Lecture 8 Carboxylic Acids and Their Derivatives PDF

Lecture 8 Carboxylic acids and their derivatives College of Pharmacy Department of Pharmaceutical Chemistry Sections -Introduction -Nom...

Lecture 8 Carboxylic acids and their derivatives College of Pharmacy Department of Pharmaceutical Chemistry Sections -Introduction -Nomenclature -Acidic character -Factors effecting acidity -Carboxylic acids and their derivatives -Class activity -References Intended Learning Outcomes (ILO’s) At the end of this unit students will be able to: Demonstrate the basic chemistry of carboxylic acid containing aromatic compounds Understand effects of substituents on acidity Describe various types of synthesis, properties in terms of acidity of carboxylic acid containing aromatic compounds 21-Dec-24 3 Introduction Carboxylic acids are the derivatives of hydrocarbons which contain one or several groups –COOH in their molecule. General Formula Specific examples 21-Dec-24 4  Continued… 21-Dec-24 5 Continued… N.B. If aliphatic side chain containing -COOH group is presents it will be taken as a parent. OH CH-COOH CH2-COOH Common: Mandelic acid Phenyl acetic acid IUPAC: 2-hydroxy-2-phenyl-ethanoic acid phenyl ethanoic acid CH3 CH=CH-COOH CH-CH2-COOH Cl Common: Cinnamic acid 3-(4-chlorophenyl) butanoic acid IUPAC: 3-phenyl propenoic acid N.B. Some common names are accepted by IUPAC e.g. Salicylic acid and benzoic acid. 21-Dec-24 6 Preparation of Carboxylic acids 1. By oxidation of Alkenes 2. By oxidation of Aldehydes and Alcohols 3. By oxidation of Alkylbenzenes 4. By Hydrolysis of Nitrile and Cyanohydrin 21-Dec-24 7 Acidity of Carboxylic Acid - 122 Carboxylic acids are typically weak acids, meaning that they only partially dissociate into H+ cations and RCOO– anions in neutral aqueous solution Acidity: Aromatic carboxylic acids> Phenols > alcohols 21-Dec-24 8 Pka value of Carboxylic Acid - Page - 122 For the ionization of the acid HA in water; [A-][H3O+] Ka = ------------------ As the concentration of water is essentially constant, [HA] Ka = acidity constant, and its magnitude allows us to classify acids as; strong acids (a large value for Ka and, consequently, a high H3O+concentration) For example, the strong acid HCl has Ka = 107. weak acids (a small value for Ka and, thus, a low H3O+ concentration) Acetic acid CH3CO2H has Ka = 1.76 × 10−5 pKa = − log10 Ka Smaller the value of pKa, the stronger is the acid; Larger the value of pKa, the weaker is the acid. 21-Dec-24 9 Electronegativity on Acidity - 125 21-Dec-24 10  Continued… 21-Dec-24 11 Inductive Effect on Acidity - 125 The inductive effects of the chlorine atoms spreading the charge of the conjugate base and thus stabilizing it. pKa 21-Dec-24 12  Continued… 21-Dec-24 13 Substitution on Benzoic acid The conjugate base of benzoic acid is stabilized by electron-withdrawing groups (EWG). This makes the acid more acidic by delocalizing the charge of the carboxylate ion. Electron-withdrawing groups deactivate the benzene ring to electrophilic attack and make benzoic acids more acidic. The conjugate base of benzoic acid is destabilized by electron-donating groups (EDG). This makes the acid less acidic by pushing more electron density toward the negative charge in the carboxylate. Electron-donating groups activate the benzene ring to electrophilic attack and make benzoic acids less acidic. 21-Dec-24 14  Continued… X pKa —N(CH3)2 6.03 —NHCH3 5.04 —OH 4.57 —OCH3 4.50 —C(CH3)3 4.38 —H 4.20 —Cl 4.00 —Br 3.96 —CHO 3.77 —CN 3.55 —NO2 3.43 21-Dec-24 15 Hybridization Effect on Acidity Since s orbitals are closer to the nucleus than p orbitals, it follows that electrons in an sp-hybridized orbital are held closer to the nucleus than those in an sp2 orbital; those in an sp2 orbital are similarly closer to the nucleus than those in an sp3 orbital. It is more favourable for the electrons to be held close to the positively charged nucleus, and thus an sp-hybridized anion is more stable than an sp2-hydridized anion. 21-Dec-24 16 Resonance/delocalization Effect on Acidity Delocalization of charge in the conjugate base anion through resonance is a stabilizing factor. 21-Dec-24 17 Q. Which of the following is more acidic and why? Benzoic acid (pKa 4.2) is a stronger acid than acetic acid (pKa 4.8), and it is also stronger than its saturated analogue cyclohexanecarboxylic acid (pKa 4.9). The phenyl group exerts an electron withdrawing effect because the hybridization of the ring carbons is sp2; consequently, electrons are held closer to the carbon atom than in an sp3-hybridized orbital. The pKa of phenylacetic acid (pKa 4.3), compared with acetic acid (pKa 4.8), demonstrates the inductive effect of a benzene ring. However, we might then expect benzoic acid to be a rather stronger acid than it actually is, since the phenyl group is closer to the carboxyl group than in phenylacetic acid. 21-Dec-24 18  Carboxylic Acids and Their Derivatives The derivatives of carboxylic acids are compounds in which the -OH of carboxylic acid is replaced by nucleophile (-X for acid halide, -OR for ester, -NH2, -NHR, -NR2 for amides, -OOCR for anhydride). Carboxylic acids derivatives can converted to carboxylic acids by simple acidic or basic hydrolysis. Acid Chloride Ester Amide Acid anhydride 21-Dec-24 19 1-Nomenclature Of Acid Chlorides Replace the -ic acid ending in the name of the parent acid by –yl chloride. O O H3C Cl Cl IUPAC: Ethanoyl chloride Benzoylchloride Propanoyl chloride Common : Acetyl chloride 21-Dec-24 20 2- Nomenclature of Esters The alkyl group (R’) is written first followed by the name of the parent acid with replacing of the ending –ic acid by –ate. (IUPAC) Ethyl ethanoate Methyl benzoate (common) Ethyl acetate O HO O (IUPAC) Methyl propanoate Isopropyl-4-hydroxy-5-methyl-5- hexenoate 21-Dec-24 21 3- Nomenclature of Amide Replace the ending oic acid of the parent acid’s by the word amide If there is R group on the nitrogen atom, it is listed first and designated with –N. O CH3CH2 C NHCH3 (IUPAC) Ethanamide Benzamide N-Methylpropanamide (Common) Acetamide N-Methylpropionamide (IUPAC) N,N-Dimethylmethanamide N-Ethyl-N-methylbenzamide (Common) N,N-Dimethylformamide 21-Dec-24 22 4- Nomenclature of Anhydride An anhydride is named by replacing the word acid in the corresponding acid by the word anhydride. (IUPAC) Ethanoic anhydride Benzoic anhydride Butandioic anhydride (Common) Acetic anhydride Succinic anhydride O O OH Preparation heat O OH O O 21-Dec-24 23 Nucleophilic Substitution Reactions O O + Nu + L R L R Nu 21-Dec-24 24 Relative reactivity of the carboxylic acid derivatives towards a nucleophilic substitution reaction. EDG : Reduces the electrophilic nature of the carbonyl group by neutralizing the partial positive charge developed on the carbonyl carbon, and thus makes the derivative less reactive to nucleophilic substitution. EWG: Increases the electrophilic nature of carbonyl group by pulling the electron density of the carbonyl bond towards itself, making the carbonyl carbon more reactive to nucleophilic substitution. 21-Dec-24 25 Derivative Substituent (X) Electronic effect of X Relative reactivity Acid chloride -Cl electron withdrawing 1 (most reactive) Acid anhydride -OC=OR electron withdrawing 2 (almost as reactive as 1) Thioester -SR weakly electron donating 3 alkoxy (-OR) group is weakly Ester -OR 4 electron donating Amide -NH2 very strongly donating 5 Carboxylate ions are not reactive because their negative Carboxylate ion -O- charge repels the approach of other nucleophiles Acid halide > acid anhydride > thioester > ester > amide 21-Dec-24 26 Preparation of Acyl chlorides and reactions of Acyl chlorides 21-Dec-24 27 Class Activity Q1. Why carboxylic acids are activated? Hint: See good and poor leaving group. Q2. Which of the following is more acidic? Q3. Why aromatic carboxylic acids are more acidic than Phenols and alcohols? https://www.khanacademy.org/test-prep/mcat/chemical-processes/carboxylic-acids/e/carboxylic-acid-questions 21-Dec-24 28 References Textbooks: T.W. Graham Solomons & Craig B. Fryhle, Organic Chemistry. John Wiley & Sons Ltd., England. Paul M Dewick, Essentials of organic chemistry. John Wiley & Sons Ltd., England. 2006,.no. 121-134 Online link & Video https://chem.libretexts.org https://www.khanacademy.org 21-Dec-24 29