Idea Transcript
CHEM 232 Organic Chemistry I
University of Illinois at Chicago
UIC
Lecture 28 Organic Chemistry 1 Professor Duncan Wardrop April 22, 2010 1
Today’s Lecture Topics Covered: 1. Aryl Halides - Bonding, Physical Properties and Reactions 2. Nucleophilic Aromatic Substitution of Chlorobenzene 3. Nucleophilic Aromatic Substitution: Addition-Elimination 4. Floxcin - Application of Nucleophilic Aromatic Substitution 5. Nucleophilic Aromatic Substitution: Elimination-Addition
2
What’s the Difference Between Ar- and Ph-? Phenyl refers specifically to this:
Aryl is a general term for all aromatic ring systems:
C
N
N O 3
Chapter 23 Aryl Halides
4
23.1 Bonding in Aryl Halides
5
Aryl Halides X
Aryl halides are halides in which the halogen is attached directly to an aromatic ring. Carbon-halogen bonds in aryl halides are shorter and stronger than carbonhalogen bonds in alkyl halides.
6
Dissociation Energies of Selected Compounds Bond Energy: kJ/mol (kcal/mol) X=H
X = Cl
CH3CH2X
sp3
410 (98)
339 (81)
H 2C
sp2
452 (108)
368 (88)
sp2
469 (112)
406 (97)
CHX X
7
Resonance Picture
X
X H
X H
C-X bonds in aryl halides have more double bond character than C-X bonds in alkyl halides
8
23.2 Sources of Aryl Halides
9
Preparation of Aryl Halides Halogenation of arenes (Section 12.5)
H Br2
FeBr3
Br HBr
electrophilic aromatic substitution
10
Preparation of Aryl Halides The Sandmeyer reaction (Section 22.17)
H
N
N
H
Cl
N Cl NaNO2 N+ O–
Primary Arylamine
O
HCl, H2O
CuCl N+ O– Aryl Diazonium Salt
O
heat
N+
O
O– Aryl Chloride
diazotization-nucleophilic aromatic substitution 11
Preparation of Aryl Halides The Schiemann reaction (Section 22.17)
H
N
Me O Primary Arylamine
N
H
BF4
F
N
1. NaNO2 HCl, H2O
H2O
2. HBF4
heat
Me O Aryl Diazonium Salt
Me O Aryl Fluoride
diazotization-nucleophilic aromatic substitution 12
Preparation of Aryl Halides Reaction of aryl diazonium salts with iodide ion (Section 22.18)
H
N
N
H
I
Cl N Me
NaNO2
Me
room temp.
HCl, H2O Primary Arylamine
Me
KI
Aryl Diazonium Salt
Aryl Iodide
diazotization-nucleophilic aromatic substitution 13
23.3 Physical Properties of Aryl Halides
14
Physical Properties of Aryl Halides resemble alkyl halides are essentially insoluble in water less polar than alkyl halides
Cl
Cl µ 2.2 D
µ 1.7 D
15
23.4 Reactions of Aryl Halides: A Review and a Preview
16
Reactions Involving Aryl Halides Electrophilic aromatic substitution (Section 12.14)
Br
Br
BrOH
(hypobromous acid)
Br
Br
Bromobenzene
35.7%
Br
Br Br 1.0%
64.3%
halide substituents are ortho-para directing & deactivating
17
Reactions Involving Aryl Halides Electrophilic aromatic substitution (Section 12.14)
ADD DDT SYNTHESIS
18
Reactions Involving Aryl Halides Formation of aryl Grignard reagents (Section 14.4)
Br
Mg
MgBr
Et2O Bromobenzene
Phenylmagnesium bromide
19
Substitution Reactions Involving Aryl Halides
We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required.
20
Nucleophilic Substitution of Chlorobenzene
Cl
OH 1. NaOH, H2O 370°C 2. H+ (97%)
This reaction does not proceed via SN2……..
21
Why is Chlorobenzene Unreactive?
the SN2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible.
22
SN1 Also Unlikely: Aryl Cations are Highly Unstable Cl
empty sp2 orbital
SN1
C + Cl Aryl Cation
SN1 not reasonable because: 1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process 2) aryl cations are highly unstable 23
SN1 Reaction is Possible with Very Powerful Leaving Groups such as Dinitrogen
N N
OH SN1
C
H2O
Aryl Cation
This is a unique case: halides are not good enough leaving groups for this process to occur. 24
What is the Mechanism of This Reaction?
Cl
OH 1. NaOH, H2O 370°C 2. H+ (97%)
25
23.5 Nucleophilic Substitution in Nitro-Substituted Aryl Halides
26
Nucleophilic Aromatic Substitution (SNAr)? H
H E
E
-H+
E
Electrophilic Aromatic Substitution
X
X Nuc
Nuc
-X-
Nuc
Nucleophilic Aromatic Substitution? 27
Electron-Deficient Haloarenes Undergo Nucleophilic Aromatic Substitution In contrast to chlorobenzene, nitro-substituted aryl halides undergo nucleophilic aromatic substitution at reasonable temperatures OCH3
Cl + NaOCH3
CH3OH
+
85°C NO2
NaCl
NO2 (92%)
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The More Electron-Deficient the Haloarene, the Faster the Substitution
Cl
Cl
–O
1.0
N+
Cl
O
7 x 1010
–O
N+
O
O–
N+
N+
O
2.4 x 1015
O–
O
–O
Cl
O N+
N+
O–
O
too fast to measure
29
Direct Displacement Doesn’t Occur!
Nuc
Br Nuc:
30
Kinetics of Nucleophilic Aromatic Substitution follows second-order rate law: rate = k [aryl halide] [nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step
31
Effect of Leaving Group Upon Rate of SN2 During SN2 reactions, the C-X bond breaks during the rate-determining step
R' R
R'
δ+
C
R'' X
Nuc
C R
R'
δ−
X R''
Nuc
C
R'' R
Reaction Rate Depends on X: I > Br > Cl > F C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol) 32
Effect of Leaving Group in Nucleophilic Aromatic Substitution X
Relative Rate*
X
F
NO2
*NaOCH3, CH3OH, 50°C
312
Cl
1.0
Br
0.8
I
0.4
C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol) 33
General Features of Mechanism
1. bimolecular rate-determining step in which nucleophile attacks aryl halide 2. rate-determining step precedes carbon-halogen bond cleavage 3. rate-determining transition state is stabilized by electron-withdrawing groups (such as NO2)
34
23.6 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution
35
Addition-Elimination Mechanism Two step mechanism: Step 1 nucleophile attacks aryl halide and bonds to the carbon that bears the halogen (slow: aromaticity of ring lost in this step) Step 2 intermediate formed in first step loses halide (fast: aromaticity of ring restored in this step)
36
Addition-Elimination Mechanism
OCH3
F + NaOCH3
CH3OH
+
85°C NO2
NaF
NO2 (92%)
37
Addition-Elimination Mechanism Step 1 - Addition
CH3
O F
bimolecular consistent with secondorder kinetics; first order in aryl halide, first order in nucleophile
NO2 Rate = k [CH3ONa] [arene] 38
Addition-Elimination Mechanism Step 1 - Addition
CH3
O F
CH3O
F H
Slow
NO2
NO2
39
Reaction Involves an Anionic Intermediate
intermediate is negatively charged formed faster when ring bears electron-withdrawing groups such as NO2 because negative charge is stabilized……..
F
CH3O
H
O
N
O
40
Stabilization of Addition Product by Electron-Withdrawing Group
CH3O
F H
O
N
O
CH3O
F H
O
N
O
41
Rapid Collapse of Cyclohexadienyl Anion Intermediate Step 2 - Elimination CH3O
OCH3
F H
O
N
O
Fast
F
NO2
42
The Role of Leaving Groups
F > Cl > Br > I is unusual, but consistent with mechanism carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F stabilizes negatively charged intermediate
43
The Role of Leaving Groups
Nuc
F
Nuc
Cl
H
O
N
O
Most Stabilized
Nuc H
O
N
O
Nuc
Br
I H
H
O
N
O
O
N
O
Least Stabilized
44
23.7 Related Nucleophilic Aromatic Substitution Reactions
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Substitution of Hexafluorobenzene OCH3
F F
F
F
F
NaOCH3
(72%)
CH3OH 65°C
F
F
F F
F
Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution.
F
F
CH3O F
F
F
F F
Anionic Intermediate 46
Substitution of 2-Chloropyridine
NaOCH3 N
Cl
CH3OH 50°C
N
OCH3
2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.
47
Substitution of 2-Chloropyridine
O
Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.
CH3 NaOCH3
N
Cl
CH3OH 50°C
N
OCH3
OCH3 N
Cl
Anionic Intermediate 48
Compare 2-Chloropyridine with Chlorobenzene
NaOCH3 N
Cl
CH3OH 50°C
N
OCH3
1. NaOH, H2O 370°C Cl
2. H+
OH
49
Synthetic Application of Nucleophilic Aromatic Substitution
50
Ofloxacin
H
Ofloxacin (trade name Floxin) is a broadspectrum quinolone N antibiotic Me
O
O
F
OH OEt
N
N Me
O H
Ofloxacin
http://www.ofloxacin.com/ 51
Synthesis of Ofloxacin, Part 1 H
O
O
F
F
F F
H
1,4-Addition F OEt
OMe
F
F HN F
OH
O OEt
NH2 Me
O
Me
-MeO
OMe OH
Elimination H
O
O
F
OEt
F
F F Me
NH OH
52
Synthesis of Ofloxacin, Part 2 H
O
H
O
O
O
Addition F
F
OEt
OEt F
F
F
NH
F
F
OH
Me
F
N
Me
OH
Elimination Nucleophilic Aromatic Substition
H
O
O
F
OEt
F
N F
Me
OH
53
Synthesis of Ofloxacin, Part 3 H
O
O
F
F
N
N F
H Nucleophilic Aromatic Substition
O
Me
O
-F H
O OEt
F Me
HO
O
F
OEt
F
H
Addition
H Elimination
O
F
OEt
F
N Me
O H
54
Synthesis of Ofloxacin, Part 4 H
O
O
H Addition
F
O
O
F
OEt
OEt
F F
N
NH Me
N
Me
O
N
H
H
N
N
Elimination
Me Nucleophilic Aromatic Substition
H
Me
O
O
F
OEt
N N
Me
O
N Me
O H
55
Synthesis of Ofloxacin, Part 5 H
O
O
F
OEt
N Me
N
N NaOH H2O
Me
O
H
H
O
O
F
OH
N Me
N
N Me
O H
Ofloxacin
56
Synthetic Application of Nucleophilic Aromatic Substitution
57
Page 238 Furosemide
Ofloxacin (trade name Floxin) is a broadspectrum quinolone antibiotic Prozac another good idea
Ofloxacin
http://www.ofloxacin.com/ 58
23.8 Benzyne & the EliminationAddition Mechanism of Nucleophilic Aromatic Substitution
59
Aryl Halides Undergo Substitution When Treated With Very Strong Bases
Cl
NH2 KNH2, NH3 -33 °C
(52%)
Ammonia: pKa = 34; b.p. = -33 °C Potassium Amide: strong base
60
Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it CH3
CH3
CH3 Br NaNH2, NH3
NH2
-33 °C NH2 Cine substitution product
61
Cine Substitution Defined
cine-substitution A substitution reaction (generally aromatic) in which the entering group takes up a position adjacent to that occupied by the leaving group.
62
Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it CH3
CH3
CH3
NaNH2, NH3 -33 °C Br
NH2 NH2
Cine substitution product
63
Regiochemistry
CH3
CH3
CH3 NaNH2, NH3 Br
CH3
NH2
-33 °C
NH2
Cine substitution product
NH2
Cine substitution product
64
Further Proof of Cine Substitution via 14C Label
Cl
*
NH2 KNH2, NH3
NH2
*
*
-33 °C (48%)
(52%)
Cine substitution product
65
Rationalization of Cine Substitution Step 1 - Elimination H H
H Cl
Cl
H
H
H H
H H
H
H
N H
H
N H
Benzyne
compound formed in this step is called benzyne
66
Benzyne - A Reactive Molecule With an Abnormal π-Bond H
H
H
H
H
H
H
H
H
H
H
H
Benzyne
2pZ-2pZ π Bond
sp2-sp2 π Bond
Benzyne has a reactive triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate. 67
Benzyne - A Reactive Aromatic Molecule With An Abnormal, In-Plane π-Bond overlapping sp2 orbitals poor overap results in a weak, reactive bond
H
R C
H C
'Normal' C-C Triple Bond
C C
C R
H
H
C
C
C
Benzyne C-C Triple Bond
68
Arynes are Highly Reactive Electrophiles Step 2 - Addition H
H
H
H H
H
N H Benzyne
H
H
N H
H
H
Aryl Anion
69
Aryl Anions are Strongly Basic Step 3 - Protonation H H
H
N
H
H H
H
H
N H Benzyne
H
H
H
H
N H
H H
N
H
H
Substitution Product
70
Hydrolysis of Chlorobenzene Cl 14C
labeling indicates that the hightemperature reaction of chlorobenzene with NaOH proceeds via benzyne.
*
OH
* (54%)
NaOH, H2O 395 °C
*
OH
(43%)
71
Substitution of Chlorobenzene Proceeds via Benzyne
*
Cl
NaOH
*
*
OH
*
OH
NaOH H2O
H Benzyne
Cine substitution product
72
Why the Temperature Difference? Cl
NH2 KNH2, NH3
Sodium amide is a considerably stronger base than hydroxide and consequently better able to carry out the ratedetermining step
-33 °C
Cl
OH 1. NaOH, H2O 370°C 2. H+
73
All is Revealed
CH3
CH3 Br
NaNH2
CH3 1. NaNH2 2. NH3
CH3 NH2 NH2
74
All is Revealed
CH3
CH3 NaNH2
CH3 1. NaNH2 2. NH3
Br
CH3
NH2 NH2
75
All is Revealed CH3
CH3
CH3
CH3 1. NaNH2
NaNH2
NH2
2. NH3 Br
1. NaNH2 2. NH3 CH3
1. NaNH2 2. NH3 CH3
NH2 NH2 76
Other Methods for the Preparation of Benzyne
Benzyne can be prepared as a reactive intermediate by methods other than treatment of chlorobenzene with strong bases. Another method involves loss of fluoride ion from the Grignard reagent of 1-bromo-2-fluorobenzene.
77
Other Methods for the Preparation of Benzyne
Br
F
MgBr
Mg THF heat
F
MgFBr
Aryl bromide faster with Mg than aryl fluoride
Benzyne 78
Preparation of Benzyne via Diazotization of Anthranilic Acid See Question 23.23 O
O OH
N
H
NaNO2 HCl, H2O
H
OH N
Cl N
Aryl Diazonium Salt
Anthranilic Acid
NaOH O O
Heat N Benzyne
N2 + CO2
N
79
23.9 Cycloaddition Reactions of Benzyne
80
What is a Cycloaddition?
Cycloaddition, n. a reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.
81
The Diels-Alder Reaction Revisited Section 10.12 A
A
B
B
cycloaddition X diene
Y
Y
X cycloadduct
dienophile
O H3C
H
100°C
H3C
H
O O
O H O isoprene
maleic anhydride
H
O
cycloadduct 82
Electron-Deficient Alkynes Behave as Dienophiles
O
CH3
O 120°C
H butadiene
but-3-yn-2-one
CH3 H cycloadduct
83
Benzyne Behaves as a Dienophile
O
O
H
CH3 H
H O
H
H O
H
H Benzyne
Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.
84
Benzyne Participates in Diels-Alder Reactions Br
Mg +
F Diene
THF heat Cycloadduct (46%)
Dienophilie
85
In the Absence of Dienes (or other nucleophiles) Benzyne Undergoes Dimerization and Trimerization
Br
F
Mg THF heat
Biphenylene Triphenylene
86
Today’s Lecture Topics Covered: 1.
Aryl Halides - Bonding, Physical Properties and Reactions
2.
Nucleophilic Substitution of Chlorobenzene
3.
Nucleophilic Aromatic Substitution: Addition-Elimination
4.
Synthetic Application of Nucleophilic Aromatic Substitution
5.
Nucleophilic Aromatic Substitution: Elimination-Addition
6.
Benzyne: Generation, Bonding and Reactions
87
Information & Suggested Problems
Suggested Problems: 23.10-23.27
88