Dynamic Stereochemistry and What role does conformation plays on stereochemistry is being exemplified in this presentation. Useful for the Undergraduate and Postgraduates students of Pharmacy, Pharmaceutical Chemistry and Chemical Sciences

1. 1

2. 2

3. 1. Introduction
2. Selection of substrates
3. Quantitative correlation between conformation
and reactivity
4. Conformation, reactivity, and mechanism : Cyclic
system
5. Conformation, reactivity, and mechanism: acyclic
systems
6. Conformational atropisomers and reactivity
7. Formation and reactions of enols and enolates
8. Reduction of cyclohexanones
9. Reference
3

4.  Concerned with stereochemical studies
of any rate process
involving bond-breaking and bond-making
or interconversion of conformers
 It correlates the stereochemistry of
starting material and products
in terms of transition states
4

5.  Substrate used for study of conformation-
reactivity correlation
divided into three categories-
Conformationally rigid
diastereoisomers
Conformationally mobile
diastereoisomers
Single substrate with
two or more isomers
5

6.  Reacting groups are locked into two different
orientations e.g.equitorial and axial
provide a direct relationship between conformation
and reactivity
 Ex: trans-2α-decalol and trans-2β-decalol
OH group is equitorial and axial respectively
(trans-2-decalol) (trans-2-decalol)
6

7. 2.2 Conformationally mobile diastereomers
 Example- 2,3,4-triphenylbutyric acid
The compound exists in threo and erythro:
(Threo) (tetralone)
(Erythro) (indanone)
Ring-closure of threo and erythro isomers of 2,3,4-
triphenylbutyric acid
The relative
specific reaction
rates of the two
diastereomers
depends on the
corresponding
rates and their
populations in the
equillibrium
mixture of each
diastereomer
7

8. 2.3 Single substrate with two or more
conformers
ni = mole fraction of i-th confomer
Ki = specific reaction rate
 Example :4-methylcyclohexanone
(2-isooctyl nitrite)
Conversion of 4-methylcyclohexanone
into optically active 2-oxyimino derivative
The overall specific
reaction rate (k) of
a substrate in
mobile equillibrium
depends both on
the ground state
population of
conformer and on
their specific
reaction rate as
given in the
equation-
k = ∑ ni ki
i
8

9. 3. Quantitative correlation between
conformation and reactivity
 Curtin-Hammett principle correlates:
The product distribution with the transition
state energies,
-for two different reaction pathways
-by two different conformers
of a substrate
-giving non-equilibrating products
 Winstein-Eliel rate equations correlates:
The overall observed specific reaction
rate(k) of a substrate with
-specific reaction rate of individual
conformers
-irrespective of whether the products are
equilibrating or non-equilibrating
S
kae
A E
ka kea ke
PA PE
P
K = =
and ke , ka << kae , kea
9

10.  E2 elimination of cyclohexyl tosylate -
equatorial conformer cannot have the tosyl group
antiperiplanar with an adjacent hydrogen
So, unable to react
Ex: trans-4-t-butylcyclohexyl tosylate lacks reactivity
cis isomer reacts with specific rate
7.1 X 10-3 mol-1sec-1 at 75˚
Specific rate constant of cyclohexyl tosylate
2.4 X 10-3 mol-1sec-1 at 75˚
Hence, K=(7.1-2.4)/2.4=2.0
10

11. a) Elimination in N,N-dimethyl-s-butylamine oxide :
 N,N-Dimethyl-s-butyl amine oxide along with 1-butene a mixture of
cis-and trans-2-butene in a ratio of 1:2
 cis-2-butene less stable due to an eclipsing interaction between the
two methyl groups
11
H
Me
Me
Me
CH3
H
O
H
NMe 2
Me
H
CH3
Me
H
NMe 2
H
H
H
H
Me
H
O
O
Me
Me
Me
Me
H
H
H
H
H
H
Me2N O Me2N O
Me2NOH + + Me2NOH
MeCH2 - CH(Me) - NMe 2
O

12. b) Quaternisation of Tropanes:
Tropanes are more sterically hindered on the side of the
piperidine ring than on pyrrolidine ring
 Conformer ‘b’ is less stable than ‘a’
(a) (b)
Methylation of tropane
12

13.  Difference in the reactivity between two
stereoisomer or conformers depends on the
transition states through
 Two factors determining the stability of the
transition state: a steric factor and a
stereoelectronic factor
13

14.  Stereoelectronic factor has little relevance
 Steric and other factors operate
 An equatorial substituent is less hindered than an
axial one and so is more reactive
 The steric requirements of the group thus becomes
markedly greater in the transition state than in the
ground state
 The difference in the free energies of the axial and
equatorial isomer is enhanced in the transition state
than in the ground state
 Axial isomer reacts at a slower rate than the
equatorial isomer
14

15. (steric hindrance) (steric assistance)
15

16.  Difference in the rates of a reaction for an
equatorial and axial isomer is diminished as the site
of crowding moves away from the ring
 Substituents at an axial group at C-3, affect the
relative rates of the equatorial and axial isomers
 Difference in the ground state free energies of an
axial and equatorial isomer is greater than that in
transition state.
 Axial isomer with its higher ground state energy
would react at a faster rate- steric assistance or
steric acceleration.
16

17. a) SN1 reaction-
Nucleophilic reactions follow a unified ion - pair
mechanism, it form the two extremes
 RX and a solvent, a common carbocation is formed from
both the axial and equatorial isomers
 solvolysis of 4-t-butylcyclohexyl tosylates
Transition state of an SN1 reaction (cyclohexyl system)
17

18.  Transition state involve a pentaco-ordinated carbon
atom
 Leaving group (X) and the incoming group (Y) are
partially bonded
 In 4-t-butylcyclohexyl bromides(X= Br), cis isomer
reacts ≈ 60 times faster than trans isomer
Transition states of an SN2 reaction
(cyclohexyl system)
18

19.  Nucleophile attacks the reacting centre from the
same side of the leaving group with retention of
configuration
 Amine-nitrous acid reaction
NH2 is replaced by OH
 Equatorial amines usually give equatorial alcohols
Stereochemistry of amine-nitrous acid reaction
19

20.  An allylic substrate, eg. R-CH=CH-CH2-X undergoes
substitution reaction with allylic rearrangement through
an SN2̍ mechanism
 Incoming nucleophile approaches γ-C from the side syn
to the leaving group
 6-alkyl-2-cyclohexenyl mesitoates react with piperidine
stereospecifically
 Cis isomer gives the cis and trans isomer and then trans
cyclohexene
Stereochemistry of SN2' reaction
20

21.  Formation of epoxide (oxiranes) from vicinal bromohydrines
Nucleophile approaches oxirane carbon from the rear side of the
oxide linkage
 C-1 of ‘b’ is antiparellel and at C-2 is parallel
Leads to chair-like transition state
Gives the diaxial product
 Parallel approach
Leads to twist-boat transition state
Gives diequitorial product
 Chair like transition
state is favoured
over twist-boat
Stereochemistry of epoxide ring opening
21

22. a) Electrophilic addition.
Br+ adds to the double bond forms cyclic intermediate, e.g.,
bromonium ion.
A nucleophile opens up the ring from the side opposite to the
electrophile
Results in trans diaxial product
Ex: Conversion of 2-cholestene into 2β,3α-dibromocholestane and
2β-hydroxy,3α-bromocholestane
Stereochemistry of addition reaction 22

23. 23
R R'
O
O
R
R
Y
Y
CH3
R
R'
H
Y
O
R
R'
H
Y
R
R'
Y
H
O
R
R
R
O
-
H+
 Addition to an isolated double bond is very rare
As π system of the double bond is electron-rich
But in enone systems-double bond is polarized by the presence
of an electron withdrawing carbonyl group
Thus 1,4-addition of nucleophiles is facile
(e.g, Michael reaction)
Stereochemistry of 1,4-addition

24.  Addition of reagents takes place through a cyclic intermediate
or transition state
 Ex: Selective oxidation of a cyclic olefin to cis-l,2-glycol with
osmium tetroxide
-Addition of the components of hydrogen peroxide to a double
bond
-Proceeds through five-membered cyclic intermediates
cis-Hydroxylation (osmylation)
24

25. Three types of elimination reactions -
1) E2 elimination (ionic)
2) cis elimination (pyrolytic)
3) 1,4-elimination leading to molecular
fragmentation
25

26.  Broad spectrum of mechanisms with E1cB and E1
In E1cB -
C-H bond is broken in the H-C-C-X fragment Elimination of X- from
carbanion.
In E1 –
C-X bond dissociates give a carbonium ion
Eliminates a β-proton
 In intermediate mechanisms
H and X are eliminated with a varying degree of concertedness
This is E2 (elimination, bimolecular)
 Stereoelectronic factor requires :
Two leaving groups, e.g., H and X must be either antiperiplanar or
synperiplanar and the elimination
is accordingly designated anti or syn
26

27. (A) (A’)
3-Menthene (B) (C) 2-Menthene (B’)
E2 elimination of menthyl neomenthyl chloride
27

28. 28
H
H
Ph
NMe 2
Ph Ph
2% 98%
85% 15%
O
H
H
Ph
NMe 2
O
• In cyclohexane system, axial-equatorial alignment of the
eliminating groups
• Methyl xanthate esters (Chugaev reaction) derived from
menthol and neomenthol. These isomers give preponderantly 3-
menthene and 2-menthene respectively

29. 29
OTs
H
Me2N
H
Me2N
H
OTs
Me2N
• In 3-Aminoalcohol derivatives, the p orbital of N with a lone pair is
antiperiplanar to 3-2 bond and is antiperiplanar to the leaving group
Undergo a concerted 1,4-elimination leading to the fragmentation* of
the molecule
• The epimeric structure cannot be so converted into the amino
olefin, shows that the stereoelectronic
requirements in the reaction (known as Grob fragmentation) are very
stringent

30. 30
OH
H
H
OH
OH
H
H
HO
1.00 3.23 1.87 62.7
• Chromic acid oxidation of a secondary alcohol to a ketone is undergo
two steps:
(i)Rapid formation of a chromate ester followed by its rate-
determining decomposition into the ketone, a chromite ion, and a proton
as shown:
R2CHOH + HCrO4 + H = R2CH-O-CrO2-OH+H2O
R2CH-O-CrO2-OH= R2C=O+HCrO3
- + H+
• In substituted cyclohexanols and in steroidal alcohols, axial alcohols
are oxidised at a faster rate than equatorial ones by a factor of 3 to 6
Relative rates of Chromic acid oxidation of
cyclohexanols

31.  If a substrate of an SN reaction contains a
nucleophilic group,
The leaving group is removed through an intramolecular
SN2 mechanism
Gives a cyclic intermediate
 The latter then reacts with the external nucleophile
by another SN2 process and the internal nucleophile
returns to its original position*, the net result being
a nucleophilic substitution
 This is called neighbouring group participation
31

32.  Two distinctive features:
 (i) an enhancement of rate (at least by a factor of
10, usually much more) which is known as anchimeric
(synartetic) assistance and
 (ii) retention of configuration at the reacting carbon
if it happens to be a chiral centre (this is a result of
two consecutive inversions).
32

33.  Example of neighbouring group participation in a cyclic system-
 Acelolysis of 2-acetoxycyclohexyl tosylate,
-cis and the trans isomers gives
trans-l,2-diacetoxycyclohexane
 Former by direct SN2 reaction and the latter through neighbouring
group participation
33

34.  A pair of π-electrons of a double bond helps in
removing a leaving group
 The anti tosylate reacts 1011 times faster than
norbornyl tosylate which proves removal of the tosyl
group (the rate determining step)
 Gives strong anchimeric assistance by the double
bond
 carbonium ion react only from the right hand side
giving an acetate with retained configuration
34

35.  Molecular rearrangement leads to ring contraction
and ring expansion
 Requirements are :
-Presence of a carbon atom (Cα) with a leaving group
(the migration terminus),
-a migrating group at Cβ (the migration origin),
-preferably an electron-donating substituent at Cβ
 The migrating group and the leaving group must be
antiperiplanar
35

36.  Deamination with nitrous acid gives rise to a very
reactive carbocation
 cis-2-amino-cyclohexanol exists in two conformations
36

37.  In the trans isomer, the conformer has the NH2
group anti to the 1-6 bond & results in ring
contraction
Deamination of trans-2-amino-cyclohexanol
37

38.  The two epimeric tricyclic chloronitriles (A) and (B)
provide an example of a concerted ring expansion and
ring contraction
38

39.  Deamination of syn- and anti-2-bornenyl-7-carbinyl
amines (A) and (B) appears to give the same
rearranged carbocation shown as ion pairs (a) and (b)
Double rearrangementmemory effect
39

40.  Acyclic molecules have relatively
free rotation around a C-C single bond
 One or more conformations satisfy the
stereoelectronic requirements of a reaction
and results in more than one product
40

41.  The difference in stereochemical behaviour of two diastereomeric
substrates towards addition reactions is illustrated by bromination
(anti addition) and bis-hydroxylation (syn addition) of maleic and
fumaric acid
41
H
CO 2H
HO 2C
H
Br2
Br
+
H
CO 2H
HO 2C
H
H
HO 2C
HO 2C
Br
H
Br
MnO 4
-
O O
Mn
HO 2C
H H
CO 2H
H
O
H
HO 2C
H
OH
COOH
O O
(A)
meso
(B)
a)
b)
CO 2H
H
HO 2C
H
Br
+
CO 2H
CO 2H
HO 2C
H
(C)+(C')
CO 2H
HO 2C
HO 2C
Br
H
Br
O O
Mn
HO 2C
H H
CO 2H
O O
H
OH
HO 2C
OH
HO 2C
H
MnO 4
-
Br2
(D)+(D')
meso

42.  In acyclic system, anti elimination is preferred with
good leaving groups such as Cl and Ots
-Syn elimination is preferred with bulky and poor
leaving groups such as onium
-Syn elimination gives predominantly the trans
olefins
 Cis olefins are obtained through anti elimination
(syn-anti dichotomy)
42

43.  The anti mode of E2 elimination in the system, eg., R-
CHX-CH2R (X = Cl or Br) has been proved by
dehydrobrotnination of deuterated 2-bromobutane
 ‘cis – effect’ due to eclipsing of two Ph groups is
shown
Dehydrochlorination of dichlorostilbenes
43

44.  The syn elimination leads predominantly to the trans
product while the anti elimination leads mainly to the
cis product
 The phenomenon known as syn-anti dichotomy
Competitive syn-anti elimination
44

45.  The threo and erythro isomers of (1,2-
diphenylpropyl) trimethylammonium salt react with t-
butoxide in t-butanol to give trans-1-methylstilbene
 β-H is first eliminated to give a carbanion undergo
rapid isomerisation at α-C followed by elimination to
the more stable trans-1-methylstilbene
Stereoconvergent elimination
45

46.  Reorganisation of bonding takes place at three
centres in a molecular rearrangement
-At the migrating group
-At the migration terminus
-At the migration origin
46

47. Stereochemistry in the
migrating group
Retention of configuration in the
migrating group
(a) is a semi-pinacol
rearrangement - chiral
alkyl group migrates
from one carbon to
another
(b) is a Hofmann
degradation - an
atropisomeric biphenyl
group migrates from a
carbon atom to a
nitrogen
(c) is a Baeyer-Villiger
oxidation - chiral alkyl
group migrates from a
carbon atom to an
oxygen atom
The configuration of the
migrating group is
retained 47

48.  If the migration origin is chiral and remains so after
rearrangement
 If the migration and attachment of a new nucleophile
at the migration origin are concerted
 Inversion at the migration origin occur
 Example-solvolysis of the tosylate of R-3-
methyl-2-phenylbutan-1-ol
Inversion of configuration at migration origin
48

49.  The migration group approaches from the side
opposite to the leaving group
Leading to inversion of configuration
 Migration terminus may be accompanied with varying
degrees of retention:
(i) Forms very reactive carbocation, inversion,
retention, or both may follow
(ii) The carbocation so formed is very stable, to form
more than one transition state of relative stabilities
Determine the stereochemistry of the migration
terminus
49

50.  Atropisomerism is restricted rotation about one or
nore single bonds
 In diastereomeric form, functional group is located in
the acyclic part
 Considered as the counterparts of rigid and
anancomeric cyclohexane systems
50

51. 51
C
H3
CH3
H
C
H3
CH2Br
H
H2C
CH3
H
C
H3
CH2OMe
H
Br
C
H3
NBS
+
+
(A) (a) (b)
(C)
(B)

52.  Enols and enolates derived from ketones
 These are basically nucleophilic
 Few organic reactions such as protonation (or
deuteration), halogenation, alkylation, acylation, and
aldolisation(all are electrophilic addition to enolic and
enolate double bond) are mediated through them
 The stereochemistry of these reactions is best
studied in cyclohexanone system.
52

53.  Enolisation of unhindered cyclohexanones with base
or acid involves the preferential abstraction of an α-
axial proton and in reverse reaction, e.g., ketonisation
of enols with proton or bromine
 The electrophile occupies the axial position in the
product
53

54. 54
O OH
LiAlH 4
Cyclohexanone cyclohexanol
• The reduction of substituted cyclohexanones gives a
mixture of axial and equatorial alcohols, the
stereochemistry of the products depending on various
factors:
Nature of the reagents,
Nature of the substrates,
Reaction reagent
Ex

55.  Cyclohexanone is hydrogenated to acyclohexanol in
presence of catalysts such as Pt and Ni in acidic or
neutral medium
 Catalyst absorbs the substrate from its less
hindered side forming a 7π -bonded intermediate and
transfers hydrogen to that side
 Rapid reduction with active catalysts (Ni or Pi)
55
CH(OCH 3)2
NO2
Ra Ni
CH(OCH 3)2
NH2

56.  Unhindered cyclohexanones on reduction with lithium
aluminium hydride or sodium borohydride afford
more stable equatorial alcohols
 Hindered cyclohexanones give less stable axial
alcohols
56

57. Ketone Stable alcohol Percentage
Group A: 4-Methylcyclohexanone
3-Methylcyclohexanone
2-Methylcyclchexanoue
4-t-Butyltyclohcxanone
Menthone
3-Cholestanone
trans (e)
Cis (e)
trans (e)
trans (e)
trans (e)
3 – β- ol (e)
81
88
70
90
79
91
Group B:
3.3,5Trimethylcyclohexanone
Camphor
Norcamphor
11-Oxosteroids
Cis (e)
endo
exo
11-a-ol (e)
45 (29)
10
11
22
57

58.  (M-P-V) reduction is a classical reaction in which a
hydride is transferred from aluminium isopropoxide
(or any other secondary alkoxide) to a carbonyl
carbon
 The reverse reaction, i.e. oxidation of aluminium
alkoxides with a ketone is known as Oppenauer
oxidation
58

59.  A few analogous reactions are known such as reduction
with sterically hindered Grignard reagents which are
kinetically controlled and are associated with high
stereoselectivity
Ketone Stable alcohol
M.P.V
equilibration
Percentage
Li – NH3
4- 1- Butylcyclohexanone
4- Methylcyclohexanone
3- Methylcyclohexanone
2- Methylcyclohexanone
3.3,S-Trimethylcyclohexanone
2- Norbornanone (norcamphor)
Camphor
79
70
-
-
94
80
71
98-99
99
94-95
99
99
9-32
79-90
59

60.  Saturated cyclic and acyclic ketones are reduced to
alcohols by alkali and alkaline earth metals dissolved
in lower alcohols (M + ROH) or better in liquid
ammonia (M+NH3)
 The latter reaction is known as Birch -reduction
60

61.  The mechanism of Birch reduction (and reduction with alkali metals in
alcohols) of a saturated ketone -
Reduction of α,β-unsaturated cyclohexenones
 The stereochemical results for a few 3,4-disubstituted cyclohex-2-enones –
R = R' = Me 86% 14%
R = R' =Et 56% 44%
R = Ph , R' = Me 6% 94%
R = R' = Ph 2% 98%
61

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