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Carboxylic Acid Derivatives: Organic Chemistry Presentation
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ORGANIC CHEMISTRY II (CHEM 234) Carboxylic acid Derivatives Dr Richard K. Amewu, Dr Jerry Joe Harrison, Dr Anita Oppong and Dr Richard B. Owoare Introduction • The carboxyl group (-CO2H) is the parent group of a family of compounds called acyl compounds or carboxylic acid derivatives 2 Nomenclature - Acid Anhydrides • Most anhydrides are named by dropping the word acid from the carboxylic acid name and adding the word anhydride 3 Nomenclature - Acid Chlorides • Acid chlorides are named by dropping the -ic acid from the name of the carboxylic acid and adding -yl chloride 4 Nomenclature- Esters • The names of esters are derived from the names of the corresponding carboxylic acid and alcohol to form the ester • The alcohol portion is named first and has the ending -yl • The carboxylic acid portion follows and its name ends with -ate or -oate 5 Physical Properties of Esters ▪ Esters cannot hydrogen bond to each other and therefore have lower boiling points than carboxylic acids ― Esters can hydrogen bond to water and have appreciable water solubility 6 Nomenclature- Amides • Amides with no substituents on nitrogen are named by replacing -ic acid in the name with amide • Groups on the nitrogen are named as substitutents and are given the locants N- or N,N- 7 Physical Properties- Amide • Amides with one or two hydrogens on nitrogen form very strong hydrogen bonds and have high melting and boiling points • N,N-disubstituted amides cannot form hydrogen bonds to each other and have lower melting and boiling points • Hydrogen bonding between amides in proteins and peptides is an important factor in determining their 3-dimensional shape 8 Nitriles, RCN • Closely related to carboxylic acids named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon numbered C1 • Complex nitriles are named as derivatives of carboxylic acids. • Replace -ic acid or -oic acid ending with -onitrile 9 Spectroscopic Properties of Acyl Compounds • IR Spectra • The carbonyl stretching frequency varies according to the type of carboxylic acid derivative present • O-H stretching vibrations of the carboxylic acid give a broad band at 2500-3100 cm-1 • N-H stretching vibrations of amides appear at 3140-3500 cm-1 10 Learning check • Write structural formulas for the following • (a) Methyl propanoate • (b) Ethyl p-nitrobenzoate • (c) Dimethyl malonate • (d) N,N-Dimethylbenzamide • (e) Pentanenitrile • (f) Dimethyl phthalate • (g) (i) 2-Bromopropanoyl bromide 11 Spectroscopic Properties of Acyl Compounds 12 Spectroscopic Properties of Acyl Compounds • 1H NMR Spectra • The a hydrogens of carboxylic acids and their derivatives appear at d 2.0-2.5 13 Spectroscopic Properties of Acyl Compounds • 13C NMR Spectra • The carbonyl carbon signal for carboxylic acids and their derivatives appears at d 160 to 180 14 Nucleophilic Addition-Elimination at the Acyl Carbon • Recall that aldehydes and ketones undergo nucleophilic addition to the carbon-oxygen double bond 15 Nucleophilic Addition-Elimination at the Acyl Carbon • The carbonyl group of carboxylic acids and their derivatives undergo nucleophilic addition-elimination • The nucleophile reacts at the carbonyl group to form a tetrahedral intermediate • The tetrahedral intermediate eliminates a leaving group (L) • The carbonyl group is regenerated; the net effect is an acyl substitution 16 Nucleophilic Addition-Elimination at the Acyl Carbon • To undergo nucleophilic addition-elimination the acyl compound must have a good leaving group or a group that can be converted into a good leaving group • Acid chlorides react with loss of chloride ion • Anhydrides react with loss of a carboxylate ion 17 Nucleophilic Addition-Elimination at the Acyl Carbon • Esters, carboxylic acids and amides generally react with loss of the leaving groups alcohol, water and amine, respectively • These leaving groups are generated by protonation of the acyl compound • Aldehydes and ketones cannot react by this mechanism because they lack a good leaving group 18 Relative Reactivity of Acyl Compounds • The relative reactivity of carboxylic acids and their derivatives is as follows: DECREASING REACTIVITY 19 Relative Reactivity of Acyl Compounds • In general, reactivity can be related to the ability of the leaving group (L) to depart • Leaving group ability is inversely related to basicity • Chloride is the weakest base and the best leaving group • Amines are the strongest bases and the worst leaving groups • As a general rule, less reactive acyl compounds can be synthesized from more reactive ones • Synthesis of more reactive acyl derivatives from less reactive ones is difficult and requires special reagents (if at all possible) 20 Preparation of Carboxylic derivatives 21 Synthesis of Acid Chlorides • Acid chlorides are made from carboxylic acids by reaction with thionyl chloride, phosphorus trichloride or phosphorus pentachloride • These reagents work because they turn the hydroxyl group of the carboxylic acid into an excellent leaving group 22 Synthesis of Acid Chlorides • Mechanism for formation of Acid Chlorides 23 Reactions of Acyl Chlorides • Acyl chlorides are the most reactive acyl compounds and can be used to make any of the other derivatives • Since acyl chlorides are easily made from carboxylic acids they provide a way to synthesize any acyl compound from a carboxylic acid • Acyl chlorides react readily with water, but this is not a synthetically useful reaction 24 Reactions of Acyl Chlorides • Both chlorine and oxygen atoms are electronwithdrawing groups, thus making the acyl carbon much electron-deficient acyl carbon is a good nucleophilic site • Chloride ion is a good leaving group which is substituted by other atoms or groups easily acyl chlorides are very reactive Reactions of Acyl Chlorides • Benzoyl chloride is much less reactive than aliphatic acyl chlorides ∵ reduction of electron-deficiency on the acyl carbon due to delocalization of electrons (resonance effect) Reactions of Acyl Chlorides Reaction with Water Acyl chlorides are hydrolyzed by water to form the parent carboxylic acids and hydrogen chloride Examples: Reactions of Acyl Chlorides 28 Synthesis of Carboxylic Acid Anhydrides • Acid chlorides react with carboxylic acids to form mixed or symmetrical anhydrides • It is necessary to use a base such as pyridine • Sodium carboxylates react readily with acid chlorides to form anhydrides 29 Synthesis of Carboxylic Acid Anhydrides • Cyclic anhydrides with 5- and 6-membered rings can be synthesized by heating the appropriate diacid • Reactions of Carboxylic Acid Anhydrides • Carboxylic acid anhydrides are very reactive and can be used to synthesize esters and amides • Hydrolysis of an anhydride yields the corresponding carboxylic acids 30 Reactions of Carboxylic Acid Anhydrides • Reactions of Carboxylic Acid Anhydrides • Carboxylic acid anhydrides are very reactive and can be used to synthesize esters and amides • Hydrolysis of an anhydride yields the corresponding carboxylic acids 31 Reactions of Carboxylic Acid Anhydrides 32 Synthesis of Esters: Esterification • Acid catalyzed reaction of alcohols and carboxylic acids to form esters is called Fischer esterification • Fischer esterification is an equilibrium process • Ester formation is favored by use of a large excess of either the alcohol or carboxylic acid • Ester formation is also favored by removal of water 33 Synthesis of Esters: Esterification • A mechanism for esterification 34 Synthesis of Esters: Esterification • Esterification with labeled methanol gives a product labeled only at the oxygen atom bonded to the methyl group ▪ The reverse reaction is acid-catalyzed ester hydrolysis ― Ester hydrolysis is favored by use of dilute aqueous acid 35 Synthesis of Esters • Esters from Acid Chlorides • Acid chlorides react readily with alcohols in the presence of a base (e.g. pyridine) to form esters So why is a base needed for the rxn? 36 Synthesis of Esters from Carboxylic Acid Anhydrides • Alcohols react readily with anhydrides to form esters 37 Base-Promoted Hydrolysis of Esters: Saponification • Reaction of an ester with a base (eg: sodium hydroxide) results in the formation of a sodium carboxylate and an alcohol 38 Base-Promoted Hydrolysis of Esters: Saponification • The mechanism is reversible until the alcohol product is formed • Protonation of the alkoxide by the carboxylic acid formed, is irreversible (why?) • A fast step, requires -O to act as a leaving group to be reversible, not likely fast 39 Transesterification • Transesterification is the process of exchanging the organic group R″ of an ester with the organic group R′ of an alcohol • Esterification is the reaction between a carboxylic acid and an alcohol whereas transesterification occurs between an ester and an alcohol • This is usually how we convert fats (triglycerides) into biodiesel (vegetable fats) Where R is part of a long chain fatty acid 40 Cyclic Esters - Lactones • g- or d-Hydroxyacids undergo acid catalyzed reaction to give cyclic esters known as g- or d-lactones, respectively 41 Cyclic Esters - Lactones • Lactones can be hydrolyzed with aqueous base • Acidification of the carboxylate product can lead back to the original lactone if too much acid is added why? 42 Synthesis of Amides • Amides From Acyl Chlorides • Ammonia, primary or secondary amines react with acid chlorides to form amides • An excess of amine is added to neutralize the HCl formed in the reaction • Carboxylic acids can be converted to amides via the corresponding acid chloride 43 Synthesis of Amides • Amides from Carboxylic Anhydrides • Anhydrides react with 2 equivalents of amine to produce an amide and an ammonium carboxylate salt amide Ammonium salt 44 Synthesis of Amides - from Carboxylic Anhydrides • Reaction of a cyclic anhydride with an amine, followed by acidification yields a product containing both amide and carboxylic acid functional groups • Heating this product results in the formation of a cyclic imide 45 Synthesis of Amides • Amides from Carboxylic Acids and Ammonium Carboxylates • Direct reaction of carboxylic acids and ammonia yields ammonium salts 46 Synthesis of Amides • Some ammonium salts of carboxylic acids can be dehydrated to the amide at high temperatures • This is generally a poor method of amide synthesis • A good way to synthesize an amide is to convert a carboxylic acid to an acid chloride and to then to react the acid chloride with ammonia or an amine as seen before 47 Synthesis of Amides • Dicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic acids and amines • DCC activates the carbonyl group of a carboxylic acid toward nucleophilic addition-elimination 48 Learning Check • Provide the missing compounds A-C in the following synthesis 49 Reactions of Amides - Hydrolysis • Heating an amide in concentrated aqueous acid or base causes hydrolysis • Hydrolysis of an amide is slower than hydrolysis of an ester 50 Hydrolysis of Amides - Mechanism 51 Nitriles from the Dehydration of Amides • A nitrile can be formed by reaction of an amide with phosphorous pentoxide or boiling acetic anhydride 52 Nitriles • Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and contain a bond • Both both are electrophiles 53 Preparation of Nitriles by Dehydration • Reaction of primary amides RCONH2 with SOCl2 or POCl3 (or other dehydrating agents) • Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN) 54 Mechanism of Dehydration of Amides • Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination 55 Reactions of Nitriles • RCN is strongly polarized with an electrophilic carbon atom • Attacked by nucleophiles to yield sp2-hybridized imine anions 56 Hydrolysis: Conversion of Nitriles into Carboxylic Acids • Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia or an amine 57 Mechanism of Hydrolysis of Nitriles • Nucleophilic addition of hydroxide to CN bond • Protonation gives a hydroxy imine, which tautomerizes to an amide • A second hydroxide adds to the amide carbonyl group and loss of a proton gives a dianion • Expulsion of NH2− gives the carboxylate 58 Reduction: Conversion of Nitriles into Amines • Reduction of a nitrile with LiAlH4 gives a primary amine • Nucleophilic addition of hydride ion to the polar CN bond, yieldis an imine anion • The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water 59 Reaction of Nitriles with Organometallic Reagents • Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone 60 Learning Check Write structural formulas for the major organic product from each of the following reactions 61 Solution Write structural formulas for the major organic product from each of the following reactions 62 Solution Write structural formulas for the major organic product from each of the following reactions 63 POLYMERS 64 Synthetic and Biological Polymers • Polymers: Large molecules (Macromolecules) formed by the covalent attachment of a set of small molecules termed monomers. • Polymers are classified as: • (1) Man-made or synthetic polymers that are synthesized in the laboratory; • (2) Biological polymer that are found in nature. • Synthetic polymers: nylon, poly-ethylene, poly-styrene • Biological polymers: DNA, proteins, carbohydrates 65 Example of addition polymers - synthetic 66 Polyesters Polyethylene Terephthalate (PETE) “Polyester” Chain Length: 4,000 – 8,000 Ester Nylon Kevlar – Poly amide Strong Network of Covalent Bonds And Polar Hydrogen Bonds Biopolymers • Nucleic acid polymers (DNA, RNA)- Genetic information for the cell • Amino acids polymers (Proteins) - Structural strength and catalysis • Sugar polymers (Carbohydrates)- Energy source Proteins • Cellulose- Cotton Sugar DNA 69 Proteins: condensation polymers ▪ Formed by condensation polymerization of amino acids ▪ Monomers: 20 essential amino acids NH2 H General structure of an amino acid R CO2H R is the only variable group Glycine (R = H) + Glycine First step toward poly(glycine) 70 71 Representation of the constitution of a protein 72 Three D representation of the structure of a protein 73
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