Neighbouring group participation

Neighbouring group participation By Hasibur Rahaman Department of Chemistry Prof. Petri Pihko’s Research Group University of Jyväskylä Email: hasibur...
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Neighbouring group participation

By Hasibur Rahaman Department of Chemistry Prof. Petri Pihko’s Research Group University of Jyväskylä 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.

Mechanism:

G

G slow

X

X G G

Fast Nu Nu-

Halide participation in NGP I

I

I

I OBs

I OAc O

OBs

O

OAc

H CH3

CH3

CH 3 TsO H3 C

H

Cl

Cl

H

H

H

CH3

H 3C

H H

Cl

OCOCF3 H3 C

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

H3C

CH 2OH

C

CH 2CH3

Br CH 3 Ag+ (H 3C)3C

CH2I

H3C

H2O

C

AgI

H3 C

CH 3 C

+

OH

Rational

H3C

CH 2CH 3

-I-

H2 C

I

C

H3C

slow

CH2 I

H 3C

CH 3

(H3C)2C

Supporting evidence H

H B

H

H B

H B 2H 6

H3 C

H3C Al

H

H 3C

CH 3 Al

C H2 Al 2(CH 3) 6

CH 3

CH 2CH3

H2O alc. prod

NGP by Alkene TsO

TsO

H

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

-BsO-

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

TsO

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

Me

AcOH, H+

OTs Me

H

Me

H

OAc

H

Me

OAc

H

Me

Me

H

Me

H

OAc

OAc Me

H

Me

H

H

M echanism Me

H

AcOH

Me

H

Me

Me H

OTs Me

H

OAc Me

Me

H

H OAc

Me

H

H

AcOH

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

Application in Carbohydrate Chemistry OR RO RO ROCO OR RO RO ROCO

OR RO RO

O

RO RO

LG

-LG

OR O

O

O

H O

O

O

O

O

OR

OR RO RO ROCO

O

RO RO

O O

OR

H

O

OR

Isomerization

RO RO

O O O

OR

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

Remote Participation for β-Selectivity Five Membered Ring S

MeS

MeS

O

O OBn

OAc

MeS

O

OBn

O OBn

OBn

OR OBn

OBn

BnO

OBn

Six membered Ring EWGO

O OBn O

EWGO

Activating agents

EWGO

O

BnO BnO

OBn O

Lg

OBn O

OR

BnO BnO

BnO BnO

OBn

OBn O

OTf OBn

BnO BnO

BnO

O

OBn O

BnO

O

BnO EWGO

O

OBn

OBn O

BnO EWGO

BnO EWGO

OBn O OR

Lg OBn

OTf

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

NGP: Solvent effect NuS

S

OH

RO

OP+Ph3 RO

RO

Nu-

OR

OR

S

S

Nu

RO OR

OR

obtained

inversion S RO Nu OR

Expected

Solvent

% Yield

Ratio1/2

THF

29

1.1

Benzene

34

0.8

CH3CN

21

6

CH2Cl2

22

1.2

DMF

Trace

..........

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

Classic Example of NGP

Cl

Cl S

Mustard gas

Cl

S

Neighboring group participation Internal SN2 O-Enzyme

Cl S

Cl

Cl

External SN2

O-Enzyme

Cl S

Cl

Temperature Dependence in NGP N3

N3

TsCl, Py

S

NaN3, DMF

S

S

S OH

OTs

S

S

S N3

N3

S

N3

2

1 Thermodynamically more stable

Reaction temperature 0 oC 25 oC 70 oC

S Ratio 1:2 22:78

N3

S

Not Observed because of unstability

32:68 46:54

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

Synthesis of Surfactants OH

OH

OH

OH N In

OH

HO

n

OR

RO

OR

RO

Nu I

N I

I

I

I

Nu I -

O

RO

OR

RO

RO

OR

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

Hydroxyl Group in NGP NaBH4, MeOH

OH

OH

O

OH

OH O OH

O

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

O

H

C 4H 9

O

OH

O

H

C4H9

O

O

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 O

Ph

O HO

10 eq NIS dry

3 eq NIS dry BnHN

OMe

Ph

O O HO

O

O

OMe 10 eq NIS wet

10 eq NIS dry then NaOMe

O O HO

Ph

2.5 h O

Ph

NBn

20 h O

NBn

NBn

HO Ph

NHBn RNHBn H

HO

NBn

O

OMe

NBn Ph Work up

Work up

O

NHBn O

O Ph

Ph

O I

Ph

Ph Work up

HO

O

BzBnN

20 min NBn

OMe

O

O HO

NH 2 OMe

HO

O H 2N

Bn 2N Ph

O O BzO

Ph

O

Ph RNHBnOBz

RNBnBz

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