Download Alkyl halides and alcohols

Alkyl halides
Nucleophilic substitution and
elimination reactions
© E.V. Blackburn, 2010
Alkyl halides - industrial
sources
H C C H
HCl
HgCl 2
H2C=CHCl
vinyl chloride
H
H
H
vinyl
© E.V. Blackburn, 2010
Alkyl halides - industrial
sources
H C C H
HCl
HgCl 2
H2C=CHCl
vinyl chloride
H2C=CH2
CH3Cl + Hg2F2
CCl4 + SbF3
Cl2
o
H2C=CHCl
500
CH3F + Hg2Cl2
CCl2F2
Freon-12
© E.V. Blackburn, 2010
Preparation from alcohols
HX
R-OH
R-X
or PX3
or SOCl 2
SOCl2 - thionyl chloride
RCH2OH + SOCl2
RCH2Cl + HCl +SO2
© E.V. Blackburn, 2010
Halogenation of hydrocarbons
X2/h
R-H
RX
CH3
CH2Br
Br2
h
lachrymatory
© E.V. Blackburn, 2010
Addition of HX to alkenes
HX
C C
C C
H X
© E.V. Blackburn, 2010
Addition of halogens to
alkenes and alkynes
C C
C C
X2
2X2
C C
X X
X X
C C
X X
© E.V. Blackburn, 2010
Finkelstein reaction
acetone
R-X + NaI
soluble
R-I + NaX
insoluble
© E.V. Blackburn, 2010
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 + Xthe leaving
group
© E.V. Blackburn, 2010
Nucleophiles
• reagents that seek electron deficient centres
• negative ions or neutral molecules having at least
one unshared pair of electrons
H3C C C CH3 + BrH3C C C + CH3-Br
H3C O + CH -I
3
H
nucleophile
CH3
H3C O
+H
+ I-
leaving group
© E.V. Blackburn, 2010
Leaving groups
• a substituent that can leave as a weakly basic
molecule or ion
Nu
CN-
Cl
Ph3P:
L
Nu
L
Br

NC

Br
+
OH2
+
Br

Cl

PH3P

OH2

Br
Nu
NC
+ L:
+ Br-
Cl
+ H2O
+
Ph3P
+ Br
-
© E.V. Blackburn, 2010
Nucleophilic substitution
CH 3Br + OH -
CH 3OH + Br -
A knowledge of how reaction rates depend on reactant
concentrations provides invaluable information about
reaction mechanisms. What is known about this
reaction?
© E.V. Blackburn, 2010
Nucleophilic substitution
CH 3Br + OH -
CH 3OH + Br -
[CH3Br]I
0.001 M
0.002 M
[OH-]I
1.0 M
1.0 M
initial rate
3 x 10-7 molL-1s-1
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
rate a [CH3Br][OH-]
rate = k[CH3Br][OH-]
© E.V. Blackburn, 2010
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.
© E.V. Blackburn, 2010
Nucleophilic substitution
CH3
CH3
CH3-C-CH3 + OHBr
[(CH3)3CBr]I
0.001 M
0.002 M
0.002 M
[OH-]I
1.0 M
1.0 M
2.0 M
CH3-C-CH3 + BrOH
initial rate
4 x 10-7 molL-1s-1
8 x 10-7 molL-1s-1
8 x 10-7 molL-1s-1
rate a [(CH3)3CBr][OH-]0
rate = k[(CH3)3CBr]
© E.V. Blackburn, 2010
The SN2 mechanism
CH 3Br + OH -
CH 3OH + Br -
rate = k[CH3Br][OH-]
-
OH
Br
HO
Br
HO
+ 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)
© E.V. Blackburn, 2010
Stereochemistry of the SN2
reaction
-
Br
OH
Br
HO
HO
+ Br -
C6H13
H
C6H13
Br
H 3C
H
C6H13
OH
H3C
HO
H
(-)-2-bromooctane
(-)-2-octanol
CH3
(+)-2-octanol
[a] = -34.6o
[a] = -9.9o
[a] = +9.9o
© E.V. Blackburn, 2010
Stereochemistry of the SN2
reaction
C6H13
H
C6H13
NaOH
Br
H3C
(-)-2-bromooctane
[a] = -34.6o
SN2
HO
H
CH3
(+)-2-octanol
[a] = +9.9o
optical purity = 100%
A Walden inversion.
P. Walden, Uber die vermeintliche optische Activät der
Chlorumarsäure und über optisch active Halogenbernsteinsäre, Ber., 26, 210 (1893)
© E.V. Blackburn, 2010
The SN1 mechanism
CH3
CH3
CH3-C-CH3 + OHBr
1.
2.
CH3-C-CH3 + BrOH
rate = k[(CH3)3CBr]
CH3
CH3
slow
H3C C CH3 + Br
H3C C CH3
+
Br
CH3
CH3
fast
H3C C CH3 + OH
H3C C CH3
+
OH
© E.V. Blackburn, 2010
Carbocations
G.A. Olah, J. Amer. Chem. Soc., 94, 808 (1972)
CH3
+
CH3CH2
+
o
1
CH3CHCH3
+
CH3
CH3CCH3
+
2o
3o
sp2
© E.V. Blackburn, 2010
Carbocation stability
R
R C+
R
3o
>
H
R C+
R
>
2o
H
R C+
H
H
> H C+
H
1o
Hyperconjugation stabilizes the positive charge.
H
H
H
H
H
© E.V. Blackburn, 2010
Stereochemical consequences of
a carbocation
1.
CH3
slow
H3C C CH3
Br
CH3
H3C C CH3 + Br
+
C6H13
H
Br
H3C
(-)-2-bromooctane
OHH2O
SN1
?
[a] = -34.6o
© E.V. Blackburn, 2010
Stereochemical consequences of
a carbocation
1.
CH3
slow
H3C C CH3
Br
CH3
H3C C CH3 + Br
+
C6H13
H
Br
H3C
(-)-2-bromooctane
OHH2O
SN1
(+)-C6H13CHOHCH3
reduced optical
purity
[a] = -34.6o
Why?
© E.V. Blackburn, 2010
Stereochemical consequences of
a carbocation
C6H13
H
H2O
+
-
X
CH3
C6H13
H
HO
CH3
inversion predominates
retention
© E.V. Blackburn, 2010
Carbocation rearrangements
C2H5OSN2
(CH3)3CCH2OC2H5
Williamson ether synthesis
(CH3)3CCH2Br
C2H5OH
SN1
(CH3)2CCH2CH3
OC2H5
+
(CH3)2C=CHCH3
a rearrangement and
elimination
© E.V. Blackburn, 2010
Carbocation rearrangements
+
CH3CH2CH2CH2
+
CH3CH2CHCH3
o
o
1
.C. C
H
2
+
.C. C
R
+
C C
+ H
C C
+ R
1,2 hydride and alkyl shifts
© E.V. Blackburn, 2010
Carbocation rearrangements
+
(CH3)3CCH2
(CH3)3CCH2Br
CH3H
+
H3C
CH3H
CH3
H3C
CH2CH3
+
CH3
H3C
CH2CH3
+
CH3
H3C
CH2CH3
+ OC2H5
H
C2H5OH
CH3
H3C
CH2CH3
+ OC2H5
H
-H+
CH3
H3C
CH2CH3
OC2H5
© E.V. Blackburn, 2010
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.
HO
Br
© E.V. Blackburn, 2010
Steric effects in the SN2
reaction
HO
Br
The order of reactivity of RX in these SN2 reactions is
CH3X > 1o > 2o > 3o
© E.V. Blackburn, 2010
Steric effects in the SN2
reaction
RBr + I-
CH3Br
reactivity
>
150
I
-
Br
RI + Br-
CH3CH2Br > (CH3)2CHBr > (CH3)3CBr
1
0.01
0.001
I
-
Br
I
-
Br
I
-
Br
© E.V. Blackburn, 2010
Structural effects in SN1
reactions
3o > 2o > 1o > CH3X
R-X
X
+
R
R + + X-
HCO2H
RBr + H2O
ROH + HBr
(CH3)3CBr > (CH3)2CHBr > CH3CH2Br > CH3Br
100,000,000
45
1.7
1
© E.V. Blackburn, 2010
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+
slow
CH3Cl + HO-  CH3OH
fast
The nucleophilicity of nucleophiles having the same
nucleophilic atom parallels basicity:
RO- > HO- >> RCO2- > ROH >H2O
© E.V. Blackburn, 2010
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- > FIn protic solvents, the smaller the anion, the greater its
solvation due to hydrogen bonding. This shell of solvent
molecules reduces its ability to attack.
© E.V. Blackburn, 2010
Nucleophilicity
Aprotic solvents tend to solvate cations rather than
anions. Thus the unsolvated anion has a greater
nucleophilicity in an aprotic solvent.
© E.V. Blackburn, 2010
Polar aprotic solvents
O
CH3
H
O
S
N
H3C
N,N-dimethylformamide
dimethyl sulfoxide
DMF
DMSO
O
(H3C)2N P N(CH3)2
N(CH3)2
H 3C
CH3
These solvents dissolve
ionic compounds.
hexamethylphosphoramide
HMPA
© E.V. Blackburn, 2010
Solvent polarity
H
-
Cl
I
H
Cl
I
H
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.
© E.V. Blackburn, 2010
Solvent polarity
R-X
less polar
+
R
X
R + + X-
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.
© E.V. Blackburn, 2010
Solvent polarity
Explain the solvent effects for each of the following second
order reactions:
a) 131I- + CH3I  CH3131I + IRelative rates: in water, 1; in methanol, 16; in ethanol, 44
b) (n-C3H7)3N + CH3I  (n-C3H7)3N+CH3 IRelative rates: in n-hexane, 1; in chloroform, 13 000
© E.V. Blackburn, 2010
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-
© E.V. Blackburn, 2010
SN1 v SN2
kinetics:
SN1
SN2
1st order
second order
reactivity: 3o > 2o > 1o > CH3X
rearrangements
partial inversion
CH3X > 1o > 2o > 3o
no rearrangements
inversion of configuration
eliminations possible
© E.V. Blackburn, 2010
Problems
Try problems 6.6 – 6.11 and 6.14 – 6.16 in chapter 6 of
Solomons and Fryhle.
© E.V. Blackburn, 2010
Functional group transformations
using SN2 reactions
CN-
R-CN nitrile
'R
C
CR C C R'
alkyne
R = Me, 1o, or 2o
© E.V. Blackburn, 2010
Problems
Try problems 6.12 and 6.17 in chapter 6 of Solomons
and Fryhle.
© E.V. Blackburn, 2010
ROH + HX - an SN reaction
ROH + HX
HX:
RX + H2O
HI > HBr > HCl
ROH: 3o > 2o > 1o
HBr or
CH3CHCH3
CH3CHCH3
OH
Br
NaBr/H2SO4
© E.V. Blackburn, 2010
Experimental facts
1. The reaction is acid catalyzed
2. Rearrangements are possible
CH 3 H
CH 3 H
HCl
H3C C C CH 3
H3C C C CH 3
Cl H
H OH
3. Alcohol reactivity is 3o > 2o > 1o < CH3OH
© E.V. Blackburn, 2010
The mechanism
+
ROH2 + X
1. ROH + HX
+
2. ROH2
+
3. R + X
+
R + H2O
RX
© E.V. Blackburn, 2010
Reaction of primary alcohols
with HX
1. ROH + HX
1o
+
2. ROH2 + X-
+
X
ROH2 +
+
X R OH2
RX + H2O
SN2
HX:
HI > HBr > HCl
© E.V. Blackburn, 2010
© E.V. Blackburn, 2010