Chlorobenzene is very unreactive with nucleophiles 370 C 2. H + Nucleophilic Aromatic Substitution Aryl Halides & Benzyne

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Margery Jones
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1 hlorobenzene is very unreactive with nucleophiles ucleophilic Aromatic Substitution Aryl alides & Benzyne 1. a,, 70. ot practical. ot sufficiently reactive. Reasons for Low Reactivity Reasons for Low Reactivity S 1 empty sp orbital Aryl ation S1 not reasonable because: 1) bond is strong; therefore, ionization to a carbocation is a high-energy process ) aryl cations are highly unstable S not reasonable because ring blocks attack of nucleophile from side opposite bond to leaving group But... nitro-substituted aryl halides do undergo nucleophilic aromatic substitution readily Effect of nitro group is cumulative especially when nitro group is ortho and/or para to leaving group a 85 a (9%) x x too fast to measure

2 Which compound will react faster with a in methanol (50 o )? A) B) ) D) Kinetics follows second-order rate law: rate = k [aryl halide][nucleophile nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step Effect of leaving group unusual order: > > Br > I General onclusions About chanism X X Br I Relative Rate* bimolecular rate-determining step in which nucleophile attacks aryl halide rate-determining step precedes carbon-halogen bond cleavage rate-determining transition state is stabilized by electron-withdrawing groups (such as ) *a,, 50 Addition-Elimination chanism The Addition-Elimination chanism of ucleophilic 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 ) intermediate formed in first step loses halide (fast: aromaticity of ring restored in this step)

3 Reaction a 85 (9%) a ow many signals would be observed in the 1 - MR of the product isolated from the reaction of p-fluoronitrobenzene with potassium methoxide in methanol? A) B) ) 4 D) 5 Identify the rate law for the addition-elimination mechanism of nucleophilic aromatic substitution. A) Rate = [aryl halide] B) Rate = [aryl halide][nucleophile nucleophile] ) Rate = [aryl halide][nucleophile] D) Rate = [nucleophile[ nucleophile] Step 1 chanism bimolecular consistent with second- order kinetics; first order in aryl halide, first order in nucleophile chanism chanism Step 1 slow intermediate is negatively charged formed faster when ring bears electron- withdrawing groups such as

4 Stabilization of Rate-Determining Intermediate by itro Group Stabilization of Rate-Determining Intermediate by itro Group chanism chanism Step Step fast Which of the structures below is the most stable resonance structure for the reaction of p- fluoronitrobenzene with sodium methoxide? Leaving Group Effects > > Br > I is unusual, but consistent with mechanism carbon-halogen bond breaking does not occur until after the rate-determining step electronegative stabilizes negatively charged intermediate A) 1 only B) only ) only D) 1 and

5 The Role of Leaving Groups uc Most Stabilized uc uc Br uc I Least Stabilized Which of the following compounds is the least reactive toward nucleophilic aromatic substitution? A) 1-chloro-4-nitrobenzene B) 1-iodo--nitrobenzene ) 1-fluoro-4-nitrobenzene D) 1-bromo--nitrobenzene Example: exafluorobenzene a Related ucleophilic Aromatic Substitution Reactions 65 (7%) Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution. Example: -hloropyridine Example: -hloropyridine a 50 -hloropyridine reacts 0,000,000 times faster than chlorobenzene under these conditions. itrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.

6 Example: -hloropyridine ucleophilic Aromatic Substitution Reactions in Synthesis itrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. Triketones Triketones ontinued erbicides that inhibit PPD ydroxyphenyl pyruvate dioxygenase TBorphan drug for tyrosine anemia TB - Pharmaceutical allisto (mesotrione) S Inhibition of PPD ydroxyphenyl pyruvate dioxygenase Third Generation Synthetic Intermediate S S S MIkado (sulfotrione) Triketones: Synthetic Intermediate floxacin S Starting from,-dichlorothiophenol which is commercially available 1) S- methylate ) EAS acylation ) oxidation S floxacin (trade name loxin) is a broadspectrum quinolone antibiotic floxacin Et

7 Synthesis of floxacin, Part 1 Synthesis of floxacin, Part 1,4-Addition Et Et Addition Et Et - Elimination Et ucleophilic Aromatic Substition Elimination Et Synthesis of floxacin, Part Synthesis of floxacin, Part 4 ucleophilic Aromatic Substition Addition Et - Elimination Et Et ucleophilic Aromatic Substition Addition Et Et Elimination Et Synthesis of floxacin, Part 5 Et a The Elimination-Addition chanism of ucleophilic Aromatic Substitution: Benzyne floxacin

8 Aryl alides Undergo Substitution When Treated With Very Strong Bases K, (5%) Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it Br a, Regiochemistry Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it a, Br a, What product will be isolated when o- bromotoluene is treated with a in? Same result using 14 label * K, A) B) ) D) Both A and B (5%) * * (48%)

9 chanism chanism Step 1 Step 1 compound formed in this step is called benzyne Benzyne Benzyne - A Reactive Molecule With an Abnormal π-bond Benzyne has a strained triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate. Benzyne Benzyne has a reactive triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate. p Z -p Z! Bond sp -sp! Bond Benzyne - A Reactive Aromatic Molecule With An Abnormal, In-Plane π-bond Step chanism overlapping sp orbitals poor overap results in a weak, reactive bond R R 'ormal' - Triple Bond Benzyne - Triple Bond

10 chanism chanism Step Step Angle strain is relieved. The two sp-hybridized ring carbons in benzyne become sp hybridized in the resulting anion. Step chanism Which of the following compounds give a single benzyne intermediate on reaction with sodium amide? A) 1 only B) 1 and ) only D) 1 and ther Routes to Benzyne Diels-Alder Reactions 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-- fluorobenzene.

11 ther Routes to Benzyne Benzyne as a Dienophile Br Mg, T heat MgBr Benzyne is a fairly reactive dienophile,, and gives Diels-Alder adducts when generated in the presence of conjugated dienes. MgBr The Diels-Alder Reaction Revisited Electron-Deficient Alkynes Behave as Dienophiles A B cycloaddition A B X Y Y X diene dienophile cycloadduct 100 isoprene maleic anhydride cycloadduct 10 butadiene but--yn--one cycloadduct Benzyne Behaves as a Dienophile Benzyne as a Dienophile Benzyne Br Mg, T heat (46%) Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.

Electrophilic Aromatic Substitution Reactions

Electrophilic Aromatic Substitution Reactions, Course Notes Archive, 1 Electrophilic Aromatic Substitution Reactions An organic reaction in which an electrophile substitutes a hydrogen atom in an aromatic