Ch. 7 Substitution Reactions of Akyl Halides

substitution - RCH2CH2Y + X - RCH2CH2X + Y elimination - RHC CH2 + HY + X

I. Substitution Reactions

H O CH + Cl H O CH3 Cl 3

Nucleophile (Nu:): nucleus- loving

- e- rich

o (lone pair or π bond): weak Nu:

o can also have negative (-) charge: strong Nu:-

- seeks e- deficient species (δ+ or +)

Electrophile (E+): electron-loving

- e- poor (δ+ or +)

- seeks e- rich species

Leaving group (LG)

- group leaves and take 2 e- with it

- stable groups (weak bases) make good LG’s (e.g Cl-, Br-, I-)

General reaction: R – LG + Nu:  R – Nu + LG:

Possible mechanism?

*simultaneous * stepwise

R Nu: Nu R LG R LG carbocation SN2 SN1

SN2: Substitution Nucleophilic Biomolecular Reaction CHM 201 Dang 1 H C O + CH Cl E.g 3 3

Mechanism: one step

C CH3O C Cl C H3C O Cl H H H CO H H H 3 H + Cl-

*Backside attack Inversion of stereochemistry Increasing steric hindrance, decreasing rate

- SN2 Kinetic Rate = k [CH3O ] [CH3Cl]

 Rate depends on both Nu:- and E+

 Biomolecular rxn

Sterics affect rate of SN2

R Group Abbreviation Carbon type Relative rate MeX H3C X = Cl, Br, I Methyl 30

EtX 1o CH3CH2 1 H3C o C 2 H IPrX 0.02 H3C

CH3 TBuX 3o 0.04 H3C C

Relative stabilities of alkyl halides

(Fastest) Methyl > 1o > 2o > 3o (NR)

CHM 201 Dang 2 SN2 E vs. POR diagram

E reactant product + LG

*if LG is too sterically hindered (3o)

- T.S is high energy

- Ea is high

- reaction is too slow (N/R)

Nu H Cl H

LG is wedge

SN2 summary

 1 – step mechanism

 Backside attack

 inversion of stereochemistry

 requires an unhindered LG and good Nu: (-charge or NH3)

 Rate (RX) Methyl > 1o > 2o > 3o (slowest or NR)

E.g Predict the major product

CHM 201 Dang 3 NH3

I NaOH

CH3 NaCN C CH2CH3 Br CH3

SN1 Substitution Nucleophilic Unimolecular

CH3 O + Cl H2O + H3C C Cl H O CCH3

Nu: CH3 E

Could this be an SN2 ?

SN1 mechanism (2 key steps but usually 3 steps) (9.4)

1. Loss of LG

CHM 201 Dang 4 SLOW CH CH3 3 rate determining step + Cl C break bond --> endothermic H3C Cl requires E H3C CH3 CH3 trigonal planar carbocation

2. Addition of Nu:

CH 3 CH3 H H O H H3C C O H3C CH3 O H FAST H CH3 H exothermic bond formed

H3C C O H

SN1 Kinetic

Rate = k [tBuCl]

 Rate determining step involves E+ only

 Rate is independent of [Nu:]

 A more stable carbocation will be formed faster

o o o Rate of SN1: benzylic/allylic > 3 > 2 >> 1 , methyl

Stereochemistry of SN1

SN1 result in racemization

CHM 201 Dang 5 CH3 from the front CH3 Nu: Nu H3CH2C CH3 H X H CH C 1:1 3 2 CH3 enantiomers

(S) from Nu the back CH2CH3

SN1 Summary

 Stepwise mechanism via carbocation

 More stable carbocation, faster reaction

 Racemization occurs

 Requires no strong Nu (usually with solvent: H2O or ROH)

E.g Predict the major product(s)

CH3 OH

CH3 C OH I H

Summary

SN2 SN1

Alkyl halides (R-X) Methyl, 1o or 2o 2o, 3o

CHM 201 Dang 6 Nucleophile (Nu) Strong Nu: or Nu:- Weak Nu:

Mechanism 1 step 2 steps

Reaction Rate = k [R-X] [Nu:-] = k [R-X]

Products Typically 1 2 products (enantiomers if chiral)

Note: If 2o R-X, then the rxn depends on the type of Nu: used

CHM 201 Dang 7