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.
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