aryl halides

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Aryl halides

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Topics Covered: Aryl Halides - Bonding, Physical Properties and Reactions Nucleophilic Aromatic Substitution of Chlorobenzene Nucleophilic Aromatic Substitution: Addition-Elimination Floxcin - Application of Nucleophilic Aromatic Substitution Nucleophilic Aromatic Substitution: Elimination-Addition Benzyne: Generation, Bonding and Reactions Today’s Lecture

Chapter 10Aryl Halides : 

Chapter 10Aryl Halides

Bonding in Aryl Halides : 

Bonding in Aryl Halides

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What’s the Difference Between Ar- and Ph-?

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Aryl Halides 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.

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sp3 X = H 410 (98) X = Cl 339 (81) Bond Energy:kJ/mol (kcal/mol) Dissociation Energies of Selected Compounds

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Resonance Picture C-X bonds in aryl halides have more double bond character than C-X bonds in alkyl halides

Sources of Aryl Halides : 

Sources of Aryl Halides

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Preparation of Aryl Halides Halogenation of arenes electrophilic aromatic substitution

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Preparation of Aryl Halides The Sandmeyer reaction diazotization-nucleophilic aromatic substitution

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Preparation of Aryl Halides The Schiemann reaction (Section 22.17) diazotization-nucleophilic aromatic substitution

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Preparation of Aryl Halides Reaction of aryl diazonium salts with iodide ion (Section 22.18) diazotization-nucleophilic aromatic substitution

Physical Properties of Aryl Halides : 

Physical Properties of Aryl Halides

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resemble alkyl halides are essentially insoluble in water less polar than alkyl halides Physical Properties of Aryl Halides

Reactions of Aryl Halides:A Review and a Preview : 

Reactions of Aryl Halides:A Review and a Preview

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Reactions Involving Aryl Halides Electrophilic aromatic substitution halide substituents are ortho-para directing & deactivating

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Reactions Involving Aryl Halides Electrophilic aromatic substitution ADD DDT SYNTHESIS

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Reactions Involving Aryl Halides Formation of aryl Grignard reagents

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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.

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Nucleophilic Substitution of Chlorobenzene This reaction does not proceed via SN2……..

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the SN2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible. Why is Chlorobenzene Unreactive?

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SN1 Also Unlikely: Aryl Cations are Highly Unstable SN1 not reasonable because: C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process aryl cations are highly unstable

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SN1 Reaction is Possible with Very Powerful Leaving Groups such as Dinitrogen This is a unique case: halides are not good enough leaving groups for this process to occur.

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What is the Mechanism of This Reaction?

23.5Nucleophilic Substitution inNitro-Substituted Aryl Halides : 

23.5Nucleophilic Substitution inNitro-Substituted Aryl Halides

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Nucleophilic Aromatic Substitution (SNAr)?

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In contrast to chlorobenzene, nitro-substituted aryl halides undergo nucleophilic aromatic substitution at reasonable temperatures Electron-Deficient Haloarenes Undergo Nucleophilic Aromatic Substitution

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The More Electron-Deficient the Haloarene, the Faster the Substitution

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Direct Displacement Doesn’t Occur!

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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

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Reaction Rate Depends on X: I > Br > Cl > F Effect of Leaving Group Upon Rate of SN2 During SN2 reactions, the C-X bond breaks during the rate-determining step C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol)

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Effect of Leaving Group in Nucleophilic Aromatic Substitution C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol)

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General Features of Mechanism bimolecular rate-determining step in whichnucleophile attacks aryl halide rate-determining step precedes carbon-halogenbond cleavage rate-determining transition state is stabilized byelectron-withdrawing groups (such as NO2)

23.6The Addition-Elimination Mechanismof Nucleophilic Aromatic Substitution : 

23.6The Addition-Elimination Mechanismof Nucleophilic Aromatic Substitution

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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)

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Addition-Elimination Mechanism

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Addition-Elimination Mechanism Step 1 - Addition bimolecular consistent with second-order kinetics; first order in aryl halide, first order in nucleophile Rate = k [CH3ONa] [arene]

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Addition-Elimination Mechanism Step 1 - Addition

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intermediate is negatively charged formed faster when ring bears electron-withdrawing groups such as NO2 because negative charge is stabilized…….. Reaction Involves an Anionic Intermediate

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Stabilization of Addition Productby Electron-Withdrawing Group

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Rapid Collapse of Cyclohexadienyl Anion Intermediate Step 2 - Elimination

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carbon-halogen bond breaking does not occuruntil after the rate-determining step electronegative F stabilizes negatively charged intermediate F > Cl > Br > I is unusual, but consistentwith mechanism The Role of Leaving Groups

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The Role of Leaving Groups

23.7Related Nucleophilic AromaticSubstitution Reactions : 

23.7Related Nucleophilic AromaticSubstitution Reactions

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Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution. Substitution of Hexafluorobenzene

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Substitution of 2-Chloropyridine 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.

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Substitution of 2-Chloropyridine Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.

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Compare 2-Chloropyridine with Chlorobenzene

Synthetic Application ofNucleophilic Aromatic Substitution : 

Synthetic Application ofNucleophilic Aromatic Substitution

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Ofloxacin http://www.ofloxacin.com/ Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic Ofloxacin

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Synthesis of Ofloxacin, Part 1

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Synthesis of Ofloxacin, Part 2

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Synthesis of Ofloxacin, Part 3

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Synthesis of Ofloxacin, Part 4

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Synthesis of Ofloxacin, Part 5

Synthetic Application ofNucleophilic Aromatic Substitution : 

Synthetic Application ofNucleophilic Aromatic Substitution

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Page 238 Furosemide http://www.ofloxacin.com/ Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic Prozac another good idea Ofloxacin

23.8 Benzyne & the Elimination-Addition Mechanismof Nucleophilic Aromatic Substitution : 

23.8 Benzyne & the Elimination-Addition Mechanismof Nucleophilic Aromatic Substitution

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Aryl Halides Undergo Substitution WhenTreated With Very Strong Bases Ammonia: pKa = 34; b.p. = -33 °C Potassium Amide: strong base

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new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it Regiochemistry Cine substitution product

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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.

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new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it Regiochemistry Cine substitution product

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Regiochemistry Cine substitution product Cine substitution product

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Further Proof of Cine Substitution via 14C Label Cine substitution product

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compound formed in this step is called benzyne Rationalization of Cine Substitution Step 1 - Elimination

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Benzyne - A Reactive Molecule With an Abnormal p-Bond Benzyne has a reactive triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate.

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Benzyne - A Reactive Aromatic Molecule With An Abnormal, In-Plane p-Bond

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Arynes are Highly Reactive Electrophiles Step 2 - Addition

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Aryl Anions are Strongly Basic Step 3 - Protonation

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Hydrolysis of Chlorobenzene 14C labeling indicates that the high-temperature reaction of chlorobenzene with NaOH proceeds via benzyne.

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Substitution of Chlorobenzene Proceeds via Benzyne Cine substitution product

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Why the Temperature Difference? Sodium amide is a considerably stronger base than hydroxide and consequently better able to carry out the rate-determining step

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All is Revealed

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All is Revealed

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All is Revealed

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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.

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Other Methods for the Preparation of Benzyne Aryl bromide faster with Mg than aryl fluoride

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Preparation of Benzyne via Diazotization of Anthranilic Acid See Question 23.23

23.9Cycloaddition Reactions of Benzyne : 

23.9Cycloaddition Reactions of Benzyne

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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.

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The Diels-Alder Reaction Revisited Section 10.12

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Electron-Deficient Alkynes Behave as Dienophiles

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Benzyne Behaves as a Dienophile Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.

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Benzyne Participates in Diels-Alder Reactions

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In the Absence of Dienes (or other nucleophiles) Benzyne Undergoes Dimerization and Trimerization

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Topics Covered: Aryl Halides - Bonding, Physical Properties and Reactions Nucleophilic Substitution of Chlorobenzene Nucleophilic Aromatic Substitution: Addition-Elimination Synthetic Application of Nucleophilic Aromatic Substitution Nucleophilic Aromatic Substitution: Elimination-Addition Benzyne: Generation, Bonding and Reactions Today’s Lecture

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Information & Suggested Problems Suggested Problems: 23.10-23.27 ----------------------------------------------------------------- Office Hour: Thursday, 3.15 P.M., SES 4446