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Chapter 2 Basic of Organic Synthesis -Preparation of Alkane- 1.Hydrogenation of Alkenes 2. Reduction of Alkyl Halides 3. Coupling of Alkyl Halides with Organometalic Compounds R - M g X H 2 O R - HR - X + M g -Preparation of Alkane- 1. Hydrogenation of alkene C n H 2 n H 2 + P t , P d , N i C n H 2 n + 2 A l k e n e A l k e n e 2.Reduction of alkyl halides a) Hydrolysis of Grignard reagent. Example: C H 3 C H 2 C H C H 3 B r C H 3 C H 2 C H C H 3 M g B r C H 3 C H 2 C H C H 3 H M g H 2 O n - B u t a n es e c - B u t y l m a g n e s i u m b r o m i d e s e c - B u t y l b r o m i d e b) Reduction by metal and acid. R - X + Z n + H + R - H + Z n 2 + + X - Example: C H 3 C H 2 C H C H 3 B r C H 3 C H 2 C H C H 3 H n - B u t a n es e c - B u t y l b r o m i d e Z n + H + 3. Coupling of alkyl halides with organometalic compounds. Example: R - X R - L i R 2 - C u L i M a y b e 1 o ， 2 o ， 3 o A l k y l l i t h i u m L i t h i u m d i a l k y l c o p p e r R - X S h o u l d b e 1 o R - R C H 3 C H 2 C l E t h y l c h l o r i d e E t h y l l i t h i u m L i t h i u m d i a l k y l c o p e r C H 3 C H 2 C H 3 C H 2 C H 3 C H 2 C u L i C H 3 ( C H 2 ) 5 C H 2 B r n - H e p t y l b r o m i d e C H 3 C H 2 C H 2 ( C H 2 ) 5 C H 3 n - N o n a n e L i L i C u I -Preparation of Alkene- 1. Dehydrohalogenation of Alkyl Halide 2. Dehydration of Alcohols 3. Dehalogenationof Vicinal Dihalides 4. Reduction of Alkynes -Preparation of Alkene- 1. Dehydrohalogenation of alkyl halide C H C X C CK O H K X H 2 O a l c o h o l E a s e o f d e h y d r o h a l o g e n a y i o n o f a l k y l h a l i d e s 3 o 2 o 1 o + + Examples: C H 3 C H 2 C H 2 C H 2 C l n - B u t y l c h l o r i d e 1 - B u t e n e K O H ( a l c o h o l ) C H 3 C H 2 H C C H 2 K O H ( a l c o h o l )C H 3 C H 2 C H C l C H 3 2 - B u t e n e 8 0 % 1 - B u t e n e 2 0 % C H 3 C H 2 H C C H 2C H 3 H C C H C H 3 s e c - B u t y l c h l o r i d e 2. Dehydration of alcohols C H C O H C C H 2 O+ a c i d E a s e o f d e h y d r o g e n a t i o n o f a l c o h o l s 3 o 2 o 1 o Examples: 2 - B u t e n e C H 3 H C C H C H 3a c i dC H 3 C H 2 C H 2 C H 2 O H n - B u t y l a l c o h o l 1 - B u t e n e C H 3 C H 2 H C C H 2 C h i e f p r o d u c t a c i d C h i e f p r o d u c t C H 3 C H 2 C H O H C H 3 2 - B u t e n e 1 - B u t e n e C H 3 C H 2 H C C H 2C H 3 H C C H C H 3 s e c - B u t y l a l c o h o l 3. Dehalogenation of vicinal dihalides Example: C H 3 C H B r C H B r C H 3 2 - B u t e n e C H 3 H C C H C H 3 2 , 3 - D i b r o m o b u t a n e Z n 4. Reduction of alkynes -Preparation of Alcohol- 1. Oxymercuration-Demercuration 2. Hydroboration-Oxidation 3. GrignardSynthesis 4. Hydrolysis of Alkyl Halides 5. Hydroxylation of Alkenes -Preparation of Alcohol- 1. Oxymercuration-demercurataion 2. Hydroboration-Oxidation 3. Grignard synthesis 4.Hydrolysis of alkyl halides Examples: 5. Hydroxylation of alkenes 6. Aldol condensation 7. Reduction of carbonyl compounds 8. Reduction of acid and esters -Preparation of Halide- 1. From Alcohols 2. Halogenationof Certain hydrocarbons 3. Addition of Hydrogen Halide to Alkenes 4. Addition of Halogen to Alkenes and Alkynes 5. Halide Exchange -Preparation of Halide- 1. From alcohols Examples: 2. Halogenation of certain hydrocarbons Examples: 3. Addition of hydrogen halide to alkenes 4. Addition of halogen to alkenes and alkenes 5. Halide exchange -Preparation of Ether- 1. Williamson Synthesis 2. Alkoxymercuration-Demercuration -Preparation of Ether- 1. Williamson synthesis Examples: 2. Alkoxymer curation-demercuration -Preparation of Alkylbenzene- 1. Friedel-Crafts Alkylation 2. Conversion of Side Chain -Preparation of Alkylbenzene- 1. Friedel-Crafts alkylation Examples: 2. Conversion of side chain -Preparation of Phenol- 1. Hydrolysis of Diazonium Salts 2. Alkli Fusion of Sulfonates -Preparation of Phenol- 1. Hydrolysis of diazonium salts A r N 2 + H 2 O + +N 2 H +A r O H Example: 2. Alkali fusion of sulfonates -Preparation of Amine- 1. Reduction of Nitro Compounds 2. Reaction of Halides with ammonia or Amines 3. Reductive Amination 4. Reduction of Nitriles 5. Hofmann Degradation of Amides -Preparation of Amine- 1. Reduction of nitro compounds A r - N O 2 o r R - N O 2 A r - N H 2 o r R - N H 2 c h i e f l y f o r a r o m a t i c a m i n e N i t r o c o m p o u n d s 1 o a m i n e m e t a l , H + o r H 2 , c a t . Examples: F e , H C l 1 - N i t r o p r o p a n e n - p r o p y l a m i n e C H 3 C H 2 C H 2 N O 2 C H 3 C H 2 C H 2 N H 2 2. Reaction of halides with ammonia or amines Examples: N H 3 R X NN H 2 N H N R R R R R R R R R R X R XR X R X R X m u s t b e a l k y l o r a r y l w i t h e l e c t r o n - w i t h d r a w i n g s u b s t i t u e n t s N H 3 N C H 3 H C H 3 C H 2C H 3 C H 2 C l C H 3 C H 2 N H 2 C H 3 C l E t h y l c h l o r i d e E t h y l a m i n e E t h y l m e t h y l a m i n e C H 2 N H 2 N H 3 B e n z y l c h l o r i d e B e n z y l a m i n e B e n z y l d i m e t h y l a m i n e 2 C H 3 I C H 2 NC H 2 C l C H 3 C H 3 N ( C H 3 ) 2 N , N - d i m e t h y l a n i l i n e P h e n y l t r i m e t h y l a m m o n i u m i o d i d e C H 3 I N ( C H 3 ) 3 I 2 , 4 - D i n i t r o c h l o r o b e n z e n e N - M e t h y l - 2 , 4 - d i n i t r o a n i l i n e C l N H C H 3 N O 2 N O 2 N O 2 N O 2 C H 3 N H 2 3. Reductive amination C O N H 3 R N H 2 R 2 N H 2 + H 2 , N i o r N a B H 3 C N 1 o a m i n e 2 o a m i n e 3 o a m i n e C H N H 2 C H N R 2 C H N H R + + H 2 , N i o r N a B H 3 C N H 2 , N i o r N a B H 3 C N Examples: N H 3 1 o a m i n e+ H 2 , N i O H 3 C H 3 C C H N H 2 H 3 C H 3 C A c e t o n e I s o p r o p y l a m i n e ( C H 3 ) 2 C H C O H N H 2 2 o a m i n e + N H C H 2 C H ( C H 3 ) 2 I s o b u t y l a l d e h y d e A n i l i n e N - I s o b u t y l a n i l i n e N a B H 3 C N 3 o a m i n e+ H 2 , N iC H 3 C H O ( C H 3 ) 2 N H C H 3 C H 2 N C H 3 C H 3 A c e t a l d e h y d e D i m e t h y l e t h y l a m i n eD i m e t h y l a m i n e 4. Reduction of nitriles C NR R C H 2 N H 22 H 2 , C a t . Examples: C H 2 C l B e n z y c h l o r i d e B e n z y l n i t r i l e 2 - P h e n y l e t h y l a m i n e C H 2 C N C H 2 C H 2 N H 2N a C N H 2 , N i , 1 4 0 o C N a C N H 2 , N i , C l C H 2 ( C H 2 ) 2 C H 2 C l N C ( C H 2 ) 4 C N H 2 N C H 2 ( C H 2 ) 4 C H 2 N H 2 1 , 4 - D i c h l o r o b u t a n e A d i p o n i t r i l e H e x a m e t h y l e n e d i a m i n e ( 1 , 6 - D i a m i n o h e x a n e ) 5. Hofmann degradation of amides + R - C O N H 2 A r - C O N H 2 O B r - 1 o A m i n eC O 3 2 - R - N H 2 A r - N H 2 Examples: C H 3 ( C H 2 ) 4 C O N H 2 1 o A m i n eC H 3 ( C H 2 ) 4 N H 2 C a p r o a m i d e ( H e x a n a m i d e ) n - P e n t y l a m i n e K O B r 1 o A m i n e K O B r B r C O N H 2 m - B r o m o b e n z a m i d e m - B r o m o a n i l i n e B r N H 2 -Reaction of Diazonium- 1. Replacement of Nitrogen 2. Coupling 1. Replacement of nitrogen -Reaction of Diazonium- a) Replacement by -Cl, -Br, -CN A r N 2 + Z : - A r Z N 2+ A r N 2 + A r X N 2+C u X Examples: C H 3 N H 2 C H 3 N 2 + C l - C H 3 N 2 + H S O 4 C H 3 C l C H 3 B r C H 3 C N o - T o l u i d i n e o - M e t h y l a n i l i n e o - A m i n o t o l u e n e o - T o l u e n e d i a z o n i u m c h l o r i d e o - C h l o r o t o l u e n e o - B r o m o t o l u e n e o - t o l u n i t r i l e o - C y a n o t o l u e n e N a N O 2 H C l H 2 S O 4 C u C l C u B r C u C N C H 3 N 2 + C l - N a N O 2 H C l N a N O 2 b) Replacement by -I Example: A r N 2 + A r I N 2+K I c) Replacement by -F K I N H 2 H 2 S O 4 N a N O 2 A n i l i n e I o d o b e n z e n e N 2 + H S O 4 - I A r N 2 + B F 4 - A r F N 2 B F 3+ +h e a tExamples: N 2 H C l N a N O 2 B F 3+ + h e a t N H 2 N 2 + B F 4 - FN 2 + C l - H B F 4 b e n z e n e d i a z o n i u m c h l o r i d e b e n z e n e d i a z o n i u m f l u o r o b o r a t e F l u o r o b e n z e n e d) Replacement by -OH A r N 2 + A r O H N 2+ H 2 O H + + N H 2 C H 3 O H C H 3 N 2 + H S O 4 - C H 3 o - T o l u i d i n e o - C r e s o l H 2 O , H + H 2 S O 4 N a N O 2 h e a t Example: e) Replacement by -H A r N 2 + A r O H N 2+ H 3 P O 2 H 2 O + H 3 P O 3 + Example: C l N H 2 H 2 S O 4 H N O H 3 P O 3 C l 2 , 4 - D i c h l o r o a n i l i n e m - D i c h l o r o b e n z e n e C l N 2 + H S O 4 - C l C l C l 2. Coupling A r N 2 + X - + G GNA r - N G m u s t b e s t r o n g l y e l e c t r o n - r e l e a s i n g g r o u p : O H , N R 2 , N H 2 , N H 2 Example: + O HNNO HN 2 + C l - B e n z e n e d i a z o n i u m c h l o r i d e p - H y d r o x y a z a b e n z e n e p - ( p h e n y l a z o ) p h e n o l -Preparation of Aldehyde & Ketone- Aldehyde 1. Oxidation of Primary Alcohols 2. Oxidation of Methylbenzene 3. Reduction of Acid chloride Ketone 1. Oxidation of Secondary Alcohols 2. Friedel-Crafts Acylation -Preparation of Aldehyde & Ketone- 1. Oxidation of primary alcohols Example: P y r i d i n i u m c h l o r o c h r o m a t e C O H C H 3 C H 2 C H 2C H 3 C H 2 C H 2 C H 2 O H n - B u t y l a l c o h o l 1 - B u t a n o l n - B u t y l a l d e h y d e B u t a n a l 2. Oxidation of methylbenzene C l 2 , h e a t C r O 3 / A c 2 O A r - C H C l 2 A r - C H ( O O C C H 3 ) 2 A r - C H OA r - C H 3 H 2 O Examples: H 2 O B r C H 3 B r C H C l 2 B r C H O C l 2 , h e a t , h v p - B r o m o t o l u e n e p - B r o m o b e n z a l d e h y d e C r O 3 / A c 2 O H 2 O N O 2 C H O N O 2 C H 3 N O 2 C H ( O A c ) 2 p - N i t r o t o l u e n e p - N i t r o b e n z a l d e h y d e 3. Reduction of acid chloride R - C O C l o r A r - C O C l L i H ( O B u - n ) 3 R - C H O o r A r - C H O Example: N O 2 C O C l L i H ( O B u - n ) 3 N O 2 C H O 1. Oxidation of secondary alcohols 2 o a l c o h o l K e t o n e R C H R O H C O R RC r O 3 o r K 2 C r 2 O 7 Example: C H 3 H O H C H H 3 C C H 3 K 2 C r 2 O 7 H 2 S O 4 C H 3 C H H 3 C C H 3 O 2. Friedel-Crafts acylation +R - C O C l R - C O - A r L e w i s a c i d A r - H Examples: +n - C 5 H 1 1 C O C l n - C 5 H 1 1 C O C a p r o y l c h l o r i d e n - p e n t y l p h e n y l k e t o n e A l C l 3 + A l C l 3C O C l C O B e n z o y l c h l o r i d e B e n z o p h e n o n e ( D i p h e n y l k e t o n e ) -Reactions of Aldehyde & Ketone- 1. Oxidation 2. Reduction 3. Addition of Cyanide 4. Addition Derivatives of ammonia 5. Addition of Alcohols 6. Cannizzaro Reaction 7. Addition of Grignard Reagent -Reactions of Aldehyde & Ketone- 1. Oxidation a) Aldehydes R - C H O o r A r - C H O R - C O O H o r A r - C O O H U s e d c h i e f l y f o r d e t e c t i o n o f a l d e h y d e K M n O 4 K 2 C r 2 O 7 A g ( N H 3 ) 2 + Example: + 2 A g ( N H 3 ) 2 +C H 3 C H O 3 O H - C H 3 C O O - 2 A g 4 N H 4 2 H 2 O T o l l e n s t e s t + + + b) Methyl ketones Examples: C O C H 3C C HC H 3 C H 3 C O O HC C HC H 3 C H 3 4 - M e t h y l - 3 - p e n t e n - 2 - o n e 3 - M e t h y l - 2 - b u t e n o i c a c i d K O C l H 2 S O 4 C O C H 3R O X - C O C H 3A r C O C X 3R C O C X 3A r C O O -R C O O -A r H 2 O H a l o f o r m r e a c t i o n + + +C O C H 3C 2 H 5 C O O -C 2 H 53 O I - C H I 3 2 O H - I o d o f o r m 2. Reduction a) Reduction to alcohols H 2 / N i , P t , P d L i A l H 4 o r N a B H 4 , t h e n H +C O C O H H Examples: O H O H H 2 , N i C y c l o p e n t a n o n e C y c l o p e n t a n o l C C H 3 O L i A l H 4 A c e t o p h e n o n e a - p h e n y l e t h y l a l c o h o l C C H 3 O H H b) Reduction to hydrocarbons C O C H H Z n ( H g ) , c o n c . H C l N 2 H 4 , B a s e C l e m m e n s e n r e d u c t i o n f o r c o m p o u n d s s e n s i t i v e t o b a s e W o l f f - K i s h n e r r e d u c t i o n f o r c o m p o u n d s s e n s i t i v e t o a c i d N 2 H 4 , B a s e O H H C y c l o p e n t a n o n e C y c l o p e n t a n e Examples: C C H 2 C H 2 C H 3O n - B u t y r o p h e n o n e C H 3 C H 2 C H 2 C O C l n - B u t y l b e n z e n e Z n ( H g ) , c o n c . H C l C H 2 C H 2 C H 2 C H 3 A l C l 3 3. Addition of cyanide +C O C C N H C N - C y a n o h y d r i n Examples: C CO H O H C N C H O H C O O H B e n z a l d e h y d e M a n d e l o n i t r i l e M a n d e l i c a c i d N a C N N a H S O 4 H 2 O H 2 S O 4 H C H 3 C C H 3 C O C H 3 O H C N C H 3 C C H 3 O H C O O H N a C N N a H S O 4 H 2 O H 2 S O 4 C H 3 a c e t o n e c y a n o h y d r i n M e t h a c r y l i c a c i d C H 2 C C H 3 C O O H 4. Addition derivatives of ammonia +C O H 2 N G C N G U s e d f o r i d e n t i f i c a i t o n N H 2 N H 2 N H 2 N H C 6 H 5 N H 2 N H C O N H 2 H y d r o x y l a m i n e H y d r a z i n e P h e n y l h y d r a z i n e S e m i c a r b a z i d e O x i m e H y d r a z o n e P h e n y l h y d r a z o n e S e m i c a r b a z o n e C N C N N H 2 C N N H C 6 H 5 C N N H C O N H 2 O HN H 2 O H B e n z a l d e h y d e p h e h y l h y d r a z o n e A c e t a l d o x i m eC N C N N H C 6 H 5 O H H H 3 C H C 6 H 5 5. Addition of alcohols +C O 2 R O H H + C O RO R Example: + H + C O C H 2 C H 3 O C H 2 C H 3 2 C H 3 C H 2 O HC H 3 C O H H C H 3 6. Cannizzaro reaction +C O H 2 s t r o n g b a s e C H 2 O HC O O - Examples: +H C O H 2 C H 3 O HH C O O -5 0 % N a O H +2 5 0 % N a O H C H O C l C O O - C l C H 2 O H C l + H C O O - 5 0 % N a O H C H O O C H 3 C H 2 O H O C H 3 O C H 3 O C H 3 C H 2 O + 7. Addition of Grignard reaction 8. Others R M g X H C O HR H H C O HR R R C O HR R C O H H C O H R C O R R 1 o 2 o 3 o -Reaction of Carbanion- 1. Halogenation of ketones 2. Nucleophilic Additon to Carbonyl Compounds 3. Nucleophilic Acyl Substitution 1. Halogenation of ketones -Reaction of Carbanion- C C OH K e t o n e a - H a l o k e t o n e X 2 = C l 2 , B r 2 , I 2X 2 H + o r O H - C C OX + Examples: + C y c l o h e x a n o n e 2 - B r o m o c y c l o h e x a n o n e B r 2 H B r H + H O B r O H 3 C C C O C H 3 C H 3 C H 3 H 3 C C C O C I 3 C H 3 C H 3 H 3 C C C O C O O - C H 3 C H 3 I 2 , O H - t e r t - B u t y l m e t h y l k e t o n e T r i m e t h y l a c e t a t e i r o n O H - 2. Nucleophilic addition to carbonyl compounds a) Aldol condensation C C O H b a s e o r a c i d C C C O HO H A l d o lC O + Examples: C H 3 C O H C H 2 C O H H C H 2 C O H C H 3 C H O H C H 3 C C H C O H H + H + N a H S O 4 h e a t A c e t a l d e h y d e 3 - H y d r o x y b u t a n a l 2 - B u t e n a l C H 3 C O C H 3 C H 2 C O C H 3 H C H 2 C O C H 3 C H 3 C H O H C H 3 C C C H 3 C O H C H 3 + H + N a H S O 4 h e a t A c e t o n e 4 - H y d r o x y - 4 - m e t h y l - 2 - p e n t a n o n e 4 - M e t h y l - 3 - p e n t e n - 2 - o n e C H 2 C C H 3 O +C O H H C C H C C H 3 H OB e n z a l a c e t o n e b) Wittig reaction + +C O P h 3 P C R R C C R R P h 3 P O Example: + +P h 3 P C H 2 P h 3 P OO C H 2 M e t h y l e n e t r i p h e n y l p h o s p h o r a n e M e t h y l e n e c y c l o h e x a n e 3. Nucleophilic acyl substitution a) Claisen condensation O C O R O CC O R C C C O R O O H C 2 H 5 O - 3 - K e t o e s t e r + Examples: O CC H 3 O C 2 H 5 O CC H 2 O C 2 H 5 C H 3 C C H 2 C O C 2 H 5 O O H C 2 H 5 O -+ E t h y l a c e t a t e E t h y l a c e t o a c e t a t e O CC H 3 O C 2 H 5 C 2 H 5 O -+ E t h y l a c e t a t e C O O C 2 H 5 C O C H 2 C O C 2 H 5 E t h y l b e n z o y l a c e t a t e O -Substitution on Aromatic Ring- 1. Nitration 2. Sulfonation 3. Halogenation 4. Friedel-Crafts Alkylation 5. Friedel-Crafts Acylation 6. Protonation -Substitution on Aromatic Ring- 1. Nitration 2. Sulfonation 3. Halogenation +A r H H O S O 3 A r S O 3 H H 2 O A r y l s u l f o n i c a c i d +A r H H O N O 2 A r N O 2 H 2 O N i t r o c o m p o u n d s +A r H A r C l H C lC l 2 A r y l c h l o r i d e F e +A r H A r B r H B rB r 2 A r y l b r o m i d e F e 4. Friedel-Crafts alkylation 5. Friedel-Crafts acylation 6. Protonation 7. Other special reactions +A r H A r R H C lR C l A l C l 3 A l k y l b e n z e n e +A r H H C lR C O C l A l C l 3 A r C O R k e t o n ea c y l c h l o r i d e A r S O 3 H H + A r H H 2 S O 4 D e s u l f o n a t i o n+ +H 2 O -Preparation of Acid- 1. Oxidation of Primary Alcohols 2. Oxidation of Alkylbenzene 3. Carbonation of Grignard Reagent 4. Hydrolysis of Nitriles -Preparation of Acid- 1. Oxidation of primary alcohols C H 2 O HR K M n O 4 C O O HR Examples: C H 3 C H C H 2 C H 2 O H C H 3 C H 3 C H C H 2 C O O H C H 3 K M n O 4 I s o b u t y l a l c o h o l I s o b u t y r i c a c i d C H 3 C H 2 C H C H 2 O H C H 3 C H 3 C H 2 C H C O O H C H 3 2 - M e t h y l - 1 - b u t a n o l 2 - M e t h y l b u t a n o i c a c i d K M n O 4 2. Oxidation of alkylbenzenes A r - R A r - C O O HK M n O 4 , o r K 2 C r 2 O 7 C H 3O 2 N p - N i t r o t o l u e n e p - N i t r o b e n z o i c a c i d C O O HO 2 NK 2 C r 2 O 7 , H 2 S O 4 Examples: C H 3 K M n O 4 , O H - o - B r o m o t o l u e n e o - B r o m o b e n z o i c a c i d B r C O O H B r 3. Carbonation of Grignard reagents R - M g XR - X R - C O O M g X R - C O O HM g C O 2 H + A r - C O O Ho r A r - X Examples: C H O C H 3 C C H 3 H p - B r o m o - i s o - p r o p y l b e n z e n e p - I s o - p r o p y l b e n z o i c a c i d C O O M g B r C H 3 C C H 3 H C O O H C H 3 C C H 3 H M g B r C H 3 C C H 3 H M g C O 2 H + M g C O 2 H + C 2 H 5 C C H 3 C l C H 3 C 2 H 5 C C H 3 M g C l C H 3 C 2 H 5 C C H 3 C O O H C H 3 t e r t - P e n t y l c h l o r i d e 2 , 2 - D i m e t h y l b u t a n o i c a c i d 4. Hydrolysis of nitriles R - C No r A r - C N R - C O O Ho r A r - C O O H a c i d o r b a s e N H 3H 2 O + Examples: n - C 4 H 9 B r N a C N a q . a l c . N a O H H +n - C 4 H 9 C N n - C 4 H 9 C O O H N a C N 7 0 % , H 2 S O 4 P h e n y l a c e t y l n i t r i l e P h e n y l a c e t i c a c i dB e n z y l c h l o r i d e C H 2 C l C H 2 C N C H 2 C O O H
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