alcohol Alcohol Alcohol Amine Alcohol

LiAlH2(OC2H4OCH3)2 Alcohol Alcohol Alcohol Alcohol Amine Alcohol

LiAlH[OC(CH3)3]3 Aldehyde Alcohol Alcohol Alcohol Aldehyde NR

NaBH4 Amine Alcohol Alcohol Alcohol NR NR

NaBH3CN Amine Alcohol NR NR NR NR

B2 H 6 Alcohol Alcohol NR Amine NR

AlH3 Alcohol Alcohol Alcohol Aldehyde Amine Alcohol

[(CH3)2CHCH(CH3)-]2BH Alcohol Alcohol NR Aldehyde NR

[(CH3)2CHCH2-]2AlH Alcohol Alcohol Aldehyde Aldehyde Alcohol

 REDUCTION OF CARBOXYLIC ACIDS TO ALCOHOLS
Reduction can be trivially realized using excess of LiAlH4 .
Borane B2H6 is unreactive towards esters and acyl halides but shows an interesting reactivity
with carboxylic acids:

Amides, are reduced to the corresponding amines:

O BH3 O BH2 OBH2 NR2 BH3

R C R C R C H R C R CH2NR2
H H
NR2 NR2 NR2

REDUCTION OF a,b-UNSATURATED COMPOUNDS

a,b Unsaturated compounds can be regioselectively reduced (1,2 o 1,4 addition):

NaBH4/CeCl 3
O OH
DIBAL-H 1,2

9-BBN

O Et3SiH
1,4
H (Ph3P)3RhCl OSiEt3

LANTHANIDE MEDIATED 1,2 REDUCTION

Lantanides (Ce, Sm) are involved in complex hydride 1,2 reduction of carbonyl derivatives

Cerium (lll) is an oxophilic specie which upon coordination with the carbonyl oxygen is able
to provide a selective 1,2 reduction with NaBH4

NaBH4
O OH 80%
CeCl3
O O O O
MeOH
 CeCl3 also displays chemoselectivity toward other electrophilic functional groups
(the oxirane ring is unaffected):

O O
NaBH4
90%
CeCl 3
O OH
MeOH, -20°C

Cerium (lll) has a faible Lewis acidity and this makes possible to differentiate an
aldehyde from a ketone in the reduction process:

O O OH
CO2Me NaBH4 CO2Me CO2Me
CeCl3
H OMe H
MeOH, -15°C
O MeO O

Practically, the more reactive function (aldehyde or a non-conjugated carbonyl) is

termporarily converted into an acetal by the alcoholic solvent.
Consequently the residual unprotected less reactive function (ketone) is free to
be reduced by the hydride. The unchanged aldehyde function is cleaved during the
acidic work-up.
O O

H NaBH4 H
85%
H OH
S CeCl3 S
O

Ease of reduction of different functional groups with Ease of reduction of different functional groups with
LiAlH4 B 2 H6
Substrates are listed in decreasing order of reactivity Substrates are listed in decreasing order of reactivity

SUBSTRATE PRODUCT SUBSTRATE PRODUCT

RCHO RCH2OH Very easy

RCOOH RCH2OH Very easy
RCOR R2CHOH

RCOCl RCH2OH RCH=CHR (RCH2CHR)3B

Lactone Diol
RHC CHR RCOR R2CHOH
RCH2C(R)HOH
O
RCOOR’ RCH2OH + R’OH RCN RCH2NH2
RCOOH RCH2OH
RHC CHR
RCOO- RCH2OH RCH2C(R)HOH
O

RCONR’2 RCH2NR’2
RCOOR’ RCH2OH + R’OH Difficult
RC N RCH2NH2

RNO2 RNH2 RCOCl Inert

ArNO2 ArN=NAr Difficult

RCO2-M+ Inert
RCH=CHR Inert
 STEREOSELECTIVITY IN THE REDUCTION OF
CARBONYL SYSTEMS

Nucleophilic attack on carbonyl systems follows a trajectory around 109° referred as the
Bürgi-Dunitz trajectory.

This allows a minimization of the repulsive interactions generated between the orbital containing
the lone pair in the nucleophile and the p orbital of the oxygen in the LUMO.

REDUCTION OF OPEN-CHAIN SYSTEMS: FELKIN-ANH THEORY

In a carbonyl system having a stereocenter in its close proximity, the most populated
rotamers are those that places the larger group (RL o L) in orthogonal position to the plane
containing the carbonyl group.

Population of rotamers A and B is quite similar since the difference in their energy is narrow.
According to the Bürgi-Dunitz trajectory (109°), reaction of the nucleophile is FASTER for
rotamer A since the approach for the carbonyl attack pass by the SMALL substituent S
(usually an hydrogen atom).
The equilibrium between rotamers A and B causes a constant conversion B ® A ensuring a
satisfactory level of diastereoselection in the reaction.

The reason for the observed orthogonal disposition of the large group L stems from the
possibility to create stabilizing p*-s* orbital interactions involving the LUMO of the C-L
antibonding orbital (s*) and the LUMO of the C=O system (p*).
The interaction between s* (C-L) and π* (C=O) produces a set of new unoccupied (empty)
orbitals X and Z. The Z orbital has an energy level which is LOWER than the π* (C=O) and thus
in the reaction with the HOMO of the nucleophile allows a better ENERGY GAIN according to
the Klopman equation (remember: the lower is the HOMO-LUMO energy gap, the higher is the
energy gain!!)
 ELECTRON-WITHDRAWING SUBSTITUENTS ALTER THE
PREFERRED ROTAMERIC STRUCTURE

When one of the substituents, let’s say the medium one, is an electron-withdrawing group
(EWG) such as Cl, Br, OR, NR2 etc. the most populated rotamers are those that places the
EWG group in orthogonal position.

According to the molecular orbital theory, the presence of electron-withdrawing groups

has the effect of lowering the energy of the corresponding orbital.
This is also valid for antibonding orbitals so that the σ* of C-EWG has a LOWER energy
compared to σ* of C-L.
Consequently, the interaction σ* C-EWG with π* (C=O) produces an orbital W which has a
LOWER energy than the orbital Z obtained by interaction between σ* C-L with π* (C=O).
This in turn will provide a better energy gain in the reaction with HOMO of the nucleophile.
EWGs containing coordinating lone pairs (OR, NR) give stereocomplementary results depending
on the nature of the metal counterion employed:

K-Selectride® is a typical
NON-chelating reducing agent
which gives Felkin-type products:
 ENANTIOSELECTIVE REDUCTIONS
Are used in order to obtain enantiopure (or enentioenriched) alcohols;

CHIRAL REAGENTS
Are used in stoichiometric amount.
Li+
May be obtained by reaction of aluminium
hydrides with chiral alcohols such as
O H
binaphtol. Al (S)-BINAL-H
The obtained reagent brings the chiral O OEt
information allowing the chiral
discrimination between the enantiotopic
faces of the ketone.
ee%
R= Me 95
O OH
(S)-BINAL-H
n-Pr 100
R R
-78°C
n-Bu 100

t -Bu 44

ee%

R= C5H11 84
(S)-BINAL-H
R R
C11H23 92
O OH
i-Pr 57

CHIRAL CATALYSTS

Optically active OXAZABOROLIDINEs (OAB) introduced by Corey are prepared starting

from L or D-proline as follows:

Mechanism:

As usual the role of the catalyst is to allow the preferential attack of the borane reagent
on a selected enentiotopic face of the ketone. However, the catalyst MUST also provide an
ACTIVATION both on the ketone (Lewis acid effect of boron) and on borane (through
interation with nitrogen).
The latter feature prevents the couple borane-ketone to react OUTSIDE the catalyst
sphere avoiding the background reaction to occur.
 ee%
O OH
BH3 R= Me 97
R R
OAB Et 97

ClCH2 95

O OH

CO2Me BH3 CO2Me

OAB
MeO MeO
OMe OMe

95% ee

O OH
BH3
OMe OMe
OAB
OMe OMe

93% ee

Because of the known mechanism of action the absolute configuration of the obtained alcohol is
PREDICTABLE on the basis of the stereochemical attributes of the used oxazaborolidine.
The second example also shows that a CHEMOSELECTIVE reaction is observed when C=C bonds
are present in the molecule.

TOTAL REDUCTION OF CARBONYLS

WOLFF-KISHNER AND RELATED REACTIONS

NH2NH2 Base H
O N NH2
D H

Mechanism:
 The original process occurs under VERY HARSH CONDITIONS (high temperature,
strong base), therefore a first modification has been introduced (HUANG-MINLON)

CO2H 85% NH2NH2

CO2H
KOH 195°C
(HOCH2CH2)2O

A considerable lowering of the temperature is involved in the CRAM process.

O NH2NH2
Ph Ph
Ph Ph t-BuOK-DMSO
100 °C

The CAGLIOTI reaction employs TOSYLHYDRAZONES as substrates using

LiAlH4 in THF as base and reductant:

Mechanism:

H Al
H Al
R H LiAlH4
N R LiAlH4
N Ts N
-H2 N Ts
R R -Ts-

R N - N2­ R H2O R H
H N H
R R R H

CHEMOSELETTIVE REACTIONS can be carried out using NaBH4 or NaCNBH3 :

NNHTs
NaBH4
CN CN

AcOH

O O
NaBH4
O NNHTs O
AcOH
 SHAPIRO REACTION
Tosylhydrazones of unactivated ketones can be reduced to alkenes using very strong
bases such as alkyllithiums

NNHTs
R' 1. RLi - Et2O R'
R R
2. H3O+

Mechanism:

This is REGIOSELECTIVE reaction since the position of the double bond in the
final product depends from the stereochemistry of the tosylhydrazone.

N 2eq. BuLi
NHTs
TMEDA
H

Since in the second step deprotonation of the α-hydrogen is needed, the nature
of the base can be suitably tuned according to its level of acidity.