ORGANIC SYNTHESIS
Organic synthesis is the construction of more complex organic molecules from simpler
ones using chemical reactions.
Most organic molecules contain more than one functional group and most functional
groups can react in more than one way, so organic chemists have to predict:
i. which functional group will react - this is known as Chemoselectivity
ii. where the functional group will react - known as Regioselectivity
iii. how the functional group will react as regards to the stereochemistry of the product
- known as Stereoselectivity
OXIDATION–REDUCTION REACTIONS
Oxidation is a loss of electrons, and reduction is a gain of electrons. However, in the
context of organic chemistry, oxidation means the loss of hydrogen, the addition of oxygen
or the addition of halogen. A general symbol for oxidation is [O]. Thus, oxidation can also
be defined as a reaction that increases the content of any element more electronegative
than carbon. The conversion of ethanol to acetaldehyde and that of acetaldehyde to
ethanoic acid are oxidation reactions, and the reverse reactions are reduction reactions.
In the synthesis of organic compounds, there are various reagents which perform various
specific functions.
Oxidizing agents are reagents that seek electrons, and are electron-deficient species, e.g.
chromic acid (H2CrO4), potassium permanganate (KMnO4) and osmium tetroxide (OsO4).
Therefore, oxidizing agents are classified as electrophiles.
In the process of gaining electrons, oxidizing agents become reduced.
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Oxidation results in an increase in the number of C- O bonds or a decrease in the
number of C-H bonds.
OXIDATION REACTIONS
I. JONES REAGENT
The Jones Reagent is a mixture of chromic trioxide or sodium dichromate in diluted
sulfuric acid, which forms chromic acid in situ.
Secondary alcohols are oxidized to ketones, and primary alcohols can be oxidized to either
an aldehyde or a carboxylic acid.
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II. COLLINS REAGENT
Collins reagent: CrO3.2C5H5N diluted in dichloromethane (DCM)
Preparation of Collin’s Reagent
It is used to oxidize primary alcohols to aldehyde without over-oxidation.
It is useful for oxidizing acid-sensitive compounds, and the process is known as Collins
oxidation.
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III. PYRIDINIUM DICHROMATE
Pyridinium dichromate (PDC) is a mild and selective oxidizing agent mainly used to oxidize
primary and secondary alcohols.
PDC in dichloromethane (DCM) or dimethylformamide (DMF) is also called as Corey-
Schmidt reagent): (C5H5NH)2Cr2O7.
In this case, PDC is maintained in anhydrous conditions
PDC selectively oxidizes 1o alcohol to carboxylic acid followed by lactonization
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OH
IV. PYRIDINIUM CHLOROCHROMATE (PCC)
Pyridinium chlorochromate (PCC) is a milder version of chromic acid.
Pyridinium Chlorochromate (PCC) in DCM: [C 5H5NH]+[CrO3Cl]- is also called Corey-Suggs
reagent.
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PCC oxidizes alcohols one rung up the oxidation ladder, from primary alcohols to
aldehydes and from secondary alcohols to ketones.
In contrast to chromic acid, PCC will not oxidize aldehydes to carboxylic acids.
Here are two examples of PCC in action.
V. MANGANESE DIOXIDE, MnO2
Manganese dioxide is a mild oxidizing agent that selectively oxidizes primary or secondary
allylic and benzylic alcohols. Primary alcohols yield aldehydes and secondary alcohols
form ketones.
The reagent is generated in situ by treatment of an aqueous solution KMnO 4 with a Mn(II)
salt, typically the sulfate. MnO2 oxidizes allylic alcohols to the corresponding aldehydes
or ketones
cis-RCH=CHCH2OH + MnO2 → cis-RCH=CHCHO + MnO + H2O
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VI. POTASSIUM DICHROMATE (K2Cr2O7) and SODIUM DICHROMATE (Na2Cr2O7)
Potassium dichromate is an oxidizing agent in organic chemistry, and is milder than
potassium permanganate.
It is used to oxidize alcohols. It converts primary alcohols into aldehydes and, under more
forcing conditions, into carboxylic acids.
Secondary alcohols are converted into ketones. For example, menthone may be prepared
by oxidation of menthol with acidified dichromate.
Tertiary alcohols cannot be oxidized.
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VII. POTASSIUM PERMANGANATE
Potassium permanganate, KMnO4, is a powerful oxidizing agent, and has many uses in
organic chemistry.
KMnO4 is able to oxidize carbon atoms if they contain sufficiently weak bonds, including
Carbon atoms with π bonds, as in alkenes and alkynes
Carbon atoms with weak C-H bonds, such as
C-H bonds in the alpha-positions of substituted aromatic rings
C-H bonds in carbon atoms containing C-O bonds, including alcohols and aldehydes
Carbons with exceptionally weak C-C bonds such as
C-C bonds in a glycol
C-C bonds next to an aromatic ring and an oxygen
KMnO4 also oxidizes phenol to para-benzoquinone.
Aldehydes RCHO are readily oxidized to carboxylic acids.
Alcohols
Primary alcohols such as octan-1-ol can be oxidized efficiently by KMnO4, in the presence
of basic copper salts
Alkenes
Under mild conditions, potassium permanganate can effect conversion of alkenes to
glycols. It is, however, capable of further oxidizing the glycol with cleavage of the carbon-
carbon bond, so careful control of the reaction conditions is necessary. A cyclic
manganese diester is an intermediate in these oxidations, which results in glycols formed
by syn addition.
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Reaction of an alkene with hot basic potassium permanganate (KMnO 4) results in
cleavage of the double bond, and formation of highly oxidized carbons. Therefore,
unsubstituted carbon atoms become CO2, mono-substituted carbon atoms become
carboxylates, and di-substituted carbon atoms become ketones.
With addition of heat and/or more concentrated KMnO 4, the glycol can be further
oxidized, cleaving the C-C bond.
More substituted olefins will terminate at the ketone
Alkynes
Instead of bis-hydroxylation that occurs with alkenes, permanganate oxidation of alkynes
initially leads to the formation of diones.
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Aromatic side-chains
The reaction only works if there is at least one hydrogen attached to the carbon. However,
if there is at least one hydrogen, the oxidation proceeds all the way to the carboxylic acid.
VIII USE OF PERACID OR PEROXY-ACID
Alkenes are also oxidized to epoxides by peracid or peroxyacid (RCO 3H), e.g.
peroxybenzoic acid (C6H5CO3H). A peroxyacid contains an extra oxygen atom compared
with carboxylic acid, and this extra oxygen is added to the double bond of an alkene to
give an epoxide. For example, cyclohexene reacts with peroxybenzoic acid to produce
cyclohexane oxide.
The addition of oxygen to an alkene is stereospecific. Therefore, a cis-alkene produces a
cis-epoxide, and trans-alkene gives a trans-epoxide
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Syn-hydroxylation of alkenes: Preparation of syn-diols
Hydroxylation of alkenes is the most important method for the synthesis of 1,2-diols (also
called glycol). Alkenes react with cold, dilute and basic KMnO 4 or osmium tetroxide (OsO4)
and hydrogen peroxide to give cis-1,2- diols. The products are always syn-diols, since the
reaction occurs with syn addition
Anti-hydroxylation of alkenes: Preparation of anti-diols
Alkenes react with peroxyacids (RCO3H) followed by hydrolysis to give trans-1,2-diols. The
products are always anti-diols, since the reaction occurs with anti addition.
Oxidative cleavage of syn-diols: preparation of ketones and aldehydes or carboxylic
acids
The treatment of an alkene by syn-hydroxylation, followed by periodic acid (HIO4)
cleavage, is an alternative to the ozonolysis, followed by reductive work-up. Syn-diols are
oxidized to aldehydes and ketones by periodic acid (HIO4). This oxidation reaction divides
the reactant into two pieces, thus it is called an oxidative cleavage
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IX USE OF OZONE (OZONOLYSIS OF ALKENES)
Alkenes can be cleaved by ozone followed by an oxidative or reductive work-up to
generate carbonyl compounds. The products obtained from an ozonolysis reaction
depend on the reaction conditions. If ozonolysis is followed by the reductive work-up
(Zn/H2O), the products obtained are aldehydes and/or ketones. Unsubstituted carbon
atoms are oxidized to formaldehyde, mono-substituted carbon atoms to aldehydes, and
disubstituted carbon atoms to ketones.
When ozonolysis is followed by the oxidative work-up (H2O2/NaOH), the products
obtained are carboxylic acids and/or ketones. Unsubstituted carbon atoms are oxidized
to formic acids, mono-substituted carbon atoms to carboxylic acids and di-substituted
carbon atoms to ketones.
Preparation of aldehydes and ketones
Alkenes are directly oxidized to aldehydes and/or ketones by ozone (O 3) at low
temperatures (78 oC) in methylene chloride, followed by the reductive work-up. For
example, 2-methyl-2-butene reacts with O3, followed by a reductive work-up to yield
acetone and acetaldehyde. This reducing agent prevents aldehyde from oxidation to
carboxylic acid
Preparation of carboxylic acids and ketones
Alkenes are oxidized to carboxylic acids and/or ketones by ozone (O3) at low temperatures
(78 oC) in methylene chloride, followed by oxidative work-up. For example, 2-methyl-2-
butene reacts with O3, followed by an oxidative work-up to give acetone and acetic acid.
Notes compiled by: Dr. BMW Amos-Tautua, MCSN, MRSC, MACS, FICCON
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