CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Vegetable il (C 2 ) 7 (C 2 ) 7 (C 2 ) 7 LL (a triacylglyceride in soybean oil) (1) transesterification ac 3 Biodiesel 3 C 3 C (C 2 ) 7 methyl linoleate (2) (C 2 ) 7 methyl oleate (3) Lecture'11:'February'21,'2013 Reac&ons*of*Deriva&ves*(21.4521.9)
Reac%vity*of*Deriva%ves Increasing Carbonyl Stability Increasing Reactivity R Cl acid chloride R' S R' R' R' R' carboxylic acid thiol alcohol amine water 3 C anhydride R' R SR' thioester R R' ester R R' 2 amide rganic Chemistry II (CM 224) R carboxylic acid Slide 2
Reac%ons*of*Acid*Chlorides 3 C anhydride R' 3 C ester R' 3 C R' 2 amide R' R' alcoholysis R' 2 aminolysis 3 C carboxylic acid 2 hydrolysis 3 C Cl acid chloride R' 2 CuLi 3 C R' ketone rganic Chemistry II (CM 224) Slide 3
Reac%ons*of*Acid*Chlorides 3 C Cl + 3 C Cl 3 C Cl 3 C acid chlorides are reactive enough that activation of the carbonyl by protonation is not required neutral nucleophiles add directly rganic Chemistry II (CM 224) Slide 4
Reac%ons*of*Acid*Chlorides To Anhydrides 3 C Cl diethyl ether + a + 3 C pyridine pyridine acetyl chloride sodium benzoate acetic benzoic anhydride Cl 3 C a + diethyl ether + Cl 3 C pyridine Cl sodium acetate benzoyl chloride acetic benzoic anhydride pyridinium chloride two methods for preparation of unsymmetrical anhydrides nucleophile typically carboxylate (more nucleophilic than acid) pyridine added to neutralize Cl produced (also a catalyst! how?) rganic Chemistry II (CM 224) Slide 5
Reac%ons*of*Acid*Chlorides To Esters: Schotten-Baumann Reaction Cl + diethyl ether pyridine benzoyl chloride cyclopentanol cyclopentyl benzoate 3 C Cl acetyl chloride C 2 Cl 2, Et 3 + -78 ºC 4-(hydroxymethyl)cyclohexanol 3 C (4-hydroxycyclohexyl)methyl acetate add neutral alcohol as nucleophile 1º alcohols react faster (less sterically hindered) with acid chlorides than 2º or 3º; this reaction can be chemoselective rganic Chemistry II (CM 224) Slide 6
Reac%ons*of*Acid*Chlorides To Amides: Schotten-Baumann Reaction 3 C 3 C C 3 Cl + morpholine a, 2 3 C 3 C C 3 3,4,5-trimethoxybenzoyl chloride morpholino(3,4,5-trimethoxyphenyl)methanone (Trimetozine: commerical sedative) 3 C Cl + 2 diethyl ether 3 C + Cl 3-methylbenzoyl chloride diethylamine,-diethyl-3-methylbenzamide,-diethyl-m-toluamide (DEET: insect repellent in FF) diethylammonium chloride add 3, 1º or 2º neutral amines as nucleophiles (no 3º) generally, no chemoselectivity since amines such good nucleophiles if no additional base added, 2 equiv. of amine added to neutralize Cl rganic Chemistry II (CM 224) Slide 7
Reac%ons*of*Acid*Chlorides To Amides: Schotten-Baumann Reaction 2 S + Cl 33% aac (aq) 2:TF (1:1) rt, 12 h, 48% S ceramide analogue add 3, 1º or 2º neutral amines as nucleophiles (no 3º) chemoselective for amides over alcohols (amides better nucs) more basic amide = better nucleophile if no additional base added, 2 equiv. of amine added to neutralize Cl rganic Chemistry II (CM 224) Slide 8
Reac%ons*of*Acid*Chlorides To Alcohols Cl C 3 MgBr (2 equiv) diethyl ether C 3 C 3 benzoyl chloride 2-phenylpropan-2-ol C 3 C 3 Cl C 3 C 3 acetophenone (cannot be isolated) add two equiv. of Grignard reagent Grignard adds twice in two separate addition/elimination steps rganic Chemistry II (CM 224) Slide 9
Reac%ons*of*Anhydrides 3 C R' ester R' alcoholysis 3 C carboxylic acid 2 hydrolysis 3 C anhydride R R' 2 aminolysis 3 C R' 2 amide rganic Chemistry II (CM 224) Slide 10
Reac%ons*of*Anhydrides To Esters: Schotten-Baumann Reaction + 3 C C 3 a, 2 2-hydroxybenzoic acid (salicylic acid) acetic anhydride C 3 phenol a stronger nucleophile than a carboxylic acid 2-acetoxybenzoic acid (aspirin) acetic anhydride widely used to acetylate alochols and phenols rganic Chemistry II (CM 224) Slide 11
Reac%ons*of*Anhydrides morphine diacetylmorphine (heroin) rganic Chemistry II (CM 224) Slide 12
Reac%ons*of*Anhydrides To Amides: Schotten-Baumann Reaction 2 C 3 + 3 C C 3 4-hydroxylaniline acetic anhydride -(4-hydroxyphenyl)acetamide (common: acetaminophen) (trade: Tylenol) acetic anhydride widely used to acetylate alcohols and amines more chemoselective than acetyl chloride since a weaker electrophile amines are better nucs = chemoselective acylation over alcohols rganic Chemistry II (CM 224) Slide 13
Esters*Everywhere! 3 C C 3 C 3 3-methylbutyl acetate (bananas) methyl salicylate (oil of wintergreen) aspirin (analgesic) 3 C Me cocaine (analgesic) procaine, "ovocaine" (analgesic) rganic Chemistry II (CM 224) Slide 14
Reac%ons*of*Esters Synthesis Review Alkaline 1º alkyl halides a, C 3 Br 1. S 2 C 3 Acidic Simple alcohols C 3, PTSA 2. Fisher Esterification C 3 ~eutral Common; general 1. SCl 2, Et 3 2. C 3 3. Acid Chloride Intermediate C 3 rganic Chemistry II (CM 224) Slide 15
Reac%ons*of*Esters To Carboxylic Acids: ydrolysis 1. a, 2 * + * 2. 3 + 3 + / 2 + esters are a common functional groups in organic substances and synthetic intermediates as well as biological molecules hydrolyzed under acidic or basic conditions saponification = alkaline ester hydrolysis rganic Chemistry II (CM 224) Slide 16
Mechanism*of*Ester*ydrolysis Board Work: 1. Acid and base mechanism 2. Alternatives? 3. Why is saponificaiton irreversible? rganic Chemistry II (CM 224) Slide 17
Saponifica%on*Gives*Soap LL (a triacylglyceride in soybean oil) saponification a glycerol a + a + linoleate linoleate a + oleate rganic Chemistry II (CM 224) Slide 18
Soap*in*Ac%on lipophilic chains of soap are attracted to oils and dirt and trap them in the center of the micelle hydrophilic ends point outward to maximize interaction with water (polar!) rganic Chemistry II (CM 224) Slide 19
Reac%ons*of*Esters To Esters: Transesterification (C 2 ) 7 (C 2 ) 7 Vegetable il esters can be converted to other esters by adding an alkoxide (most common) or an alcohol under acidic conditions (C 2 ) 7 LL (a triacylglyceride in soybean oil) (1) 3 C 3 C transesterification ac 3 (C 2 ) 7 methyl linoleate (2) (C 2 ) 7 Biodiesel methyl oleate (3) methyl esters of fatty acids can be used as biodiesel (the vapor pressure of oil is too high to burn efficiently in a diesel engine which has no spark plug) would not want fatty acids as fuel, soaps in engines = trouble! rganic Chemistry II (CM 224) Slide 20
Reac%ons*of*Esters To Alcohols: Reduction 1. LiAl 4, TF C 3 2. 3 + / 2 esters cannot be reduced to alcohols with ab4 esters, like carboxylic acids, are easily reduced with LiAl4 (LA) rganic Chemistry II (CM 224) Slide 21
Reac%ons*of*Esters To 3º Alcohols: Grignard Addition C 3 PhMgBr (2 equiv) diethyl ether Ph Ph methyl benzoate triphenylmethanol Ph Ph Cl Ph Ph acetophenone (cannot be isolated) add two equiv. of Grignard reagent Grignard adds twice in two separate addition/elimination steps rganic Chemistry II (CM 224) Slide 22
Reac%ons*of*Esters To 3º Alcohols: Grignard Addition R R C 3 tertiary alcohol with two or three identical alkyl groups cannot prepare 3º alcohols directly from carboxylic acids; convert to ester first (actually there are advanced methods we won t discuss) Grignard adds twice in two separate addition/elimination steps rganic Chemistry II (CM 224) Slide 23
Reac%ons*of*Amides To Carboxylic Acids: ydrolysis C 3 3 + / 2 or a/ 2 To Alcohols: LA Reduction 1. LiAl 4, TF C 3 2. 3 + / 2 rganic Chemistry II (CM 224) Slide 24
Reac%ons*of*Amides To Alcohols: LA Reduction Faux Mechanism Better Mechanism R 2 Al 3 Al 3 R 2 rganic Chemistry II (CM 224) Slide 25
Reac%ons*of*itriles To Carboxylic Acids: ydrolysis C 2 S 4 / 2 or a then 3 + C + 3 We covered both mechanisms when we completed this lab. Proceeds through an imine intermediate; from there hydrolysis step are the same as seen before for imines rganic Chemistry II (CM 224) Slide 26
Reac%ons*of*itriles To Ketones: Grignard Addition C 1. C 3 MgBr, Et 2 2. 3 + / 2 C C3 + 3 C 1. PhMgBr, Et 2 C Ph 2. 3 + / 2 + 3 Grignards add to carbon of nitrile Proceeds through an imine intermediate; from there hydrolysis steps are the same as seen before for imines rganic Chemistry II (CM 224) Slide 27
Grignard*Addi%on*to*itriles*Mechanism Board Work: 1. Addition step gives imine 2. Imine hydrolyzed in separate step after adding acid and water. rganic Chemistry II (CM 224) Slide 28
Reac%ons*of*Thioesters ucleophilic acyl substitution in nature usually through thioesters Acetyl CoA is an acylating agent Acetyl adenylate from pyruvate decarboxylation Acetyl CoA can enter citric acid cycle (Krebs) rganic Chemistry II (CM 224) Slide 29
Reac%ons*of*Thioesters chitin in exoskeletons: a polymer of -Acetylglucosamine rganic Chemistry II (CM 224) Slide 30
CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Experiment'39 Prepara&on*of*Benzocaine
Prepara%on*of*Benzocaine:*Fischer*Esterifica%on 3 C C 3 2 2 S 4 2 p-aminobenzoic acid (PABA) Bacteria produce folic acid from PABA benzocaine Sulfonamides (sulfa drugs) = generally, antibacterial by inhibiting folic acid synthesis Me 2 S F 3 C C 3 S 2 folic acid 2 Celecoxib (Celebrex) rganic Chemistry II (CM 224) Slide 32
Prepara%on*of*Benzocaine:*Fischer*Esterifica%on 3 C C 3 2 2 S 4 2 p-aminobenzoic acid (PABA) benzocaine nerve is stimulated some sodium (a + ) gates (transmembrane proteins) open a + rushes into the cell more a + gates induced to open as threshold potential is released polarization is reversed hypothesis: benzocaine binds to a + gates, preventing depolarization of nerve cell and propagation of action potential Sodium Gate Sodium Pump rganic Chemistry II (CM 224) Slide 33
Prepara%on*of*Benzocaine:*Fischer*Esterifica%on 3 C C 3 2 2 S 4 2 p-aminobenzoic acid (PABA) benzocaine benzocaine is poorly water soluble Sodium Gate generally, nontoxic since not readily absorbed site specific few other biological activities Sodium Pump rganic Chemistry II (CM 224) Slide 34
Effec%ng*Comple%on*of*Reversible*Reac%on? 2 3 C 2 S 4 2 C 3 + 2 p-aminobenzoic acid (PABA) benzocaine Take Advantage of LeChatlier Principle: Use excess alcohol (maybe as solvent) Remove water (molecular sieves, azeotropic distillation, Dean Stark apparatus) rganic Chemistry II (CM 224) Slide 35
Benzocaine*Synthesis:**Intermediates*&*Solubility S 4 3 2 S 4 2 Et 2 S 4 2 C 3 + 2 PABA 2 S 4 p-aminobenzoic acid (PABA) benzocaine Water Insoluble a 2 C 3 (aq) (10% w/w) a 2 C 3 2 S 4 a C 3 2 sodium p-aminobenzoate Water Soluble S 4 3 benzocaine 2 S 4 Water Soluble rganic Chemistry II (CM 224) Slide 36
CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie ext'lecture.'.'. Ch.*21