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.

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

6. Reaction mechanism

7. Migratory aptitude
• The relative migratory aptitudes of different groups
in Beckmann rearrangement is illustrated below.
7

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.

9. Scheme- 1
Step- 2

10. Applications in drug synthesis:-
• An alternative industrial synthesis method for
Paracetamol.
7
• 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.

15. Reaction Mechanism

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.

17. Support forthemechanism
• Intermediates have been isolated.(N- haloamide,
Isocyanate etc.)
• These intermediates yield the product of Hofmann
degradation.

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).

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.

29. Mechanism
 Significance of this reaction is that it is also given by
ketones, aldehydes, alcohols and alkenes ( intramolecular
and intermolecular rearrangement).

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

35. References
 https://en.wikipedia.org/wiki/Beckmann_rearrangement#
/media/File:Beckmann-rearrangement_mechanism.svg
 https://smallpdf.com/result#r=b8db075d95fecb88f8a583
3f53c800ce&t=pdf-to-ppt
 https://en.wikipedia.org/wiki/Curtius_rearrangement
 https://en.wikipedia.org/wiki/Schmidt_reaction
 Organic Synthesis by Dr. Jagdamba Singh and Dr. L.D.S.
Yadav