Recall Alkyl Halides (Haloalkanes)

Structure, bonding and nomenclature (Ch 10)

+ -
C X X = F, Cl, Br/I

the polarity and strength

sp 3 carbon
of the C-X bond
Alkyl halide Bond length Bond strength Dipole moment
0 -10
(A , 1x10 m) (kJ/mol) (D)

CH3 F 1.39 452 1.85

CH3 Cl 1.78 351 1.87
CH3 Br 1.93 293 1.81
CH3 I 2.14 234 1.62
Reactivity trend?

SN1, SN2, E1, E2 reactions (Ch 11)

1
 Preparation of Alkyl Halides
i) From alkanes (radical substitution; section 5.3 and 10.3-10.5
1. initiation:

h/ . .
Cl Cl Cl Cl
e.g.
note for ease just showing unpaired electron on Cl
rather than all of the valence electrons

2. propagation:

. .
Cl H CH 3 CH3 + HCl

. .
Cl Cl CH3 Cl + ClCH3

3. Termination

. .
Cl Cl Cl2

. .
Cl CH3 ClCH3

. .
CH3 CH3 CH3 CH3

h/ 2
CH 4 + Cl 2 CH 3 Cl + HCl
 Regioselectivity of radical halogenation
Alkane halogenation, particularly with Cl2, often does not stop cleanly
but goes further to give a mixture of di, tri and even tetrachlorinated
products
Bromination under the radical conditions is a bit more controllable and
selective
e.g.
CH 3 CH 3 CH 3
Br 2
CH 3 CHCH 3 CH 3CCH 3 CH 3CCH 2 Br
h
2-methylpropane Br H

2-bromo-2-methylpropane 1-bromo-2-methylpropane
>99% <1%

Why do you think the 2-bromo product dominates?

3
 ii) From alkenes (via radical/electrophilic addition)
see alkene lecture notes
HBr Br
recall ionic
H2C C HCH3 H3C CHC H3

iii) From Alcohols Whats the mechanism?

a) ROH + HX RX + H 2O (X = Cl, Br, I)
generally best for tertiary alcohols as other alcohols are slower to
react and need higher reaction temperatures
for tertiary alcohols, the reaction can often be done at 00C in an
inert solvent (e.g. diethyl ether) with HCl/HBr bubbled into the
reaction mixture
Can also use aqueous HX 4
 iii) From Alcohols 10.6

b) use of SOCl2 (thionyl chloride) or PBr3 (phosphorus

bromide) are better procedures for conversion of alcohols
to alkyl chlorides and alkyl bromides (respectively)
these reactions normally takes place under mild conditions
(even for primary and secondary alcohols) and are less
acidic and less likely to cause acid catalysed
rearrangements than the HX method
predominantly used for primary and secondary alcohols

5
 pyridine
b) use of SOCl2 (thionyl ROH + SOCl2 RCl + SO2(g) + HCl

chloride) N
N

for primary and

the pyridine mops up the acid produced to
secondary alcohols form the salt - in this case pyridine hydrochloride +
N
also known as pyridinium chloride Cl -
1. - Cl H
H S O
O +
O + Cl-
S H 3C .. N
Cl + Cl H ..
CH2 CH3

H
..
H 3C OH
.. nucleophilic alcohol attacks electrophilic sulfur
pyridine then deprotonates the oxygen
CH2 CH3
2.
Cl
+
H S O
.. N
+ Cl- H3 C O + H
..
SN2 process CH2 CH3
the chloride ion attacks the
secondary carbon in an S N 2 manner

3.

H + SO2
+
stereospecific inversion Cl CH3
CH 2CH 3
+ N
H
Cl -

6
inversion of stereochemistry obtained
b) use of PBr3 (phosphorus tribromide) - mechanism similar to thionyl
chloride 1. Br
P Br Br H
+
+ Br-
e.g. P
Br + Br
H 3C
CH2 CH3
O..
H

H
..
H 3C OH nucleophilic alcohol attacks electrophilic phosphorus
..
CH2 CH3

2.
Br
SN2 process H
+
P Br
the bromide ion attacks the
Br- H3C O secondary carbon in an SN 2 manner
..
stereospecific inversion CH2CH3 H noted as protonated here

3.
H
Br CH 3
+ HOPBr 2
C H 2C H 3

inversion of stereochemistry obtained

4. HOPBr 2 then reacts with another alcohol to give (HO) 2 PBr, which further reacts to give
(HO) 3 P, i.e. 1 mole PBr 3 reacts with 3 moles of ROH 7
 O
c) Allylic bromination H N Br Br
O
O
+ N H
h
CCl 4 (solvent) O
succinimide
allylic positions

use a non-polar solvent such as CCl4 so the reactive bromine species

(Br. and Br2) to be produced in low concentrations due to low
solubility of NBS
the light energy leads to breaking of the N-Br bond of NBS to form
the bromine radical and the resonance stabilised succinimide
radical 1.

O O
h .
N Br CCl (solvent) N . + Br
4

O O
resonance stabilised radical

8
 the Br radical abstracts an
2. H
H H
. allylic H to form an allylic
. + HBr
Br radical and HBr

allylic radical

3. O
HBr then reacts with
O
NBS to produce a
N Br HBr N H Br 2
dilute solution of Br2
O O

4.
H
. H Br
Br2 then reacts with the
Br Br allylic radical to form the
+ Br . brominated product

9
 Chemospecificity - Allylic bromination

Why dont you see dibromination of the double bond?

i.e.
Br 2 Br

h
Br
CCl 4 (solvent)

The non-polar solvent (and high dilution) disfavours

formation of the polar bromonium ion intermediate (see
earlier lectures) making addition of bromine directly to the
double bond unlikely

+
Br

cyclic bromonium ion disfavoured in non-polar solvent

10
 Chemospecificity-Allylic bromination

Why dont you see addition of a bromine radical to the double bond?
the allylic radical is more stable than the radical derived from
addition of a bromine radical to the double bond (due to resonance
stabilisation) therefore the allylic radical is more readily formed

H H
.
. Br
Br
. .

allylic radical relatively stable alkyl radical not resonance stabilised

11
 Alkyl Halides (C-X) - 3 Major Types of Reactions
-Organometallic reactions (e.g. Grignard reaction)
(Carbon center of C-Metal-X is a carbanion ion equivalent,
i.e. a good nucleophile AND a good base)

-Nucleophilic substitutions
(Carbon center of C-X is an electrophilic center that stays
saturated after the reaction)

-Elimination reactions (to give alkenes and alkynes)

(Carbon center of C-X is an electrophilic center that
becomes unsaturated after the reaction)
12
 Organometallic Reactions
Alkyl halides, aryl halides (halogen connected to aromatic
ring) and vinyl halides (halogen connected to a double
bond) react with many metals: the metal often inserts
between the carbon atom and the halogen
As the metal is electropositive (+) this leads to a reversal
of polarity, which is sometimes referred to as Umpolong
+ - Mg - + transfer of electrons in
H3 C Cl H3 C MgCl an oxidation-reduction
anhydrous ether
methylmagnesium reaction from the metal
chloride
(a methyl Grignard reagent) (gets oxidised) to the
more electronegative
+ - 2 Li - +
H3C Cl H3C Li carbon atom (gets
+ Li + Cl -
anhydrous ether methyllithium
reduced)
(an organolithium reagent) carbon metal bond is a
Mg
polar covalent bond with
H3C Br H3C MgBr partial ionic character
13
methylmagnesium bromide
 Organometallic Reactions
Partial ionic character of carbon-metal bonds
C-Metal bond Electronegativity Electronegativity Electronegativity Ionic character (%)
of Carbon of Metal difference
C-Mg 2.5 1.2 1.3 52%
C-Li 2.5 1.0 1.5 60%
C-Al 2.5 1.5 1.0 40%
C-Cu 2.5 1.9 0.6 24%
C-B 2.5 2.0 0.5 20%

Due to the partial ionic character, organometallic compounds can be

written as fully ionic, but generally should be referred to as a very
polar covalent bond
- + +
-
H3C MgCl H 3C MgCl

showing polar covalent bond showing ionic character

character

14
 Organometallic Reactions
The partial ionic carbon atom bonded to the metal is a
strong base and a strong nucleophile (especially the
organomagnesium or organolithium compounds)
e.g. as a base
- + +
H O H H 3C M gCl CH - MgCl
4 HO
(= HOMgCl)

All organometallic reagents must be prepared in the

absence of water or alcohols, which are acidic enough
to protonate carbanions (e.g. In Experiment 4 of
CBMS204, what happens if the ether solvent is a bit wet
(contains water) ?)
15
 Organometallic Reactions
Organometallic reagents are strong nucleophiles
e.g. Recall Grignard reaction with carbonyls
H . H
Mg + .. -
Forming the Grignard H Br
.
H .
Mg : Br :
i) . ..
H H H H
H H

H H + .. -
H + .. - H Mg : Br :
.
Mg : Br : ..
ii)
. ..
H H H H
H H

Br
-
MgBr OMgBr
nucleophilic attack by the
+ OMg
- MgBr CHCH3 organometallic reagent on
anhydrous ether
H3 CCH
+
to the carbonyl (1,2
bromobenzene phenylmagnesium
bromide addition) to form an ionic
O OMgBr OH alkoxide
O H H CHCH3 CHCH3
-
H3 CCHO + MgBr
H+ OH
CH CH 3 CHCHan
an alkoxide 3 alcohol
H2 O 1-phenylethanol
+ HOMgBr
16
1-phenylethanol
 Lithium Diorganocopper Reagents
(Gilman reagent)
When an organolithium (i.e. alkyllithium) reagent is treated with
CuI (typically in anhydrous ether solvent) a lithium diorganocopper
reagent is formed = Gilman reagent (good nucleophile)
e.g.
ether
2 CH 3Li + CuI (CH 3) 2CuLi + LiI

lithium dimethyl copper

(a Gilman reagent)
(CH 3) 2CuLi + CH 3CH 2I ether
CH 3 CH 2 CH 3 + LiI + CH 3 Cu

Chemoselectivity : Gilman reagent (good nucleophile) will

under go 1,4-addition (later section) over 1,2-addition
(addition to a carbonyl)
17
 Recall-Nucleophilic Substitution (Ch 11)
alkyl halides (C + and halogen -) undergo nucleophilic substitution reactions
-
Nu- + +R-X -> Nu-R + X-
X - : Cl -, Br -, I -
+
or Nu + R-X -> Nu-R + X-
nucleophile substrate substitution product leaving group
Nu- : HO-, RO- (R = alkyl), NC - , RS -, H - or Nu: H2O, ROH, NH3

Examples: NaOH + CH3CH2Br -> NaBr + CH3CH2OH

(HO- is nucleophile; ethyl bromide is substrate; Br- is leaving group)
H .. H
.. Cl O+
H O
.. H + H3 C CH3 H3 C CH3 + Cl-
H H
nucleophilic substitution step
H .. H
O
..
H .. H H ..
O+ O:
H3 C CH3 H 3C CH 3 + H3 O+
H H
18
deprotonation step
 Nucleophilic Substitution (Ch 11)
Recall major mechanisms - SN1 and SN2

SN 2

S = substitution
bimolecular rate determining step

N = nucleophile

SN 1

S = substitution
unimolecular rate determining step

N = nucleophile

19
 R
S N2 R
R' C X
-
Nu C X
-
Nu
R
C R'
Nu- R'' R' R''
R''
Backside attack of the nucleophile; inversion of stereocenter
transition state
fastest for methyl halides, then primary halides, + X-
then secondary halides; tertiary halides too NO intermediate
sterically hindered to react
concerted bond breaking and bond making so two reactants involved in TS (Rate
determining step is bimolecular: rate = k [Nu][alkyl halide])

R
S N1 R
R' C
R''
X
slow
C+ + X-
Nu-
R
R' C
R''
Nu
+
R' R''
higher activation fast R
planar Nu C R'
energy barrier
carbocation R''
intermediate 1:1 ratio
fastest for tertiary halides, then mixed case for
secondary halides; methyl halides and primary Racemic mixture
halides not reactive by this mechanism

Carbocation intermediate formed first (Rate determining step is unimolecular:

rate = k[alkyl halide]) with loss of stereochemical information
20
 Nucleophilic Substitution and the Solvent
SN1 reactions: carbocation intermediate in SN1 stabilised by polar
protic solvents (contain OH or NH groups), e.g. water, alcohols, etc
H
e.g. -
H
-
R : O:
: O: H
C+
H
R' R''
favourable interactions between
- on oxygen and + on C

(CH3 )3 CCl + ROH (CH3) 3COR + HCl

solvent: 100% ethanol; 40% water/60% ethanol; 80% water/20% ethanol; 100% water
1 100 14,000 100,000
100,000
relative rate of increase in the reaction

increase polarity of solvent, rate of SN1 reaction increases

21
S N1
polar protic solvents stabilise the carbocation intermediate;
hence lower the ground state energy of the carbocation;
hence lower the activation energy barrier;
hence the reaction is faster in polar protic solvents

22
SN2 reactions : No intermediate
Polar protic solvents are generally the worst solvents for SN2 reactions as the
solvents solvate the nucleophiles and make them less available for reactions
H
: O:
H H H
+
: O: : O:
H + Nu- + H

+
H
: O:
H

The nucleophile gets solvated due to

favourable interactions between
+ on hydrogen and - on Nu
(or lone pairs if neutral nucleophile)

But polar aprotic solvents increase the rate of SN2 reactions by raising the ground
state energy of the nucleophile (examples of plar aprotic solvents:
hexamethylphosphoramide (HMPA, [(CH3)2N]3PO); acetonitrile (H3CCN),
dimethylformamide (DMF, HCON(CH3)2); dimethylsulfoxide (DMSO, (CH3)2SO))
these solvents dissolve many compounds, including salts, but they tend to surround
cations, rather than nucleophilic anions, leaving the nucleophile bare and
therefore reactive 23
SN2 reactions and polar aprotic solvents
e.g.
NaN3
CH3CH 2CH 2CH 2Br (sodium azide) CH3 CH2 CH2 CH2 N3 + Br-

solvent: CH3OH H2O DMSO DMF CH3 CN HMPA

1 7 1,300 2,800 5,000 200,000
relative rate of increase in the reaction

polar protic solvents stabilise the nucleophile

24
SN2 reactions: rate = k [Nu][alkyl halide]
rate dependent on the nucleophile and alkyl halides, favoured by good
(hence reactive) nucleophiles such as:
HS-, NC-, Br-, I-, CH3S-, HO-, CH3O- (negatively charged)
e.g. moderate nucleophiles: RSH, NH3, RNH2, R2NH (generally neutral)
e.g. poor nucleophiles: H2O, ROH, RCO2H and RCO2-

SN1 reactions : rate = k[alkyl halide]

Dependent on the leaving group of the alkyl halide and the solvent for
carbocation stabilisation
The more stable the leaving group is (once it has left) the easier it can
leave; only I, Br and Cl usually act as leaving groups; I is a better leaving
group than Br, which is better than Cl ( stability of I- > Br- > Cl-)
Favoured by polar protic solvents that stabilise carbocations
25
 Incomplete (Mixed) SN1/SN2 Mechanism
Incomplete racemisation - ion-pair hypothesis
often reactions that are expected to undergo SN1 process do not lead to
racemisation, but give an excess of the inversion product (typically
0-20% excess)
H 3C H 3C CH3
e.g. H2O
CH3 CH2 C Cl CH3CH2 C OH + HO C CH2 CH3
CH3 CH2 CH2 CH3 CH2 CH2 CH2CH2CH3
40% 60%
retention of configuration inversion of configuration

formation of an ion pair: the leaving group does not completely leave

the ion-pair shields one side of the carbocation from the nucleophile;
hence greater backside attack to give more inversion of the
stereochemistry 26
 Incomplete SN1/SN2 Mechanism
Incomplete racemisation - ion-pair hypothesis

R R
R
R' C X C+ R' C Nu
1. SN1 R'' - X- R' R'' R''
R
+
Nu C R'
R''
Nu- 1:1 ratio

When the leaving group leaves completely, the planar carbocation can be attacked on either
side with an equal likelihood by the nucleophile

BUT when the leaving group doesn't completely leave one side is shielded and
backside attack occurs

R
R R
+ X-
2. incomplete R' C
R''
X
R'
C
R''
Nu C R'
R''
-

backside blocked/
attack shielded
Nu-

27
 Recall- Elimination Reactions of Alkyl Halides
E2 mechanism: rate = k[base][alkyl halide] (bimolecular); a strong base
needed (e.g. NaOEt, NaNH2, etc); Follows Zaitsevs rule (alkene with
the most substituted double bond will be the major product)
e.g. EtO -
H CH 3 H3 C CH 3
H 3C CH 3
CH 3 + EtOH + Br -
Br H3 C
H3 C
major product

E1 mechanism: rate = k[alkyl halide] (unimolecular); with weak base

(e.g. water, alcohols, etc)
tertiary alkyl halides that form stabilised carbocations are most reactive;
primary alkyl halides unreactive
not a practical route to alkenes due to competition of nucleophilic
substitution products
28
Stereochemistry of E2 Base -
E2 reactions always occur with an anti-periplanar H R''
geometry, i.e. all 4 reacting atoms in a plane and R R'''
the H atom and leaving halide group anti in R' X
configuration (opposite sides)
H X
Why? H
1. Anti-periplanar with H and X in the staggered
Geometry (more stable than the eclipsed geometry
X
of syn-periplanar unfavoured due to steric interactions
anti-periplanar syn-periplanar

2. This geometry allows maximum overlap of the developing p orbitals in

the transition state for the formation of the bond.

29
 E2 Reactions of Alkyl Halides
Consequences of anti-periplanar geometry for E2
e.g.
H
Base

E2 reaction
Cl
elimination occurs in the above conformation
BUT not in the conformation below
as anti-periplanar relationship between H and Cl
not available

H
H Base
H No reaction from this conformation
Cl E2 reaction
H

30
 E2 Reactions of Alkyl Halides
Support for E2 mechanism - the Deuterium Isotope Effect
The C-H bond is ~ 5 kJ/mol weaker than the C-D bond, i.e. the C-H bond is easier to
break and the rate of C-H bond cleavage is faster than the rate of C-D bond cleavage
for E2 reactions, the rate of elimination when a D-bond is involved is always slower,
which proves that the C-H (and C-D) bond breaking is involved in the rate
determining step - one step process
e.g.
H
Base
C CH2Br CH C H2
H

faster reaction

D
Base
C CH2Br CD CH2
D

slower reaction 31
 Nucleophilic Substitution and Elimination of Alkyl Halides

Nucleophiles can act as both nucleophiles and bases and this leads to
both nucleophilic substitution and elimination being able to occur
Below is a summary to show what occurs when

Alkyl halide Possible Reactions

CH 3 X (X=Cl, Br/I) S N 2 only
RCH 2X (primary) S N 2 mainly except when bulky base (then E2). Never S N 1 or E1
unless allylic/benzylic/other stabilised carbocation.
RRCHX (secondary) E2 if strong base. Mainly S N 2 if weak ve base, e.g. halogens
(good nucleophiles). S N 1 and E1 if neutral nucleophile/base
( e.g. H 2O).
RRRCX (tertiary) E2 if strong base. Mainly S N 1 if weak ve base. S N 1 and E1 if
neutral nucleophile/base. Never S N2.

32