CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

Weblinks :

1.pubs.acs.org/doi/abs/10.1021/ed047p42

2.www.sciencedirect.com/science/article/pii/S0040403901955923

3.www.researchgate.net/.../51642051_Neighboringgroup_participation

4.euch6f.chem.emory.edu/neighboring.html

5.chemcool.tumblr.com/post

Glossary A

Acetoxy: Acetoxy group (AcO or OAc) is a chemical functional group of the structure CH3-C(=O)-O-. It

differs from the acetyl group CH3-C(=O)- by the presence of one additional oxygen atom.

Anchimeric Assistance: An increase in the rate nucleophilic substitution reaction due to participation of

neighboring group is known as anchimeric assistance. The neighbouring group helps in the removal of the

leaving group to form a reactive intermediate that leads to the formation of the product.

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

B

β-position: The second carbon atom attached to a functional group, is called the beta carbon. Groups like

acetoxy, hydroxy, oxygen, halogen etc., attached to β-carbon can act as nucleophiles in NGP ractions.

E

Endo-Exo isomers: The prefix endo is used for the isomer with the substituent located closest or syn to

the longest bridge and exo is reserved for the isomer with the substituent located farthest or anti to the

longest bridge. This type of molecular geometry is found in norbornane systems.

I

Inversion of Configuration: A product is said to be formed with inversion of configuration, if the

reactant undergoes reversal of configuration at a center of chirality attained by forming a new bond on the

opposite face from the site where a bond is broken. SN2 mechanism is associated with inversion of

configuration.

N

Non-classical carbocation: In a non-classical carbocation the positive charge is delocalised by single,

double or triple bond that is not in the allylic position. The intermediate involved in NGP reaction by

C=C, C-C, and C-H is a non-classical carbocation. The energy difference between classical carbocations

and non-classical isomers is often very small.

S

Synartetic Acceleration: 'Synartetic acceleration' is the special case of anchimeric assistance ascribed to

participation by electrons binding a substituent to a carbon atom in a β-position relative to the leaving

group attached to the α-carbon atom. According to the underlying model, these electrons then provide a

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

three-centre bond (or bridge) 'fastening together' (as the word 'synartetic' is intended to suggest) the α-

and β-carbon atoms between which the charge is divided in the intermediate bridged ion formed (and in

the transition state preceding its formation). The term synartetic acceleration is not widely used.

Do you know?

Role of NGP in Chemical Glycosylation:

A chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl

acceptor forming a glycoside.

The stereochemical outcome of a glycosylation reaction may in certain cases be affected by the

type of protecting group employed at position 2 of the glycosyl donor. A participating group,

typically one with a carboxyl group present, will predominantly result in the formation of a β-

glycoside. Whereas a non-participating group, a group usually without a carboxyl group, will

often result in an α-glycoside.

Below it can be seen that having an acetyl protecting group at position 2 allows for the formation

for an acetoxonium ion intermediate that blocks attack to the bottom face of the ring therefore

allowing for the formation of the β-glycoside predominantly.

bottom or top face. Since the α-glycoside product will be favoured by the anomeric effect, the α-

glycoside usually predominates.Alternatively, the absence of a participating group at position 2,

allows for either attack from the

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

Neighboring group participation in the transition state of human purine nucleoside

phosphorylase:

The X-ray crystal structures of human purine nucleoside phosphorylase (PNP) with bound

inosine or transition-state analogues show His257 within hydrogen bonding distance of the 5'-

hydroxyl. The mutants His257Phe, His257Gly, and His257Asp exhibited greatly decreased

affinity for Immucillin-H (ImmH), binding this mimic of an early transition state as much as

370-fold (Km/Ki) less tightly than native PNP. In contrast, these mutants bound DADMe-ImmH,

a mimic of a late transition state, nearly as well as the native enzyme. These results indicate that

His257 serves an important role in the early stages of transition-state formation. Whereas

mutation of His257 resulted in little variation in the PNP x DADMe-ImmH x SO4 structures,

His257Phe x ImmH x PO4 showed distortion at the 5'-hydroxyl, indicating the importance of H-

bonding in positioning this group during progression to the transition state. Binding isotope

effect (BIE) and kinetic isotope effect (KIE) studies of the remote 5'-(3)H for the arsenolysis of

inosine with native PNP revealed a BIE of 1.5% and an unexpectedly large intrinsic KIE of

4.6%. This result is interpreted as a moderate electronic distortion toward the transition state in

the Michaelis complex with continued development of a similar distortion at the transition state.

The mutants His257Phe, His257Gly, and His257Asp altered the 5'-(3)H intrinsic KIE to -3, -14,

and 7%, respectively, while the BIEs contributed 2, 2, and -2%, respectively. These surprising

results establish that forces in the Michaelis complex, reported by the BIEs, can be reversed or

enhanced at the transition state.

Time line

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

Year Description Image

1939 In 1939 Lucas and Winstein published an

important paper on the stereochemical role of

neighboring bromine in displacement reactions,

providing an elegant proof that the bromine on

the carbon atom adjacent to the reactive center

formed a cyclic bromonium ion intermediate.

Winstein was to be the foremost creator of these

bridged ions. Most of Winstein’s work can be

traced to the studies with Young and Lucas, the

major interest always being the nature of the

cationic intermediates in organic reactions.

1951 Saul Winstein (October 8, 1912 – November

23, 1969) was the Canadian chemist who

discovered the Winstein reaction, in which he

argued a non-classical cation was needed to

explain the stability of the norbornyl cation.

He was awarded with ACS award in Pure

Chemistry in 1948 and National Medal of

Science in 1970.

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

1987 Donald J. Cram shared the Nobel Prize in

Chemistry with Jean-Marie Lehn and Charles J.

Pederse "for their development and use of

molecules with structure-specific interactions of

high selectivity."

Suggested readings

Jerry March, Advanced Organic Chemistry, Fourth

Edition.

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

William Brown, Christopher

Foote, Brent Iverson, Eric

Anslyn, Organic Chemistry,

Enhanced Edition

CHEMISTRY

PAPER No. 5: Organic chemistry-2 (Reaction Mechanism-1) MODULE No. 15: The Neighbouring Mechanism, Neighbouring Group Participation by π and σ Bonds

Raj K Bansal, Organic

Reaction Mechanisms,

Fourth Edition.

P. S. Kalsi, Organic

Reactions And Their

Mechanisms