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CH 11 REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
The C-X bond in alkyl halides is polar. Alkyl halides are electrophiles (E+) that react with
nucleophiles (Nu: -) and bases. X = F, Cl, Br, or I.
There are 2 basic kinds of reactions of alkyl halides with nucleophiles ...
1. Substitution:
H
H
-
Nu:
+
C
C
C
-
X
+
C
Nu
X
2. Elimination:
H
-
Nu:
+
C
C
C
C
+
X-
+
Nu
H
X
Kinetics of Nucleophilic Substitution (SN) Reactions:
Consider the reaction of methyl bromide and NaOH ...
HO- + CH3-Br  HO-CH3 + Br Experimentally, it is observed that the reaction rate  [OH-] and [CH3Br]
Thus: Rate = k [OH-][CH3Br]
Note: This is a 2nd order rate equation. The rate doubles
when the concn of either reactant is doubled and the rate quadruples when the concn of both
reactants is doubled, etc.
SN2 Reactions:
A nucleophilic substitution reaction with 2nd order kinetics is called an SN2 reaction.
SN2 = Substitution, Nucleophilic, 2nd order (called 'bimolecular').
An essential feature of an SN2 mechanism is that the reaction occurs in a single step, without
intermediates, i.e., as the Nu:- bonds, the X leaves and the configuration inverts.
The Nu:- must attack the substrate (R-X) from the back side, i.e., 180 from the leaving group,
causing an umbrella-like stereochemical inversion.
The transition state is trigonal planar for the 3 atoms that remain bonded to C.
Note that the ‘substrate’ is the piece that forms the basic structure of the molecule, the bulk of the
molecule (the alkyl halide in these examples).
The substituent is the piece/part attached to the substrate. In the preceding equation, OH- is the
nucleophile, CH3Br is the substrate and Br (the leaving group) is a substituent (the substituted
part of the substrate).
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
1
Factors Affecting SN2 Reactions:
Four factors which affect SN2 reactions are 1) nature of the substrate (alkyl halide), 2) nature of
the Nu:-, 3) nature of the leaving group, and 4) nature of the solvent.
1) Bulky (sterically hindered) substrates (alkyl halides) slow down SN2 reactions by raising
the activation energy (G*) by blocking the attacking Nu:Hindered alkyl halides (3) have high
activation energies. They react slowly
by an SN2 mechanism.
G*
Energy
Unhindered alkyl halides (Me & 1)
have low activation energies. They
react quickly by an SN2 mechanism.
G*
Nu
R
X
R
X
G
exothermic
Nu
transition state
+
Nu
+
X
R
The relative order of reactivity of substrates is as follows ...
Me
1C
e.g.,
methyl
ethyl
relative
rates
200,000
40,000
C Br
H
isopropyl
CH3
C Br
H
3C
<1
CH3
CH3
C Br
H
phenyl
vinyl
t-butyl
500
H
H
H
2C
CH3
CH3
C Br
<1
<1
Br
CH2
CHBr
CH3
SN2 reactions can occur only at unhindered sites, i.e., Me halides, 1, and some 2.
Note that vinylic halides (R2C=CRX) and aryl halides (-X) fail to undergo SN2 reactions
because both these substrates sterically block Nu:- attack.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
2
2) The attacking Nu:- also affects the rate/extent of reaction:
Note that when the nucleophile is negative, a neutral product is obtained but when the
nucleophile is neutral, the product is positive...
Nu:- + R-Y  Nu-R + Y:Nu:
e.g. OH-
+ R-Y  Nu+-R + Y:-
e.g. :NH3
The effectiveness of a Nu:- is termed 'nucleophilicity' and means the 'affinity of a Nu:- for the C
atom of an alkyl halide in a substitution reaction
Nu:- + CH3-Br  Nu-CH3 + Br -
Consider the reaction:
The relative nucleophilicities of various Nu:- are as follows ...
HS-
CN-
I-
CH3O-
HO-
NH3
Cl-
H2O
ROH
125,000
125,000
100,000
25,000
16,000
1000
700
1
0.01
Trends of nucleophilicity are predicted as follows ...
1. For Nu:- with the same attacking atoms, nucleophilicity parallels basicity, i.e., OH- is a
better Nu:- (and stronger base) than H2O.
Again, nucleophilicity measures the affinity of a Lewis base for C in an SN reaction.
Basicity measures the affinity of a base for a proton.
2. Nucleophilicity usually increases down a group, e.g., HS- > HO-, I- > Br- > Cl- >> F-
3) The leaving group usually has a negative charge.
Groups which best stabilize a '-' charge are the best leaving groups, i.e., the weakest bases
are most stable as anions are the best leaving groups. These are salts of strong acids
(conjugate bases of strong acids), e.g., HI + H2O  I- + H3O+
pKb = 23
pKb = 22
pKb = 21
pKb = 11
pKb = -1.7
pKb = -2
pKb = -21
TosO-
I-
Br -
Cl-
F-
HO-
RO-
H2N-
60,000
30,000
10,000
200
1
0
0
0
In the transition state, the negative charge is spread over both the Nu: - and the leaving group
so the leaving group best able to stabilize (delocalize) the negative charge is most reactive.
The energy of the transition state is lowered by a good leaving group.
Note: F-, OH-, RO-, & NH2- are rarely displaced by nucleophiles, i.e., they are lousy leaving
groups. Therefore, R-F, R-OH, R-OR, & R-NH2 do not usually undergo SN2 reactions.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
3
4) The solvent also affects SN reactions:
Protic solvents, which contain -OH or -NH groups inhibit SN2 reactions.
Polar aprotic solvents, which contain strong dipoles but no -OH or -NH groups, enhance SN2
reactions.
Protic solvents (e.g., MeOH, EtOH, etc.) cluster around Nu:- (solvate it) and lower its energy
(stabilize it) and reduce its reactivity via H-bonding.
d
+
d
-
OR
H
d
H
X:-
RO H
+
d
d
+ dOR
A solvated anion (Nu:-) has reduced nucleophilicity,
reduced reactivity and increased stability
H OR
+ dd
Polar aprotic solvents increase SN2 reaction rates by raising the energy and reactivity of the
nucleophile.
Examples include acetonitrile (CH3CN), dimethylformamide (DMF)
[(CH3)2NC=OH], dimethyl sulfoxide, DMSO [(CH3)2SO], hexamethylphosphoramide, HMPA
{[(CH3)2N]3PO} and dimethylacetamide (DMA).
:O :
:O:
: O:
..
H
C
.. ..
CH3
N
S
H3C
CH3
CH3
..
[(CH3)2N]3P O
..
H3C
C
N
CH3
CH3
HMPA
DMSO
DMF
DMA
These polar aprotic solvents dissolve ionic salts due to their high polarity but they tend to
solvate metal cations rather than nucleophilic anions.
d
Polar aprotic solvents solvate metal cations
leaving the anion counterion (Nu: -) bare and
thus more reactive
.. _
+
:
CH3C O
.. Na
+
d
C CH3
N
..
H3C
:O:
-
+
d
d
C N:
:O:
Na
CH3CN :
+
: N C CH3
- +
d
d
+
.. _
:
CH3C O
..
..
N C CH3
- +
d
d
Thus bare, unsolvated anions have greater nucleophilicity and show increased reaction rates.
Consider ...
CH3(CH2)2CH2-Br + N3-
 CH3(CH2)2CH2N3 + Br -
The relative reaction rates as a function of solvent are given as follows ...
HMPA
CH3CN
DMF
DMSO
H2O
CH3OH
200,000
5000
2800
1300
7
1
Non polar solvents (ether, benzene, CHCl3) do not solvate or stabilize nucleophiles and thus
gives rise to a higher G* than polar aprotic solvents. Thus, compared to polar aprotic
solvents, non polar solvents inhibit SN2 reactions as do polar solvents.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
4
SN1 Reactions:
C(CH3)3Br + H2O + heat  C(CH3)3OH +
e.g.,
HBr

3 alkyl halides are essentially inert to substitution by the SN2 mechanism because of steric
hindrance at the back side of the 3 alkyl halide substrate. Despite this, 3 alkyl halides do
undergo nucleophilic substitution reactions quite rapidly, but by a different mechanism, i.e.,
the SN1 mechanism.

SN1 = Substitution, Nucleophilic, 1st order (unimolecular).

Unlike the SN2 reactions of 1 and 2 alkyl halides, the rate depends only upon the concn of
1 reactant, the alkyl halide-not the nucleophile

The order of reactivity of substrates for SN1 reactions is the reverse of SN2 ....
3
>
R3C-Br
2
>
R2HC-Br
1
vinyl
RH2C-Br
> phenyl >
CH2=CH-Br
-Br
Me
H3C-Br
Kinetics of SN1 Reactions:
SN1 reactions obey 1st order kinetics, i.e., Rate = k[RX]. These reactions have 3 steps.
H
(CH3)3C
1.
slow
Br
t-butyl bromide
- Br-
..
O
..
H
+
(CH3)3C
(CH3)3C
2.
rapid
3º C + intermediate
.. H
O
+ H
3.
rapid
(CH3)3C
- H+
+
OH + H3O + Br
t-butyl alcohol
..
H2O
..
Reaction Steps …
1. a slow rate-limiting dissociation of the alkyl halide forming a C+ intermediate
2. a rapid nucleophilic attack on the C+ (forming a protonated alcohol intermediate in this case)
3. a rapid deprotonation of the alcohol intermediate forming the product alcohol
The Nu:- is not involved in the slow, rate-limiting step. In this example, H2O is the Nu:- as well
as the solvent. Reaction with a solvent is called 'solvolysis' and in this case 'hydrolysis'.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
5
Factors Affecting SN1 Reactions:
Factors include: nature of the substrate, nature of the leaving group, nature of the Nu: -, and
nature of the solvent. In general, factors that lower G*, either by stabilizing C+ intermediate or
by raising the reactant energy, favor faster SN1 reactions. Conversely, factors that raise G*,
either by destabilizing the C+ intermediate or by lowering reactant energy level, slow down SN1
reactions.
1. As noted, highly substituted alkyl halides (substrates) form a more stable C+. In
addition, allyl and benzyl C+ are unusually stable due to their resonance forms which
delocalize charge over an extended  system ..
H2C
H2C+
+
CH
CH2
HC CH2
H2C
2º allyl carbocation
H
1º benzylic
H
+
C
H
H
>
3º allylic
1º C +
CH3
H
CH3
C+
>
CH3
H
CH3
+
CH2 CH CR2
Relative Stability of Carbocations
2º C +
CH3
C+
R
1º benzylic
2º benzylic
CH3
H
+
C
H
H
+
C H2
3º C +
>
2º benzylic
C
C
+
C HR
HC CHR
H
H
C
3º benzylic
H2C
CHR
1º allyl carbocation
+
C R2
+
+
CH
+
CH2 CH CHR
H
+
C+
>
+
CH2 CH
vinyl C
H
>
>
+
phenyl
H C+
H
+
m ethyl C
+
CH2 CH CH2
1º allylic
2º allylic
The heterolytic bond dissociation energies of various alkyl groups are given on page 18 of section
1 of your notes (ORGANIC CHEMISTRY INTRO notes). For example, note the trend in the
heterolytic bond dissociation energies of alkyl chlorides, R-Cl  R+ + Cl-.
group
Dissociation
energy
(kcal/mol)
3
1 benzylic
2
1 allylic
1
vinyl
phenyl
methyl
157
166
170
173
190
207
219
227

As expected, this stability order of the C+ stability applies directly to the order of reactivity of
alkyl halides and alkyl tosylates in SN1 reactions.

Note that 1 allylic and 1 benzylic halides are very reactive in SN2 reactions as well as SN1’s.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
6
2. Nature of the Leaving Group:
Recall that for SN2 reactions, the best leaving groups are the most stable anions, i.e.,
conjugate bases (e.g., I-) of very strong acids (e.g., HI). The same order of reactivity of
leaving groups applies to SN1 reactions because the leaving group is directly involved in the
rate limiting step.

Thus the reactivity order of leaving groups for SN1 reactions is .....
TosO-
>
I-
>
Br-
>
Cl-
>
H2O
Note: When SN1 reactions are carried out in acidic conditions 3 alcohols readily undergo
substitution by HX (the protonated alcohol eliminates a neutral H2O molecule forming a
3 C+).
(CH3)3C
..
OH
..
+
H
Br
+
(CH3)3C OH
.. 2
- H2O
(CH3)3C +
(CH3)3C
..
:
Br
..
+
H2O
.. : Br :
..
This is also a qualitative test for identifying alcohols, i.e, the Lucas test. HCl with ZnCl 2
catalyst are used. 3 alcohols react quickly, 2 slowly, and 1 don’t react.
Note that 1 and 2 alcohols will react with special reagents to produce alkyl halides (i.e.,
thionyl chloride, SOCl2, or PBr3) and in this case react via an SN2 mechanism.
3. The Nature of the Nucleophile:
The type of Nu:- has great influence on the rate of SN2 reactions but has no influence on SN1
reaction rates because the rate determining step does not involve the Nu: .
e.g., t-butanol reacts with HI at the same rate as with HBr and HCl.
4. The Solvent: For SN2 reactions the solvent affects the rate if it affects the nucleophile.

polar aprotic solvents (e.g., CH3CN) accelerate rxns. because they solvate and
stabilize the metal cation, leaving the Nu:- bare. This raises the energy of the Nu:- and
thus lowers  G*.

protic solvents (e.g., MeOH) retard these rxns. as they solvate and stabilize the Nu: by hydrogen bonding. This raises G*.

nonpolar solvents (e.g., CCl4) do not solvate Nu:- (or the transition state). This inhibits
SN2 rxns.
For SN1 rxns., the solvent affects the rate only if it influences the stability of the charged
transition state. The Nu:- is not involved in the rate determining step so solvent effects on the
Nu:- do not affect the rate of SN1 reactions.
CH 11

polar solvents, both protic and aprotic, will solvate and stabilize the charged transition
state (C+ intermediate), lowering G*, and accelerating SN1 rxns.

nonpolar solvents do not lower G* thus making SN1 rxns. relatively slower.
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
7
Solvent polarity is usually expressed by the “dielectric constant”, , which is a measure of the
ability of a solvent to act as an electric insulator. Polar solvents are good electric insulators
because their dipoles surround and associate with charged species.

Dielectric constants of some common solvents are given in the following table...
name
dielectric constant
name
dielectric constant
aprotic solvents
protic solvents
hexane
1.9
acetic acid
6.2
benzene
2.3
acetone
20.7
diethyl ether
4.3
ethanol
24.3
chloroform
4.8
methanol
33.6
HMPA
30
formic acid
58.0
DMF
38
water
80.4
DMSO
48
the relative rates of an SN1 rxn. due to solvent effects are given…

(CH3)3C-Cl + ROH  (CH3)3C-OR + HCl
H2O
20% EtOH (aq)
100,000
40% EtOH (aq)
14,000
EtOH
100
1
Elimination Reactions of Alkyl Halides:
A Russian chemist, Alexander Zaitsev, noted that in elimination of HX from alkenes, the more
highly substituted (more stable) alkene product predominates (Zaitsev’s Rule).
CH3CH2O-Na+
Br
CH3CH
CH3CH2CHCH3
EtOH
CHCH3
+
CH3CH2CH
2-butene
minor product
( < 20%)
major product
( > 80%)
E2 Reactions:
CH2
1-butene
E2 = Elimination, Bimolecular (2nd order).
Elimination occurs when an alkyl halide is treated with a strong base such as OH-, OR-, NH2-, H-,
etc.
B:H
C
R
C
R
R
CH 11
R
X
d
B
+
R
H
R
C
C
C
R
R
Xd
R
R
R
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
+
C
B H +
X-
R
8

The B: - H  bond formation, the C - H  bond breaking, the C - C  bond formation, and the
C - X  bond breaking all occur simultaneously. Reactions in which several steps occur
simultaneously are called ‘concerted’ reactions.

E2 reactions have 2nd order kinetics, i.e., Rate = k  [RX]  [Base]

E2 eliminations occur with anti-periplanar geometry, i.e., periplanar means that all 4 reacting
atoms - H, C, C, & X - all lie in the same plane. Anti means that H and X (the eliminated
atoms) are on opposite sides of the molecules. See the Figure on p. 401.

E2 rxns. are like SN2 in that in both cases, the attacking atom is opposite the leaving group
and in that no C+ intermediate forms.
E1 Reactions:
Just as SN2 rxns. are analogous to E2 rxns., so SN1 rxns. have an analog, E1 rxn.
E1 = Elimination, unimolecular (1st order); Rate = k  [RX]
CH3
CH3
CH3
slow
C Br
- Br-
CH3
CH3
H
rapid
C+
C
H
CH3
C
H
H
+
C
B H
+
Br
-
H
CH3
-
B:

E1 eliminations, like SN1 substitutions, begin with unimolecular dissociation, but the
dissociation is followed by loss of a proton from the -carbon (attached to the C+) rather than
by substitution. E1 & SN1 normally occur in competition, whenever an alkyl halide is treated in
a protic solvent with a nonbasic nucleophile. Note: The best E1 substrates are also the best
SN1 substrates, and mixtures of products are usually obtained.

As with E2 reactions, E1 reactions also produce the more highly substituted alkene (Zaitsev’s
rule). However, unlike E2 reactions where no C+ is produced, C+ rearrangements can occur
in E1 reactions.

e.g., t-butyl chloride + H2O (in EtOH) at 65 C  t-butanol + 2-methylpropene
CH3
CH3
H2O, EtOH
C Cl
CH3
65ºC
CH3
CH3
C OH
CH3
C
+
C
H
CH3
64%
S N1
product

H
CH3
36%
E1
product
In most unimolecular reactions, SN1 is favored over E1, especially at low temperature.
Such reactions with mixed products are not often used in synthetic chemistry.
If the E1 product is desired, it is better to use a strong base and force the E2 reaction.
Note that a high concentration of nucleophile or increasing the strength of the nucleophile
favors SN1 over E1. Can you postulate an explanation?
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
9
General Guidelines for Predicting Reaction Mechanism:
1.
Non basic, good Nu-‘s like Br- and I-, substitute. They do not force elimination. For Me, 1,
and 2 alkyl halides, the rxn. is SN2. The Nu- attacks the unhindered substrates quickly,
before ionization for SN1 occurs. In the case of 3 alkyl halides is SN1 faster than SN2.
2.
All strong bases, like OH- and OR-, are good Nu-‘s. Substitution and elimination compete.
Substitution (SN2) is faster for Me and 1 alkyl halides, whereas elimination (E2) is faster for
2 and 3 substrates. Strong bulky bases, like t-butoxide, favor E2 rxns. in all but Me halides.
Note that strong bases always cause 2nd order rxns.
3.
Weakly basic, weak Nu-‘s, like H2O, EtOH and CH3COOH, cannot react unless a C+ is formed
+
and this can only occur (at room temp.) with 2 and 3 alkyl halides. Once the C is formed the
weak Nu ‘s react and both SN1 or E1 occur. At room temp. SN1 is favored over E1.
4.
High temperature favors elimination. Elimination causes an increase in the number
molecules and hence an increase in entropy (S). From Gibbs Free Energy equation,
G = H - TS, it can be seen that the (-TS) term grows larger in magnitude (more
negative) as T increases thus making G more negative. The more negative G is, the more
the equilibrium shifts toward formation of products, i.e., elimination products in this case.
5.
Protic solvents, like H2O and ROH, stabilize C+s through solvation thus favoring unimolecular
reactions (SN1 and E1).
Polar aprotic solvents, like DMSO, favor bimolecular rxns. (SN2 and E2) by activating the Nu .
pKb = 22
pKb = -2
-
-
pKb = -4
alkyl
halide
(substrate)
good Nu
nonbasic
good Nu
strong base
e.g., bromide
e.g., ethoxide
Br
C2H5O
Me
SN2
SN2
SN2
no rxn.
1 unhindered
SN2
SN2
E2 (SN2)
no rxn.
2
SN2
E2
E2
E1, SN1
3
SN1
E2
E2
E1, SN1
alkyl
halide
(substrate)
-
-
good Nu
pKb = 20
-
strong bulky base
e.g., t-butoxide
(CH3)3CO
pKb =
pKb =
……….. Nu………. .base
……….. Nu……….. base
……….. Nu
……….. base
e.g., cyanide
e.g., alkyl sulfide
e.g., carboxylate
CN-
RS-, also HS-
RCOO
-
very poor Nu
nonbasic
e.g., acetic acid
CH3COOH
pKb =
-
-
HI
alcohol
(substrate)
Me
Me
1 unhindered
1 unhindered
2
2
3
3
CH 11
-
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
HBr
HCl
10
Substitution Reactions in Synthesis:
1. Recall the alkylation of acetylide anions  internal alkenes
R-C  C-H
+

NaNH2
R-C  C:- Na+ + NH3
 the acetylide anion is a good Nu:- which can substitute (replace) halogen atoms in methyl or 1
alkyl halides producing longer terminal alkynes 
R-C  C:- Na+ + CH3CH2 - X
 R-C  C-CH2CH3 + NaX
where X = Cl, Br, I, or OTos
 The reaction is straightforward with Me and 1 alkyl halides and proceeds via an SN2
mechanism
 acetylide anion is also a strong base (pKb = -11) as well as a good Nu:-, so E2 competes
with SN2 for 2 and 3 alkyl halides.
CH3(CH2)3CC:-Na+ + CH3-CH(Br)-CH3  CH3(CH2)3CCCH(CH3)2 (7% SN2)
+ CH3(CH2)3CCH + CH3CH=CH2 (93% E2)
2.
Recall the prep'n of alkyl halides from alcohols by rxn. with HX, i.e., the substitution of X on a
protonated alcohol.
 OH- is a poor leaving group, i.e., is not displaced directly by nucleophiles. Reaction in acid
media protonates the OH group producing a better leaving group (H2O). 2 and 3 alcohols
react by SN1 but 1 alcohols react by SN2.
 Alternately, alcohols can be converted to alkyl halides by reaction with PBr 3 which
transforms OH- into a better leaving group allowing substitution (SN2) to occur without
rearrangement.
3º
..
(Lucas Test)
(CH3)3C OH
SN1
..
1º
SN2
CH3CH2
+
H
- H2O
+
(CH3)3C OH
.. 2
Cl
..
OH
..
+
H
Cl

CH3CH2
1º
CH3(CH2)4CH2
..
OH
..
+
OH2
Br
CH3CH2Cl
.. : Cl :
..
H2O
+
H2O
Br
Br
CH3(CH2)4CH2
ether
+ PBr2
O
..
H
CH3(CH2)4CH2Br
Br
-

Draw the mechanism of the reaction of isopropyl alcohol with HBr.

What product forms if concentrated H2SO4 or H3PO4 is used in place of HCl? Why?
CH 11
+
.. : Cl :
..
:P
SN2
..
(CH3)3C Cl :
..
(CH3)3C +
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
11
3. Recall the preparation of alkenes from alkyl halides with strong base (page 8 of your notes on
Alkenes).
Dehydrohalogenation of alkyl halides, i.e., elimination of HX by a base (e.g., KOH)
e.g., bromocyclohexane + KOH  cyclohexene (80 % yield)
KOH in ethanol
Br
+
KBr
+
H2O
-HBr

These are elimination reactions in which KOH (a strong base and good nucleophile) removes
HX from a 2 or 3 alkyl halide producing an alkene.

What is the mechanism of this reaction? Draw the mechanism of the reaction of cyclohexyl
bromide and KOH.

If the reaction is attempted with methyl or 1 alkyl halides, what type of product and what type
of mechanism will occur?

Write the reaction and show the mechanism for the reaction of isobutyl bromide and KOH.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
12
Summary of SN /Elimination Reactions:
Alkyl Halide Substrate Reactivity:
methyl
1º
2º
3º
H
H
CH3
CH3
H
CH3
C Br
C Br
CH3
CH3
H
H
H
C Br
C Br
CH3
hindered substrates. S N2 increasingly unfavorable, E2 is OK
form increasingly stable C +
favors SN1 and E1. E2 is OK
unhindered substrates favor S N2
do not form a stable C +
do not react by S N1 or E1
E2 reactions possible with strong bases
E2 reactions possible with strong bulky bases (t-butoxide)
Reactivity of Nucleophiles: (See table in appendix of your purchased notes for complete list)
HS-
CN-
I-
CH3O-
HO-
NH3
Cl-
H2O
125,000
125,000
100,000
25,000
16,000
1000
700
1
good nucleophiles which are
weak bases favor SN reactions
good nucleophiles which are
also strong bases favor elimination
Note that poor nucleophiles which are also weak bases (H2O, ROH, CH3COOH, etc.) do not
undergo any reaction unless a C+ is formed first. If a C+ can form (as with a 2º, 3º, any benzylic,
or any allylic halides), then E1 and SN1 generally occur together.
Leaving Group Activity:
pKb = 23
pKb = 22
pKb = 21
pKb = 11
pKb = -1.7
pKb = -2
pKb = -21
TosO-
I-
Br -
Cl-
F-
HO-
RO-
H2N-
60,000
30,000
10,000
200
1
0
0
0
good leaving groups favor both
substitution and elimination reactions
poor leaving groups make both
substitution and elimination
reactions unfavorable
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
13
ORGANOMETALLIC COMPOUNDS PREPARED FROM ALKYL HALIDES
Sec. 10.8 & 10.9
Compounds in which C is bonded to a metal (Me) are called ‘organometallic’, for example:
R-Li
organolithium
R-Na
R-MgX
R2CuLi or (R-Cu-R)- Li+
organosodium
Grignard reagent
Gilman reagent
(organomagnesium halide) (dialkyllithium cuprate)
In organometallic compounds the C-to-Me bond is reverse-polarized compared to that of the
C-to-X bond in an alkyl halide .

In a C-X bond, C is d+ (electrophilic – electron deficient) while the halogen (X) is
d- (nucleophilic – electron rich).

In a C-Me bond, C is d- (nucleophilic) while the metal is d+ (electrophilic).
Although the C-Me bond is polar, the bond behaves as if it were ionic, yielding a carbanion (R: -).
Organometallic compounds (like carbanions) are both strongly basic and very good nucleophiles.
dC
+
d
Me
C:
-
+
Me
CH3CH2
charge
separated
polarized
R
Mg
Organometallic compounds are soluble in hydrocarbon
solvents and especially in ethers.
The ether solvent is said to be ‘coordinated’ to the
metal via ether-oxygens’ non bonded electrons.
..
O
..
..
O
..
CH3CH2
CH2CH3
X
CH2CH3
Preparation of Organometallic Compounds:
1. Gilman Reagent is prepared by reacting an alkyllithium (prepared from an alkyl halide) with
copper I iodide (CuI) in ether. All types of alkyl halides work, including aryl and vinyl halides.
C4H9Br
2 C4H9
Li
+
CuI
+
2 Li
ether
C4H9
Li
ether
C4H9
n-butyllithium
Cu
C4H9
Li+Br-
+
-
Li+
or
simply
(C4H9)2CuLi
+
LiI
a Gilman reagent
2. Grignards are prepared by reacting finely divided Mg with an alkyl halide in ether. Mg is
inserted between the C-X bond (forming R-Mg-X). The reaction works with Me, 1, 2 and 3
alkyl halides as well as aryl and vinyl halides.
Mg in ether
Br
phenyl bromide
Mg
Br
phenyl magnesium bromide
( a Grignard)
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
14
All organometallic preparations are exothermic and are carried out at or near 0C.
Organometallic compounds are rarely isolated. They are formed in solution and used
immediately for the desired reaction. Sensitive to air and moisture, they are handled under
rigorous air-free, dry conditions.
The order of reactivity of alkyl halides in these preparations is iodide > bromide > chloride. Alkyl
fluorides are unreactive.
Uses/Reactions of Organometallic Compounds:
Organopotassium (R-K) and organosodium (R-Na) compounds are the most reactive because
EN (C-Metal) is largest, i.e., 1.5. These reagents are spontaneously flammable in air. As a
result they are no longer commonly used.
Grignard reagents [EN(C-Mg) = 1.3] and Gilman reagents [EN(C-Cu) = 0.7] are the most
important organometallics.
The alkyl group in all organometallic compounds is a very good nucleophile and a strong Lewis
base, which readily deprotonates even very weak acids like H2O.

Grignard syntheses can be used to convert alkyl halides to alkanes, since Grignards also
react on contact with weak acids such as water.
Mg in THF
Br
H
Mg Br
..
O
..
H
MgBrOH
KOH in ethanol
H2 / Ni
- (KBr + H2O)
However, the organometallic route is difficult compared to dehydrohalogenation with KOH
to an alkene followed by catalytic hydrogenation. When might the first route be preferred?

Another important use of Grignard reagents is the preparation of alcohols from carbonyl
compounds such as aldehydes and ketones. This will be studied in the chapter on
alcohols.

Gilman reagents are useful in building large carbon compounds from smaller alkyl halides.
The mechanism of this reaction is not fully understood, but it not a typical nucleophilic
substitution since Me, 1 and 2 alkyl halides as well as aryl and vinyl halides all react with
Gilman reagents readily. This is called the Corey-House reaction.
I
CH3
1 (CH3)2CuLi
+
+
2 H3O
+
H
CH 11
+
C
I
+
LiI
H
H
C
CH3Cu
1 (C6H5)2CuLi
+
2 H3O
C
C
+
C6H5Cu
+
LiI
H
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
15
With 2° alkyl halides there is some elimination, but it is usually small enough that the
substitution reaction is still useful. With 3° alkyl halides, however, elimination (rather than
substitution) predominates. Why?
Recall that aryl halides and vinyl halides do not react by any of the reactions studied thus far.
They form unstable carbocations, so SN1 and E1 are unfavorable. They are also hindered
substrates so SN2 is not possible. E2 is also difficult with vinyls and near impossible with
aryls. But, aryl and vinyl halides can be converted to Gilman or Grignard reagents and
combined with other compounds. In this way, larger organic molecules can be synthesized
from smaller molecules. The discovery of these methods was considered of such great
importance that they earned the Nobel prize in Chemistry.
Interestingly, Grignard and Gilman, although similar in nature, react differently:

Grignards are generally unreactive with alkyl halides, but very reactive with carbonyl
groups in aldeydes, ketones, esters, etc. (as we will see later).

By comparison, Gilman reagent is reactive with alkyl halides and relatively unreactive
with carbonyl groups.
These differences afford versatility in directing reactions to specific functional groups in
compounds containing more than one reactive site. The following example illustrates.
O
O
Br
1 equiv, 0°C in ether
1 (CH3CH2)2CuLi
+
2 H3O
Gilman
Gilman preferrentially replaces
the halide group leaving
the carbonyl group intact.
CH2CH3
ether
1 CH3CH2MgBr
2
H3O+
HO
CH2CH3
Grignards react with carbonyls
(as we will later study) but are
unreactive with most alkyl halides.
Grignard
Br

Do problems 10.12b,c, 10.24e,f,g and 10.38.
CH 11
REACTIONS OF ALKYL HALIDES (SN1, SN2, E1, AND E2 REACTIONS)
16