1 YSU YSU YSU YSU 2 YSU YSU YSU YSU 3 Completely - - PDF document

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H C H H H

YSU YSU ~1800 – Organic Chemistry : the chemistry of natural products based

• n carbon

2010 – Organic Chemistry : “molecular engineering”

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12 Reactions of benzene – electrophilic aromatic substitution 13 Spectroscopy – how do you know what the structure is? 14 C-C bond formation using organometallic compounds 15 Chemistry of alcohols, diols and thiols 16 Chemistry of ethers, epoxides and sulfides 17 Aldehydes and ketones – preparation and uses 18 Enols and enolates in the formation of C-C bonds

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18 Enols and enolates in the formation of C C bonds 19 Carboxylic acids – preparation and uses 20 Nucleophilic acyl substitution 21 Ester enolates – formation and uses in C-C bond formation 22 Chemistry of amines 25 Overview of carbohydrate chemistry 26 Overview of lipid chemistry 27 Overview of amino acid, peptide and protein chemistry

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YSU YSU Completely delocalized (6) pi system lends stability (aromatic) YSU YSU

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Alkenes react by addition

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Benzene reacts by substitution

YSU YSU Resonance-stabilized cation

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Energy diagram for EAS in benzene Figure 12.1 YSU YSU 12.3 Nitration YSU YSU 12.4 Sulfonation 12.5 Halogenation Br

Br2, Fe

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Problems: Alkyl groups may rearrange during reaction Products are more reactive than benzene Uses: Alkyl benzenes readily oxidized to benzoic acids using KMnO4

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(CH3)3CCl AlCl3 CH3 CH3 CH3 YSU YSU

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AlCl3 Cl H3C CH3 C CH3 CH3 CH3

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Products react more slowly than benzene - cleaner reaction No carbocation rearrangements

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Make the acyl benzene first (clean, high yielding reaction) Reduce the ketone group down to the methylene (C=O to CH2) Avoids rearrangement problems, better yields

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Make the acyl benzene first (clean, high yielding reaction) Reduce the ketone group down to the methylene (C=O to CH2) Intermolecular and intramolecular variants both useful

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Make the nitro benzene first, clean high yielding reaction Reduce the nitro group down to the amine Difficult to introduce the amino group by other methods

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Relative rates in nitration reaction; now bringing in a second substituent

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CH3 is said to be an ortho/para director (o/p director) - Regioselectivity

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CF3 HNO3, H2SO4 CF3 NO2 CF3 NO2 CF3 + + YSU YSU NO2 6% 91% 3%

CF3 is said to be a meta director (m director) - Regioselectivity

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• Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene)

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• Fig. 12.6 – Energy diagrams for CF3C6H5 nitration (vs. benzene)

Definitions: Activating = reacts faster than benzene in EAS Deactivating = reacts slower than benzene in EAS In General : all activating groups are o/p directors YSU YSU g g p p halogens are slightly deactivating but are o/p directors strongly deactivating groups are m directors Typical:

• OH, -NO2, -NH2, -Br, -Cl, -CH3, -CO2H, -COCH3

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R alkyl HO hydroxyl RO alkoxy RCO acyloxy O

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Example: OCH3 HNO3, H2SO4 OCH3 NO2 OCH3 NO2 + Alkyl groups stabilize carbocation by hyperconjugation Lone pairs on O (and others like N) stabilize by resonance

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Second substituent goes meta by default – best carbocation Carbocations for o/p processes destabilized

YSU YSU Reactivity (i.e. rate) is a balance between inductive effect (EW) and resonance effect (ED) – larger Cl, Br, I do not push lone pair into pi system as well as F, O, N, which are all first row (2p)

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Regioselectivity - second substituent goes o/p – better carbocations

• /p processes stabilized by lone pairs

AlCl3 99% CH3 CH3 CH3

H3C O O O CH3

CH3 O CH3 87% NHCH3 NHCH3 Br Cl Cl Br2, acetic acid

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99% 86% CH3 CH3 Br NO2 NO2 Br2, Fe 87% 88% CH3 CH3 NO2 C(CH3)3 C(CH3)3 HNO3, H2SO4

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Have to be careful about when to introduce each substituent Remember – isomers (e.g. o/p mixtures) may be separated

90% CH3CCl AlCl3 O O CH3 but not O CH3 SO H

12.17 Naphthalene

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N HgSO4, 230 oC SO3, H2SO4 N SO3H O O O CH3

H3C O O O CH3

BF3

12.18 Heterocycles