Reactive intermediates and their applications

Reactive intermediates and their applications by Dr. Anand S. Burange
Topics covered: Carbocation history, work of George Olah, carbocation synthesis, Carbene and carbanion, Wagner Meerwein,Friedel Crafts reaction, Simmons Smith Cyclopropanation, Appel reaction, Pinalcol-pinacolone rearrangement, and many more.

1. By
Dr. Anand S Burange
Ph.D. (ICT, Mumbai), CSIR-NET, GATE,
CSIR-Nehru PDF (NCL, Pune), CSIR-RA
Asst. Professor in Chemistry
Wilson College, Mumbai
26
th
August 2021
Reactive intermediates and their applications
Suzuki coupling : Burange et al.,
ChemistrySelect, 2016, 1, 2673 – 2681

2. REACTIVE INTERMEDIATES
The intermediates formed during the reactions: short lived, mostly non
isolable, quickly converted into more stable molecule.
Reactive
intermediates
Carbocation
Carbanion
Carbene
Nitrene
Radical
Aryne

3. Carbocation
REACTIVE INTERMEDIATES:CARBOCATION
For many years they were called as carbonium ions; in
1902 it was suggested inappropriate to use suffix ‘onium’
ion for lesser covalency which is often used for higher
covalency than neutral atom. e.g. ammonium,
hydronium ion. Finally accepted by IUPAC in 1987 after
Olah’s discovery. SP
2
Hybridization
CH
5
+
species: Possible????
George Olah et al., found an
intermediate of carbon where
actually covalency of carbon is five
(higher), i.e. CH
5
+
Methanonium ion
(carbonium ion).
Chemtech, 1971, 1, 566; JACS 1972, 94, 808
Stability order of alkyl carbocation
3
o
>2
o
>1
o
> methyl
Reason: Hyperconjugation and Field
effect
Lot of literature available: work by Olah and his
co-workers

4. CARBOCATION
Can we prepare carbocation? YES
Alcohols, alkenes, and even alkanes
give carbocations when treated with
super acid.
JOC 1971, 36, 2354; JACS 1967, 89, 3576.
Super Acid
FSO
3H + SbF
5 dissolved in SO
2 or
SO
2ClF is known as super acid.
Which gas evolves when alkanes are treated
with super acid?
JACS 1967, 89, 4739
Evidence for stability of carbocation?
➢Both propyl fluorides gave
isopropyl cation.
➢ All four butyl fluorides gave tert-
butyl cation.
➢All seven pentyl fluorides gave tert-
pentyl cation.
To date no primary cation survived long enough
for detection.

5. CARBOCATION
Allylic, benzylic and cyclopropyl carbocations
Benzylic are more
stable than simple
allylic cations
Cyclopropyl
methyl cations are
even more stable
than benzylic.
More the canonical
forms; more is the
stability.
Reason for extra stability of cyclopropyl methyl carbocation
Non
classical
Norbornyl cation
7- Norbornenyl cation

6. CARBOCATION
Acyl-cation
Acyl or acetyl cation is as stable as tert-butyl cation.
Q. Which of the following carbocations do not exist? Which one is more stable?
•It is impossible to form carbocation at bridgehead atoms in [2.2.1] systems
since they can not be planar.
•However, larger bridgehead carbocations can exist.
•Cyclopropyl group provides extra stability already discussed in previous
slide.

7. CARBOCATION
How they exist?
➢ More stable ones can be prepared in
solution and in some case they even exist
as solid salts.
➢ In solution, carbocations may be free
i.e. in case of polar solvents they are
solvated.
➢ In non-polar solvents they exist as an
ion pair i.e. closely associated with
negative ion/counter ion.
Commercially available carbocation
Ph
3C
+
BF
4
-
Aryl methyl carbocations are further
stabilized by electron donating
groups at ortho- and para- position
(s).

8. Applications of carbocations in
Organic reactions
8

9. Wagner-Meerwein Rearrangement and Friedel Crafts
# Problems
#1 How will you synthesize n-butyl
benzene?
#2 Predict the product
The acid catalyzed nucleophilic 1,2 migration of alkyl, aryl or hydride
group from an alcohol to alkene is known as Wagner-Meerwein
Rearrangement
Ans: FC Acylation followed by reduction
Ans: Formation of carbocation, followed by –Me migration,
and later loss of proton

10. Problems
?
?

11. Pinacol-pinacolone rearrangement
1,2 diol (pinacol:trivial name), undergoes acid catalyzed rearrangement which
involve formation of carbocation, alkyl/aryl group migration to yield carbonyl
compound.
Spirocycles can also be prepared by this reaction.
?
?
?

12. Semipinacol rearrangement
In presence of base, less hindered hydroxyl group of
pinaocol reacts with TsCl to form tosylate. Formed
tosylate further gives carbonyl compound in non-acidic
condition (basic/neutral).
Less hindered
?
?

13. Tiffeneau-Demjanov rearrangement
Semipinacol rearrangement
of diazonium salts derived
from 2-amino alcohols
sometimes called as
Tiffeneau_Demjanov
rearrangement.
Orbital
Approach
Anti pariplanar relationship

14. Tiffeneau-Demjanov rearrangement-Problems
?
?
?
?

15. REACTIVE INTERMEDIATE: CARBENE
Carbene Highly reactive species. Practically all having lifetime
considerably under 1 sec.
Carbenes have been isolated only by entrapment in
matrices at low temperature (77K or less).
Ex. :CH
2 (methylene); :CCl
2 (dichlorocarbene)Six electron species
Types of Carbene
How to distinguish between singlet
and triplet carbene?
Method developed by Skell, where
different type of carbene on reaction
with cis-2-butene give different
stereoisomer.
H-C-H bond angle
103
o
SP
2
hybridized
H-C-H bond angle
136
o
SP
3
hybridized

16. Applications of carbene
16

17. CARBENE
Reaction of singlet and triplet carbenes
: Skell et al , JACS 1956, 78, 4496; Tetrahedron 1985, 41, 1427

18. SIMMONS SMITH CYCLOPROPANATION
In Simmons-Smith, zinc carbenoid behaves like singlet carbene and
its addition to alkene are stereospecific.
?
?

19. Reimer Tiemann Reaction
?
?

20. REACTIVE INTERMEDIATE: CARBANION
Carbanion
Simple carbanion of R
3C- could assume a
pyramidal (SP
3
) or a planar (SP
2
)
configuration or may be something between
depending upon the nature of R.
SP
3
or SP
2
Stability order
Why alpha hydrogen of carbonyls are acidic?
Stabilized by electron
withdrawing group.
Methyl> 1
o
> 2
o
> 3
o

21. Applications of carbanion
21

22. Acetoacetic Ester Synthesis/Claisen Condensation
Why α- hydrogen atoms are acidic?
Acetoacetic ester
Application
Concept of 1,3-dianion
How many α- hydrogen atoms
are present in acetoacetic ester?
Less
stable
anion
more
stable
anion
Which anion is more reactive?
Less stable anion is more reactive
since stable anion is involved in
delocalization with two EWGs.

23. # PROBLEMS
JACS, 1974, 96, 1082
Tet. Lett, 1996, 37, 471

24. Appel Reaction
# PROBLEM

25. Thank you