Chemistry 3720 - Organic Chemistry II Dr. Peter Norris 6014 Ward Beecher (330) 941-1553 pnorris@ysu.edu http://www.as.ysu.edu/~pnorris/public_html Lecture needs: Carey Molecular models Adobe Acrobat Reader Web access Lab needs: Pavia, Lampman, Kriz and Engel Goggles Lab coat Bound notebook 1 3 7 2 0 We b R e s o u r c e s http://www.as.ysu.edu/~chemistry http://www.as.ysu.edu/~pnorris/public_html (Contains lab and lecture material, problem sets and old exams) Need the Adobe Acrobat Reader to download printed material, links to the site are on the web page Chemistry 3720 page includes practice problems on NMR spectroscopy (Chapter 13) Message board linked to 3720 home page for asking questions, especially before exams http://www.as.ysu.edu/~chem/ http://www.as.ysu.edu/~pnorris/ 2 Chemistry Computer Lab North end of Ward Beecher on the 5th floor Dell Pentium 4 machines Hewlett Packard network laserjet printers Student assistant (?) All PC’s have MS Office, ChemDraw, ChemSketch, ACD NMR prediction software, Spartan molecular modeling package, Netscape Navigator and MS Internet Explorer Open 9-5 Mon through Fri (see lab door for schedule) Class Requirements (see s yllabus) 3720 Lecture: 3 term exams, 100 points each 1 Final exam, 200 points No dropped tests 3720 Lab: 100 points total. Must pass lab (>60%) in order to pass 3720/3720L Misconduct: Any copying or other forms of cheating will be dealt with severely Why a year of Organic Chemistry? Organic Chemistry chemical synthesis New Materials materials chemistry New Compounds medicinal chemistry New Medicines Biochemistry and Chemical Biology Nanotech, Engineering Proteomics, Genetics Pharmacy, Medicine 3 Chemistry 3719-3720 H C H H H ~1800 – Organic Chemistry : the chemistry of natural products based on carbon 2008 – Organic Chemistry : “molecular engineering” 3720 Overview of Chapters 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 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 Chapter 12 - Reactions of Benzene - EAS 12.1 Introduction to benzene vs. alkenes 12.2 Mechanistic principles of Electrophilic Aromatic Subsitution 12.3 Nitration of benzene, reduction to aminobenzenes 12.4 Sulfonation of benzene 12.5 Halogenation of benzene 12.6 Friedel-Crafts alkylation of benzene 12.7 Friedel-Crafts alkylation of benzene 12.8 Alkylbenzenes via acylation then reduction 12.9 Rate and regioselectivity in EAS 12.10 Nitration of toluene - rate and regioselectivity 12.11 Nitration of CF3 -benzene - rate and regioselectivity 12.12 Substituent effects in EAS: Activating Substituents 12.13 Substituent effects in EAS: Strongly Deactivating Substituents 12.14 Substituent effects in EAS: Halogens 12.15 Multiple substituent effects in EAS 12.16 Regioselective synthesis of disubstituted aromatic compounds 12.17 12.18 Substitution in Naphthalene Substitution in heterocyclic aromatic compounds 4 Introduction – Benzene vs. Alkenes Br Br Br no heat dark Br Br Br no colour change (no reaction) no heat dark Completely delocalized (6) pi system lends stability (aromatic) 12.2 Mechanistic Principles of EAS Alkenes react by addition E Y E E Y Y Benzene reacts by substitution E Y Y H E -H Y E Resonance-stabilized cation 5 General Mechanism of EAS on Benzene Energy diagram for EAS in benzene Figure 12.1 Electrophilic Aromatic Substitutions on Benzene H HNO 3 , H 2 SO 4 NO 2 12.3 Nitration H SO 3H SO 3 , H 2 SO 4 12.4 Sulfonation H Br Br 2, Fe 12.5 Halogenation 12.6 Friedel-Crafts Alkylation of Benzene H CH2CH3 CH3CH2Cl AlCl3 CH3 H C CH3 (CH3)3CCl CH3 AlCl3 H H3C Cl CH3 CH3 C CH3 CH 3 AlCl3 Problems: Alkyl groups may rearrange during reaction Products are more reactive than benzene Uses: Alkyl benzenes readily oxidized to benzoic acids using KMnO4 6 12.7 Friedel-Crafts Acylation of Benzene H O O RCCl C R AlCl3 O H HC 3 O O O CCH3 CH 3 AlCl3 O AlCl 3 RCCl O RC R C O Products react more slowly than benzene - cleaner reaction No carbocation rearrangements 12.8 Alkylbenzenes via Acylation/Reduction Zn, HCl O C H H C R (Clemmensen) R or NH2NH2, KOH heat (Wolff-Kischner) O AlCl3 Cl Zn, HCl O 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 Aminobenzenes via Nitration/Reduction (not in text) H O N H Sn, HCl N O HNO3, H2SO4 NO2 H Sn, HCl H N H 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 7 12.9 Activation and Deactivation by Substituents (Rates) X X HNO 3, H2SO 4 NO2 CF3 0.000025 H CH3 1.0 25 Relative rates in nitration reaction now bringing in a second substituent 12.9 Nitration of Toluene vs Nitration of (Trifluoromethyl)benzene CH3 CH3 HNO3, H2 SO4 CH3 CH3 NO2 + + NO2 NO2 63% 3% 34% CH3 is said to be an ortho/para director (o/p director) - Regioselectivity CF3 CF3 HNO3, H2SO4 CF3 CF3 NO2 + + NO2 NO2 6% 91% 3% CF3 is said to be a meta director (m director) - Regioselectivity 12.10 Rate and Regioselectivity in Nitration of Toluene CH3 CH3 HNO3 , H2 SO4 CH3 CH3 NO2 + + NO2 NO2 63% 3% 34% Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene) 8 12.11 Rate and Regioselectivity in Nitration of CF3C6H5 CF3 CF3 HNO3, H2SO4 CF3 CF3 NO2 + + NO2 NO2 6% 91% 3% Fig. 12.6 – Energy diagrams for CF3C6H5 nitration (vs. benzene) 12.12 Substituent Effects – Activating Substituents General : all activating groups are o/p directors halogens are slightly deactivating but are o/p directors strongly deactivating groups are m directors Activating Substituents O R HO alkyl RO hydroxyl RCO alkoxy OCH 3 acyloxy OCH 3 HNO3 , H2 SO4 Example: OCH 3 NO2 + NO2 Alkyl groups stabilize carbocation by hyperconjugation Lone pairs on O (and others like N) stabilize by resonance 12.13 Subst. Effects – Strongly Deactivating Substituents O O O HC R C HO C aldehyde ketone carboxylic acid O O Cl RO C C N O HO S C ester acyl chloride O2 N O nitrile sulfonic acid NO2 nitro NO2 Br 2 , Fe Example: Br Second substituent goes meta by default – best carbocation 9 12.14 Substituent Effects – Halogens X X X X = F, Cl, Br X = F, Cl, Br 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) Example: Cl Cl HNO3, H2 SO4 Cl Cl NO2 + + NO2 NO2 30% 1% 69% Regioselectivity - second substituent goes o/p – better carbocations 12.15 Multiple Substituent Effects CH3 O H3C NHCH3 CH3 O O O CH3 NHCH3 Br2, acetic acid CH 3 Br AlCl3 Cl CH3 CH3 Cl 99% 87% CH3 CH3 CH3 Br Br2, Fe NO2 C(CH 3)3 NO2 NO2 CH3 HNO3, H2SO4 C(CH3)3 86% 88% Interplay between power of directing group and size of substituents 12.16 Regioselective Synthesis of Disubstituted Derivs. O O CH3 O CH3 CH3 Br Br NO2 CO2 H CH2CH3 Br NO2 Have to be careful about when to introduce each substituent Remember – isomers (e.g. o/p mixtures) may be separated 10 12.17-12.18 Substitution in Other Aromati c Systems 12.17 Naphthalene O CH3 O O CH3 CCl CH3 but not AlCl3 90% 12.18 Heterocycles SO3H SO3, H 2 SO4 N HgSO4 , 230 o C O H3C N O O CH 3 CH3 O BF 3 O O 11