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.
