R-Z, Z = electron withdrawing group substitution elimination Leaving group sp 3 Nucleophilic Substitution Reaction Alkyl halides are good model to study substitution and elimination reactions.

Highly polarized C-X bond This polarity is the cause of substitution and elimination. Two mechanisms each of substitution and elimination.

1. Attraction of nucleophile 2. Heterolytic C-X bond breaking

How to determine the reaction mechanism? Reaction kinetics: study of reaction rate This rate law tells two species (bimolecular) are involved in RDS. = second-order kinetics Rate ∞ [RX] × [nucleophile] Rate = k × [RX] × [nucleophile] where k = rate constant

Ingold and Hughes coined the term S N 2 mechanism Substitution, Nucleophilic, Bimolecular Basis of their conclusion: 1. Second-order kinetics. 2. Steric hindrance of substrate alkyl halides. (Table 10.1) 3. Inversion of configuration

1.One-step reaction explains second-order kinetics, ie bimolercular reaction at RDS. 2.Nucleophilic attack from backside of the carbon bonded to halogen explains steric effect of RXs. (vide infra)

Back-side attack can be explained by HOMO-LUMO interaction

Steric hindrance Steric effect on back-side attack

Comparison of reaction coordinate diagram for unhindered and sterically hindered alkyl halide.

S N 2 rate dependent on number as well size of alkyl group

The reaction mechanism explains inversion of configuration (= Walden inversion).

basicity The weaker the basicity of a group, the better is its leaving ability. Weaker base = more stable base

Basicity vs nucleophilicity Stronger bases are better nucleophiles. Charged base is better nucleophile than neutral base.

Moving on in a same row

Polarizability of Iodide ion Always so?  depends on conditions

Aprotic polar solvent vs protic solvent basicity

How protic solvent makes strong base less reactive in S N 2? Ion-dipole interaction

Aprotic polar solvent: F-F- unsolvated

Bulky tBuO- cannot approach the back-side of substrate.

Diversity of S N 2 Reaction Wide variety of organic compounds are synthesized by S N 2.

Why S N 2 seems to take place in one direction only? Compare leaving tendency of leaving group and nucleophile!

Reversible vs irreversible S N 2 reaction

Driving a reversible reaction irreversible: Use Le Châtelier’s principle - remove the primary product

The following reaction is very fast, though SN2 mechanism predicts poor reaction. The reaction must proceed by a mechanism other than S N 2. Kinetics rate = k × [alkyl halide]

S N 1 reaction Substitution, Nucleophilic, Unimolecular 1.The rate law indicates 1 st -order kinetics. Unimolecular at RDS. 2.The more hindered the substrate, the higher the rate of S N 1. (Table 10.2) 3. Chiral alkyl halide reacts in S N 1 mechanism to form racemate.

1. Rate depends on only [R-X]; 1 st -order kinetics 2. Relative reactivities of R-X; relative stabilities of carbocations Leaving group departs before nucleophile attack. Mechanism of S N 1 Reaction 3. Determined by pH

The 1 st step must be RDS, because the rate depends on only [RX] very fast

3. Racemization of chiral R-X; planar carbocation

The Leaving Group Same as S N 2 The weaker the base, the less tightly it is bonded to the carbon. Carbocation stabilities The Nucleophile Has no effect. Nu- attacks carbocation after RDS. Usually solvent is Nu- in S N 1: Solvolysis

Walden inversion

Complete racemization vs partial racemization

Ion pair mechanism: intimate ion pair

Cyclic compound SN2SN2 SN1SN1 inversion racemization

Both S N 2 and S N 1 possible for benzylic and allylic RX

Carbocation rearrangement possible for allylic RX

Vinylic and aryl halide: Neither S N 1 nor S N 2 1.No S N 2 due to steric hindrance 2.Vinylic and aryl carbocaion too unstable to exist. 3. sp 2 is more difficult to break than sp 3

When structure of RX allows both S N 1 and S N 2: 1.Conc of Nu - 2.Reactivity of Nu - 3.Solvent

Overall, Increasing [Nu - ] facilitates S N 2 Increasing k 2 favors S N 2 Poor Nu - favors S N 1

Dielectric constant : measure of a solvent how well the solvent insulate the opposite charges from each other.

Reactant(s) in RDS is charged  polar solvent  decrease the rate nonpolar solvent  increase the rate TS is charged  polar solvent  increase the rate nonpolar solvent  decrease the rate

Charge on TS < charge on reactantsCharge on TS > charge on reactants

Dispersed charge at TS Nu - 1.Nonpolar solvent: solubility problem 2. Use aprotic polar solvent: DMF, DMSO, HMPA

Intermolecular vs intramolecular for a bifunctional molecule

1.Conc of reactant: low conc favors intramolecular rxn 2.Size of ring: 5- or 6-membered ring favored

3-membered ring is rel. easier to form: entropy effect

organic biological

Examples: SAM

FIN

10.6 Comparison of the S N 2 and S N 1 Reactions

Inversion of configuration under S N 2 condition Racemization of configuration under S N 1 condition

– More stereochemistry in S N 1 and S N 2; cyclic compounds

10.7 Elimination Reactions of Alkyl Halides RX undergoes elimination reaction in addition to nuclear substitution.

The E2 Reaction Elimination, Bimolecular Reaction kinetics Rate = k[R-X][Base]

The mechanism shown below is consistent with 2 nd -order kinetics. E2 is one-step reaction

The E1 Reaction The kinetics of this reaction is 1 st -order. rate =k[R-X] E1 stands for Elimination, Unimolecular.

No effect on rate

10.8 Products of Elimination Reactions E2 reactions: Hydrogen from  -carbon is removed.

When 2 different  -carbons are present, two products result in. More substituted alkene is obtained when a hydrogen is removed from  -carbon that is bonded to the fewest hydrogens. = More substituted alkene forms from elimination. cf. Markovnikov rule: H added to carbon that has more hydrogens

Why 2-butene predominates? More stable alkene cf. 4.6

Order of relative rate of E2 among alkyl halides Reactivity of RX/ stability of alkene

another example

10.9 Competition Between S N 2/E2 and S N 1/E1 Prediction of reaction product Nu - in nucleophilic substitution reaction is also a base in elimination reaction.

1.Two factors determines S N 2/E2 and S N 1/E1 concentration of nucleophile/base - no effect on S N 1 and E1 - affect S N 2 and E2 reactivity of nucleophile/base - no effect on S N 1 and E1 - affect S N 2 and E2 (k 2, k 4 ) 2.Conclusion S N 2 and E2 favored by good Nu/ strong base S N 1 and E1 favored by poor Nu/ weak base - poor Nu/ weak base disfavors S N 2/ E2 OH -, CH 3 O - H 2 O, CH 3 OH rate = k sn1 [RX] + k sn2 [RX][Nu] + k e1 [RX] + k e2 [RX][B-]

10.10Competition Between Substitution and Elimination S N 2/E2 condition i.e. high conc of good Nu/ strong base Product differs among 1 o,2 o,3 o RX

1 o Alkyl halide S N 2 favored over E2

2 o Alkyl halide Both substitution and elimination

3 o Alkyl halide Least reactive in S N 2 Most reactive in E2

S N 1/E1 Conditions: poor Nu/ weak base

10.11Biological Methylation Reagents