Nucleophilic

1
Chapter 10

• Nucleophilic
• Substitution
• The SN1 and SN2
• Mechanisms

2
Assignment for Chapter 10

• We will cover all the sections in this chapter,
  except Sections 10.12 and 10.13

3
Problem Assignment for Chapter 10

• In-Text Problems
• 1 - 15 17, 18 19 (SN2 react)
• 20 (SN1 reaction), 21, 22, 24, 25, 26,
• 27, 28
• End-of-Chapter Problems
• 30 - 37 39 - 42 44 49
• 51 - 55

4
Sect. 10.1 Nomenclature of alkyl halides --
common names

• methylene chloride CH2Cl2
• chloroform CHCl3
• carbon tetrachloride CCl4

5
More common and IUPAC names
isopropyl chloride (2-chloropropane) sec-butyl
chloride (2-chlorobutane) isobutyl chloride
(1-chloro-2-methylpropane) tert-butyl chloride
(2-chloro-2-methylpropane) allyl chloride
(3-chloro-1-propene) vinyl chloride
(chloroethene) benzyl chloride
(chloromethylbenzene) phenyl chloride
(chlorobenzene)
6
Sect. 10.2 Overview of nucleophilic substitution

• The substitution reaction SN1 and SN2
• Primary halides SN2
• Secondary halides both mechanisms!
• Tertiary halides SN1
• Leaving groups halogens most common
• There are a number of different nucleophiles!!

7
Nucleophilic Substitution (SN2)
8
Nitrogen as a nucleophile (SN2)
9
Carbon as a nucleophile (SN2)
10
energy
Reaction coordinate
11
The SN1 Mechanism
carbocation
12
energy
intermediate
Reaction coordinate
13
Sect. 10.3 SN2 Mechanism

• reaction and mechanism
• kinetics
• stereochemistry
• substrate structure
• nucleophiles
• leaving groups
• solvents

14
The SN2 Reaction
Sterically accessible compounds react by this
mechanism!!
Methyl group is small
15
SN2 Mechanism kinetics

• The reactions follows second order (bimolecular)
  kinetics
• Rate k R-Br1 OH-1

16
energy
Reaction coordinate
17
SN2 Reaction stereochemistry
Inversion of configuration
18
For an SN2 Reaction
EVERY REACTION EVENT ALWAYS LEADS TO INVERSION
OF CONFIGURATION
19
SN2 Reaction substrate structure (Table 10-5)
KI in Acetone at 25
20
Chloromethane Iodide as the Nucleophile
Fast
I-
21
tert-Butyl Chloride Iodide as the Nucleophile
No reaction
I-
22
SN2 Reaction substrate structure
Reactivity order---- fastest to slowest!
23
SN2 Reaction nucleophilicity
24
Predict which is more nucleophilic
25
Relative Nucleophilicity
1) In general, stronger bases are better
nucleophiles 2) However, iodide doesnt fit that
pattern (weak base, but great nucleophile!) 3)
Cyanide is an excellent nucleophile because of
its linear structure 4) Sulfur is better than
oxygen as a nucleophile
26
SN2 Reaction Leaving Groups

• Best leaving groups leave to form weak Lewis
  bases.
• Good leaving groups
• Br, I, Cl, OTs, OH2
• Lousy leaving groups
• OH, OR, NH2,, F

27
Sulfonate Leaving Groups
28
Tosylate leaving group
29
Inversion of Configuration
30
SN2 Reaction solvents

• SN2 reactions are accelerated in polar, aprotic
  solvents. Consider Na -OEt as an example of a
  nucleophile.
• Why are reactions accelerated? The Na cation is
  complexed by the negative part of the aprotic
  solvent molecule pulling it away from OEt.
• Now that the sodium ion is complexed, the oxygen
  in the nucleophile OEt is more available for
  attack.

31
Aprotic solvents

• These solvents do not have OH bonds in them.
  They complex the cation through the lone pairs on
  oxygen or nitrogen

32
How cations are complexed with aprotic solvents
33
Now that the Na is complexed, the OEt can react
more easily
34
SN2 Reaction solvents

• SN2 reactions are retarded (slowed) in polar,
  protic solvents. Protic solvents have O-H
  groups.
• Why are reactions retarded? Nucleophile is
  hydrogen bonded to solvent!

35
Protic solvents

• 
  Typical protic solvents

abbreviations
36
Sect. 10.4 SN1 Mechanism

• reaction and mechanism
• kinetics
• stereochemistry
• substrate structure
• nucleophiles
• leaving groups
• solvents

37
Solvolysis of tert-Butyl Bromide
Acetone is used to dissolve everything! Water is
the solvent and nucleophile (solvolysis).
38
The SN1 Mechanism
carbocation
1935 Hughes Ingold
39

intermediate

energy
intermediate
Reaction coordinate
40
SN1 Reaction kinetics

• The reactions follows first order (unimolecular)
  kinetics
• Rate k R-Br1

41
SN1 Reaction stereochemistry
With chiral R-X compounds, the product will be
racemic (50 of each enantiomer).
42
Stereochemistry in SN1 reactions racemic product
43

intermediate

energy
intermediate
Reaction coordinate
44
SN1 Reaction substrate structure
Solvolysis in water at 50C
45
SN1 Reaction substrate structure

• tertiarygtsecondarygtprimary gt methyl
• Primary and methyl halides are very
  unreactive! They dont go by SN1 reactions.

46
(No Transcript)
47
Nucleophiles

• Usually SN1 reactions are run in polar protic
  solvents compounds with O-H groups.
• The polar protic solvent acts as BOTH nucleophile
  as well as the solvent.
• Common solvent/nucleophiles include
• water, ethanol, methanol, acetic acid, and
  formic acid.

48
A protic solvent acts as both a solvent and
nucleophile in SN1 reactions - solvolysis

abbreviations
49
Typical solvolysis reaction
Polar solvent stabilizes the carbocation!
Solvent is the nucleophile
50
Leaving groups

• Leaving groups are the same as in SN2 reactions
• Cl, Br, I, OTs are the usual ones.

51
SN1 Reaction solvent polarity

• SN1 solvolysis reactions go much faster in
  trifluoroacetic acid and water (high ionizing
  power).
• SN1 solvolysis reactions go slower in ethanol and
  acetic acid (lower ionizing power).
• See table 10-9.

52
SN2 versus SN1 Reactions

• A primary alkyl halide or a methyl halide should
  react by an SN2 process. Look for a good
  nucleophile, such as hydroxide, methoxide, etc.
  in an polar aprotic solvent.
• A tertiary alkyl halide should react by an SN1
  mechanism. Make sure to run the reaction under
  solvolysis (polar protic solvent) conditions!
  Dont use strong base conditions -- it will give
  you nothing but E2 elimination!
• A secondary alkyl halide can go by either
  mechanism. Look at the solvent/nucleophile
  conditions!!

53
SN2 versus SN1 Reactions (continued)

• If the reaction medium is KI or NaI in acetone,
  this demands an SN2 mechanism.
• If the reaction medium is AgNO3 in ethanol, this
  demands an SN1 mechanism.
• If the medium is basic, look for SN2.
• If the medium is acidic or neutral, expect SN1.

54
Comparison of SN1 and SN2 Reactions

• See Table 10-10 on page 936. Great table!!
• Section 10-5 Solvent effects been there done
  that!!

55
Sect. 10.6 classification tests

• Sodium iodide and potassium iodide in acetone are
  typical SN2 reagents!!
• Silver nitrate in ethanol is a typical SN1
  reagent!!

56
Sect. 10.7 Special Cases

• Neopentyl compounds are very unreactive in SN2
  reactions.

57
Effect of b-substitution on SN2 reactivity
(Table 10-11)
b
b
b
b
KI in Acetone at 25
58
Neopentyl Transition State
Y
R1
Y
R1
H
C
C
R2
H
R3
Nu
Nu
59
Allylic and Benzylic compounds

• Allylic and benzylic compounds are especially
  reactive in SN1 reactions.
• Even though they are primary substrates, they
  are more reactive most other halides! They form
  resonance stabilized carbocations.

60
Solvolysis Rates SN1Table 10-13
80 Ethanol-water at 50
61
Allylic and Benzylic compounds

• Allylic and benzylic compounds are especially
  reactive in SN2 reactions.
• They are more reactive than typical primary
  compounds!

62
Reaction with KI in Acetone SN2Table 10-14
60 C
63
Vinyl and Phenyl Compounds
64
Reactivity order for SN1
65
Reactivity order for SN2
About same reactivity
66
Sect. 10.8 Cyclic Systems

• Cyclopropyl and cyclobutyl halides are very
  unreactive in both SN1 and SN2 reactions
• Cyclopentyl halides are more reactive than
  cyclohexyl halides in SN1 and SN2 reactions.

67
Bicyclic systems Bredts Rule
You cant have p orbitals on a bridgehead
position in a rigid bicyclic molecule. -- You
cannot form a carbocation at a bridgehead
position. --You cannot have a double
bond at a bridgehead position.
bridgehead
bridgehead
68
(No Transcript)
69
Sect. 10.9 Carbocation Rearrangement
a carbocation
70
A Closer Look...
transition state
71
Carbocation Rearrangement
72
Carbocation Rearrangement
73
Carbocation Rearrangement
74
Carbocation Rearrangement
75
Carbocation Rearrangement
76
Carbocation Rearrangement
77
Carbocation Rearrangement
78
Carbocation Rearrangement
79
Sir Christopher Ingold
Source Michigan State University, Department of
Chemistry http//www.chemistry.msu.edu/Portraits/P
ortraitsHH_collection.shtml
80
Saul Winstein
Source Michigan State University, Department of
Chemistry http//www.chemistry.msu.edu/Portraits/P
ortraitsHH_collection.shtml
81
Sect. 10.10 Competing Reactions Elimination --
Table 10-16

• Lower temperatures favor substitution higher
  temperatures give more elimination.
• Highly branched compounds (secondary and tertiary
  compounds) give mostly elimination with strong
  bases. Weaker bases give more substitution. A
  basic medium favors E2 a more nucleophilic
  medium favors SN2.
• Primary compounds give mostly substitution with
  non-bulky nucleophiles. A bulky base
  (tert-butoxide) gives elimination.
• Tertiary compounds should be reacted under
  solvolysis conditions to give substitution!!!

82
Sect. 10.11 Neighboring group participation
83
Under SN2 Conditions
84
Internal SN2 reaction followed by an external SN2
reaction
85
Neighboring Group Participation
G
X
86
Neighboring group participation Summary

• Retention of configuration
• Enhanced rate of reaction

87
Mustard gas

• Mustard gas is a substance that causes tissue
  blistering (a vesicant). It is highly reactive
  compound that combines with proteins and DNA and
  results in cellular changes immediately after
  exposure. Mustard gas was used as a chemical
  warfare agent in World War I by both sides.

88
Sect. 10.13 Ion-pair mechanisms (skip!!)

• SN1 reactions are expected to give a 50-50
  (racemic) mixture of the two enantiomers!!
• But, if the leaving group doesnt get out of the
  way, you will get more inversion than retention,
  which makes it look like SN2.
• In the extreme, you could have a carbocation give
  only inversion of configuration by an SN1
  mechanism!!

89
In-Class Problem
For the following reaction,
A) Identify the mechanism of this
reaction. B) Predict the product(s) of this
reaction, and identify them as major or minor,
if appropriate.
90
The following table may be helpful as a review
91
Substitution versus Elimination