Advanced organic chemistry Moving from over functional group to another by oxidation and reduction

1. Advanced Organic Chemistry
AOC811S
Functional Group Interconversions
Dr. Marius Mutorwa
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2. References
1. Fabirkiewicz and Stowell, Intermediate Organic Chemistry, 3rd
Edition, Chapter 6
2. Carey and Sundberg, Advanced Organic Chemistry, 5th Edition,
Chapter 3
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3. Introduction
• Functional Group interconversions (FGI) or transformations (FGT)
is an important tool which is used in the synthesis of an organic
compound or target molecule of some complexity
• An important theme that relates to FGI in organic chemistry is the
concept of oxidation state of the carbons undergoing
transformation i.e. whether the carbon atom is undergoing
reduction or oxidation
• Thus a good understanding of oxidation and reduction allows us to
notice the sequence in which reactions occur or functional groups
are converted
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Definition of Oxidation and Reduction
For practical purposes in organic chemistry, oxidation and reduction are defined as follows:
Oxidation:
• addition of oxygen to the substrate
or
• removal of hydrogen
or
• removal of one electron
Reduction:
• addition of hydrogen to the substrate
or
• removal of oxygen
or
• addition of one electron
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Definition of Oxidation and Reduction
• we can define OXIDATION as a process by which a carbon atom gains bonds to more
electronegative elements, commonly oxygen.
• REDUCTION is a process by which a carbon atom gains bonds to less electronegative
elements, commonly hydrogen.
• Thus, Oxidation Reactions are those in which the central carbon atom of a functional
group is transformed into a more highly oxidized form
• Reduction Reactions are those in which the central carbon atom of the functional group
is transformed into a more highly reduced form.
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Oxidation and Reduction states of Carbon Atoms
• The FGI or oxidation states of a molecules that are bonded to one, two and three carbons is as
follows:
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Oxidation and Reduction states of Carbon Atoms
• However, most organic molecules contain more than one carbon
• Thus, for these molecules, the general rule is that:-
 The maximum oxidation state that a carbon can attain decreases gradually as the
number of bonds to other carbons increases.
 Thus, the maximum oxidation state possible for a carbon that’s bonded to one other
carbon is the carboxylic acid stage and so on.
• We can thus relate FGI based on the oxidation state of the functional group carbon. This
is illustrated on the oxidation ladders such as: -
https://www.masterorganicchemistry.com/2011/08/08/oxidation-ladders/
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9. Oxidation and Reduction
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Oxidation states in organic species are not always easy to assign, due to the covalent nature
of bonding for organic molecules.
Instead of oxidation state, we define an oxidation number on the carbon undergoing
transformation, using rules derived from Hendrickson, Cram, Hammond and Pine:
The contribution to each carbon is:
– 1 for H
0 for C
+ 1 for electronegative elements
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FGI: Carboxylic Acids and their derivatives
• Characteristic of Carboxylic acids and their derivatives is the high oxidation state of
carbon in which there are three bonds to electronegative atom
• Related derivatives include acid chlorides, anhydrides, esters, ortho esters, amides and
nitriles.
• Functional group transformation of carbonyl group may involve:
1) oxidation from hydrocarbons or other partially oxidized compounds or
2) Exchange among various electronegative atoms on the carbonyl carbon
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FGI: Carboxylic Acids Formation
• Carbons that are already partially oxidized such as alkenes or alkynes, primary alcohols,
aldehydes and methyl ketones are readily oxidized to the carboxylic acids using a variety
of reagents.
1) Oxidative Cleavage of alkenes or alkynes – see McMurry
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FGI: Carboxylic Acids Formation
• An alternative method is the combination of sodium periodate and a catalytic amount
permanganate
• The permanganate oxidizes the alkene to the glycol which is then cleaved by the
periodate to regenerate the permanganate – see ref 4, Stowell, page 164
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FGI: Carboxylic Acids Formation
• Carbons that are already partially oxidized such as alkenes or alkynes, primary alcohols,
aldehydes and methyl ketones are readily oxidized to the carboxylic acids using a variety
of reagents.
2) Oxidation of 1o Alcohols – see Stowell, Page 165
• Primary alcohols are easily by:
i) Potassium permanganate
ii) Dichromate reagents such as K2Cr2O7 or Pyridinium dichromate (PDC) in DMF
iii) Jones (CrO3, H2SO4, H2O) reagent in acetone
iv) Swern Oxidation (1. DMSO, Oxalyl Chloride, 2. Et3N)
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FGI: Carboxylic Acids Formation
2) Oxidation of 1o Alcohols
• Primary alcohols are easily by:
i) Potassium permanganate
ii) Dichromate reagents such as K2Cr2O7 or Pyridinium Dichromate (PDC) or
Pyridinium chlorochromate (PCC) or Dess-Martin Periodinane (DMP) in DMF
iii) Jones reagent (CrO3, H2SO4, H2O) in acetone
NOTE: Selectivity
• Secondary alcohols are readily oxidized
with the same reagents to ketones
• KMnO4 in aqueous NaOH will oxidize
primary alcohols but is not selective if
other functional groups are present eg.
Alkene
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FGI: Carboxylic Acids Formation
3) Oxidation of aldehydes
• Aldehydes are more readily oxidized than alcohols and thus react with the same
oxidation reagents as for 1o alcohols to form carboxylic acids
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FGI: Carboxylic Acids Formation
3) Oxidation of aldehydes – See Stowell, p165
• Where selectivity is needed, very mild reagents such as silver oxide, sodium chlorite can
be used to achieve the transformation
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FGI: Carboxylic Acids Formation
4) Same oxidation level – see Stowell, p166
• Within the same oxidation level, any acid derivative may be hydrolyzed with aqueous
acid or base, leading to the corresponding carboxylic acid or the salt thereof.
• Other reactions which involve syntheses of carboxylic acids involve the formations C-C
bond and will be discussed later e.g. Grignard reagents, malonic ester alkylation
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FGI: Review of Oxidation Reagents
Oxidation of alcohols to Aldehydes and ketones to Carboxylic acids
Jones reagent
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FGI: Carboxylic Acid Chlorides - Acylation Rxn
• The traditional method of transforming carboxylic acids into reactive acylating agents
capable of converting alcohols to esters or amines to amides is by the formation of the
acyl/acid chloride. See Stowell, p168 and Carey, p243
• Compounds which lack acid-sensitive functional groups can easily be converted to acyl
chlorides through the use of i) thionyl chloride ii) Phosphorous trichloride or iii)
phosphorous pentachloride
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FGI: Carboxylic Acid Chlorides - Acylation Rxn
• When milder conditions are necessary, the reaction of the carboxylic acid with oxalyl
chloride gives access to the acyl chloride – see ref 20, Stowell, p168 and Ref 98, Carey,
p243
• The rxn involves formation of a mixed anhydride-chloride of oxalic acid which
decomposes generating both CO2 and CO
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FGI: Carboxylic Acid Chlorides – Acylation Rxn
• Acid bromides can be made similarly through the use of phosphorous tribromide or
phosphorous pentabromide
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FGI: Carboxylic Acid Chlorides – Acylation Rxn
• Also, carboxylic acids can be converted to acid bromides in milder conditions using
triphenyl phosphine-bromide adduct
• The rxn involves an acyloxyphosphonium ion and the mechanism is analogous to the
alcohol-to-halide conversion
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FGI: Carboxylic Acid Chlorides – Acylation Rxn
• Acyl Chlorides are highly acylating agents and can react very rapidly with alcohols and other
nucleophiles
• Preparative procedures often require the use of pyridine or 4-dimethylaminopyridine (DMAP) as
catalysts
• Pyridine catalysis involve the initial formation of an acyl pyridinium ion (more reactive than the acyl
chloride), which subsequently reacts with the alcohol
• With the use of 5 – 20% DMAP in acylation rxns, the dimethyl amino group acts as a electron donor,
thus increasing both the nucleophilicity and basicity of the pyridine Nitrogen – this increases the
acylation rxn rates up to four orders of magnitude
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FGI: Carboxylic Acid Anhydrides – Acylation Rxn 2
• Another method for acylation of Carboxylic Acids is though the use of Acid Anhydrides
(AA)
• Acid anhydride – compound that has two acyl groups bonded to the same oxygen atom
• Acid anhydrides are a source of reactive acyl groups and rxn reseamble that of acyl
halides
• Most anhydrides are prepared from carboxylic acids by exchange with the readily
available acetic anhydride – see ref 21, Stowell, p169
• Rxn involve heating the CA in the presence of AA and then distilling of the acetic acid and
excess acetic anhydride, which shifts the equilibrium towards the higher boiling product
OH
O
O
O O
+
O
O O
OH
O
+
90-92%
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FGI: Carboxylic Acid Anhydrides – Acylation Rxn 2
• Acid Anhydrides can also be prepared by treatment of carboxylic acid with half an
equivalent of oxalyl chloride – see ref 99, Carey, p243
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FGI: Carboxylic Acid Anhydrides – Acylation Rxn 2
• The rxn is useful when unsymmetrical anhydrides are used as they react
selectively on one side – see ref 22 & 23, Stowell, p169
 E.g. 1 Acetic formic anhydride is a useful formylating reagent for alcohols and
amines ( i.e. nucleophilic sub at the carboxylic carbonyl carbon)
 E.g. 2 A stable solid formylating agent is formic p-methoxybenzoic anhydride
H ONa
O
Cl CH3
O
+
H O
O
CH3
O
64%
Cl
O
NaO H
O
+
O
O
H
O
89%
H3CO H3CO
catalyst
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FGI: Other Acylation Reagents
• The are other acylating reagents which can be used in combination with carboxylic acids
or acid anhydrides for sensitive substrates, leading to enhanced selectivity
 E.g. 2 the use of coupling reagents e.g Dicyclohexylcarbodiimide (DCCI) is another
example that coverts carboxylic acids to reactive acylating reagents
 This compound as been widely applied in the acylation step in the synthesis of
polypeptides from amino acids – see ref 117, 118 & Section 13.3.1, Carey page 247
 The reactive species is an O-acyl isourea, whereby the nitrogen is susceptible to
protonation and the cleavage of the acyl-oxygen bond converts the C-N bond of the
isourea to a more stable carbonyl group
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FGI: Other Acylation Reagents
• The are other acylating reagents which can be used in combination with carboxylic acids
or acid anhydrides to for sensitive substrates, leading to enhanced selectivity
 The combination of carboxyl activation by DCCI and catalysis by DMAP provides a
useful method for in situ activation of carboxylic acids for rxn with alcohols where the
rxn proceeds at room temperature – see ref 119, Carey, p247
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