Alkyl Halides

Name the following alkyl halides

(R)

Br

(S)

Cl(R)

(R)Cl

Cl

(S)

(S)Cl

Cl

(R)

Br

(S)

Cl(R)

(R)Cl

Cl

(S)

(S)Cl

Cl

How are alkyl halides prepared?

- From alkanes- Free radical halogenation

- From alkenes- Hydrohalogenation- Halogenation

- From alcohols

Free Radical Chlorination

Experimental Evidence Helps to Determine Mechanism

• Chlorination does not occur at room temperature in the dark.

• The most effective wavelength of light is blue that is strongly absorbed by Cl2 gas.

• The light-initiated reaction has a high quantum yield (many molecules of product are formed from each photon of light).

Free Radical Species are Constantly Generated Throughout the Reaction

Propagation

Termination: Reaction of any 2 Radicals

Chlorination of Propane

30%

70%

Chlorination of Methylpropane

C

CH3

CH3

CH3 H HCH3

CH3

CH2

C CH3

CH3

CH3

C.++ Cl

.

.

.

C

CH2

CH3

CH3 H

.C

CH3

CH3

CH3

+ Cl2

+ Cl2 C

CH3

CH3

CH3 Cl

C

CH2Cl

CH3

CH3 H 65%

35%

+ Cl

+ Cl

.

.

3o Radicals are Easiest to Form

Stability of Free Radicals

(1) Consider the free radical monochlorination of 2,2,5-trimethylhexane. Draw all of the unique products (Ignore stereoisomers).

(2) Consider the free radical monochlorination of 1,4-dimethylcyclohexane. The reaction affords three different products (all C8H15Cl). Draw the three products (Ignore stereoisomers).

Conversion of Alkenes into Alkyl Halides

Br2, CCl4

Br

Br

HBr Br

Br

Br

Br

+

+

Conversion of Alcohols into Alkyl Halides

Reactions with HX, SOCl2, PBr3

Conversion of Alcohol into a Leaving Group

• Form Tosylate (p-TsCl, pyridine)

• Use strong acid (H3O+)

• Convert to Alkyl Halide (HX, SOCl2, PBr3)

Alcohols to Alkyl Halides

OH

3 alcoholo

HX (HCl or HBr)X + HOH

rapid SN1

OH HX

moderate SN1

X+ HOH

2 alcoholo

What the **** is SN1?

Unimolecular Nucleophilic Substitution

X+ X

-

Nu-

Nu

Lucas Test

CH3COH

CH3

CH3

ZnCl212M HCl

CH3

CH3

CH3CCl

CH3

CH3

CH3C OZnCl2

H CH3

CH3

CH3CCl

forms is seconds

+ HOZnCl2

Qualitative test for Alcohol Characterization

OHprimary

OH

secondary

OH

tertiary

ZnCl2, HCl

Cl

Cl

Cl

1-2 seconds

<5 minutes

>10 minutes(if at all)

1o and 2o Alcohols: best to use SOCl2, PBr3, or P/I2

OH

SOCl2pyridine

PBr3Br

Cl

P, I2I(in situ prep.

of PI3)

All are SN2 Reactions

Thionyl chloride mechanism

OH

S

O

ClCl

O

H

S

O

Cl

ClO

H

SCl

O

OS

Cl

O

-H+

ClSOCl2

pyridine

N

Cl

+ SO2 + HCl

How would you prepare the following RX from the appropriate

alcohols?Cl

(A)

Br(B)

(C)

Cl(D)

Br

7.25] Draw and name the monochlorination products of the reaction of 2-methylpentane with chlorine gas. Which are chiral?

7.36] How would you prepare the ff cpds, starting from cyclopentene and any other reagents needed?a)Chlorocyclopenteneb)Cyclopentanolc)Cyclopentylmagnesium chlorided)cyclopentane

Reactions of Alkyl Halides

Grignard Reagents

Br

HH3CH2C

MgBr

HH3CH2C

Mg, Ether

MgBr

HH3CH2C

HH3CH2C

1.

2. H3O+

O OH

MgBr

HH3CH2C

HH3CH2C

H+ HOMgBr

H2O

What’s special with Grignard reagents?

Outline a synthetic scheme from the appropriate alkyl halide

OH

OH

OH

OH

Reactions of Alkyl Halides

Substitution and Elimination

Substitution, Nucleophilic, Bimolecular – SN2

C X

Nuc : C XNuc CNuc + X

transition state

Rate = k[Nuc: ][R-X]

Second Order Rate Kinetics

Reaction Profile for SN2 Reaction (Wade)

Stereochemistry of SN2 ReactionInversion of Configuration

Br

+ KCN

CN

+ KBr

(S) (R)

Proof of Inversion of Configuration at a Chiral Center

CH2

benzyl (Bz)

SO2ClCH3

p-toluenesulfonyl chloride(Ts-Cl)

CH3 S

O

O

O R

RO-H

a tosylate (ROTs)

OH

CH3BzH

[]D = -33o(S)(-)

TsClOTs

CH3BzH

(S)

KOAc

OCCH3

O

-OAc, acetate

OAc

CH3BzH

(R)OH

CH3BzH

[]D = +33o

(R)(+)

H2O

Acetate Approaches from 180o Behind Leaving Group

OTs

Bz

CH3

HAcO

Bz

CH3H

AcO OTs - -

AcO

Bz

CH3

H

(R)(S)

OTs

Inversion on a Ring is often more Obvious: Cis Trans

Substrate Reactivity

Since the energy of the transition state is significant in determining the rate of the reaction, a primary substrate will react more rapidly

than secondary (which is much more rapid than tertiary).

6

tertiary neopentyl secondary primary methyl

Rate: ~0

(CH3)3CBr CH3BrCH3CH2Br(CH3)2CHBr(CH3)3CCH2Br

+ BrClR+ ClBrR

1 500 40,000 2 x 10

1o > 2o >> 3o

Bulkiness of Substrate

Polar, Aprotic Solvents favor SN2

by solvationPolar, protic solvents lower energy of nucleophile

CH3OH

HOCH3

CH3OH HOCH3Br

acetone

O

CH3CCH3CH3CN

DMFacetonitrileDMSO

O

HCN(CH3)2

O

CH3SCH3

Solvents should be able to "cage" the metal cation

Nucleophilicity

Nucleophile strength roughly parallels basicity

CH3- > NH2

- > OH- > F-

Nucleophile strength increases going down a group

OH- < SH-

F- < Cl- < Br- < I-

NH3 < PH3

A base is always a stronger nucleophile than its conjugate acid

OCH3- > CH3OH

NH2- > NH3

Iodide vs. Fluoride as Nucleophiles

Nucleophiles(preferably non-basic)

HS- > :P(CH3)3 > CN- > I- > OCH3- > OH- > Br- > Cl- > NH3 > OAc-

basic non-basic

Good Leaving Groups are Weak Bases

TsO- MsO-

mesylate

bond is broken during RDSLGC

Sulfonates are excellent leaving groups

O

O

CH3SO

tosylate

CH3 SO

O

O

Quality of leaving groups is crucial

Common Leaving Groups

TsO- = MsO- > NH3- > I- > H2O- = Br- > Cl- >> F- Sulfonates are easily prepared from alcohols

mesylate R = CH3

CH3tosylate R =

O

O

CH3OSR + HClin pyridine

O

O

CH3OH + ClSR

SN2 and E2

C C

Br

H

R2

R1 R1

R2

H

C

NucC

Nuc:+ Br

R1

R2

H

C

Br

C C CR2

R1B:+ B-H + Br

rate = k[R-Br][B-]

SN2

E2

Bimolecular Elimination - E2Nucleophile acts as Bronsted Base

C C

Br

HBase:

-Elimination

C C + base-H

+ Br

C C

Br

HBase

SN2 Competes with E2

CH3CHCH3

Br

CH3CO2

wk. base

CH3CH2O

Substitution EliminationOAc

CH3CHCH3

OEt

CH3CHCH3str. base

CH2=CHCH3

CH2=CHCH3

100% 0%

20% 80%

Depends on the Nature of the Nucleophile

SN2 Competes with E2

15%

90% 10%CH3CH2CH2CH2Br

CH3CH2O

(CH3)3CO

str. bulky base

str. baseCH3CH2CH=CH2

CH3CH2CH=CH2

CH3CH2CH2CH2OEt

CH3CH2CH2CH2OtBu85%

Depends on the Size of the Base

SN2 Competes with E2

CH3CH2CH2CH2BrCN

CH3CH2CH2CH2CN1o 100%

(CH3)3CBr CN CH2=C(CH3)2

100% E2

SN2

3o

str. nuc.; wk. base

Depends on the Nature of the Substrate

Stereochemistry of E2

H on carbon is anti to leaving group

second order rate kineticsrate = k[R-X][base]

+ Br

+ CH3OHCCC C

H

Br

CH3O

Anti-Coplanar Conformation

3(R),4(R) 3-Bromo-3,4-dimethylhexane

CH2CH3

CH2CH3

Br CH3

H CH3

NaOCH3

in CH3OHheat

H and Br Anti-coplanar orientation

(R) (R)

CEt

Me

Me

EtC

CH3O

EtMe Br

H

C

EtMe

C

H

MeEt

Et

Br

Me Me EtMeEt

OCH3

In a Cyclohexane, Leaving Group must be Axial

OTsKOC(CH3)3

in t-BuOH /+ KOTs

OTsOTs

HH

OtBuhas no anti-coplanar H

Zaitsev’s Rule

Br

NaOCH3

in CH3OH+

Zaitsev's Rule: In an elimination reaction, themore highly substituted alkene (usually) predominates

85% 15%

More Stable Alkene Predominates

Hyperconjugation bond associates with adjacent C-H bond

C

C

C

mono-substituted disubstituted

C

1-butene trans 2-butene

With Bulky Base, Hofmann Product Forms

Which will react more rapidly?

CH3

CH(CH3)2

Cl

CH3

CH(CH3)2

Cl

Menthyl chloride

Neomenthyl chloride

NaOEt in EtOHheat

heatNaOEt in EtOH

Reactive Conformations

CH3

Cl(CH3)2CH CH3

Cl

(CH3)2CH

HH

CH3Cl

CH(CH3)2H

Menthyl chloride Neomenthyl chloride

stable stable and reactive

reactive

flip

NaOEt

CH(CH3)2

CH3

NaOEt

CH(CH3)2

CH3

E2 Reaction of (R,R) 2-iodo-3-methylpentane

CH3CHCHCH2CH3

I

CH3

NaOCH2CH3

in ethanol C C

CH3

CH2CH3CH3

H

H

CH3

CCH2CH3

CH3

C

OR(R,R)

CH2=CHCHCH2CH3

CH3OR

Stereochemistry is Important

CH3

CC

CH3

H

ICH2CH3

H

(R,R) OEt

I

CH3H

CH3CH3CH2

H

C=C

CH3CH2

CH3

H

CH3

reactive conformation

Unimolecular Substitution and Elimination – SN1 and E1

C

CH3

BrCH3

CH3

in warm CH3OH

CH3

CH3 OCH3

CH3

C + C=CH2

CH3

CH3

SN1 E1Rate = k[R-Br]

1st order rate kinetics

+ HBr

SN1 mechanism (Wade)

1st step is rate determining

Reaction Profiles (Wade)

SN1 SN2

SN1 Transition State

SN1 Solvent Effects

C Cl

CH3

CH3

CH3

ROH

CH3

CH3

CH3

ORC + HCl

EtOH 40% H2O / 60% EtOH 80% H2O / 20% EtOH H2O

react.: 1 100 14,000 100,000

Transition state energy is lowered by polar protic solvents

Partial Racemization in SN1

Carbocation Stabilitymore highly substituted, lower energy

Carbocation Stability

C

CH3

CH3

CH3

>

CH3

CH3

H

C CH2=CH CH2=

tertiary > secondary = primary allylic = primary benzylic > primary

= CH2 > CH3CH2

resonance stabilized

Carbocations can Rearrange1,2-Hydride Shift

C C CH3

CH3

HBr

H

CH3H2O

CH3

H

H

C CH3

CH3

OH

C + HBr

Hydride shift

H

H

2 3o o

Hydrideshift

E1 Mechanism

E1 and SN1 Compete

OTs

CH3

CH3OH /

CH3

OCH3+

CH3

CH3

HCH3

H

Zaitsev

CH3OH

CH3OHa)

b)

b)a)

Dehydration of Alcohols – E1

OH

H2SO4 (aq)

OHH

cat.

H

H

+ H2O

HSO4or H2O

-H2O

Hregenerated

Can R-X form a good LG?

YesNo

no reaction classification of carbon

12

3o

o

o

nuc. hindered, strong base?nuc. a strong base?

Yes No

E2 good nuc., non-basic?

Yes No

SN2 (slow SN2)

Yes No

E2 good nuc., nonbasic?

Yes No

SN2 solvent polar?

(some SN2)

Yes SN1*E1

strong base? YesE2

No

polar solvent?Yes SN1*

E1

* SN1 is favored over E1 unless high temp. and trace amounts of base are used.

Draw the Major Product & Predict the Mechanism

120oC, distill6M H2SO4

OH

CH3

E1 CH3

120oC, distill6M H2SO4

OH

CH3

OTs

NaNH2 in liq. NH3

NaNH2 in liq. NH3

OTsE2

in acetone, 20oC

KBr H

OTs

CH3 CH2CH3

SN2

CH3 CH2CH3

Br

Hin acetone, 20oC

KBr H

OTs

CH3 CH2CH3

Br 1% AgNO3

in CH3CH2OH

Br 1% AgNO3

in CH3CH2OHSN1

CH3CH2O

+ AgBr

warm

CH3CH2CH2OHBr

BrCH3CH2CH2OH

warm

+

OCH2CH2CH3

SN1/E1

in CH3CN

NaSCH2CH3

Br

CH3

Br

CH3NaSCH2CH3

in CH3CN

CH3

SCH2CH3SN2

in refluxing ethanol

NaOCH2CH3

I

CH3

CH3

E2 CH3

CH3in refluxing ethanol

NaOCH2CH3

I

CH3

CH3

Which Reacts More Rapidly in E2 Reaction?

BA

I(CH3)2CHI(CH3)2CH

Cis Reacts more Rapidly

I(CH3)2CH

I

CH(CH3)2stablereactive

trans

cis I

(CH3)2CH

Hreactive & stable

reacts more rapidly

What is an E1CB reaction?

• Poor LG 2 carbons away from a carbonyl carbon (beta alcohol)

• Proceeds via a carbanion intermediate stabilized by resonance.

• Step 1: Abstraction of alpha proton• Step 2: Ejection of leaving group.