NUCLEOPHILIC SUBSTITUTION

REACTION

Amit PanditM. Pharmacy II sem

Neucleophile As electron pair donors, nucleophiles must

either contain an electron pair that is easily available because it is nonbonding or they must contain a bonding electron pair that can be donated from the bond involved and thus be made available to the reaction partner.

From this it follows that nucleophiles are usually anions or neutral species but not cations.

Good and Poor Nucleophiles Within a group of nucleophiles that

attack at the electrophile with the same atom, the nucleophilicity decreases with decreasing basicity of the nucleophile

Nucleophilicity is a measure of how readily a compound (a nucleophile) is able to attack an electron-deficient atom.

Nucleophilicity of O nucleophiles with different basicities.

Nucleophilicity of N and O nucleophiles that are sterically hindered to different degrees.

Nucleophilicity decreases with increasing electronegativity of

the attacking atom.

In comparisons of atomic centers from the same group of the periodic

table.

The nucleophilicity of a given nucleophilic center is increased by attached

heteroatoms that possess free electron pairs (-effect)

Nucleophilic Aliphatic substitution

To ensure that reaction occurs in homogeneous solution, solvents are chosen that dissolve both the alkyl halide and the ionic salt. The alkyl halide substrates are soluble in organic solvents, but the salts often are not. Inorganic salts are soluble in water, but alkyl halides are not. Mixed solvents such as ethanol–water mixtures that can dissolve enough of both the substrate and the nucleophile to give fairly concentrated solutions are frequently used. Many salts, as well as most alkyl halides, possess significant solubility in dimethyl sulfoxide (DMSO), which makes this a good medium for carrying out nucleophilic substitution reactions.

Type of Nucleophilic Aliphatic substitution Reaction

The SN2 Mechanism a single step process Involves no intermediates Involves only one transition state, which is of

low polarity Follows second order (bimolecular) kinetics.

That is, rate=k[substrate][nucleophile] backside attack

Energy diagram

Factors Affecting SN2 Reactions

The Leaving Group The Nucleophile The Effect of the Solvent Steric Effects

Factors Affecting SN2 Reactions :The Leaving Group

The weaker the basicity of a group, the better is its leaving ability.

Factors Affecting SN2 Reactions : The Nucleophile the stronger bases are the better

nucleophiles

Nucleophilicity

The Effect of the Solvent In a protic solvent, is the smallest atom the poorest

nucleophile even though it is the strongest base. Protic solvents are hydrogen bond donors. The interaction between the ion and the dipole of the

protic solvent is called an ion–dipole interaction. Because the solvent shields the nucleophile, at least

one of the ion–dipole interactions must be broken before the nucleophile can participate in a SN2 reaction.

Weak bases interact weakly with protic solvents, whereas strong bases interact more strongly because they are better at sharing their electrons.

The Effect of the Solvent

STERIC EFFECTS IN SN2 REACTIONS

Stereochemistry of SN2 Substitutions

AN ENZYME-CATALYZED NUCLEOPHILIC SUBSTITUTION OF AN ALKYL HALIDE

Enzymes that catalyze these reactions are known as haloalkane dehalogenases.

The haloalkane dehydrogenase is believed to act by using one of its side-chain carboxylates to displace chloride by an SN2 mechanism

THE SN1 NUCLEOPHILIC SUBSTITUTION Hughes and Ingold observed that the

hydrolysis of tert-butyl bromide, which occurs readily, is characterized by a first-order rate law:

Mechanism

Experimental Evidence 1. The rate law shows that the rate of the reaction depends

only on the concentration of the alkyl halide. This means that we must be observing a reaction whose rate-determining step involves only the alkyl halide.

2. When the methyl groups of tert-butyl bromide are successively replaced by hydrogens, the rate of the SN1reaction decreases progressively . This is opposite to the order of reactivity exhibited by alkyl halides in SN2 reactions.

3. The reaction of an alkyl halide in which the halogen is bonded to an asymmetric carbon forms two stereoisomers: one with the same relative configuration at the asymmetric carbon as the reacting alkyl halide, the other with the inverted configuration.

Reactivity

Factors Affecting SN1 Reactions

The Leaving Group The Solvent Carbocation Rearrangements

The Leaving Group two factors affect the rate of an reaction:

the ease with which the leaving group dissociates from the carbon

the stability of the carbocation that is formed. The weaker the base, the less tightly it is

bonded to the carbon and the easier it is to break the carbon–halogen bond.

As a result, an alkyl iodide is the most reactive and an alkyl fluoride is the least reactive of the alkyl halides

The Solvent The major effect of the solvent is on the rate of

nucleophilic substitution, not on what the products are.

The higher the dielectric constant of solvent (polar) , the better the medium is able to support separated positively and negatively charged species.

The rate of solvolysis of tert-butyl chloride increases dramatically as the dielectric constant of the solvent increases.

Aprotic solvents, lack OH groups and do not solvate anions very strongly, leaving them much more able to express their nucleophilic character.

Carbocation Rearrangements

Stabilization of Carbocation

STEREOCHEMISTRY OF SN1 REACTIONS

Stereochemistryof an SN1 reaction thattakes place via a contact ion pair. The reactionproceeds with 66% inversion of configurationand 34% racemization.

SN1 and SN2

SN1 and SN2

SN1 and SN2

Representative Nucleophilic Substitution Reactions

Reference Advanced Organic Chemistry Reaction

Mechanisms Elsevier, 2002 ORGANIC CHEMISTRY Francis A. Carey

University of Virginia MARCH’S ADVANCED ORGANIC

CHEMISTRY REACTIONS, MECHANISMS, AND STRUCTURE, SIXTH EDITION Michael B. Smith, Jerry March

ORGANIC CHEMISTRY , PAULA YURKANIS BRUICE, 4th edition