The following slides presents molecular rearrangements involving electron deficient nitrogen as an intermediate. And electron deficient nitrogen intermediate is nitrene. Such molecular rearrangements are: Beckmann rearrangement, Hofmann rearrangement, Curtius rearrangement, Schmidt rearrangement.
Molecular rearrangements involving electron deficient nitrogen as an intermediate
1. Submitted to: Dr. Mridula Verma
Submitted by: Anjali Rani
MSc. 4th semester
Molecular rearrangements
involving electron deficient
Nitrogen as an intermediate
2. Migration to electron deficient
Nitrogen
This type of reaction takes place where the reaction
intermediate is nitrene. One means of generating a
nitrene is via decomposition of an acyl azide(scheme-
1).
3. Important Rearrangements involving
electron deficient Nitrogen
The Beckmann Rearrangement
The Hofmann Rearrangement
The Curtius Rearrangement
The Schmidt Rearrangement
4. The Beckmann Rearrangement
Acid catalyzed conversion of a ketoxime into N-
substituted amides.
Variety of protic acids like Lewis acids, acid
anhydrides and acyl halides cause the reaction to
occur.
Role of these catalysts is to convert the hydroxyl
group into a better leaving group.
This rearrangement is occurs in both cyclic and
acyclic compounds .
Aldoximes are less reactive.
5. • Cyclic oximes yield lactams and acyclic oximes
yield amides.
• Stereospecific in nature and involves the
migration of alkyl group anti to leaving
group(protonated -OH of oxime).
• The migrating group always retains its geometry.
• Certain conditions have been known
to racemize the oxime geometry, leading to the
formation of both regioisomers.
Oxime Amide
7. Migratory aptitude
• The relative migratory aptitudes of different groups
in Beckmann rearrangement is illustrated below.
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8. Migratory aptitude contd.
Electron withdrawing group (-R group) attached to the
migrating aryl group retard the rate of the reaction.
Presence of electron donating group (+R) has an
accelerating influence, since the migrating group is then
better able to render arichimeric assistance to the
removal of the leaving group via the transition state.
The stereochemistry of the reaction indicates the
rearrangement is concerted with the departure of the
leaving group as indicated by step-2 of scheme -1 in the
next slide.
10. Applications in drug synthesis:-
• An alternative industrial synthesis method for
Paracetamol.
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• The Beckmann rearrangement is also used
in the synthesis of
• DHEA
• Benazepril
• Etazepine etc.
11. Applications in polymer synthesis:-
• Beckmann rearrangement can be rendered catalytic using
cyanuric chloride and zinc chloride as a co-catalyst. For
example, cyclododecanone can be converted to the
corresponding lactam, the monomer used in the
production of Nylon 12.
12. Applications in polymer synthesis:-
• The Beckmann rearrangement is also
used in the synthesis of Nylon 6.
1
2
13. The Hofmann Rearrangement
• Amides with no substituent on the nitrogen react
with solutions of bromine or chlorine in sodium
hydroxide to yield amines through a reaction
known as the Hofmann rearrangement or
Hofmann degradation.
14. Reaction Mechanism
The reaction of bromine with sodium hydroxide forms sodium
hypobromite in situ, which transforms the primary amide into an
intermediate isocyanate.
The Hofmann rearrangement involves a 1,2-shift of group with
its electron pair to an electron-deficient NITROGEN.
MECHANISM :- The reaction is believed to proceed through
following steps---
Step 1: Bromination of nitrogen.
Step 2: Extraction of H +by OH - &
rearrangement of anion.
Step 3: Hydrolysis.
16. Reaction Mechanism contd.
1. Base abstracts an acidic N-H proton, yielding an anion.
2. The anion reacts with bromine in an α-substitution
reaction to give an N- bromoamide.
3. Base abstraction of the remaining amide proton gives a
bromoamide anion.
4. The bromoamide anion rearranges as the R group
attached to the carbonyl carbon migrates to nitrogen at
the same time the bromide ion leaves, giving an
isocyanate.
5. The isocyanate adds water in a nucleophilic addition
step to yield a carbamic acid (aka urethane).
6. The carbamic acid spontaneously loses CO2, yielding
the amine product.
18. Stereochemistry
• An interesting stereo chemical observation is that if the
migrating group (R) is chiral , its configuration is retained in
the product amine.
• Thus this rearrangement is INTRAMOLECULAR , the
migrating group does not become free , but remains attached
with the substrate in some way e.g. via bridged transition
state.
19. Applications
1. Synthesis of 10 aliphatic & aromatic amines.
2.Preparation of aldehyde.
3.In the preparation of anthranilic acid from
phthalamide.
20. The Curtius Rearrangement
The Curtius Rearrangement is the thermal decomposition of
carboxylic azides to produce an isocyanate. These intermediates
may be isolated, or their corresponding reaction or hydrolysis
products may be obtained.
The isocyanate then undergoes attack by a variety
of nucleophiles such as water, alcohols and amines, to yield a
primary amine, carbamate or urea derivative respectively.
21. The acyl azide is usually made from the reaction of acid
chlorides or anydrides[6] with sodium azide or trimethylsilyl azide
a reactive acylating agent or by diazotization of an acyl hydrazide.
The isocynates themeselves are isolated if the reaction is carried
out in an inert solvent(e.g., benzene).
22. Mechanism
Key step in this rearrangement is the thermal or
photochemical conversion of an azyl azide to an
isocyanate.
Curtius rearrangement is concerted and does not
involve the intermediacy of a nitrene (scheme- 1 in
the next slide).
Evidence to support the existence of nitrene when
tertiary alkyl azides undergo Curtius rearrangement
to form imines is shown in scheme-2 (in the next
slide).
23.
24. Stereochemistry
Studies shows that optically active azides in which
the chiral carbon is directly bonded to the carbonyl
group have shown that these reactions occur with
retention of the configuration .
Intramolecular nature has been supported by the
azide.
Azide
25. Applications
The Curtius rearrangement is tolerant of a large
variety of functional groups, and has significant
synthetic utility, as many different groups can be
incorporated depending on the choice
of nucleophile used to attack the isocyanate.
Used in the syntheses of the drugs like
tranylcypromine, candesartan, bromadol and more.
26. The Schmidt Rearrangement
Acid catalyzed conversion of carboxylic acid to
primary amines.
Catalysts are Bronsted or Lewis acid mainly
concentrated sulphuric acid.
Carboxylic acid Primary amine
27. Mechanism
• Azides may add to suitably activated
electrophiles in presence of conc. Sulphuric acid.
• Upon addition, the newly bound nitrogen atom
becomes electron-deficient and is subject to 1,2-
migration of a carbon or hydrogen substituent
with loss of a molecule of dinitrogen as shown in
Scheme- 1 in next slide.
28.
29. Mechanism
Significance of this reaction is that it is also given by
ketones, aldehydes, alcohols and alkenes ( intramolecular
and intermolecular rearrangement).
30.
31.
32.
33.
34. Applications
Synthesis of aliphatic and aromatic primary amines.
Synthesis of disubstituted amino acids.
Intramolecular Schmidt reactions have utility in
synthesis of natural products.
Intramolecular Schmidt reactions
