Chemoselectivity and Regioselectivity.pdf

Dd

1. 4/10/2018
1

2. Stereo selectivity
Regioselectivity
Chemo selectivity
Diastereoselectivity
Cram’s Rule
FelkinAnh Model
CONTENTS
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3. Stereo selective Reaction
A reaction where one stereoisomer of a product is formed preferential
over another.
A stereo selective reaction is one in which thereactant is not necessary
chiral.
Example
????????????
+
+ Br2
H
H
????????????
−
Cyclohexene
+
????????????
H
????????????
−
????????????
−
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4. Regioselectivity
REGIOSELECTIVE REACTIONS:
A reaction which predominantly produces one of several possible structural
isomers is called regioselectivereactions.
Example Michel Reaction
R R
O
1-4 Or Michel Addition
1-2 Or Direct Addition
α,β-unsaturated carbonyl
compound
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5. 1,2-versus 1,4-addition inα,β-
unsaturated carbonyl compounds
A no. of factors govern the direction of addition of nucleophiles
to α,β-unsaturated aldehydes & ketones. some of them are
Reactivity of carbonyl group:
Since thealdehydegroup are much more reactive than ketone
towards nucleophile, so majority of the addition reactions are
1,2-addition reactions.
Conversely, sinceketones are less reactive than aldehydes, so
majority of reactions of ketones are1,4-addition reactions.
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6. Examples Aldehide
CH2CH C H + HCN CH2 CH CHCN
O OH
CHCH C H CH3 CH3
Ph9-10
CH3MgBr/Ether
H+/H2O
pent-3en-2ol
AcroleinCynohydrin
Acrolein
But-2en-1al
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7. Examples ketone
(CH3)2NH
C CH2 CH CH3
O O
Ph9-10
H+
CH3
CH3
CH3
CH3
CN
+
C CH C CH3+ HCN
MesitylOxide
2,2-Dimethyl-4-oxopentanenitrile
But-3en-2-one
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8. Reactivity of the reagent :
Organolithiumcompounds being more nucleophilicpredominantly
undergo 1,2-addition to a α,β-unsaturated ketones whereas Grignard
reagents give mainly 1,4-additionproducts.
CH3MgBr/Ether
CH3Li/Hexane
H+/H2O
H+/H2O
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9. Sterichindranceatthecarbonylgroupfavours1,4-additionwhereas
sterichindranceat3-positionfavour1,2-addition.
For example :
1,4-addition
1,2-addition
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10. 1,4-AdditionorconjugateadditionofGrignardreagentscanbemade
topredominateifthereactioniscarriedoutinpresenceofCu
+
ions
,cuprouschloride,CuClorcupricacetate,Cu(OAc)
2.
Catalysis by cuprous salts :
Cyclohex-2-en-1-one 3-Alkaylcyclohexanone
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11. Itisbelievedthatundertheseconditions,Grignardreagentreactwith
Cu
+
iontoformalkylcopperreagentwhichbeinglessreactivethan
Grignardreagentexclusivelygives1,4-additionproducts.
Forsimilarreasonslithiumdialkylcopperreagents,R
2CuLiaddtoα,β-
unsaturatedaldehydes&ketonestogiveconjugateaddition
products.
Catalysis by cuprous salts :
Cyclohex-2-en-1-one 3-Alkaylcyclohexanone
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12. Regioselectivityin addition of unsymmetrical alkene
CH3CH CH2+ HCl
CH3CH CH3
Cl
CH3CH2CH2
Cl
Markovnikovproduct
Major
product
Minor
product
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13. Markovnikovrule
In the ionic addition of unsymmetrical reagent to double bond , the
positive part of the adding reagent adds itself to the carbon atom of
double bond gives more stable carbocation as an intermediate,
Formation of two different carbocation on addition of positive part of
reagent
CH3CH CH2+ HX
CH3CH CH3
CH3CH2CH2
+
+
secondary
primary
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14. Secondarycarbocationismorestablethenprimary
carbocationdueto+Ieffect.
+Ieffectdispersedthechargeoncarbocationwhich
stabilizesit
Otherexample
CH3
CH3
CH3
I
HI
I
+
+
Major
product
Minor
product
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15. Anti-MarkovnikovAddition
Anti-markovnikovaddition is observed if alkene bears a powerful
electron-withdrawinggroup attach directly to the double bond carbon.
CF3 CH CH2+ HBr
CF3CH CH3
CF3CH2CH2
Br
Br
Major
product
Minor
product
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16. Formation of alkene by dehydration
Manyalcoholsgiverisetomixtureofisomericalkenesondehydration.
Butoneofthealkenesformedinpredominantlylargeamount.
CH3CH2 CHOH CH3
CH3CH2 CH CH2
CH3CH CH CH3
H3PO4-AL2O3
-H2O
Major
Minor
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17. Explanation Saytzeffrule
The preferred product is the alkene which is more highly alkylated
at the double bond carbon atom.
In alkene more the no of alkyl group, grater the stablaty.
R2C= CR2> R2C=CHR > R2C=CH2> RCH=CH2> CH2=CH2
The grater the number of alkyl group attached to doubly bounded
carbon atom, more the number of hydrogen and grater
possibility of hyperconjugation.
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18. Reduction of alkene
Regioselectivity in But-2-yene
CH3 C CCH3
C CC C
CH3
CH3CH3CH3 H
H H H Cis-But-2-ene Trans-But-2-ene
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19. Regioselectivity in cleavage of epoxides
CH3C CH2
O
CH3
CH3OH + + CH3O
-
CH3OHBasic MediumH+ Acidic Medium
CH3C CH2
CH3
OHCH3O
CH3C CH2
CH3
OH OCH3
2,2-Dimethyloxirene
2-Methoxy-2-Dimethylpropan-1-ol 3-Methoxy-2-Dimethylpropan-2-ol
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20. InbasicmediumRingopeningisanSN2displacementbythenucleophile
onunprotonatedoxirane.
AsinotherSN2reactiontheattacktakesplaceatthelesssubstitutedand
lesshinderedcarbon.
Explanation
CH3C CH2
O
CH3
The lesssatirically
hindered carbon
undergoesSN2attack
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21. Inacidicmediumfirststepisprotonationoftheoxygenatom.
Duetoelectronreleasinggroupattachedtothemoresubstitutedcarbon
positivelychargedoxygenattractstheelectronpairofitsbondwiththis
carbontograterextendthentheelectronpairofthebondwiththeless
substitutedcarbon.
Asaresult,themoresubstitutedcarbonoxygenbondbecomeweakerthen
thelesssubstitutedcarbonoxygenbond.
Thereforeringopeningtakeplacethemoresubstitutedcarbonoxygen
bond.
Explanation
CH3C CH2
O
CH3
Thisweakerbondis
preferentiallyattacked
bynucleophile
H+ CH3C CH2
O
CH3
H
:
+
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22. CHEMO SELECTIVITY
CHEMOSELECTIVITY REACTION: In a bi functional
compound , if areagent reacts with one functional group preferentially,
preferentially, even though the other is apparently susceptible to the
reaction conditions, the reaction is called Chemo selective.
Example:
1 the reduction of carbonyl group in presence of acyano, nitro,
alkoxycarbonylgroup,
2 the acylation of an aromatic amino groupin presence of a phenolic
group
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23. Example 1
Reduction of carbonyl group in presence of nitro group
O2N COOH
COOH
O2N CH2OH
CH2OH H3N H3N
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24. Example 2
Acylation of aromatic amino group in presence of phenolic group
HO NH2
HO NHCOCH3
NH2CH3COO NHCO
CH3
CH3COO
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25. Guideline 1 : when two functional groups of unequal reactivity are present
in a molecule, the more reactive can always be made to react alone.
For example : let us consider synthesis of acid (1) ; the phenolateion is
more reactive than the carboxylate ion (pKadifference about 5 ) ,hence
the phenol is alkylated.
GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
COOH
OH
COO
O
-
-
I
COOH
O
Alkali Medium
1
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26. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline 2 :When one functional group can react twice, the starting
material & the first product will compete for the product.
The reaction will be successful only if the first product is less reactive than
the starting material.
O ClPh
O
OHPh
Cl
O
Cl
First product
Starting material
1
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27. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Is less reactive
then
Cl
O
Cl
Conjugation with
Oxygen
Due to
:
:
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28. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline : 3
Unfavourable cases from guidelines 1 & 2 may be solved
by the use ofprotecting groups.
Protecting group : A group whose use makes possible to
react a less reactive functional group selectively in the
presence of a more reactive group is known as a
protecting group.
Protecting groupblocks the reactivity of a functional group
group by converting it into a different group which is inert
to the conditions of some reaction(s) that is to be carried
out as part of a synthetic route.
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29. For example :
if we make phenylmagnesiumbromide to react with the less
reactive ester group rather than the more reactive keto
group.
OEt
OH
Ph
Ph
Desired product
Must not react
from hare to get
desired product
Must react from
hare to get desired
product
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30. For example :
As expected ,simply adding PhMgBrto acetoaceticester ,
addition to more electrophilic ketone mainly takes place.
OEt
OEt
Ph
OH
2PhMgBr
H+/H2O
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31. For example :
One way of preparing the desired alcohalis to protect the
ketone as a ketal, i.e, a ketalprotecting group is (dioxolane
) is used in this case.
OEt
H+
OH
Ph
Ph
O O
OH
Ph
Ph
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32. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline 4 :
One of two identical groups may react if the product is less reactive than
the starting material ,
For example : partial reduction of m-dinitrobenzene.
NO2
NO2
NH2
NO2
NaHS
MeOH
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33. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline 5 :
One of two identical functional groups may react withone equivalent of
of reagent using the statistical effect.
This is an unreliable method , but if successful it avoids protecting
groups.
For example : the diol(1) can be monoalkylatedin reasonable yield by
using one equivalent of sodium in xylene to generate mostly the
monoanion(2) .
Na
xylene
EtBr
1 2
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34. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline 6 :
A more reliable method with two identical functional groups is to use a
derivative which can react only once
.
The most important example –is a cyclic anhydride.
When the anhydride has combined once with a nucleophile , e.g, to
the half ester , the product is no longer reactive. Further reactions can
maintain the distinction , e.g, to give half acid chloride .
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35. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
COOH
COOH
COOMe
COOH
COOMe
COCl
Ac2O
MaOH
SOCl2
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36. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO
SELECTIVITY
Guideline 7:
When two groups are nearly but not quite identical , as in (8) & (9) ,
avoid attemps, to make only one of them react.
OH OH OMe OH
OH
OH
OMe
OH
Bese
Bese
MeI
MeI
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37. DIASTEREOSELECTIVITY
Distereomersare the stereoisomers that arenot mirror image of each
other i.e, diastereomersare stereo isomers that are not enantiomers.
Example tartaric acid have two enantiomers and miso tartaric acid is
distereomersof both enantiomers
2R,3R 2S,3S
2R,3S
Enantiomers
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38. DIASTEREOSELECTIVITY
A Diatereoselectivereaction is one in which one diastereomeris
formed in preference to another
CH3
C6H5
CH3 H
C
*
HO CN
CH3
C6H5
CH3 H
OHCN
CH3
C6H5
CH3 H
+
HCN
Distereomers4/10/2018
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39. DIASTEREOSELECTIVITY
Diastereotopicligands When the replacement of either of the
two homomorphicligands by different test ligand gives diastereomers
then such ligands are terms as diastereotopic.
ClH
CH3
Cl
H H
ClH
CH3
Cl
Z H
ClH
CH3
Cl
H Z
Distereomers
replace
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40. DIASTEREOSELECTIVITY
The two faces of carbonyl group close to a stereocenterare
diastereotopic.
Thus addition of HCNto methyl--phenethylketonegives
diastereomers.
CH3
C6H5
CH3 H
C
*
HO CN
CH3
C6H5
CH3 H
OHCN
CH3
C6H5
CH3 H
+
HCN
Distereomers4/10/2018
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41. Similarlyachirial4-t-butylcyclohexanonehasdiastereotopicfaces
sinceadditionofhydrideoccurfromaxialorequatorialsidetogive
duastereomers.
+
H-
DIASTEREOSELECTIVITY
4-t-butylcyclohexanone
(achiral)
Trans-4-t-butylcyclohexanol
Cis-4-t-butylcyclohexanol
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42. Ifligandsareinterchangeablebysymmetryoperationlikerotational
axisormirrorplanetheyareenantiotopicnotdiastereotropicexample
DIASTEREOSELECTIVITY
ClH
Hb
H
Ha
Cl
HaandHbareenantiotopic
because these are
interchangeable by
operationC2
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43. On the reduction with lithium aluminum hydride gives exclusively the
equatorial alcohol by attack of the reagent from less hindered face of the
molecule
DIASTEREOSELECTIVITYin
reduction of cholestan-3-one
H H
H
H
CH3
CH3
R
H-
H-
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44. Nucleophilicattackonacycliccarbonylcompound
For certain addition to carbon oxygen double bond of aldehyde and
ketone having achiral--carbon , cram’s rule is useful to product which
diastereomersof two will predominate.
The molecule is generally knows as diastereotopicaldehyde or ketone in
which four group are attach to the stereo center i.e, COR,S,M and L. S is
for small , M is for medium, L is for large
L
M S
COR
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45. Carm’sRULE
The oxygen of the carbonyl orients itself so as to between the small and the
medium sized groups.
Thus L Being the largest group is oriented as far as possible from the
carbonyl group.
In the orientation L is ellipseto the group R.
M S
L
O
R
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46. The rule is that the incoming group prefferentlyattacks on the side
of plane containing the small group i.e, LESS HINDRED FACE.
Carm’sRULE
M S
L
O
R
Nu
Nu
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47. M S
LR
Nu
M S
L
OH
R
O
Nu
M S
L
OH
RNu
Major
product
Minor
product
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48. H CH3
C6H5H
O
OH
H CH3
C6H5
H
CH3
OH
HCH3
C6H5
H
CH3
CH3MgBr
Major
product
Minor
product
Example
Erythro
(2R,3S)
Threo
(2R,3S)
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49. Important to note
Thepreferenceoftheoneoftheproductstereomersover
theotherdependonthedifferenceinthesizeofS,MandL
group.
IncasetheSandMareverysimilar,thereislikelytobe
littledifferenceintheinteractionwiththeincoming
nucleophileanddistereoslectivityofsuchmoleculeisvery
poor.
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50. Stereo selectivity
Regioselectivity
Chemo selectivity
Diastereoselectivity
Cram’s Rule
FelkinAnh Model
CONTENTS
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51. Case of failure of carm’srule
Case 1 Case 2
One of the substituent
on the stereo center is
complexeinggroup
One of the substituent on
the stereo center is highly
electronegative
CH3
C6H5
H3CO H
C
*
CH3
C6H5
Cl H
C
*
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52. Case 1 If one complexinggroup is present
If one substituent on the stereo centre is an alk-oxy ,hydroxyl, or any
other complexingagent.
Then the cations(lithium cations) of reagent effectively coordinate
with these oxygen atoms.

CH3
Li+
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53. For example reduction with LiAlH4
The reagent brings about the reduction by first acting as a conformation
locker by coordinating by both the methoxyoxygen and ketone oxygen.
CH3
C6H5 p-tolyl
H
Li+
CH3
C6H5 p-tolyl
H
LiAlH4
H3Al-H
T.S
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54. H
T.S
Backside attack which is away from Phgroup is preferred
Minor
product
Major
product
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55. CASE 2 when one substituent is strongly electronegative (example chlorine)
The preferred transition state is
The negatively polarized oxygen and chlorine atoms always tends to
remain far away from each other .
L S
Cl
O
R
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56. L S
ClR
Nu
L S
Cl
OH
R
O
Nu
L S
Cl
OH
RNu
Major
product
Minor
product
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57. Felkinarguedthatthecrammodalsufferedmajordrawback
aneclipsedconformationinthetransitionstatebetween-
carbonylsubstituentandβ-carbonylsubstituent.
Hedemonstratedthatbyincreasingthestericbulkofthe
substituentfrommethyltoethyltoisopropyltoisobutyl
thestereoslectivityalsoincreasewhichisnotpredictedby
thecram’srule.
CFelkinAnhmodal
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58. R EyrthroThreo
Me 74% 26%
Et 76% 24%
i-Pr 83% 17%
t-Bu 98% 2%
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59. CFelkinAnhmodal
In the FelkineAnhmodal C-L bond is positionedperpendicular to the
carbonyl group.
This is un like cram’s rule where L is assumed to beantipariplanerto the
C=O group.
This argument removes unfavorable eclipsinginteraction between L and
R.
There are two such conformation
L
S
R
O
M
L
S
R
O
M
Interconverted via
rotation around
central C-C bond
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60. In Falkin-Ahnmodification a large group is positioned at right
angles to the carbonyl group and not apposite to it.
Nucleophile opts to approach from the side remote from large
group as given blow.
L
S
R
O
M
L
S
R
O
M
Interconverted via
rotation around
central C-C bond
Nu Nu
L
S R
OHM
Nu
CLASH
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61. Example
H2O+
LiAlH4
H2O+
LiAlH4
H-
H-
CLASH
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Threo
(2R,3S)
Erythro
(2S,3S)

62. FACTORS AFFECTING FELKIN
AHN MODEL
Size of nucleophile greatly effects diastereo
selectivityof addition .
Larger the nucleophile generally give rise to
greater diastereoselectivity.
The size of substituent on the substrate will also
effect the diastereoselectivity
Larger group result in greater selectivity.
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63. Case of failure of falkinanh
Case 1 Case 2
One of the substituent
on the stereo center is
complexeinggroup
One of the substituent on
the stereo center is highly
electronegative
CH3
C6H5
H3CO H
C
*
CH3
C6H5
Cl H
C
*
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64. The major difference b/w cram
and FelkinAnhas shown as:-
Nu
Nu
T,S by FelkinAnh T,S by Charm
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65. 4/10/2018
6565
Noelapsingstrainis
presentbetween
carbonylsubstituentand
othersubstituent
Elapsingstrainispresent
between carbonyl
substituentandother
substituent
Oxygenatomgoes
perpendiculartolarge
group.
Oxygenremainasfaras
pssiblefromlargegroup.
Diastereoslectivitydepend
onsize carbonyl
substituent.
Diastereoslectivity
independentofsizeof
carbonylsubstituent.
Nucleophileattackfrom
sidebetweensmalland
mediumgroup.
Nucleophileattackfrom
sidebetweensmalland
largegroup.
FelkinAnh Carm

66. Me
Et
H
O
Me
HEt H OH
LiAlH4
(1) 3R,6S (2) 3S,6S
(2) 3R,6R (4) 3S,6R
Hint –Use Carm’srule
Q Stereochemistry of product is ?
Problem from U.G.C N.E.T dec2014
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67. Stereo selectivity(P.S. Kalsistereochemistry)
Regioselectivity(B.Sc.Books)
Chemo selectivity(JagdambasinghO.S)
Diastereoselectivity(P.S. Kalsistereochemistry)
Cram’s Rule(P.S. Kalsistereochemistry)
FelkinAnhModel(P.S. Kalsistereochemistry)
References
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68. Jai hind
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