alkylgghhhhhhhyyggghyyyyyuuu_halides.pptx

Alkyl halides
Nucleophilic substitution and
elimination reactions
© E.V. Blackburn, 2010

Alkyl halides - industrial
sources
H C C H
HCl
HgCl2
H2C=CHCl
vinyl chloride
H H
H
vinyl

Alkyl halides - industrial
sources
H C C H
HCl
HgCl2
H2C=CHCl
vinyl chloride
H2C=CH2
Cl2
500o
H2C=CHCl
CH3Cl + Hg2F2
CCl4 + SbF3
CH3F + Hg2Cl2
CCl2F2
Freon-12

Preparation from alcohols
R-OH
HX
R-X
or PX3
or SOCl2
SOCl2 - thionyl chloride
RCH2OH + SOCl2
RCH2Cl + HCl +SO2

Halogenation of hydrocarbons
R-H
X2/h
RX
CH3
CH2Br
Br2
h
lachrymatory

Addition of HX to alkenes
C C
HX
C C
H X

C C
X2
C C
X X
C C
2X2
X X
C C
X X
Addition of halogens to
alkenes and alkynes

R-X + NaI
acetone
R-I + NaX
soluble insoluble
Finkelstein reaction

Nucleophilic substitution
reactions
The halide ion is the conjugate base of a strong acid. It
is therefore a very weak base and little disposed to share
its electrons.
When bonded to a carbon, the halogen is easily displaced
as a halide ion by stronger nucleophiles - it is a good
leaving group.
The typical reaction of alkyl halides is a nucleophilic
substitution:
R-X + Nu R-Nu + X-
the leaving
group

Nucleophiles
• reagents that seek electron deficient centres
• negative ions or neutral molecules having at least
one unshared pair of electrons
-
3 3
H C C C + CH -Br 3
H C C C CH3 + Br-
H3C O
H
+ CH3-I H3C O
CH3
+ H
+ I-
nucleophile leaving group

Leaving groups
• a substituent that can leave as a weakly basic
molecule or ion
Nu L
Nu + L Nu + L:
Br
 
NC Br NC
CN-
+ Br-
2
 
OH Cl OH2
Cl-
Cl 2
+ H O
+
Br

PH3P

Br
+
Ph3P + Br
-
3
Ph P:

CH3Br + CH3OH + Br-
OH-
A knowledge of how reaction rates depend on reactant
concentrations provides invaluable information about
reaction mechanisms. What is known about this
reaction?

rate  [CH3Br][OH-]
rate = k[CH3Br][OH-]
CH3Br + CH3OH + Br-
OH-
[CH3Br]I
0.001 M
[OH-]I
1.0 M
initial rate
3 x 10-7 molL-1s-1
0.002 M 1.0 M 6 x 10-7 molL-1s-1
0.002 M 2.0 M 1.2 x 10-6 molL-1s-1

Order - a summary
The order of a reaction is equal to the sum of the
exponents in the rate equation.
Thus for the rate equation rate = k[A]m[B]n, the overall
order is m + n.
The order with respect to A is m and the order with
respect to B is n.

Br
CH3
CH3-C-CH3
OH
CH3
CH3-C-CH3 + OH-
+ Br-
rate  [(CH3)3CBr][OH-]0
rate = k[(CH3)3CBr]
[(CH3)3CBr]I
0.001 M
[OH-]I
1.0 M
initial rate
4 x 10-7 molL-1s-1
0.002 M 1.0 M 8 x 10-7 molL-1s-1
0.002 M 2.0 M 8 x 10-7 molL-1s-1

+ Br-
References of interest:
E.D. Hughes, C.K. Ingold, and C.S. Patel, J. Chem. Soc., 526 (1933)
J.L. Gleave, E.D. Hughes and C.K. Ingold, J. Chem. Soc., 236 (1935)
CH3Br + CH3OH + Br-
OH-
rate = k[CH3Br][OH-]
The SN2 mechanism
OH- Br HO
-
HO
-
Br

Stereochemistry of the SN2
reaction
OH- Br
-
HO
-
Br
Br
C6H13
H
H3C
(-)-2-bromooctane
[] = -34.6o
OH
C6H13
H
H3C
(-)-2-octanol
[] = -9.9o
(+)-2-octanol
[] = +9.9o
HO
HO
+ Br-
C6H13
H
CH3

A Walden inversion.
P. Walden, Uber die vermeintliche optische Activät der
Chlorumarsäure und über optisch active Halogen-
bernsteinsäre, Ber., 26, 210 (1893)
Stereochemistry of the SN2
reaction
Br
C6H13
H
H3C
HO
C6H13
H
CH3
(-)-2-bromooctane
[] = -34.6o
(+)-2-octanol
[] = +9.9o
optical purity = 100%
NaOH
N
S 2

The SN1 mechanism
rate = k[(CH3)3CBr]
Br
CH3
CH3-C-CH3 + OH-
CH3
CH3-C-CH3
OH
+ Br-
CH3
1. H3C C CH3
Br
CH3
+
H3C C CH3 + Br-
2.
CH3
+
H3C C CH3 + OH-
CH3
H3C C CH3
OH
slow
fast

Carbocations
G.A. Olah, J. Amer. Chem. Soc., 94, 808 (1972)
CH3
CH3 CH3CH2
+ +
1o
CH3CHCH3 CH3CCH3
+ +
2o
3o
sp2

Carbocation stability
R
R C +
R
3o
H
> R C +
R
2o
H
> R C + >
H
1o
H
H C +
H
Hyperconjugation stabilizes the positive charge.
H
H
H
H
H

Stereochemical consequences of
a carbocation
CH3
1. H3C C CH3
Br
CH3
H3C C CH3
+
+ Br-
slow
OH-
H O
2
SN1
Br
C6H13
H
H3C
(-)-2-bromooctane
[] = -34.6o
?

a carbocation
CH3
H3C C CH3
+
+ Br-
slow
6 13
(+)-C H CHOHCH3
OH-
H O
2
SN1
reduced optical
purity
Br
CH3
1. H3C C CH3
Br
C6H13
H
H3C
(-)-2-bromooctane
[] = -34.6o
Why?

retention
a carbocation
CH3
H
C6H13
X-
+
C6H13
CH3
inversion predominates
H
HO
H2O

Carbocation rearrangements
(CH3)3CCH2Br
C2H5O-
SN2
C2H5OH
SN1
(CH3)3CCH2OC2H5
Williamson ether synthesis
(CH3)2CCH2CH3
OC2H5
+
(CH3)2C=CHCH3
a rearrangement and
elimination

1,2 hydride and alkyl shifts
+
CH3CH2CH2CH2
1o
+
CH3CH2CHCH3
2o
.C
. C
+
H
C C
+ H
.C
. C
+
R
C C
+ R

(CH3)3CCH2Br (CH3)3CCH2
+
CH3H
CH3H
H3C +
CH3
H3C + CH2CH3
CH3
H3C + CH2CH3
CH3
H3C CH2CH3
H
+OC2H5
C2H5OH
CH3
H3C CH2CH3
H
+OC2H5
-H+ CH3
H3C CH2CH3
OC2H5

HO Br
- -
Steric effects in the SN2
reaction
OH- Br HO
+ Br-
-
HO
-
Br
Look at the transition state to see how substituents might
affect this reaction.

reaction
The order of reactivity of RX in these SN2 reactions is
CH3X > 1o > 2o > 3o
HO
Br
- -

reaction
> (CH3)2CHBr
0.01
CH3Br >
150
reactivity
CH3CH2Br
1
RBr + I-
RI + Br-
- -
I Br - -
I Br - -
I Br
-
-
I Br
> (CH3)3CBr
0.001

Structural effects in SN1
reactions
3o > 2o > 1o > CH3X
R-X
+ -
R X R+
+ X-
HCO2H
RBr + H2O ROH + HBr
(CH3)3CBr > (CH3)2CHBr > CH3CH2Br > CH3Br
100,000,000 45 1.7 1

Nucleophilicity
Rates of SN2 reactions depend on concentration and
nucleophilicity of the nucleophile.
A base is more nucleophilic than its conjugate acid:
CH3Cl + H2O  CH3OH2+
CH3Cl + HO-  CH3OH
slow
fast
The nucleophilicity of nucleophiles having the same
nucleophilic atom parallels basicity:
-
RO- > HO- >> RCO2 > ROH >H2O

Nucleophilicity
When the nucleophilic atoms are different, their relative
strengths do not always parallel their basicity.
In protic solvents, the larger the nucleophilic atom, the
better:
I- > Br- > Cl- > F-
In protic solvents, the smaller the anion, the greater its
solvation due to hydrogen bonding. This shell of solvent
molecules reduces its ability to attack.

Nucleophilicity
Aprotic solvents tend to solvate cations rather than
anions. Thus the unsolvated anion has a greater
nucleophilicity in an aprotic solvent.

Polar aprotic solvents
H
O
N
CH3
H C
3
N,N-dimethylformamide
DMF
O
H3C
S
CH3
dimethyl sulfoxide
DMSO
These solvents dissolve
ionic compounds.
O
(H3C)2N P N(CH3)2
N(CH3)2
hexamethylphosphoramide
HMPA

Solvent polarity
more polar transition state less
solvated than reagents
A protic solvent will decrease the rate of this reaction and
the reaction is 1,200,000 faster in DMF than in methanol.
Cl- I
H
H
H
Cl
- -
I

Solvent polarity
R-X
+ -
R X R+
+ X-
less polar more polar
greater stabilization by
polar solvent
The transition state is more polarized.
Therefore the rate of this reaction increases with
increase in solvent polarity.
A protic solvent is particularly effective as it stabilizes
the transition state by forming hydrogen bonds with the
leaving group.

Solvent polarity
Explain the solvent effects for each of the following second
order reactions:
131I-
3
a) + CH3I  CH 131I + I-
Relative rates: in water, 1; in methanol, 16; in ethanol, 44
b) (n-C3H7)3N + CH3I  (n-C3H7)3N+CH3 I-
Relative rates: in n-hexane, 1; in chloroform, 13 000

Leaving group ability
Weak bases are good leaving groups.
They are better able to accommodate a negative charge
and therefore stabilize the transition state.
Thus I- is a better leaving group than Br-.
I- > Br- > Cl- > H2O > F- > OH-

SN1 v SN2
SN2
second order
CH3X > 1o > 2o > 3o
no rearrangements
inversion of configuration
reactivity: 3o > 2o > 1o > CH3X
rearrangements
partial inversion
eliminations possible
kinetics:
SN1
1st order

Problems
Try problems 6.6 – 6.11 and 6.14 – 6.16 in chapter 6 of
Solomons and Fryhle.

Functional group transformations
using SN2 reactions
CN-
R-CN nitrile
'R
C
C-
R C C R'
alkyne
R = Me, 1o, or 2o

Problems
Try problems 6.12 and 6.17 in chapter 6 of Solomons
and Fryhle.

ROH + HX - an SN reaction
CH3CHCH3
OH
ROH + HX RX + H2O
HX: HI > HBr > HCl
ROH: 3o
> 2o
> 1o
HBr or
NaBr/H2SO4
CH3CHCH3
Br

Experimental facts
1. The reaction is acid catalyzed
2. Rearrangements are possible
HCl
H3C C C CH3 H3C C
H OH Cl
CH3 H CH3 H
C CH3
H
3. Alcohol reactivity is 3o > 2o > 1o < CH3OH

The mechanism
1. ROH + HX
+
ROH2 + X-
2. ROH2
+
+
R + H2O
+
-
3. R + X RX

Reaction of primary alcohols
with HX
SN2
HX: HI > HBr > HCl
1. ROH + HX
+
ROH2 + X-
1o
+
2. ROH2 + X-
- +
X R OH2 RX + H2O

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