ORGANIC CHEMISTRY LECTURE

ORGANIC CHEMISTRY LECTURE - Electrophilic Aromatic...

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Unformatted text preview: Electrophilic Aromatic Substitution O H C C C H C O CH3 CH3 Lecture 12 Exam We will try to get it back on Tuesday Performance looked pretty good Key will be posted outside of exam room Structure need not be perfect to get a "good" score Let's look at a couple of the questions Chemistry 618B Some Isomers!! 3.61 3.61 3.59 3.59 3.59 3.59 9 8 3.35 C H3 O HC C H3 O 7 3.60 3.62 3.62 3.62 3.62 3.62 3.59 6 3.58 5 3.58 3.58 3.58 3.58 4 1.12 1.13 1.88 3 3.60 2 1 0 3.59 3.61 3.62 3.58 3.5 3.0 2.5 2.0 1.5 1.0 3.12 3.13 3.11 9 8 3.61 O HC 7 O 3.13 3.14 3.10 6 3.09 5 4 3 CH3 CH3 1.35 1.36 3.10 2 1 0 3.5 3.13 3.13 3.14 3.12 3.11 3.11 3.09 2.03 3.0 2.5 2.0 1.5 Chemistry 618B H + +E Y E +H Y Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution H E + + H E + H+ E Please be sure that you can do this and that it makes sense to you!! H + H E + E H H Chemistry 618B The Friedel-Crafts Reaction.. Circa 1877 Charles Friedel James Craft Making C-C bonds is.... Chemistry 618B DANGER !!!! Hydrogenolysis O CH3COCl AlCl3 H2 Pd/C There are two nice tricks hidden here Please be sure to remember this reaction!!! Chemistry 618B Di- and Polysubstitution Existing groups on a benzene ring influence further substitution in both orientation and rate Orientation: certain substituents direct preferentially to ortho & para positions; others direct preferentially to meta positions substituents are classified as either ortho-para directing or meta directing Chemistry 618B Di- and Polysubstitution Rate: certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower substituents are classified as activating toward further substitution, or deactivating Chemistry 618B Relative rates of Nitration OH H Cl NO2 1000 1.0 Reactivity 0.033 6x10-8 Chemistry 618B Real Fast Pretty fast Kinda slow Pretty slow Slow Real Slow Chemistry 618B Effect on Regioselectivity Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Meta directors direct an incoming electrophile to positions meta to themselves. All meta directors are deactivating All ortho-para directors are activating except halogen Chemistry 618B Di- and Polysubstitution Some Observations Alkyl groups, phenyl groups, and all groups in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other groups are meta directing. All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating Chemistry 618B Theory of Directing Effects So...what's going on here???? The rate of EAS is limited by the slowest step in the mechanism...duh For EAS, the rate-limiting step is attack of E+ on the aromatic ring to form a resonance-stabilized cation intermediate The more stable this cation intermediate, the faster the ratelimiting step and the faster the overall reaction Chemistry 618B ortho Nitration of Toluene CH3 H + H H NO2 H H ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H + H H NO2 H H ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H + H H NO2 H H CH3 H H + NO2 H H H this resonance form is a tertiary carbocation ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H + H H NO2 H H CH3 H H H + NO2 H H the rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character meta Nitration of Toluene CH3 H H H + H H NO2 meta Nitration of Toluene CH3 H H H + H H NO2 H H + CH3 H H NO2 H meta Nitration of Toluene CH3 H H + H H NO2 H H + CH3 H H NO2 H H CH3 H + H NO2 H H H all the resonance forms of the rate-determining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon Nitration of Toluene: Interpretation The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations. Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. This explains why the major products are o- and p-nitrotoluene. Nitration of Toluene: Partial Rate Factors The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions. Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene. Nitration of Toluene: Partial Rate Factors CH3 1 1 1 1 1 1 42 2.5 58 42 2.5 All ring positions in toluene are more reactive than any position of benzene. A methyl group activates all of the ring positions but the effect is greatest at the ortho and para positons. Steric hindrance by the methyl group makes each ortho position slightly less reactive than para. Let's try Some More Adding a Second Substiuent Methoxy is is therefore an "o-p director" Chemistry 618B Adding a Second Substiuent Nitro is therefore a "meta director" Chemistry 618B Di- and Polysubstitution Sequence matters! CH3 HNO3 H2 SO 4 CH3 NO2 K2 Cr 2 O7 H2 SO 4 NO2 p-Nitrobenzoic acid CO2 H HNO3 H2 SO 4 NO2 m-Nitrobenzoic acid CO2 H CO2 H K2 Cr 2 O7 H2 SO 4 Chemistry 618B Synthesis of m-Bromoacetophenone Br CH3 O Br O CH3 Which substituent should be introduced first? Chemistry 618B Let's use it!! HNO3 H2SO4 CH3CH2Cl AlCl3 NO2 NO2 CH3CH2Cl AlCl3 CH2CH3 HNO3 H2SO4 CH2CH3 NO2 One of these is very wrong !! CH2CH3 Chemistry 618B Make this... Br Work Backwards!! CH3CH2Cl Br Br2 FeBr3 AlCl3 H2, Pd/C O Br Br Br2 FeBr3 O O CH3C Cl AlCl3 Chemistry 618B Multiple Substituent Effects The Simplest Case all possible EAS sites may be equivalent CH3 O O + CH3COCCH3 CH3 CH3 99% AlCl3 CH3 O CCH3 Another Straightforward Case CH3 Br2 Fe NO2 NO2 86-90% directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group CH3 Br Generalization regioselectivity is controlled by the most activating substituent The Simplest Case all possible EAS sites may be equivalent strongly activating NHCH3 Br2 acetic acid Cl NHCH3 Br Cl 87% When activating effects are similar... CH3 HNO3 H2SO4 C(CH3)3 CH3 NO2 C(CH3)3 88% substitution occurs ortho to the smaller group Steric effects control regioselectivity when electronic effects are similar CH3 HNO3 CH3 H2SO4 NO2 98% position between two substituents is last position to be substituted CH3 CH3 Regioselective Synthesis of Disubstituted Aromatic Compounds Factors to Consider order of introduction of substituents to ensure correct orientation Synthesis of m-Bromoacetophenone Br Which substituent should be introduced first? O CCH3 Synthesis of m-Bromoacetophenone Br para If bromine is introduced first, p-bromoacetophenone is major product. O CCH3 meta Synthesis of m-Bromoacetophenone Br O CCH3 O O CH3COCCH3 AlCl3 O CCH3 Br2 AlCl3 Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics Synthesis of m-Nitroacetophenone NO2 Which substituent should be introduced first? O CCH3 Synthesis of m-Nitroacetophenone NO2 If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. O CCH3 Synthesis of m-Nitroacetophenone O2N O CCH3 O O CH3COCCH3 AlCl3 O CCH3 HNO3 H2SO4 Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics sometimes electrophilic aromatic substitution must be combined with a functional group transformation Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 CH3 Which first? (oxidation of methyl group or nitration of ring) NO2 Synthesis of p-Nitrobenzoic Acid from Toluene CO2H nitration gives m-nitrobenzoic acid CH3 oxidation gives p-nitrobenzoic acid NO2 CH3 Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 CH3 HNO3 H2SO4 NO2 NO2 Na2Cr2O7, H2O H2SO4, heat Substitution in Naphthalene Naphthalene H H H H H two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2 H 1 2 H H EAS in Naphthalene O O CH3CCl AlCl3 90% is faster at C-1 than at C-2 CCH3 EAS in Naphthalene E H + E H + when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained EAS in Naphthalene + E H + E H when attack is at C-2 in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed Substitution in Heterocyclic Aromatic Compounds Generalization There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive.. Pyridine N Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes electrons to be held more strongly than in benzene. Pyridine SO3, H2SO4 N HgSO4, 230C N 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. SO3H Pyrrole, Furan, and Thiophene N O S H Have 1 less ring atom than benzene or pyridine to hold same number of electrons (6). electrons are held less strongly. These compounds are relatively reactive toward EAS.. Example: Furan O O O + CH3COCCH3 BF3 O O CCH3 75-92% undergoes EAS readily C-2 is most reactive position ...
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This note was uploaded on 04/23/2009 for the course ORGANIC CH 2410 taught by Professor Unknown during the Spring '09 term at Toledo.

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