1 3720 Web Resources 3720 Web Resources - PDF document

Chemistry 3720 Chemistry 3720 - - Organic Chemistry II 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

3720 Web Resources 3720 Web Resources 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 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 syllabus) Class Requirements (see syllabus) 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? Why a year of Organic Chemistry? Organic Chemistry chemical synthesis New materials New medicinal New Materials Compounds Medicines chemistry chemistry Biochemistry and Chemical Biology Nanotech, Proteomics, Pharmacy, Engineering Genetics Medicine 3

Chemistry 3719 Chemistry 3719- -3720 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 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 - Chapter 12 - Reactions of Benzene Reactions of Benzene - - EAS 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 CF 3 -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 Substitution in Naphthalene 12.18 Substitution in heterocyclic aromatic compounds 4

Introduction – Introduction – Benzene vs. Alkenes Benzene vs. Alkenes Br Br Br no heat Br dark Br Br no colour change (no reaction) no heat dark Completely delocalized (6) pi system lends stability ( aromatic ) 12.2 Mechanistic Principles of EAS 12.2 Mechanistic Principles of EAS Alkenes react by addition E Y E E Y Y Benzene reacts by substitution Y H E Y E E - H Y Resonance-stabilized cation 5

General Mechanism of EAS on Benzene General Mechanism of EAS on Benzene Energy diagram for EAS in benzene Figure 12.1 Electrophilic Aromatic Substitutions on Benzene Electrophilic Aromatic Substitutions on Benzene H NO 2 HNO 3 , H 2 SO 4 12.3 Nitration H SO 3 H SO 3 , H 2 SO 4 12.4 Sulfonation H Br Br 2 , Fe 12.5 Halogenation 12.6 Friedel 12.6 Friedel- -Crafts Crafts Alkylation Alkylation of Benzene of Benzene H CH 2 CH 3 CH 3 CH 2 Cl AlCl 3 CH 3 H C CH 3 (CH 3 ) 3 CCl CH 3 AlCl 3 H 3 C CH 3 Cl H C CH 3 CH 3 CH 3 AlCl 3 Problems: Alkyl groups may rearrange during reaction Products are more reactive than benzene Uses: Alkyl benzenes readily oxidized to benzoic acids using KMnO 4 6

12.7 12.7 Friedel Friedel- -Crafts Crafts Acylation Acylation of Benzene of Benzene O O H C RCCl R AlCl 3 O O O H CCH 3 H 3 C O CH 3 AlCl 3 O AlCl 3 O R C O RCCl RC Products react more slowly than benzene - cleaner reaction No carbocation rearrangements 12.8 12.8 Alkylbenzenes Alkylbenzenes via via Acylation Acylation/Reduction /Reduction Zn, HCl O H H C C (Clemmensen) R R or NH 2 NH 2 , KOH heat (Wolff-Kischner) O AlCl 3 Zn, HCl Cl O Make the acyl benzene first (clean, high yielding reaction) Reduce the ketone group down to the methylene (C=O to CH 2 ) Avoids rearrangement problems, better yields Aminobenzenes Aminobenzenes via Nitration/Reduction (not in text) via Nitration/Reduction (not in text) H O Sn, HCl N N H O H H NO 2 N HNO 3 , H 2 SO 4 Sn, HCl 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 12.9 Activation and Deactivation by Substituents (Rates) (Rates) X X HNO 3 , H 2 SO 4 NO 2 CF 3 H CH 3 0.000025 1.0 25 Relative rates in nitration reaction now bringing in a second substituent 12.9 Nitration of Toluene vs 12.9 Nitration of Toluene vs Nitration of ( Nitration of (Trifluoromethyl)benzene Trifluoromethyl)benzene CH 3 CH 3 CH 3 CH 3 HNO 3 , H 2 SO 4 NO 2 + + NO 2 NO 2 63% 3% 34% CH 3 is said to be an ortho / para director ( o / p director) - Regioselectivity CF 3 CF 3 CF 3 CF 3 HNO 3 , H 2 SO 4 NO 2 + + NO 2 NO 2 6% 91% 3% CF 3 is said to be a meta director ( m director) - Regioselectivity 12.10 Rate and Regioselectivity Regioselectivity in Nitration of Toluene in Nitration of Toluene 12.10 Rate and CH 3 CH 3 CH 3 CH 3 HNO 3 , H 2 SO 4 NO 2 + + NO 2 NO 2 63% 3% 34% Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene) 8

12.11 Rate and 12.11 Rate and Regioselectivity Regioselectivity in Nitration of CF in Nitration of CF 3 3 C C 6 6 H H 5 5 CF 3 CF 3 CF 3 CF 3 HNO 3 , H 2 SO 4 NO 2 + + NO 2 NO 2 6% 91% 3% Fig. 12.6 – Energy diagrams for CF 3 C 6 H 5 nitration (vs. benzene) 12.12 Substituent Effects 12.12 Substituent Effects – – Activating Activating Substituents 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 Activating Substituents O R HO RO RCO alkyl hydroxyl alkoxy acyloxy OCH 3 OCH 3 OCH 3 HNO 3 , H 2 SO 4 NO 2 Example: + NO 2 Alkyl groups stabilize carbocation by hyperconjugation Lone pairs on O (and others like N) stabilize by resonance 12.13 Subst Subst. Effects . Effects – – Strongly Deactivating Strongly Deactivating Substituents Substituents 12.13 O O O O O HC HO C Cl C RO C R C ester aldehyde ketone carboxylic acid acyl chloride O N C HO S O 2 N O nitrile sulfonic acid nitro NO 2 NO 2 Br 2 , Fe Example: Br Second substituent goes meta by default – best carbocation 9

12.14 Substituent Effects 12.14 Substituent Effects – – Halogens 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 Cl Cl HNO 3 , H 2 SO 4 NO 2 + + NO 2 NO 2 30% 69% 1% Regioselectivity - second substituent goes o/p – better carbocations 12.15 Multiple Substituent Effects 12.15 Multiple Substituent Effects CH 3 CH 3 O NHCH 3 NHCH 3 O O Br 2 , acetic acid Br H 3 C O CH 3 CH 3 AlCl 3 CH 3 Cl Cl CH 3 87% 99% CH 3 CH 3 CH 3 CH 3 Br NO 2 Br 2 , Fe HNO 3 , H 2 SO 4 NO 2 NO 2 C(CH 3 ) 3 C(CH 3 ) 3 86% 88% Interplay between power of directing group and size of substituents 12.16 Regioselective Regioselective Synthesis of Synthesis of Disubstituted Disubstituted Derivs Derivs. . 12.16 O O O CH 3 CH 3 CH 3 Br Br NO 2 CO 2 H CH 2 CH 3 Br NO 2 Have to be careful about when to introduce each substituent Remember – isomers (e.g. o / p mixtures) may be separated 10

12.17- 12.17 -12.18 Substitution in Other Aromatic Systems 12.18 Substitution in Other Aromatic Systems 12.17 Naphthalene O CH 3 O O CH 3 CCl CH 3 but not AlCl 3 90% 12.18 Heterocycles SO 3 H SO 3 , H 2 SO 4 HgSO 4 , 230 o C N N O O H 3 C O CH 3 CH 3 O BF 3 O O 11