CHEM 232 University of Illinois Organic Chemistry I 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 carbon- halogen 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)
2 H2C CHX sp 452 (108) 368 (88)
X sp2 469 (112) 406 (97)
7 Resonance Picture
X X X H 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 Br FeBr3 Br2 HBr
electrophilic aromatic substitution
10 Preparation of Aryl Halides
The Sandmeyer reaction (Section 22.17)
N H H N N Cl Cl
NaNO2 CuCl
O HCl, H2O O heat O N+ N+ N+ O– O– O– Primary Aryl Diazonium Aryl Chloride Arylamine Salt
diazotization-nucleophilic aromatic substitution
11 Preparation of Aryl Halides
The Schiemann reaction (Section 22.17)
N H H N BF4 N F
1. NaNO2 HCl, H2O H2O
2. HBF4 heat Me Me Me O O O
Primary Aryl Diazonium Aryl Fluoride Arylamine Salt
diazotization-nucleophilic aromatic substitution
12 Preparation of Aryl Halides
Reaction of aryl diazonium salts with iodide ion (Section 22.18)
N H H N Cl N I Me Me Me NaNO2 KI
HCl, H O room 2 temp.
Primary Aryl Diazonium Aryl Iodide Arylamine Salt
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 Br Br BrOH
(hypobromous acid) Br Br Bromobenzene Br 35.7% 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 MgBr Mg
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
empty sp2 orbital Cl S 1 N 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 C SN1 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 -H+ E E
Electrophilic Aromatic Substitution
X X Nuc -X- Nuc 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
Cl OCH3
CH3OH + NaOCH3 + NaCl 85°C
NO2 NO2 (92%)
28 The More Electron-Deficient the Haloarene, the Faster the Substitution
Cl Cl Cl O O– Cl O N+ N+ N+ O– O O–
N+ N+ N+ –O O –O O –O O
1.0 7 x 1010 2.4 x 1015 too fast to measure
29 Direct Displacement Doesn’t Occur!
Br Nuc
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+ δ C Nuc C X C R R'' Nuc R'' X R 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 312 Cl 1.0 Br 0.8 NO2 I 0.4
*NaOCH3, CH3OH, 50°C 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
F OCH3
CH3OH + NaOCH3 + NaF 85°C
NO2 NO2 (92%)
37 Addition-Elimination Mechanism
Step 1 - Addition
bimolecular
CH3 O consistent with second- F order 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 CH3O F charged H formed faster when ring bears electron-withdrawing groups such as NO2 because negative charge is stabilized…….. N O O
40 Stabilization of Addition Product by Electron-Withdrawing Group
CH3O F CH3O F H H
N N O O O O
41 Rapid Collapse of Cyclohexadienyl Anion Intermediate
Step 2 - Elimination
OCH3 CH3O F H Fast F
N NO2 O O
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 Nuc Br Nuc I H H H H
N N N N O O O O O O O O
Most Stabilized Least Stabilized
44 23.7 Related Nucleophilic Aromatic Substitution Reactions
45 Substitution of Hexafluorobenzene
F OCH3 F F F F NaOCH3 (72%) CH3OH F F 65°C F F F F
Six fluorine CH3O F substituents stabilize F F negatively charged intermediate formed in rate-determining step F F and increase rate of F nucleophilic aromatic substitution. Anionic Intermediate
46 Substitution of 2-Chloropyridine
NaOCH3
CH3OH N Cl 50°C N OCH3
2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.
47 Substitution of 2-Chloropyridine
O CH3
Nitrogen is more NaOCH3 electronegative than carbon, stabilizes CH OH 3 N OCH the anionic N Cl 50°C 3 intermediate, and increases the rate at which it is formed.
OCH3
N Cl
Anionic Intermediate
48 Compare 2-Chloropyridine with Chlorobenzene
NaOCH3
CH3OH N Cl 50°C N OCH3
1. NaOH, H2O 370°C
+ Cl 2. H OH
49 Synthetic Application of Nucleophilic Aromatic Substitution
50 Ofloxacin
H O O Ofloxacin (trade F name Floxin) is OOHEt a broad- spectrum N N quinolone N O Me antibiotic Me H
Ofloxacin
http://www.ofloxacin.com/
51 Synthesis of Ofloxacin, Part 1
H O O H O O 1,4-Addition F F OEt OEt
OMe F F OMe F F HN F NH F 2 OH Me OH -MeO Me Elimination H O O F OEt
F F NH F OH Me
52 Synthesis of Ofloxacin, Part 2
H O O H O O Addition F F OEt OEt F F F N NH F F F OH OH Me Me Elimination Nucleophilic Aromatic H O O Substition F OEt
F N F OH Me
53 Synthesis of Ofloxacin, Part 3
H O O H O O Addition F F OEt OEt
F N F N F F Me HO Me O H H -F Elimination Nucleophilic H O O Aromatic Substition F OEt
F N O Me H
54 Synthesis of Ofloxacin, Part 4
H O O H O O Addition F F OEt OEt F F N N N Me O O Me NH H H N N Me Me Elimination
Nucleophilic Aromatic H O O Substition F OEt
N N N O Me Me H
55 Synthesis of Ofloxacin, Part 5
H O O F OEt
N N Me NaOH N O H O Me 2 H H O O F OH
N N N O Me Me H Ofloxacin
56 Synthetic Application of Nucleophilic Aromatic Substitution
57 Page 238 Furosemide
Ofloxacin (trade name Floxin) is a broad- spectrum quinolone antibiotic
Prozac another Ofloxacin good idea
http://www.ofloxacin.com/
58 23.8 Benzyne & the Elimination- Addition Mechanism of Nucleophilic Aromatic Substitution
59 Aryl Halides Undergo Substitution When Treated With Very Strong Bases
Cl NH2
KNH2, NH3 (52%) -33 °C
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 NH2 Br NH 2 Cine substitution product
63 Regiochemistry
CH3 CH3 CH3 CH3
NH2 NaNH2, NH3
-33 °C Br NH2
Cine substitution NH2 product Cine substitution product
64 Further Proof of Cine Substitution via 14C Label
Cl NH2 NH2 * * KNH2, NH3 * -33 °C
(48%) (52%)
Cine substitution product
65 Rationalization of Cine Substitution
Step 1 - Elimination
H H H Cl H Cl
H H H H N H H N H H H 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 2 2 Benzyne 2pZ-2pZ sp -sp π Bond 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 H R C C C H C C C C C R H
'Normal' C-C Triple Bond Benzyne C-C Triple Bond
68 Arynes are Highly Reactive Electrophiles
Step 2 - Addition
H H H H
H H H H N N H H H H Benzyne Aryl Anion
69 Aryl Anions are Strongly Basic
Step 3 - Protonation H N H H H H H H H H N H H H H N H N H H H H Substitution Benzyne Product
70 Hydrolysis of Chlorobenzene
Cl 14C labeling indicates * that the high- temperature reaction of chlorobenzene with NaOH proceeds NaOH, H2O via benzyne. 395 °C OH * * OH
(54%) (43%)
71 Substitution of Chlorobenzene Proceeds via Benzyne
* OH Cl * NaOH * NaOH H O H 2 Benzyne * OH Cine substitution product
72 Why the Temperature Difference?
Cl NH2
KNH2, NH3
-33 °C Sodium amide is a considerably stronger base than hydroxide and consequently better able Cl OH to carry out the rate- 1. NaOH, H O determining step 2 370°C
2. H+
73 All is Revealed
CH3 CH3 CH3 CH3
Br NH2 NaNH2 1. NaNH2
2. NH3 NH2
74 All is Revealed
CH3 CH3 CH3 CH3
NaNH2 1. NaNH2
2. NH3 NH2
Br NH2
75 All is Revealed
CH CH 3 3 CH3 CH3
1. NaNH NH2 NaNH2 2
2. NH3
Br 1. NaNH2 1. NaNH2 2. NH3 2. NH3
CH3 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 MgBr Mg
THF F heat F
Aryl bromide faster MgFBr with Mg than aryl fluoride
Benzyne
78 Preparation of Benzyne via Diazotization of Anthranilic Acid
See Question 23.23
O O
OH NaNO2 OH
H HCl, H2O N N Cl N H Aryl Diazonium Anthranilic Salt Acid NaOH
O
Heat O
N Benzyne N N2 + CO2
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 Y Y X diene dienophile cycloadduct
O H O H3C H H3C 100°C O O H H O O isoprene maleic anhydride cycloadduct
82 Electron-Deficient Alkynes Behave as Dienophiles
O CH3 O
120°C CH3
H H butadiene but-3-yn-2-one cycloadduct
83 Benzyne Behaves as a Dienophile
H O O 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 + THF F heat Diene Cycloadduct (46%)
Dienophilie
85 In the Absence of Dienes (or other nucleophiles) Benzyne Undergoes Dimerization and Trimerization
Br Mg
THF F 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