HL Organic Chemistry:

1
HL Organic Chemistry

• NUCLEOPHILIC
• SUBSTITUTION
• REACTIONS

2
Types of Halogenoalkanes
methyl primary secondary
tertiary
The carbon attached to the halogen determines
whether the haloalkane is considered methyl
only hydrogens primary (1) one methyl or
alkyl secondary (2) two methyls or
alkyls tertiary (3) three methyls or
alkyls
3
SUBSTITUTION REACTIONS
One group takes the place of another.


Y takes the place of X ( Substitution )
Y displaces X
4
NUCLEOPHILIC SUBSTITUTION
NUCLEOPHILIC DISPLACEMENT
leaving group
substrate
product
nucleophile
The nucleophile displaces the leaving group.
This is a substitution reaction
Nu substitutes for X (takes its place).
5
EXAMPLE 1

(s)
soluble
insoluble
iodide displaces bromide at carbon

NaI is soluble in acetone, NaCl and NaBr are not
6
E1 competes
EXAMPLE 2
solvolysis of t-butyl chloride in water
water displaces chloride at carbon

The extra proton is taken by a second water
molecule.
7
DISPLACEMENT REACTIONS
NUCLEOPHILIC SUBSTITUTION REACTIONS
( substitution at carbon )
can be compared to ..
ACID-BASE REACTIONS
( substitution at hydrogen )
8
COMPARE THESE SUBSTITUTIONS
DISPLACEMENT AT CARBON
nucleophile
substrate
product
leaving group
DISPLACEMENT AT HYDROGEN
base
acid
conjugate acid
conjugate base
9
THESE REACTIONS HAVE A WIDE RANGE OF SUBSTRATES
10
COMMON SUBSTRATES
( Leaving group varies )
alkyl halides
alcohols
alcohols require acid and then H2O leaves
tosylates
ABBREVIATION
alkyl p-toluenesulfonate
11
THERE ARE ALSO A WIDE RANGE OF
NUCLEOPHILES
A WIDE VARIETY OF COMPOUNDS CAN BE MADE
12
NUCLEOPHILES
A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE
THE SYNTHESIS OF MANY TYPES OF ORGANIC COMPOUNDS
R-Y Nu R-Nu Y
Nucleophile
Product
Class
alkyl halides
R
X
alcohols
R
O
H


ethers
R
O
R
nitriles
C
N
R
O
esters
R
'
C
O
R
alkynes
R
'
C
C
R
thiols
S
H
R
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THE NUCLEOPHILE DOES NOT HAVE TO BE CHARGED

-
O
H
O
H
R

R
B
r

B
r
H
H
O
H
Under some circumstances water will react.
H
-

O
H
R


B
r
H
O
3
Nucleophile
Product
Class
alcohols
O
R
H
ethers


O
R
R
amines
R
N
H
2
amines
R
'
N
H
R
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REACTION 1 THE SN2 REACTION
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55oC
rate k2 RBr NaOH
k2 0.022 liter/mole-sec
-
bimolecular concerted
SN2
substitution
nucleophilic
bimolecular
16
Concerted (one step) reaction
Concerted (one step) reaction
SN2
E
N
E
Ea
R
G
Y
starting
D
H
material
product
17
REACTION 2 THE SN1 REACTION
18
55oC
rate k1 RBr
k1 0.010 liter/mole-sec
unimolecular two steps
slow
SN1
fast
substitution
also
nucleophilic
alkene (via E1)
unimolecular
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TWO STEP REACTION
carbocation
SN1
intermediate
TS
1
TS
E
2
N
E
Ea
2
R
G
Ea
1
Y
starting
step 1
step 2
D
H
material
product
20
A QUICK SUMMARY OF TWO SUBSTITUTION
REACTIONS
SN1 / SN2
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Two similar reactions, different kinetics.
1)
First Case
55oC
methyl
22
2)
Second Case
55oC
tertiary
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MANY PARAMETERS INFLUENCE NUCLEOPHILIC
SUBSTITUTION
24
NUCLEOPHILIC SUBSTITUTION
MANY FACTORS INFLUENCE SN1 AND SN2 REACTIONS
SOME PARAMETERS
a) solvent
b) temp.
c) pH
d) DH
a) structure
a) structure of R, stereochemistry
a) nature of X
a) bond strength
b) atom used
b) atom used
b) concentration
c) concentration
c) base strength
c) bond strength
d) base strength
e) solubility
f) size
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STRUCTURE OF THE SUBSTRATE
SN1
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SN1 - SUBSTRATE AND CARBOCATION
slow
R-X
R
X-

R
Nu-
R-Nu

fast
The energy of the carbocation intermediate is an
important factor for an SN1 reaction.
The better ion will have the lower energy
pathway.
3o lt 2o lt 1o
27
SOLVOLYSIS OF tert-BUTYL BROMIDE
acetone
SN1
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SOLVOLYSIS OF t-BUTYL BROMIDE
tertiary
H3O
Br-
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EFFECT OF INCREASING SUBSTITUTION - SN1
100
RBr H2O
ROH HBr
HCOOH
methyl primary secondary
tertiary
1.0
1.7
45
Guess ?
relative rate
increasing rate
rate
rel rate
rate CH3Br
EFFECT OF SUBSTRATE ON RATE
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STRUCTURE OF THE SUBSTRATE
SN2
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SN2 - SUBSTRATE
R
..

H
O
large groups introduce steric hindrance
..

C
Br
R
R
H
easy access no steric hindrance

C
Br
H
H
32
EFFECT OF DEGREE OF SUBSTITUTION - SN2
methyl primary secondary
tertiary
decreasing rate
EFFECT OF SUBSTRATE ON RATE
33
EFFECT OF BULKY SUBSTITUENTS - SN2
( substitution on the a carbon )
NEOPENTYL slower than t -butyl
decreasing rate
ALL ARE PRIMARY !
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Summary for Substrates
Notice that benzyl and allyl are good for both
SN1 and SN2
SN1
SN2
(fastest)
(fastest)
tertiary
methyl
BEST
BEST
benzyl
benzyl
allyl
allyl
secondary
primary
primary
secondary
tertiary
bridgehead
WORST
(bicyclic)
(slowest)
neopentyl
WORST
bridgehead
APPROXIMATE RATE ORDERS
(slowest)
(bicyclic)
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IS THE NUCLEOPHILE IMPORTANT IN BOTH SN1 AND SN2
REACTIONS ?
36
NUCLEOPHILES IMPORTANCE IN
SN1 AND SN2 REACTIONS
Nucleophiles are unimportant in an SN1
reaction they are not involved in the
rate-determining step.
SN1 rate K1 RX
The nature of a nucleophile is only important
to an SN2 reaction.
SN2 rate K2 RXNu
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WHAT IS A GOOD NUCLEOPHILE ?
SN2 REACTIONS
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WHAT IS THE IDEAL NUCLEOPHILE ?
SN2 REACTIONS
LARGE
STERIC PROBLEMS
no way ! bad
R
SMALL

C
Br
good
R
R
Smaller is better !
For an SN2 reaction the nucleophile must find
the back lobe of the sp3 hybridized orbital to
which the leaving group is bonded.
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EXPECTED IDEAL NUCLEOPHILES
cyanide
-
ROD OR SPEAR SHAPED
C N
-
-

N N N
azide
SMALL SPHERES
These types should be able to find the target !
-
-
etc.
Generally this idea is correct.
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OUR EXPECTATION .
We would expect the halides to be good
nucleophiles
ionic radii
1.36 A 1.81 A 1.95 A
2.16 A
smallest ion
-
-
-
-
F
Br
I
Cl
and we would expect the smallest one (fluoride)
to be the best nucleophile,
.. however, that is not usually the case.
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RELATIVE RATES OF REACTION FOR THE HALIDES
MeOH
CH3-I NaX
CH3-X NaI
Rate k CH3I X-
SN2
k
slowest
F-
5 x 102
Cl-
2.3 x 104
Br-
6 x 105
fastest
I-
2 x 107
MeOH solvates like water but dissolves
everything better.
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COMPETITIVE NUCLEOPHILES
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SN1 REACTIONS
IN SN1 REACTIONS ALL NUCLEOPHILES REACT EQUALLY
WELL
HOH, H
-
..
solvolysis
Br

..
slow
..
-
Cl
..
-
..
I
..
All react equally with the carbocation. The
amounts of RCl, RBr and RI reflect their starting
concentrations in the solution.
44
SN2 REACTIONS
FOR SN2 REACTIONS, THE SIZE AND NATURE OF THE
NUCLEOPHILE IS IMPORTANT
-
Cl
-
-
Br
I
Different amounts of RCl, RBr, and RI are
found even when they are equi- molar in the
original solution.
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THE BOTTOM LINE
SN1
CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY
The nucleophile is not involved in the
rate-determining step.
SN2
BETTER NUCLEOPHILES REACT FASTER GIVING MORE
PRODUCT
The nucleophile is involved in the
rate-determining step.
46
HOW CAN YOU TELL IF IT IS SN1 OR SN2 ?
1) LOOK FIRST AT THE NUCLEOPHILE
You cannot do a reasonable SN2 reaction without a
good Nu.
If you have a poor nucleophile, SN1 is probable.
2) NEXT CHECK THE SUBSTRATE
Primary is bad for SN1 ..
Tertiary is bad for SN2
3) FINALLY LOOK AT THE SOLVENT
SN2 is best in nonpolar and polar aprotic
solvents, but can also happen in water or EtOH.

SN1 needs a polar solvent.
47
SOME HELPFUL HINTS !
DECISION CHART
LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE
GOOD NUCLEOPHILE

Good Nucleophile in high concentration SN2
unless it is a strong base
however, 1o substrates can give SN2 at low T
RO-
HO-
H2N-
. however, SN2 needs a 1o or 2o substrate (or
1o benzylic) not 3o
SUBSTRATE
. prefers a nonpolar solvent but will proceed
even in a polar solvent (aprotics best)
SOLVENT
strong bases like all substrates with a beta
hydrogen (anti-coplanar) 3o gtgt 2o gt 1o
STRONG BASE
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SOME HELPFUL HINTS !
DECISION CHART
LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE
POOR NUCLEOPHILE

Poor nucleophile (solvolysis) SN1
or low concentration
. however, the substrate needs to be 3o or
benzylic or allylic (or 2o)
SUBSTRATE
. also, in SN1 the carbocation needs a
reasonably polar solvent
SOLVENT
watch for rearrangements
REARRANGEMENT
49

• Summary of material you
• MUST know for the
• HL Chemistry exam

50
Sec 20.2 IB Style Rxn Pathways

• Haloalkanes are the starting reactants for all
  substitution reactions
• SN1 uses slow heterolytic cleavage of the carbon
  halogen bond to form a carbocation intermediate
  as the rate limiting step
• The intermediate then reacts rapidly with a
  nucleophile (Nu-) to form the final product
• The energy profile for an SN1 reaction shows two
  humps in the reaction pathway (see slide)
• You MUST USE CURLY ARROWS to show this process
  for IB exam credit!

51
SN1 General Example
L Leaving Group (in this case a halogen)
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SN1 General Example (IB Version)
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10.5.1SN1 NaOH Example (IB)
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TWO STEP REACTION
carbocation
SN1
intermediate
TS
1
TS
E
2
N
E
Ea
2
R
G
Ea
1
Y
starting
step 1
step 2
D
H
material
product
55
Sec 20.2 IB Style Rxn Pathways

• The SN2 reaction involves the simultaneous
  breaking of the carbon-halogen bond and the
  formation of the carbon-nucleophile bond
• The transition state has a 5 bonded metastable
  carbon complex which releases the halogen while
  the covalent bond to the nucleophile remains
• Again, you must be able to use CURLY ARROWS to
  write out this mechanism

56
SN2 General Example

• The halogen is a specialized case of a leaving
  group (L)
• Note the 5 bonded carbon in the single step
  mechanism transition state
• The double cross on the center diagram is the
  symbol for transition state
• The energy profile only has a single curve

57
SN2 General Example (IB)
58
10.5.1SN2 NaOH Example (IB)
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20.2SN2 Amine Example (IB)
60
20.2SN2 Nitrile Example (IB)
61
Concerted (one step) reaction
Concerted (one step) reaction
SN2
E
N
E
Ea
R
G
Y
starting
D
H
material
product
62
Summary of IB SN Information (1)

• Slightly positive charged carbons are attacked by
  negative nuclophiles
• Primary halogenoalkanes react via SN2
• Rate kR-XOH
• Tertiary halogenoalkanes react via SN1
• Rate kR-X
• Secondary halogenoalkanes can react via either
  route, and will probably not be asked on the DP
  exam

63
Summary of IB SN Information (2)

• As the halogen changes from Cl? Br? I,
  carbon-halogen bond polarity decreases, whereas
  reaction rate increases
• SN1 reactions occur faster than SN2
• The rate of reaction for halogenoalkanes is
• Tertiary gt Secondary gt Primary
• Nitriles can be converted into (1) amines using
  hydrogen gas (with a nickel catalyst) or (2)
  carboxylic acids using an acid (typically HCl)

64
20.2.6 Reactions of Nitriles (IB)
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Words to the Wise

• You have just seen the minimum you need to know
  about Nucleophilic Substitution Reactions in
  this mini-review
• Read both your IB Text Book and review book for
  more details