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Reduction [H]
Organic Synthesis
Chem-706
How to Define Reduction
Reduction means
Gain of electron
Formation of C-H bond
Loss of C-O bond (or its equivalence)
Over all
An organic molecule lose
oxygen and/or gain hydrogen
General symbol [H]
In organic chemistry
A reduction results in a net increase in
the number of C-H bonds, or a net
decrease in the number of C-O
bonds (or equivalent, such as C-Cl, CBr, etc).
A general order between
Oxidation & Reduction
Reduction -- Common ways on Basis of
H2 Addition
TYPE I
TYPE II
TYPE III
Reduction via Metal Hydride Reagents
Addition of a hydride (H-) and a proton (H+)
These reagents reduced the multiple bonds,C=O, C=N &
, by transferring an
hydride H¯ to the substrate, and then a proton is added from H2O or an alcohol.
A common presentation of reaction:
Most commonly known reagents are sodium borohydride (NaBH4) and lithium
aluminum hydride (LiAlH4). All metal hydride reagent contains boron (B) or aluminium
(Al) which are boned to one or more H atoms.
Functional groups interconversion via different
Reducing agents
Catalytic Hydrogenation [H2]
Substrates
Catalysts
Pressure
(atm)
Catalyst/Compound
ration (wt%)
Reduction
Products
Alkene
5% Pd/C
1-3
5-10%
Alkane
Alkyne
5% Pd (BaSO4)
1
2% + 2% quinoline
Alkene
Aldehyde or
Ketone
PtO2
1
2-4%
Alcohol
Halide
5% Pd/C
1
1-15% KOH
Alkane
Nitrile
Raney Ni
35-70
3-30%
Amine
Ref: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 188: Washing DC, 1996, P. 8.
List of Reagents used in Metal Hydride(H-) Reduction
Substrates
Hydride Donors
LiAlH4
DIBAL
NaAlH(OtBu)3
AlH3
NaBH4
NaCNBH4
Na(AcO) 3BH
B2H6
Li(Et)3
BH
H2
(catalyst)
Aldehyde or
Ketone
Alcohol
Alcohol
Alcohol
Alcohol
Alcohol
(slow)
Alcohol
(slow)
Alcohol
Alcohol
Alcohol
Alcohol
Iminium
ion
Amine
--
--
--
Amine
Amine
Amine
--
--
Amine
Acid Halide
Alcohol
Alcohol
Aldehyde
Alcohol
--
--
--
--
Alcohol
Alcohol
Ester
Alcohol
Alcohol
or
Aldehyde
Alcohol
(Slow
Alcohol
Alcohol
(slow)
Alcohol
Alcohol
Amide
Amine
Amine
or
Aldehyde
Amine
(slow)
Amine
--
--
Amine
(slow)
Amine
(slow)
Alcohol
(tertiary
amide)
Amine
Carboxylate
Salt
Alcohol
Alcohol
--
Alcohol
--
--
--
Alcohol
--
--
Alcohol
(slow)
Alcohol
Ref: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 188: Washing DC, 1996, P. 8.
Reduction of Carbonyl Compounds
Angle of Nucleophilic Attack
The Bürgi–Dunitz angle Bürgi and Dunitz deduced this trajectory by examining crystal structures of compounds
containing both a nucleophilic nitrogen atom and an electrophilic carbonyl group. They found that, when the two
got close enough to interact, but were not free to undergo reaction, the nitrogen atom always lay on or near the
107° trajectory decribed here. Theoretical calculations later gave the same 107° value for the optimum angle of
attack. ( Ref: Organic Chemistry. By J. P. Clayden, N. Greeves, S. Warren, and P. D. Wothers; Oxford University
Press, 2001, ISBN 0 19 850346 6, 53 Chapters).
Reduction of Aldehyde & Ketone
Alkane
Deoxygenation of Tosylhydrazon
Alkane
Hydride Donors
Sodium Cynaoborohydride, Sodium
triacetoxyborohydride or catecholborane.
A mild and selective type of reduction for the purpose of carbonyl deoxygenation.
Most useful to convert hindered carbonyl groups to corresponding Alkane .
Also compatible with esters, amides, nitriles, nitro groups and alkyl halides.
However, electron deficient aryl aldehyde and ketone prove to be resistant to
reduction.
Only proposed when inductive effects and/or conformational constraints favour the
tautomerization of the hydrazone to an azohydrazine
In the case of a, b-saturated system, the addition of hydride ion occurs in a
concerted way via 1,5-sigmatropic rearrangement.
The Mechanism of such "alkene walk" appears to proceeds through diazene
intermediate with transfer hydride. The double still retain in this reduction process.
Ref: Miller, V. P.; Yang, D.-y; Weigel, T. M.; Han, O.; Liu, H.-w. J. Org. Chem. 1989, 54, 4175-4188.
Ref: Chai, Y.; Vicic, D. A.; Mcintosh, M. C. Org. Lett. 2003, 7, 1039-1042.
Ref: Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190-5192.
N-tosylhydrazone a versatile intermediate
Mechanism
Ref: Ye, F.; Shi, Y.; Zhou, L.; Xiao, Q.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5020-5023.
Review : N-Tosylhydrazones: versatile reagents for metal-catalyzed and metal-free cross-coupling
reactions Shao, Z.; Zhangb, H. Chem. Soc. Rev., 2012, 41, 560-572 (impact factor 25)
Wolff-Kishner Reduction
Alkane
Wolff–Kishner reduction
reduced the Aldehydes & Ketones to Alkanes.
Condensation of the carbonyl compound with hydrazine forms the hydrazone, and
treatment with base induces the reduction of the carbon coupled with oxidation of the
hydrazine to gaseous nitrogen, to yield the corresponding alkane.
Numerous modified procedures to the classic Wolff–Kishner reduction have been
reported. In general, the improvements have focused on driving hydrazone formation to
completion by removal of water, and by the use of high concentrations of hydrazine.
The two principal side reactions associated with the Wolff–Kishner reduction are
azine formation and alcohol formation.
Ref: Piers, E.; Zbonzny, M.; Can. J. Chem. 1979, 57, 1064-1074.
Mechanism
http://www.organic-chemistry.org/
Advancement
N-tert-butyldimethylsilylhydrazone (TBSH) derivatives serve as superior alternatives
to hydrazones.
TBSH derivatives of aliphatic carbonyl compounds undergo Wolff-Kishner-type
reduction at 23 °C; derivatives of aromatic carbonyl undergo reduction at 100 °C.
Ref: Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436-5454. impact factor = 11
Advancement
Typical way
Typical way
Grainger, R. S. et. al. 2013, 11, 6856-6862
Desulfurzation with Raney Nickel
Alkane
Thioacetal (or thioketal) reduction or Mozingo reduction with Raney nickel and hydrogen is
a classic method to prepare a methylene group from a carbonyl compound.
Raney Nickel was developed in 1926 by American engineer Murray Raney. ( "Method of
producing finely-divided nickel,"U.S. patent 1,628,190, filed: 1926)
A thioketal is first produced by reaction of the ketone with an appropriate thiol. The
product is then hydrogenolyzed to the alkane, using a Raney nickel catalyst. This method is
much milder than either the Clemmensen or Wolff-Kishner reductions, which employ
strongly acidic or basic conditions, respectively, that might interfere with other functional
groups present in the molecule.
• The most common limitation of the desulfurization method is the competitive hydrogenation
of alkenes.
Ref: 1) Francis A. Carey; Richard J. Sundberg (2007). Advanced Organic Chemistry: Reactions and synthesis.
2) Jonathan Clayden; Nick Greeves, Stuart Warren (2012). Organic Chemistry (2 ed.).
Applications:
Ref: Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1948, 70, 2107-2115.
Brik, A. et. al. Highly efficient one-pot ligation and
desulfurization. Chem. Sci., 2013, 4, 2496-2501
(impact fctor = 8.3)
NCL (Native Chemical Ligation)
convenient method ---- chemical
synthesis of proteins well over 100 amino
acids in length; --- 166-amino-acid
polypeptide chain of the synthetic variant
of the erythropoiesis protein and the 203
amino acid HIV-1 protease.
Ligation methods (e.g. ICL, NCL)
combined with desulfurization have
becoming increasingly useful in protein
synthesis
Clemmensen Redution
Alkane
Clemmensen reduction of ketones and aldehydes using zinc and hydrochloric acid is
a classic method for converting a carbonyl group into a methylene group.
Typically, the classic Clemmensen reduction involves refluxing a carbonyl substrate
with 40% aqueous hydrochloric acid, amalgamated zinc, and an organic solvent such as
toluene. This reduction is rarely performed on polyfunctional molecules due to the harsh
conditions employed.
Anhydrous hydrogen chloride and zinc dust in organic solvents has been used as a
milder alternative to the classic Clemmensen reduction conditions.
This reaction is named after Erik Christian Clemmensen, a Danish chemist.
Mechanism
http://www.organic-chemistry.org/
Application in Natural product synthesis
Li, W.-D. Z.; Wang, Y.-Q. J. Org. Chem. 2003, 5, 2931-2934.