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Aldehyde, Ketone, carboxylic acids and acyl transfer

by: Gris Nunez

Aldehyde, Ketone, carboxylic acids and acyl transfer CHM 2211

Marketplace > Florida State University > CHM 2211 > Aldehyde Ketone carboxylic acids and acyl transfer
Gris Nunez
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These 3 chapters of notes deal with the conversion of aldehydes and ketones into alcohols. Synthesis of carboxylic acids and acyl transfer.
Organic Chemistry 2
Edwin Hilinski
Class Notes
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This 66 page Class Notes was uploaded by Gris Nunez on Tuesday April 5, 2016. The Class Notes belongs to CHM 2211 at Florida State University taught by Edwin Hilinski in Fall 2015. Since its upload, it has received 29 views.


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Date Created: 04/05/16
3/11/2016 Chapter 19 Carboxylic Acid Derivatives:  Nucleophilic Acyl Substitution 1 1) Naming 2 1 3/11/2016 Carboxylic acid derivatives acyl group 3 Nomenclature – acyl chloride pentanoyl chloride 3‐butenoyl chloride O Cl p‐fluorobenzoyl chloride cyclopentanecarbonyl chlori4e 2 3/11/2016 Nomenclature – acid anhydride acetic anhydride benzoic anhydride benzoic heptanoic anhydride 5 Anhydrides that go by common names maleic anhydride succinic anhydride phthalic anhydride 6 3 3/11/2016 Nomenclature ‐ ester ethyl acetate methyl propionate methyl propanoate 2‐chloroethyl benzoate 7 Nomenclature – amide 3‐methylbutanamide N‐ethyl‐3‐methylbutanamide N‐ethyl‐N,3‐dimethylbutanamide 8 4 3/11/2016 Nomenclature ‐ nitrile A couple of common names acetonitrile benzonitrile 9 2) General reactivity trend 10 5 3/11/2016 Nucleophilic acyl substitution in acyl chlorides Nucleophile is alcohol or water: 11 Nucleophilic acyl substitution in acyl chlorides Nucleophile is amine: 12 6 3/11/2016 Nucleophilic acyl substitution of acid anhydrides Alcohol or water derived nucleophiles: 13 Nucleophilic acyl substitution in acid anhydrides Amine nucleophiles: O O C( 3 2H (2 mol) O 14 7 3/11/2016 Acyl substitution reactivity Reactivity to H O  (neutral pH) Seconds to minutes hours Thousand of years Billions of  years 15 Explain the reactivity trend • Two factors: – Electrophilicity of the carbonyl – the quality of the leaving group 16 8 3/11/2016 3) Baeyer‐Villiger ketone  oxidation ‐ Ester synthesis 17 Ester from Baeyer‐Villiger oxidation of ketone peroxy acid ester lactone 18 9 3/11/2016 When R groups are different, the “bigger”  group migrates 19 Physical properties of ester –w aer  solubility O O + C2H5 OH CH 2H 3 +H 2O H3C OH H 3 O Soluble  Soluble  (miscible) (miscible) Solubility low 20 10 3/11/2016 4) Reactions of Esters (addition‐elimination mechanism) 21 Acid‐catalyzed ester hydrolysis  –the  reverse of esterification • Which one is nucleophile? Which one is electrophile? • Given the conditions, what is the most likely first  step? 22 11 3/11/2016 Base‐catalyzed ester hydrolysis ‐ saponification 23 How to tell these two mechanism apart? SN2 Ad‐El 24 12 3/11/2016 Another cool mechanistic experiment retention of absolute configuration 25 Ester + amine gives amide (acyl transfer) 26 13 3/11/2016 Ester + Grignard x 2 = tertiary alcohol 27 Review –G rgard  + carbonyl • Aldehyde: Grignard adds once to give 2 alcohol. • Ketone: Grignard adds once to give 3 alcohol. • Ester: Grignard adds twice to give 3 alcohol. 28 14 3/11/2016 Ester + LiAlH 4hydride is the nucleophile) 29 5) Amide chemistry A prelude to peptide/protein  chemistry 30 15 3/11/2016 H bond‐acceptor H bond‐donor • Most stableamong common carboxylic acid  derivatives. • Least electrophilic (referring to the carbonyl). • Strong tendency to form H‐bonds, as both donor and  acceptor.  31 Making amides from  • Acyl chlorides • Acid anhydrides • Esters • Amide is the most stable among all common  carboxylic acid derivatives.  32 16 3/11/2016 Amide hydrolysis to carboxylic acid • Hard! • Requires either a strong acid or a strong base. • Mechanisms 19.4 and 19.5; similar to ester hydrolysis. 33 Lactams – cyclic amides N‐methylpyrrolidone ε‐caprolactam 34 17 3/11/2016 Penicillin 35 6) Nitriles 36 18 3/11/2016 Amide dehydration gives nitrile 37 Problem 19.24 • Show how ethyl alcohol could be used to prepare (a)  CH 3N and (b) CH CH 3N. 2long with alcohol you  may use any necessary inorganic reagents.  38 19 3/11/2016 Hydrolysis of nitriles 39 Addition of Grignard to nitriles electrophile nucleophile 40 20 3/11/2016 Reduction by LiAlH 4 41 7) Spectroscopic characterization  of acyl derivatives 42 21 3/11/2016 Infrared (IR) spectra of carboxylic acid derivatives ‐1 • Acetyl chloride – ν(C=O) 1822 cm ‐1 • Acetic anhydride ‐ ν(C=O) 1748, 1815 cm • Methyl acetate ‐ ν(C=O) 1736 cm ‐1 • Acetamide ‐ν (C=O) 1694 cm ‐1 43 1H NMR of ethyl acetate 44 22 3/11/2016 Methyl propanoate 45 Summary • Addition‐elimination mechanism • Reactivity trend • Hydrolysis • Inter‐conversions between these classes of  compounds • Baeyer‐Villiger oxidation of ketone 46 23 3/11/2016 Chapter 18 Carboxylic Acids 1 ‐COOH O O OH H3C OH O O CH 3 Aspirin 2 1 3/11/2016 1) Naming and structures 3 Nomenclature formula Systematic  (IUPAC) name Common name n a h t e HCO H M oic acid Formic acid 2 n a t CH(3H e2 3CO2H P oic acid Valeric acid CH 3H(OH)CO H22 ‐hydroxypropanoic acid Lactic acid e n e z n C 6 5CO 2 B carboxylic acid Benzoic acid e n HaO2CCH 2 CH2uO2H B dioic acid Succinic acid 4 3/11/2016 Name this compound 5 Boiling points (@ 1 atm) alkene ketone alcohol carboxylic acid 31 °C 80 °C 99 °C 141 °C Dipole moment; HB capability 6 3 3/11/2016 Strong intermolecular interactions – carboxylic  dimer formation 7 2) Acid‐base chemistry 8 4 3/11/2016 Carboxylic acid is ‘acidic’ 9 Substitution on acid strength • Acetic acid  pKa= 4.7 • Chloroacetic acid pKa = 2.9 • Dichloroacetic acid pK = 1.3 a • Trichloroacetic acid pKa = 0.9 • Acrylic acid pK = 4.3 a • Benzoic acid pKa = 4.2 10 5 3/11/2016 Carboxylate Potassium hydrogen Lithium acetate Sodium p‐chlorobenzoate hexanedioate 11 Carboxylate with a long alkyl tail When you put enough of these molecules in water, 12 6 3/11/2016 Micelle formation 13 Detergent removes grease by micelle formation Sodium dodecyl sulfate 14 7 3/11/2016 Dicarboxylic acids –t wo  pK ’a 15 Just like sulfuric acid 16 8 3/11/2016 Inductive effect on acidity of diacids formula name pKa1 HO 2CO H2 Oxalic acid 1.2 HO 2CH C2 H 2 Malonic acid 2.8 HO 2CH )2 5 H2 Heptanedioic acid 4.3 17 3) Synthesis of carboxylic acids 18 9 3/11/2016 Sources of carboxylic acids • Industrial synthesis of acetic acid • Oxidation of alcohol or aldehyde (Chapter 15) • Oxidation of alkylbenzene (Chapter 11) 19 The addition of Grignard (nucleophile) to CO 2 (electrophile) 20 10 3/11/2016 Problem 18.7 • 2,6‐Dimethoxybenzoic acid was needed for a  synthesis of the ‐lactam antibiotic methicillin. Show  how this carboxylic acid could be synthesized from 2‐ bromo‐1,3‐benzenediol.  21 Cyanide (nucleophile) + alkyl halide electrophile 22 11 3/11/2016 Followed by hydrolysis of nitrile 23 Problem 18.8 • Of the two procedures just described, preparation  and carboxylation of a Grignard reagent or formation  and hydrolysis of a nitrile, only one is appropriate to  each of the following RX → RCO H c2nversions.  Identify the correct procedure in each case, and  specify why the other will fail. • bromobenzene → benzoic acid • 2‐chloroethanol → 3‐hydroxypropanoic acid • tert‐butyl chloride → 2,2‐dimethylpropanoic acid 24 12 3/11/2016 Preparation of ‐hydroxy carboxylic acids 2‐pentanone (cyanohydrin) 2‐hydroxy‐2‐methyl pentanoic acid 25 4) Reactions of carboxylic acids 26 13 3/11/2016 Acid‐catalyzed esterification benzoic acid methyl benzoate 18 O =  O 27 Intramolecular esterification affords “lactone” 28 14 3/11/2016 Decarboxylation emovl  of carboxyl group by  releasing C2 29 How does that happen? Six‐membered ring  transition state H O O slow OH OC O + HO O HO CH 2 tautomerizatiofast see Chap. 9 O (carboxylic acid) HO CH3 30 15 3/11/2016 Swapping –OH with an –R group should work too ‐keto acid (ketone) 31 Decarboxylation of ‐keto acid 32 16 3/11/2016 5) Spectroscopic characterization  of carboxylic acids 33 IR of 4‐phenylbutanoic acid 34 17 3/11/2016 1 H NMR of 4‐phenylbutanoic acid 35 Summary • Acid‐base chemistry • Preparing carboxylic acid – Oxidation of aldehyde and alcohol – Oxidation of alkylbenzene – Grignard + CO 2 – Hydrolysis of nitrile • Reactions of carboxylic acid – Esterification (mechanism) – Decarboxylation (mechanism) 36 18 3/11/2016 Chapter 17 Nucleophilic addition to carbonyls 1 1) Nomenclature 2 1 3/11/2016 Aldehydes and ketones aldehyde ketone acyl group formyl group 3 Nomenclature – aldehyde, acyclic and cyclic 4,4‐dimethylpentanal 5‐hexenal 2‐phenylbutanedial cyclopentanecarbaldehyde 4 2 3/11/2016 Nomenclature –f rmylroup  (‐CHO) has higher  priority than ‐OH 5‐hydroxypentanal trans‐4‐hydroxycyclohexanecarbaldehyde p‐hydroxybenzenecarbaldehyde or p‐hydroxybenzaldehyde 5 A few common names of aldehydes and ketones formaldehyde acetaldehyde acetone benzaldehyde acetophenone benzophenone 6 3 3/11/2016 (Substitutive) nomenclature ‐ ketone 3‐hexanone 4‐methyl‐2‐pentanone 4‐methylcyclohexanone 7 Priority: aldehyde (formyl) > ketone (oxo) >  alcohol (hydroxyl) 4‐methyl‐3‐penten‐2‐one 2‐methyl‐4‐oxopentanal 8 4 3/11/2016 Functional class nomenclature ‐ ketone Ethylpropyl ketone benzyl ethyl ketone divinyl ketone 9 2) Structure and bonding 10 5 3/11/2016 Effects on the physical properties of carbonyls CH 3H C2=CH 2 CH3CH 2H=O CH 3H 2H O2 Molecular weight 56 58 60 Name 1‐butene propanal propanol b.p. (1 atm) 9 ‐6 C 4 7  C 9  C Solubility in water negligible 20 Miscible in all  (g/100 mL) proportions 11 Effect on the chemical reactivity of carbonyl 12 6 3/11/2016 3) Preparing aldehydes and  ketones 13 A Synthetic Problem • Prepare 3‐heptanone from propanal and other  necessary organic and inorganic reagents.  14 7 3/11/2016 Problem 17.5 • Show how 2‐butanone could be prepared by a  procedure in which all of the carbons originate in  acetic acid (CH 3O H2. 15 4) Nucleophilic addition to carbonyl 16 8 3/11/2016 Nucleophilic addition to carbonyl (Ch. 14) (Ch. 15) (Ch. 117 Cyanide as the nucleophile 2,4‐dichlorobenzaldehyde cyanohydrin 18 9 3/11/2016 Problem 17.7 • Cyanohydrin formation is reversible. Using NaOH as  the base, use curved arrows to show the elimination  of HCN from acetone cyanohydrin to afford acetone.  19 If the nucleophile is water –h yraon  reaction 20 10 3/11/2016 Base‐catalyzed hydration mechanism – activating the nucleophile (H O) 2 Overall reaction: electrophile nucleophile 21 The reaction coordinate (addition/protonation) 22 11 3/11/2016 Acid‐catalyzed hydration mechanism – activating  the electrophile Overall reaction: electrophilenucleophile 23 Hydration equilibrium ▯▯▯▯▯▯▯▯▯ • ▯ ▯▯▯▯ ▯ ▯▯▯▯▯▯▯▯▯ ▯▯▯▯▯▯▯▯▯ 24 12 3/11/2016 Tendency of hydration as measured by K hydr Carbonyl  K Percent conversion hydr compound to hydrate 2,300 >99.9 O 1.0 50 H 0.2 17 0.0014 0.14 22,000 25 Relate hydration trends to structural features 26 13 3/11/2016 Alcohol as the nucleophile hemiacetal (half way to an acetal) acetal 27 Mechanism of hemiacetal formation  (acid catalyzed) Overall reaction: electrophile nucleophile 28 14 3/11/2016 The four most common mechanistic steps • Add a proton (protonation) • Remove a proton (deprotonation) • Nucleophilic attack • Leaving group departure 29 Mechanism of acetal formation (acid‐catalyzed) Overall reaction: 30 15 3/11/2016 Cyclic hemiacetal and acetal 31 Hemiacetal and acetal formations are reversible 32 16 3/11/2016 Using acetal to “protect” carbonyl group Ketone needs to be “protected”.  33 Protection step no longer electrophilic Deprotection step 34 17 3/11/2016 Primary amine (RNH ) as th2 nucleophile See more amine chemistry in Chapter 21. 35 Other similar condensation reactions hydroxylamine oxime phenylhydrazine phenylhydrazone semicarbazide semicarbazone 36 18 3/11/2016 Secondary amine as nucleophile Iminium ion enamine 37 Mechanism of enamine formation • Typica  laddition‐elimination to reach iminium. • Deprotonation of iminium to give enamine.  38 19 3/11/2016 A very useful class of carbon nucleophile – ylide Prepare a ylide: phosphonium salt 39 Ylide addition to aldehyde or ketone to afford  alkene –W tg  reaction say “Vittig” 40 20 3/11/2016 Ylides stabilized via resonance 41 Nucleophilic addition to carbonyl • (Almost) irreversible reaction (carbon nucleophiles) – Grignard (C) – Acetylide (C) – Cynide (C) – Wittig (C) – Hydride (H) • Reversible reaction (heteroatom nucleophiles) – Water (O), alcohol (O), amine (N) 42 21 3/11/2016 A synthesis problem (17.20) • How do you prepare 3‐methyl‐3‐heptene via a  couple of steps from an alkyl halide and a ketone? 43 Synthesis problem vs. mechanism problem • Synthesis problems require you to show a series of  reactions to take the reactants to the product, under  given conditions.   • In a mechanism problem, you need push the arrows,  i.e., electrons, to show how exactly bonds break and  form in each elementary step.  44 22 3/11/2016 Stereoselective nucleophilic addition to carbonyl major minor 45 5) Spectroscopic analysis of  aldehydes and ketones Infrared; NMR; UV‐VIS; MS 46 23 3/11/2016 Infrared –the  C=O stretch 47 1H NMR of aldehydes –t he  aldehyde C‐H peak 48 24 3/11/2016 1C NMR of aldehydes or ketones  –he  carbonyl  carbon 49 Summary • Carbonyl is polar and electrophilic. • Nucleophilic addition to carbonyl – Addition‐elimination mechanism – Acid (activating electrophile), or base (activating  nucleophile) catalysis – Hydration (addition) – Enamine formation (addition‐elimination) – Wittig reaction – Reduction by hydride sources (addition) 50 25


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