Why study Organic Synthesis? Organic Chemistry of Fine Chemicals Spring 2006 Why study Organic Synthesis? Heart of Chemistry Broad applications Petrochemicals Pharmaceuticals Agrochemicals (Bio)Polymers Dyes & Pigments Cosmetics Food (Additives) Household products Electrochemicals Display materials Semiconductors Organic electronics and so on….. “Chemists make new things and we study reactions. That’s the core of this profession” - D.G. Nocera (MIT) in C&EN (Jan. 1998) OCFC-Intro-Chap2 Introduction-Chap2

Petrochemicals phenol acetone OCFC-Intro-Chap2

Pharmaceuticals & Medicinal Chemistry OCFC-Intro-Chap2

Agrochemicals OCFC-Intro-Chap2

Polymers & Biopolymers OCFC-Intro-Chap2

Biology & Biochemistry OCFC-Intro-Chap2

Electrochemicals OCFC-Intro-Chap2

Display Materials OCFC-Intro-Chap2

Components of Organic Synthesis Synthetic work experimental procedures TARGET Retrosynthetic analysis Synthetic design ‘disconnection approach’ 1. C-C bond formation 2. functional group interconversion (FGI) OCFC-Intro-Chap2

Disconnection Approach: An Example alkylation synthons LiN(iPr)2  acetal H+ (-H2O) synthetic equivalents OsO4 oxidation multistriatin: a pheromone of the elm bark beetle ? OCFC-Intro-Chap2

A Stereorandom Synthesis of Multistriatin OCFC-Intro-Chap2

A Stereoselective Synthesis of Multistriatin OCFC-Intro-Chap2

Design and Synthesis Retrosynthetic Analysis Synthesis 1. recognise the functional groups in the target molecule 2. disconnect by known methods and reliable reactions 3. repeat 1 and 2 until the readily available starting materials are obtained 4. design as many alternative retrosynthetic routes as possible Synthesis 1. write down the synthetic schemes containing the detailed reaction conditions according to the analyses 2. compare the pros and cons between the syntheses designed; the number of steps, availability of reagents/starting materials, selectivity (chemo-/regio-/stereo-), economy, process, etc 3. modify the selected synthetic plan whenever unexpected problems are encountered OCFC-Intro-Chap2

What to Know for Organic Synthesis molecular structure reaction mechanisms stereochemistry dependable reactions availability of compounds selectivity analytical methods lab technique process creativity economy OCFC-Intro-Chap2

공 부 하 는 방 법 “그저 익숙하도록 읽는 것뿐이다. 글을 읽는 사람이, 비록 글의 뜻은 알았으나, 만약 익숙하지 못하면 읽자마자 곧 잊어버리게 되어, 마음에 간직할 수 없을 것은 틀림없다. 이미 읽고 난 뒤에, 또 거기에 자세하고 익숙해질 공부를 더한 뒤라야 비로소 마음에 간직할 수 있으며, 또 흐뭇한 맛도 있을 것이다.” - 퇴계 이황 (금장태 著) OCFC-Intro-Chap2

Chapter 2 Functional Group Transformations Organic Chemistry of Fine Chemicals Spring 2006 Chapter 2 Functional Group Transformations selectivity/specificity: chemo-, regio- & stereo- functionalization of alkanes: unreactive radical reaction: selectivity;  5 bottom functionalization of alkenes: addition & substitution addition to double bonds:  6 Scheme 2.1 ‘(anti)Markovnikov’/oxymercuration/hydroboration/HBr:  7 top stereoselectivity:  7 bottom allylic substitution: radical;  8 top & 188~189 (oxidation) OCFC-Intro-Chap2 Introduction-Chap2

Chemoselectivity regioselectivity & stereoselectivity H2, Pt NaBH4 OCFC-Intro-Chap2

Regioselectivity more electropositive metals: Mo, W 1. BH3•THF H3O+ 2. H2O2, NaOH Hg2+, H2O/NaBH4 more electropositive metals: Mo, W OCFC-Intro-Chap2

Diastereoselectivity (I) major minor OCFC-Intro-Chap2

Diastereoselectivity (II) OCFC-Intro-Chap2

Enantioselectivity OCFC-Intro-Chap2

Functionalization of Alkynes Organic Chemistry of Fine Chemicals Spring 2006 Functionalization of Alkynes addition / substitution reactions:  9 Scheme 2.2 reduction to alkenes:  165 bottom – 166 C-C bond formation:  51 – 52 top electrophilic addition: largely anti addition a mixture of products: syn addition & participation of the reaction solvent,  8 bottom – 9 top ketones with oxymercuration:  9 middle OCFC-Intro-Chap2 Introduction-Chap2

Functionalization of Aromatic Hydrocarbons Organic Chemistry of Fine Chemicals Spring 2006 Functionalization of Aromatic Hydrocarbons electrophilic substitution: the ring;  10 Scheme 2.3 substituted benzenes: depending on the substituents the rate & the orientation:  11 Table 2.1 &  12 lower selectivity with a radical substitution:  13 top nucleophilic substitution: p-chloronitrobenzene Chichibabin reaction ( 14 & 44) & benzyne intermediate benzylic oxidation: the side chain;  189~192 autoxidation of cumene: acetone & phenol;  11 top chlorination/bromination: radical mechanism;  11 top OCFC-Intro-Chap2 Introduction-Chap2

Functionalization of Aromatic Heterocycles Organic Chemistry of Fine Chemicals Spring 2006 Functionalization of Aromatic Heterocycles pyridine: weak base & e--poor ring,  14 Scheme 2.4 electrophilic substitution: difficult but higher e--density at C-3 nucleophilic substitution at C-2: ‘Chichibabin’;  14 Scheme 2.5 substitution of pyridine-N-oxide at C-4:  15 Scheme 2.6 pyrrole, furan, thiophene: e--rich;  16 Scheme 2.7 substitution at C-2 / C-5: resonance-stabilized OCFC-Intro-Chap2 Introduction-Chap2

Interconversion of Functional Groups Organic Chemistry of Fine Chemicals Spring 2006 Interconversion of Functional Groups alcohols & phenols: less basic;  17 Scheme 2.8 amines: basic & nucleophilic;  20 Scheme 2.9 amines as electrophiles: pyridinium ions;  18 bot & 19 top halides: good leaving groups;  21 Scheme 2.10 aryl nitro compounds:  22 Scheme 2.11 aldehydes & ketones: addition, substitution, enolates carboxylic acids:  23 Scheme 2.12 OCFC-Intro-Chap2 Introduction-Chap2