Carboxylic Acids PCH312 2023-2024 PDF

2023_2024 SESSION PCH312: PHARMACEUTICAL ORGANIC CHEMISTRY CARBOXYLIC ACIDS AND THEIR DERIVATIVES Carboxylic acids belong to a class of organic compounds in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond and to a hydroxyl group (−OH) by a single bond. A fourth bond links...

2023_2024 SESSION PCH312: PHARMACEUTICAL ORGANIC CHEMISTRY CARBOXYLIC ACIDS AND THEIR DERIVATIVES Carboxylic acids belong to a class of organic compounds in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond and to a hydroxyl group (−OH) by a single bond. A fourth bond links the carbon atom to a hydrocarbon group (R). The carboxyl (COOH) group is named after the carbonyl group (C=O) and hydroxyl group. Diagram of a carboxylic molecule In general, carboxylic acids undergo a nucleophilic substitution reaction where the nucleophile (-OH) is substituted by another nucleophile (Nu). The carbonyl group (C=O) gets polarized (i.e. there is a charge separation), since oxygen is more electronegative than carbon, it pulls the electron density towards itself. As a result, the carbon atom develops a partial positive charge (δ+) and the oxygen atom develops a partial negative charge (δ-). In some cases, in the vicinity of a strong electrophile, the partially negatively charged carbonyl oxygen (δ-) can act as a nucleophile and attack the electrophile. Compounds in which the −OH group of the carboxylic acid is replaced by other functional groups are called carboxylic acid derivatives, the most important of which are acyl halides, acid anhydrides, esters, and amides. Overview of some of the reactions that we would be discussing in this lecture. Schematic overview of carboxylic molecule reactions Some common properties of some of the carboxylic acid derivatives shown above. Each derivative contains a common group, termed an acyl group (R-C=O), which is attached to a heteroatom They can all be synthesized from the “parent” carboxylic acid They are all formed through a nucleophilic substitution reaction On hydrolysis (i.e. reaction with H2O) they all convert back to their parent carboxylic acid Synthesis of Carboxylic acids and their Derivatives Carboxylic acids undergo reactions to produce derivatives of the carboxylic acid. The most common derivatives formed or synthesized are acyl halides, acid anhydrides, esters and amides. The oxidation of primary alcohols is a common method for the synthesis of carboxylic acids: RCH2OH → RCOOH. This requires a strong oxidizing agent, the most common being chromic acid (H 2CrO4), potassium permanganate (KMnO4), and nitric acid (HNO3). A few examples are shown below: CARBOXYLIC ACID DERIVATIVES 1. ACID HALIDES Acid chlorides are formed when carboxylic acids react with thionyl chloride (SOCl 2), phosphorus trichloride (PCl3) or phosphorus pentachloride (PCl5). They are the most reactive derivatives of carboxylic acid. The formation of acid chloride (ROCl) Mechanism of acid chloride formation with SOCl2 (Please follow the movement of electrons carefully) Diagram of the mechanism of acid chloride formation with SOCl2 The electrophilic sulfur atom is attacked by the nucleophilic oxygen of carboxylic acid to give an intermediate six membered transition state; which immediately decomposes to the intermediate (A) and HCl, respectively. This intermediate (A) then reacts with the HCl molecule, just produced, to give an intermediate (B) which then collapses to form the corresponding acyl chloride, sulfur dioxide and hydrogen chloride. This final step is irreversible because the byproducts, SO2 and HCl are gases that evaporate off and thus push the reaction in the forward direction. 2. ESTERS (RCOOR’) Esters are derived when a carboxylic acid reacts with an alcohol. Esters containing long alkyl chains (R) are main constituents of animal and vegetable fats and oils. Many esters containing small alkyl chains are fruity in smell, and are commonly used in fragrances. Diagram of the formation of ester (RCOOR’) FISCHER ESTERIFICATION ❖ The acid-catalyzed esterification of carboxylic acids with alcohols to give esters is termed Fischer esterification. In the Fischer esterification method, an alcohol is reacted with an acid in an acidic medium. The reaction exists in an equilibrium condition and does not go to completion unless a product is removed as fast as it is formed. Mechanism of Fischer esterification Simplified mechanism of the Fischer reaction. The Fischer esterification proceeds via a carbocation mechanism. In this mechanism, an alcohol is added to a carboxylic acid by the following steps: 1. The carboxyl carbon of the carboxylic acid is protonated. 2. An alcohol molecule adds to the carbocation produced in Step 1. 3. A proton is lost from the oxonium ion generated in Step 2. 4. A proton is picked up from solution by a hydroxyl group. 5. A pair of unshared electrons from the remaining hydroxyl group helps the water molecule leave. 6. The oxonium ion loses a proton to generate the ester. IRREVERSIBLE ESTER FORMATION Esters can also be prepared in an irreversible reaction of an acid with an alkoxide ion. The irreversible esterification reaction proceeds via a nucleophilic substitution reaction. 1. Acting as a nucleophile, the alkoxide ion is attracted to the carbon atom of the carboxyl group. 2. The oxonium ion loses a proton. 3. An unshared electron pair from the alkoxide ion moves toward the carbonyl carbon, assisting the hydroxyl group's exit. 3. Thioester (RCOSR’) THIOESTERIFICATION: A thioester is formed when a carboxylic acid reacts with a thiol group (RSH) in the presence of an acid. Scheme of the formation of thioester (RCOSR’) Thioesters are commonly found in biochemistry, the best-known example being acetyl CoA. The mechanism of thioesterification is the same as esterification (discussed above); only difference being that instead of an alcohol (R’OH), a thioalcohol (R’SH) is involved. 4. ACID ANHYDRIDES Diagram of the formation of acid anhydride As you can see, an acid anhydride is a compound that has two acyl groups (R-C=O) bonded to the same oxygen atom. Anhydrides are commonly formed when a carboxylic acid reacts with an acid chloride in the presence of a base. The mechanism by which a carboxylic acid anhydride is synthesized is shown below. Diagram of mechanism by which a carboxylic acid anhydride is synthesized Similar to the Fischer esterification, this reaction follows an addition-elimination mechanism in which the chloride anion Cl- is the leaving group. In the first step, the base abstracts a proton (H+) from the carboxylic acid to form the corresponding carboxylate anion (1). The carboxylate anion's negatively charged oxygen attacks the considerably electrophilic acyl chloride's carbonyl carbon. As a result, a tetrahedral intermediate (2) is formed. In the final step, Cl-, a good leaving group is eliminated from the tetrahedral intermediate to yield the acid anhydride. 5. AMIDES Amides are compounds that contain the following groups A or B, when it is substituted. O O O C C C R RHN R R2R1N R H2N A B An amide name is based on the name of the carboxylic acid of the same number of carbon atoms, but the ‐oic ending is changed to amide. Amides with alkyl groups on the nitrogen are substituted amides and are named the same as N‐substituted amides, except the parent name is preceded by the name of the alkyl substituent and a capital N precedes the substituent name. Amides are generally prepared by a reaction of acid chlorides with ammonia or amines. However, the direct conversion of a carboxylic acid to an amide is difficult because amines are very basic and tend to convert carboxylic acids to their highly unreactive carboxylate ions. Therefore, DCC (Dicyclohexylcarbodiimide) is used to drive this reaction. Diagram of the synthesis of amide The structure of DCC (Dicyclohexylcarbodiimide) is shown below A carboxylic acid first adds to the DCC molecule to form a good leaving group, which can then be displaced by an amine during nucleophilic substitution to form the corresponding amide. The reaction steps are shown below: Step 1: Deprotonation of the acid. Step 2: Nucleophilic attack by the carboxylate. Step 3: Nucleophilic attack by the amine. Step 4: Proton transfer. Step 5: Dicyclohexylurea acts as the leaving group to form the amide product. Relative reactivity of the carboxylic acid derivatives towards a nucleophilic substitution reaction Diagram of nucleophilic substitution reaction with a nucleophile (Nu) Let’s view the carboxylic acid derivatives as an acyl group, R-C=O, attached to a substituent (X). These derivatives also undergo a nucleophilic substitution reaction with a nucleophile (Nu) as shown above. The reactivity of these derivatives towards nucleophilic substitution is governed by the nature of the substituent X present in the acid derivative If the substituent (X) is electron donating, it 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 If the substituent (X) is electron withdrawing, then it 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. Thus, on a reactivity scale, the order of reactivity of various carboxylic acid derivatives towards nucleophilic substitution is as follows: Substituent Relative Derivative (X) Electronic effect of X reactivity 1 (most Acid chloride -Cl electron withdrawing reactive) Acid 2 (almost as anhydride -OC=OR electron withdrawing reactive as 1) Thioester -SR weakly electron donating 3 alkoxy (-OR) group is weakly electron Ester -OR donating 4  Substituent Relative Derivative (X) Electronic effect of X reactivity Amide -NH2, NR2 very strongly donating 5 Carboxylate ions are not reactive Carboxylate -O- because their negative charge repels the 6 (least ion approach of other nucleophiles reactive) ORGANIC REACTIONS OF CARBOXYLIC ACIDS 1. DECARBOXYLATION REACTION Decarboxylation is the loss of the acid functional group as carbon dioxide from a carboxylic acid. The reaction product is usually a halocompound or an aliphatic or aromatic hydrocarbon. a. The following illustration shows the sodalime (a mixture of NaOH and CaO) method: Alipathic and aromatic acids can be decarboxylated using simple copper salts as shown in the reactions below. 2. HUNSDIECKER REACTION In a Hunsdiecker reaction, the silver salt of an aromatic carboxylic acid is converted by bromine treatment to an acyl halide. 3. KOLBE ELECTROLYSIS In Kolbe electrolysis, electrochemical oxidation occurs in aqueous sodium hydroxide solution, leading to the formation of a hydrocarbon. REDUCTION OF CARBOXYLIC ACIDS Carboxylic acids also undergo reduction reactions. Acid halides, esters, and amides are easily reduced by strong reducing agents, such as lithium aluminum hydride (LiAlH 4). Most reductions of carboxylic acids, acid halides, and esters lead to the formation of primary alcohols. While the amide derivatives are reduced to amines. Like other carboxylic acid derivatives, amides can be reduced by lithium aluminum hydride. The product of this reduction is an amine. PHYSICAL PROPERTIES OF CARBOXYLIC ACIDS Carboxylic acids hydrogen bond to themselves to form a dimer: Carboxylic acids also form hydrogen bonds with water molecules: Since carboxylic acids can form more than one set of hydrogen bonds, their boiling points are usually higher than those of other molecules of the same molecular weight (MW). Low-MW carboxylic acids are generally liquids at room temp. (often, they are somewhat oily); while higher MW carboxylic acids are generally waxy solids. Carboxylic acids with 12 to 20 carbon atoms are often referred to as fatty acids, since they are found in triglycerides in fats and oils. Short-chain carboxylic acids are also generally more soluble in water than compounds of similar MW, since they can hydrogen bond to more than one water molecule. As the number of carbons in a carboxylic acid series becomes greater, the boiling point increases and the solubility in water decreases. Many carboxylic acids that are liquids at room temperature have characteristically sharp or unpleasant odors. ❖ Ethanoic acid/acetic acid is the main ingredient in vinegar. ❖ Butanoic acid is partially responsible for the odor of locker rooms and unwashed socks. ❖ Hexanoic acid is responsible for the odor of Limburger cheese. ❖ Like most acids, carboxylic acids tend to have a sour taste (e.g., vinegar, citric acid, etc.) CHEMICAL PROPERTIES OF CARBOXYLIC ACIDS The Acidity of Carboxylic Acids Carboxylic acids are weak acids. In water, they dissociate to produce hydronium ions and carboxylate ions A 1.0 M solution of acetic acid is about 0.5% dissociated into hydronium and acetate ions: All derivatives of carboxylic acid are readily hydrolyzed by water. RCOCl + H2O RCOOH + HCl RCOOR1 + H2O RCOOH + R1OH RCONH2 + H2O + HCl RCOOH +NH4Cl EXCRETION The carboxylic acid derivatives used as drugs in pharmacy undergo phase I metabolism majorly by hydrolysis in the liver and are excreted in a water soluble form in phase II drug metabolism in the urine via the renal system. USES OF CARBOXYLIC ACID DERIVATIVES IN PHARAMCY The carbonyl group is present in many natural products which include prostaglandins, lipids, hormones and flavouring substances. Some important medicinal compounds such as acetylsalicylic acid, acetaminophen, methyl salicylate, niclosamide, paraldehyde and procainamide have the carbonyl group in their moiety. These also include semisynthetic compound like ampicilin. Organic materials with the carbonyl group that are used in biological and industrial sectors as well as laboratory include formaldehyde, acetic acid, acetone, ethyl acetate etc.  OH O O CH3 HN O Acetylsalicylic acid (Aspirin) CH3 Acetaminophen NH2 H CH3 CH3 Ampicillin O SULPHONIC ACIDS AND THEIR DERIVATIVES Compounds containing the –SO2- groups are known as sulphonyl compounds while those with RSO3H are called sulphonic acids. They are generally stronger acids than carboxylic acids because the resonance stabilized anion resulting from loss of a proton is usually more efficient. Derivatives of sulphonic acids include chlorides RSO2Cl, ester (RSO2R) and amides (primary (RSO2NH2), secondary and tertiary (RSO2NR). These derivatives are similar in properties to their counterparts in the carboxylic acid series. Important sulphonic acid derivatives in pharmacy are sulphonamide drugs such as the synthetic antibacterial (sulphamethoxazole), the antimalarial agent, sulphadoxine, used in combination with pyrimethamine in intermittent preventive treatment of malaria in pregnancy (IPTp) and some diuretics (hydrochlorothiazide and frusemide). These groups of drugs are called sulfa or sulphon drugs. They are carefully prescribed because they can result in hypersensitivity reactions.