Nucleophilic Aromatic Substitution Aryl Halides

S N 2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible. Chlorobenzene is quite unreactive with nucleophiles

S N 1 is also unlikely: Aryl Cations are Highly Unstable S N 1 not reasonable because: 1) 1)C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process 2) 2)aryl cations are highly unstable

nitro-substituted aryl halides do undergo nucleophilic aromatic substitution readily But...Cl NO 2 + NaOCH 3 CH 3 OH 85°C OCH 3 NO 2 + NaCl (92%)

especially when nitro group is ortho and/or para to leaving group Effect of nitro group is cumulative Cl1.0Cl NO 2 7 x Cl NO 2 O2NO2NO2NO2N 2.4 x Cl NO 2 too fast to measure

follows second-order rate law: rate = k [aryl halide][nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step Kinetics

Effect of leaving group unusual order: F > Cl > Br > I X NO 2 X Relative Rate* F Cl Br I *NaOCH 3, CH 3 OH, 50°C

bimolecular rate-determining step in which nucleophile attacks aryl halidebimolecular rate-determining step in which nucleophile attacks aryl halide rate-determining step precedes carbon-halogen bond cleavagerate-determining step precedes carbon-halogen bond cleavage rate-determining transition state is stabilized by electron-withdrawing groups (such as NO 2 )rate-determining transition state is stabilized by electron-withdrawing groups (such as NO 2 ) General Conclusions About Mechanism

The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution

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) Addition-Elimination Mechanism

ReactionF NO 2 + NaOCH 3 CH 3 OH 85°C OCH 3 NO 2 + NaF (93%)

Mechanism OCH 3 – NO 2 F H H H H bimolecular consistent with second- order kinetics; first order in aryl halide, first order in nucleophile Step 1

Mechanismslow OCH 3 – NO 2 F H H H H NO 2 F H H H H – OCH 3 Step 1

Mechanism NO 2 F H H H H – OCH 3 intermediate is negatively charged formed faster when ring bears electron- withdrawing groups such as NO 2

Stabilization of Rate-Determining Intermediate by Nitro Group N F H H H H OCH 3 OO + – –

Stabilization of Rate-Determining Intermediate by Nitro Group N F H H H H OCH 3 OO + – – N F H H H H OCH 3 OO + – –

Mechanism NO 2 F H H H H – OCH 3 Step 2

Mechanism fast OCH 3 NO 2 H H H H F H H H H – OCH 3 F – Step 2

carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F stabilizes negatively charged intermediate Leaving Group Effects F > Cl > Br > I is unusual, but consistent with mechanism

The Role of Leaving Groups

Related Nucleophilic Aromatic Substitution Reactions

Example: Hexafluorobenzene FFF F F F NaOCH 3 CH 3 OH 65°C F OCH 3 F F F F (72%) Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution.

Example: 2-Chloropyridine NaOCH 3 CH 3 OH 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions. Cl N OCH 3 N 50°C

Example: 2-Chloropyridine Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. Cl N OCH 3 –

Example: 2-Chloropyridine Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. Cl N OCH 3 – Cl N –

Nucleophilic Aromatic Substitution Reactions in Synthesis

Triketones Herbicides that inhibit HPPD Hydroxyphenyl pyruvate dioxygenase NTBC- orphan drug for tyrosine anemia

Triketones Continued Inhibition of HPPD Hydroxyphenyl pyruvate dioxygenase Third Generation Synthetic Intermediate

Synthetic Intermediate Triketones: Synthetic Intermediate Starting from 2,3-dichlorothiophenol which is commercially available 1)S- methylate 2)EAS acylation 3)oxidation

Ofloxacin Ofloxacin (trade name Floxin) is a broad- spectrum quinolone antibiotic Ofloxacin

Synthesis of Ofloxacin, Part 1

Synthesis of Ofloxacin, Part 2

Synthesis of Ofloxacin, Part 3

Synthesis of Ofloxacin, Part 4

Synthesis of Ofloxacin, Part 5

The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution: Benzyne

Aryl Halides Undergo Substitution When Treated With Very Strong Bases Cl NH 2 KNH 2, NH 3 –33°C (52%)

CH 3 NH 2 new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it Regiochemistry + NaNH 2, NH 3 –33°C CH 3 Br NH 2

new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it Regiochemistry CH 3 Br + NaNH 2, NH 3 –33°C CH 3 NH 2 CH 3 NH 2

Regiochemistry + NaNH 2, NH 3 –33°C CH 3 NH 2 CH 3 NH 2 CH 3 Cl + NH 2

Same result using 14 C label Cl * KNH 2, NH 3 –33°C NH 2 * + * (48%)(52%)

Mechanism NH2NH2NH2NH2 – Step 1 HH H H Cl H

Mechanism NH2NH2NH2NH2 – Step 1 HH H H Cl H HHH H NH2NH2NH2NH2 H Cl – compound formed in this step is called benzyne

Benzyne HHH H Benzyne has a strained triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate.

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

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

Mechanism NH2NH2NH2NH2 – Step 2 HHH H

Mechanism NH2NH2NH2NH2 – Step 2 HHH H HHH H NH2NH2NH2NH2 – Angle strain is relieved. The two sp-hybridized ring carbons in benzyne become sp 2 hybridized in the resulting anion.

Mechanism Step 3 HHH H NH2NH2NH2NH2 – NH2NH2NH2NH2 H

Mechanism NH2NH2NH2NH2 – Step 3 HHH H NH2NH2NH2NH2 – NH2NH2NH2NH2 H H HHH H NH2NH2NH2NH2

Hydrolysis of Chlorobenzene Cl * NaOH, H 2 O 395°C OHOHOHOH * + OHOHOHOH* (54%)(43%) 14 C labeling indicates that the high- temperature reaction of chlorobenzene with NaOH goes via benzyne.

Diels-Alder Reactions of Benzyne

Other Routes to 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.

Other Routes to Benzyne BrF Mg, THF heat MgBr F FMgBr +

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

The Diels-Alder Reaction Revisited

Electron-Deficient Alkynes Behave as Dienophiles

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

Benzyne as a Dienophile Br F Mg, THF heat + (46%)