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Neighbouring Group Participation

IUPAC defines neighbouring group participation as the interaction of a reaction center with a lone pair of electrons in an atom or the electrons present in a sigma bond or pi bond. When NGP is in operation: 1) It is normal for the reaction rate to be increased. 2) It is also possible for the stereochemistry of the reaction to be abnormal (or unexpected) when compared with a normal reaction.

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255 views15 pages

Neighbouring Group Participation

IUPAC defines neighbouring group participation as the interaction of a reaction center with a lone pair of electrons in an atom or the electrons present in a sigma bond or pi bond. When NGP is in operation: 1) It is normal for the reaction rate to be increased. 2) It is also possible for the stereochemistry of the reaction to be abnormal (or unexpected) when compared with a normal reaction.

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AbdulManan
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© © All Rights Reserved
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Neighbouring group participation

By Hasibur Rahaman Department of Chemistry Prof. Petri Pihkos Research Group University of Jyvskyl Email: [email protected], [email protected]

Definition:
Neighbouring group participation or NGP in organic chemistry has been defined by IUPAC as the interaction of a reaction centre with a lone pair of electrons in an atom or the electrons present in a sigma bond or pi bond . When NGP is in operation: 1) It is normal for the reaction rate to be increased. 2) It is also possible for the stereochemistry of the reaction to be abnormal (or unexpected) when compared with a normal reaction.

Who does participate?


-Cl, -Br, -I, -NH2, -OH, -OR, -S-, -OOCR.
G slow G X

Mechanism:

X G G Fast Nu Nu-

Halide participation in NGP


I I OBs O H CH3 O I I I OAc OBs OAc

CH 3 TsO H3 C H Cl H Cl H

CH3

H 3C H

CH3 H Cl H3 C OCOCF3 F3COCO H 3C H Cl H

Peterson, P. E. Acc. Chem. Res. 1971, 4, 407 Olha, G. A., Peterson, P. E. J. Am. Chem. Soc. 1968, 90, 4675.

S - Bridged complexes: Alkyl Participation


CH 3 HBr (H3C)3C CH 2OH H3C C Br CH 3 Ag+ (H 3C)3C CH2I H2O H3C C OH H3 C H2 C -II slow CH 3 H3C H 3C C CH2 I (H3C)2C CH 2CH3 H2O alc. prod CH 2CH 3 + AgI CH 2CH3

Rational
CH 3 H3C C

Supporting evidence
H B H H B 2H 6 H B H H 3C H H3C Al C H2 Al 2(CH 3) 6 H3 C Al CH 3 CH 3

NGP by Alkene
TsO TsO

H TsO

-OTs

The II orbitals of an alkene can stabilize a transition state by helping to delocalize the positive charge of the carbocation.

TsO

OBs

TsO

TsO

TsO

-BsO-

Even, if the alkene is more remort f rom the reacting center the alkene can still act in this way.

NGP by Aromatic Ring


OBs
OBs

An aromatic ring can assist in the formation of a carbocationic intermediate called a phenonium ion by delocalising the positive charge. Example:
Me H OTs Me H Me H
AcOH, H+

Me

H OAc Me

Me

H OAc

Me

H OAc

Me

H OAc

Me

Me

M echanism
Me H Me OTs Me H Me H H Me H OAc Me H

AcOH

Me

Me

H OAc

AcOH

Cram, D. J. JACS 1952, 74, 2129

Application in Carbohydrate Chemistry


OR RO RO ROCO OR RO RO ROCO O RO RO O OR O O LG

-LG RO RO O

OR O

H O O

H RO RO

OR O O O

OR RO RO ROCO O OR RO RO

OR O O O OR

Isomerization

Schmidt, R. R.et al. Angew Chem Int Ed. 2009, 48, 1900 Turnbull, W. B. et al. OBC 2009, 7, 4842

Remote Participation for -Selectivity


Five Membered Ring
MeS O OBn OAc MeS O OBn S O
OBn

MeS O OBn OR

OBn

OBn

BnO

OBn

Six membered Ring


EWGO BnO BnO Lg OBn O OBn O Activating agents OBn O OBn O EWGO BnO BnO OTf OBn O EWGO BnO BnO OBn O OR

BnO BnO BnO EWGO Lg OBn OBn O O O

O BnO OBn BnO EWGO OTf OBn O

BnO BnO EWGO

OBn O OR

Kim, K. S. et al. JACS 2009, 131, 17705

NGP: Solvent effect


NuS RO OR S OH RO OR OP+Ph3 RO Nuinversion S RO Nu OR Expected S RO OR OR obtained S Nu

Solvent THF Benzene CH3CN CH2Cl2 DMF

% Yield 29 34 21 22 Trace

Ratio1/2 1.1 0.8 6 1.2


..........

Yoshimura, Y. et al. JOC 1998, 63, 6891

Classic Example of NGP

Cl S

Cl

Cl S

Cl

Mustard gas

Neighboring group participation Internal SN2 O-Enzyme External SN2

Cl Cl S

Cl S

O-Enzyme

Cl

Temperature Dependence in NGP


N3 S S TsCl, Py S OH S N3 2 OTs S N3 S 1 Thermodynamically more stable S Ratio 1:2 22:78 32:68 46:54 N3 S

N3

NaN3, DMF

S N3

Reaction temperature 0 oC 25 oC 70 oC

Not Observed because of unstability

Hartley, R. C. et al. TL, 2003, 44, 2841

Synthesis of Surfactants
OH OH OH OH N In OH OR RO OR
N I

HO

RO

Nu I I I O I

Nu I -

RO

OR

RO

RO

OR

Grindley, T. B. et al. JOC 2009, 74, 7762

Hydroxyl Group in NGP


NaBH4, MeOH

OH

O OH O OH O

OH

OH

OH

OR O OR'

OR

OR

OR'

OR'

When R = R' = H: only deacyl pdt R = H; R' = Me only alkene pdt R = R' = Me: on reaction

H-OMe

C 4H 9

C4H9

OH

Bell, K. H. Aus. J. Chem. 1969, 22, 601. Braddock, D. C. et al. TL 2001, 42, 7527

Tuneable Method for N-Debenzylation by NGP


Ph O O HO BnHN O 3 eq NIS dry OMe Ph O O HO Bn 2N Ph O O HO O 10 eq NIS dry then NaOMe O Ph 10 eq NIS dry O O BzO H 2N O OMe

OMe 10 eq NIS wet Ph O O HO BzBnN O

NH 2 OMe

OMe

20 min
HO NBn O NBn

2.5 h
O NBn

20 h

O I

NBn Ph Work up

Ph

Ph Work up

Ph Work up

HO

NBn

HO Ph

NHBn RNHBn H O

HO O

NBn

NHBn O

Ph

Ph RNBnBz

Ph RNHBnOBz

Davis, B. G. et al. OL 2005, 7, 2361

Conclusion
Neighboring group participation is a useful tool for synthetic chemists. In SN2 reactions, retention of configuration of the reaction center can be obtained instead of the expected inversion of configuration. Also, if the neighboring group helps stabilize the intermediate produced in the rate determining step, rate acceleration occurs. In the case study, the effects of solvent polarity on the competition between neighboring group participation and SN2 direct substitution were addressed. It was observed that polar solvents increased neighboring group participation. Use of polar solvents seemed to help stabilize the cyclic cation intermediate. Also, the strength of the nucleophile was found to affect the reaction outcome. When strong nucleophiles were used, only direct substitution was observed.

Thank You

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