Generalized Polar Reactions An electrophile, an electron-poor species, combines with a nucleophile, an electron-rich species An electrophile is a Lewis acid A nucleophile is a Lewis base The combination is indicate with a curved arrow from nucleophile to electrophile

Nucleophilic Substitution If the nucleophile and substrate are neutral, the product will be positively charged. If the nucleophile is a negative ion and substrate is neutral, the product will be neutral. The unshared pair of electron in the nucleophile can be used to make new covalent bond.

The Nucleophile Neutral or negatively charged Lewis base Reaction increases coordination at nucleophile ◦ Neutral nucleophile acquires positive charge ◦ Anionic nucleophile becomes neutral

Nucleophilic reactions: nucleophilic substitution (SN) Nucleophilic substitution: > reagent is nucleophil > nucleophil replaces leaving group > competing reaction (elimination + rearrangements)

Carbocation Stability Carbocations are stabilized by inductive effect and by hyperconjugation.

Effect of variables on SN Reactions  the nature of substituents bonded to the atom attacked by nucleophile  the nature of the nucleophile  the nature of the leaving group  the solvent effect

In the left box, all are strong nucleophiles except chloride and acetate which are medium. In the right box, H 2 O and ROH are weak, the others medium. 1)The nature of the nucleophile

2)The nature of the Leaving Group the best leaving groups in this series are the halogens I-, Br-, and Cl- OH-, RO-, and NH2- are such poor leaving groups that they are rarely if ever displaced in nucleophilic substitution reactions

Leaving Group

3) the solvent effect The solvent chosen for the reaction medium can have a significant effect on the products formed Polar Protic Solvent—polar solvent that can form hydrogen bonds ◦ Ex: Water & Acetic Acid Polar Aprotic Solvent—polar solvent that cannot hydrogen bond to the nucleophile ◦ Ex: Acetone & DMSO

SN1SN1

The S N 1 Reaction The S N 1 reaction is a unimolecular nucleophilic substitution. It has a carbocation intermediate. Rate = k [alkyl halide]. Racemization occurs.

S N 1 Mechanism If the nucleophile is an uncharged molecule like water or an alcohol, the positively charged product must lose a proton to give the final uncharged product. Step 1: Formation of the carbocation. Step 2: Attack of the nucleophile.

S N 1 Energy Diagram and Mechanism Rate-determining step is formation of carbocation rate = k[RX]

S N 1 reaction

Effect of Leaving Group on S N 1 Critically dependent on leaving group ◦ Reactivity: the larger halides ions are better leaving groups. In acid, OH of an alcohol is protonated and leaving group is H2O, which is still less reactive than halide. p-Toluensulfonate (TosO-) is excellent leaving group. 18

Solvent Effect Protic solvent: Protic solvent: a solvent that contains an -OH group these solvents favor S N 1 reactions; the greater the polarity of the solvent, the easier it is to form carbocations in it

Characteristics of S N 1 reactions

SN2SN2

SN2 Reaction Bimolecular nucleophilic substitution (S N 2). Concerted reaction: New bond forming and old bond breaking at same time. Reaction is second order overall. Rate =k [alkyl halide][nucleophile].

Structure of Substrate on S N 2 Reactions Relative rates for S N 2: CH3X > 1° > 2° >> 3° Tertiary halides do not react via the S N 2 mechanism, due to steric hindrance.

Characteristics of the S N 2 Reaction Occurs with inversion of chiral center Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides )

S N 2 Transition State S N 2 Transition State The transition state of an S N 2 reaction has a planar arrangement of the carbon atom and the remaining three groups

SN2: Nucleophilic Strength Stronger nucleophiles react faster. Strong bases are strong nucleophiles, but not all strong nucleophiles are basic.

Solvent Effect Aprotic solvent: Aprotic solvent: does not contain an -OH group ◦ it is more difficult to form carbocations in aprotic solvents ◦ aprotic solvents favor S N 2 reactions 27

Characteristics of S N 2 reactions

A QUICK SUMMARY OF TWO SUBSTITUTION REACTIONS S N 1 / S N 2

Nucleophiles are unimportant in an S N 1 reaction; they are not involved in the rate-determining step. S N 1 rate = K 1 [RX] The nature of a nucleophile is only important to an S N 2 reaction. S N 2 rate = K 2 [RX][Nu] NUCLEOPHILES IMPORTANCE IN S N 1 AND S N 2 REACTIONS

CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY SN1SN1 SN2SN2 BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT The nucleophile is not involved in the rate-determining step. The nucleophile is involved in the rate-determining step. WHAT IS A GOOD NUCLEOPHILE ?

Effect of substituents on S N reactions Effect of electronic and steric factors in competition between S N 1 and S N 2 reactions

A better leaving group increases the rate of both SN1 and SN2 reactions. Leaving Group in predicting S N 1 vs S N 2 mechanisms:

S N 1 or S N 2 Mechanism? SN2SN2SN1SN1 CH 3 X > 1º > 2º3º > 2º Strong nucleophileWeak nucleophile (may also be used as solvent) Polar aprotic solventPolar protic solvent Rate = k[alkyl halide][Nuc]Rate = k[alkyl halide] Inversion at chiral carbonRacemization No rearrangementsRearranged products

HYDROLYSIS OF ESTER The hydrolyses of ordinary esters are catalysed by a number of agents, such as acids, bases and enzymes. The acid and base catalysis in aqueous solution is largely of the specific type, being brought about by the H ₃ O ⁺ and OH ⁻ ions. Molecule for molecule the enzymes are very much mor effective catalysts than the H ₃ O ⁺ and OH ⁻ ions, as is shown by the comparison in Table.

Ester CatalystT ( ⁰ C) Rate constant (liter mole ⁻ ¹sec ⁻ ¹) Activation energy(Kcal) Ethyl benzoate H₃O⁺H₃O⁺ x10 ⁻⁵ 19.6 Ethyl benzoate OH ⁻ x10 ⁻⁴ 17.7 Benzoyl-L- tyrosine ethyl ester chymotryp sin x10 ⁻⁴ 0.8 Methyl hydrocinnam- ate chymotryp sin Comparison of Second-Order Rate Constants for Ester Hydrolysis

Acid Hydrolysis of Esters The main reaction of esters is hydrolysis, reaction with water ◦ This reaction is also called hydration = cleavage of any bond by the addition of a water molecule However, the uncatalyzed reaction is slow and requires heat Mineral acid is used as a catalyst 14.2 Esters

Mechanism of Ester Hydrolysis under acidic condition

Base hydrolysis of Esters The base catalyzed hydrolysis of an ester: Saponification or soap-making Products are: ◦ Acid salt ◦ Alcohol Acid can’t exist in basic conditions, so the product is the salt of the carboxylic acid using the cation of the base catalyst 14.2 Esters

Mechanism of Ester Hydrolysis under basic condition Hydroxide anion is the nucleophilic attacking species