Carboxylic Acids and Their Derivatives

Carboxylic Acids

  • Definition: The combination of a carbonyl group and a hydroxyl group on the same carbon atom is referred to as a carboxyl group.

  • Nature and Importance:

    • Compounds containing the carboxyl group are called carboxylic acids and are distinctly acidic.

    • These compounds are abundant in nature and contribute to familiar odors.

    • Carboxylic acids are prevalent in many pharmaceuticals used to treat various conditions.

  • Instructor: Mr. Kevin Corridus

Acyl Compounds

  • Related Compounds: Carboxyl group is the parent group of a large family called acyl compounds or carboxylic acid derivatives.

Physical Properties of Carboxylic Acids

  • Boiling Point:

    • Carboxylic acids have significantly higher boiling points than alcohols, ketones, or aldehydes of similar molecular weights.

    • The high boiling points are due to the formation of a stable hydrogen-bonded dimer involving an eight-membered ring connected by two hydrogen bonds, effectively doubling the molecular weight of the molecules in the liquid phase, thus requiring more energy to boil.

  • Melting Point:

    • Carboxylic acids containing more than eight carbon atoms are generally solids unless they contain double bonds.

    • The presence of double bonds, particularly cis double bonds, disrupts the formation of a stable crystal lattice, resulting in lower melting points.

    • Dicarboxylic acids exhibit relatively high melting points due to strong hydrogen bonding resulting from two carboxyl groups per molecule, requiring high temperatures to break the hydrogen bond lattice for melting.

  • Solubility:

    • Carboxylic acids can form hydrogen bonds with water, leading to miscibility with water for lower molecular-weight acids (up to four carbon atoms).

    • As the length of the hydrocarbon chain increases, solubility decreases, resulting in acids with more than 10 carbon atoms being nearly insoluble in water.

Carboxylic Acids at Physiological pH

  • The blood's physiological pH is approximately 7.3, whereby:

    • The ratio of carboxylate ions to carboxylic acid is about 1000:1.

    • At physiological pH, carboxylic acids exist primarily as carboxylate salts.

Substituent Effects on Acidity

  • The presence of electron-withdrawing substituents significantly affects the acidity of carboxylic acids.

    • The pKa decreases with each added chlorine substituent due to the inductive effects of chlorine atoms, which stabilize the conjugate base.

    • The impact of an electron-withdrawing group is greater when located at the α position and diminishes with increasing distance from the carboxylic acid group.

Preparation of Carboxylic Acids

  1. Oxidation of Aldehydes and Primary Alcohols:

    • Aldehydes can be oxidized to carboxylic acids using mild oxidizing agents, such as ext{Ag(NH}3)2^+ ext{HO}^-.

    • Primary alcohols are oxidized using ext{KMnO}4 and chromic acid (H2 ext{CrO}_4 in aqueous acetone) to yield carboxylic acids.

  2. Hydrolysis of Nitriles:

    • A nitrile can be converted to a carboxylic acid when treated with aqueous acid in a process called hydrolysis. This provides a two-step method to convert an alkyl halide to a carboxylic acid, involving:

      • An ext{SN2} reaction where cyanide acts as a nucleophile.

      • The resulting nitrile undergoes hydrolysis, producing a carboxylic acid with one more carbon atom than the original alkyl halide.

      • Note: This process cannot occur with tertiary alkyl halides due to steric hindrance.

  3. Carboxylation of Grignard Reagents:

    • Carboxylic acids can be formed by reacting Grignard reagents with carbon dioxide.

      • Mechanism: The Grignard reagent attacks the electrophilic carbon of carbon dioxide, forming a carboxylate ion. Upon treatment with a proton source, the carboxylic acid is obtained following the completion of the Grignard reaction.

  4. Benzylic Oxidation of Alkylbenzenes:

    • Primary and secondary alkyl groups attached directly to a benzene ring can be oxidized using ext{KMnO}4 to yield a -CO2H group.

Reactions of Carboxylic Acids

  • Fundamental Reaction Differences:

    • Carboxylic acids display different reaction pathways compared to ketones and aldehydes, which usually undergo nucleophilic addition to carbonyl groups.

    • Carboxylic acids and their derivatives predominantly engage in nucleophilic acyl substitution, where one nucleophile replaces another at the acyl carbon.

Mechanism of Nucleophilic Acyl Substitution

  • Step 1: Nucleophilic addition at the carbonyl carbon is facilitated by the steric openness of the carbonyl and the ability of the carbonyl oxygen to accommodate an electron pair from the carbon-oxygen double bond.

  • Step 2: The tetrahedral intermediate eliminates the leaving group (denoted as L in the mechanism), regenerating the carbon-oxygen double bond, resulting in a substitution product.

Requirement for Acyl Substitution

  • Requires a leaving group at the carbonyl carbon, which is typically good, or can be protonated to become a good leaving group.

Examples of Acyl Substitutions

  1. Acyl Chlorides Formation:

    • Acid chlorides are formed by treating carboxylic acids with thionyl chloride (SOCl_2).

  2. Aminolysis of Acid Chlorides:

    • Acid chlorides react with ammonia to form amides. Two equivalents of ammonia are needed: one for nucleophilic attack and another for neutralizing the produced HCl.

  3. Preparation of Acid Anhydrides:

    • Acid anhydrides are synthesized by treating acid chlorides with carboxylate ions acting as nucleophiles.

Reactions of Acid Anhydrides

  • Similar to acid chlorides but differ in the identity of the leaving group:

    • The leaving group for acid chlorides is the chloride ion (producing HCl), while for acid anhydrides, it is a carboxylate ion (which is a conjugate base of a weak acid). Thus, no pyridine is needed in reactions with anhydrides as HCl is not generated.

  • Acetylation with Acetic Anhydride:

    • Acetic anhydride is commonly used to acetylate alcohols or amines, particularly in the commercial production of drugs like aspirin and Tylenol.

Esters

  • Definition: Esters are carboxylic acid derivatives where the hydroxyl group (-OH) is replaced by an alkoxy group (-OR), formed from the combination of carboxylic acids and alcohols, with the loss of one water molecule.

Physical Properties of Esters

  • Esters are polar but do not form strong hydrogen bonds due to the absence of a hydrogen atom attached to oxygen, resulting in boiling points that are comparatively lower than those of acids and alcohols of similar molecular weights.

  • Boiling points of esters match those of comparable aldehydes and ketones.

  • Unlike low-molecular-weight acids, esters tend to have pleasant fruity odors, contributing to their use in synthetic flavor production.

Preparation Methods for Esters

  1. SN2 Reaction with Strong Base and Alkyl Halide:

    • Carboxylic acids can be converted into esters by deprotonation to yield a carboxylate ion, which then acts as a nucleophile, attacking an alkyl halide via an SN2 reaction. Note: Tertiary alkyl halides cannot be used in this method due to expected limitations of SN2 processes.

  2. Fischer Esterification:

    • Combining carboxylic acids with an alcohol in the presence of an acid catalyst results in ester formation, termed Fischer esterification.

  3. Alcoholysis of Acid Chlorides:

    • When treated with alcohol, acid chlorides transform into esters, mirroring Fischer esterification.

Reactions of Esters

  • Saponification:

    • Esters can be hydrolyzed into carboxylic acids using sodium hydroxide followed by an acid.

  • Acid-Catalyzed Hydrolysis of Esters:

    • Esters can also undergo hydrolysis under acidic conditions.

  • Reduction with Hydride Reducing Agents:

    • Treatment with lithium aluminum hydride reduces esters to yield alcohols.

  • Reactions with Grignard Reagents:

    • Esters can also be reduced by Grignard reagents to form alcohols, with the addition of two alkyl groups.

Amides

  • Definition: An amide consists of a carboxylic acid combined with ammonia or an amine.

  • Formation: An acid reacts with an amine to create an ammonium carboxylate salt, which, upon heating above 100°C, drives off water and yields an amide.

  • Significance:

    • Amides, along with acids and esters, are prevalent in living organisms as they form major components of proteins and nucleic acids.

    • Amides exhibit low reactivity compared to other common acid derivatives, enhancing their stability in biological conditions.

    • Cyclic amides are referred to as lactams, formed from amino acids when carboxyl and amino groups participate in an amide formation.

Physical Properties of Amides

  • All simple amides are solids, except formamide (HCONH2), which is a liquid.

  • Lower molecular weight amides are water-soluble, transitioning to borderline solubility at five or six carbon atoms.

  • Solutions of amides in water are generally neutral, with amides displaying high boiling and melting points due to their polar nature and ability to form hydrogen bonds.

Preparation of Amides

  • Amides can be synthesized from various carboxylic acid derivatives through nucleophilic addition-elimination reactions mediated by ammonia or amines at the acyl carbon.

  1. From Acid Chlorides:

    • Rapid reaction of primary amines, secondary amines, and ammonia with acid chlorides forms amides, using an excess of ammonia or amine to neutralize formed HCl.

  2. From Carboxylic Anhydrides:

    • Acid anhydrides react with ammonia or amines to yield amides analogously to acid chlorides.

  3. From Carboxylic Acids & Ammonium Carboxylate:

    • Carboxylic acids can form ammonium salts with aqueous ammonia, but subsequent evaporation of water and heating induces a transformation to yield an amide. This method is usually inefficient; thus, converting the acid to an acyl chloride first provides a better pathway.

Reactions of Amides

  • Amides can undergo hydrolysis in aqueous acid or base.

  • Hydrolysis can convert amides back to carboxylic acids in acidic medium; however, this process is substantially slow and often requires heat.

  • The mechanism is akin to the acid-catalyzed hydrolysis of esters, driving the reaction to completion through carboxylate formation.

  • Amides can also undergo hydrolysis in basic conditions, albeit slowly, similar to ester saponification, leading to irreversible reactions through carboxylate ion formation, with final acid workup yielding carboxylic acids.

Nitriles from Dehydration of Amides

  • Amides can be transformed into nitriles by reacting with ext{P}4 ext{O}{10} (phosphorus pentoxide) or boiling acetic anhydride.

Pharmaceutical Applications

  • Sedatives:

    • Sedatives reduce anxiety and promote sleep, with natural sedatives like melatonin regulating sleep-wake cycles, containing an amide group common in sedative pharmaceuticals.

  • Anxiolytic Agents:

    • Medications for anxiety treatment resemble benzodiazepines with significant research revealing relationships between structure and activity, noting that while the amide group isn't essential, it enhances potency.

  • Aspirin Mechanism:

    • Aspirin, synthesized from salicylic acid, achieves its effect by blocking prostaglandin synthesis. This discovery earned the Nobel Prize for John Vane and others.

    • Prostaglandins, produced from arachidonic acid, are crucial in inflammation and fever regulation, with cyclooxygenase interacting with aspirin by transferring an acetyl group, deactivating the enzyme and slowing inflammation.

  • Esters as Prodrugs:

    • Certain drugs are administered in inactive forms known as prodrugs, which are metabolized into active compounds, offering advantages such as improved membrane crossing and extended release over time.

    • Example: Haloperidol can be esterified into haloperidol decanoate to allow prolonged release post-injection.

  • Paliperidone:

    • Another schizophrenia treatment, paliperidone, is prepared as a prodrug (paliperidone palmitate) with a long hydrophobic chain, enhancing retention and slow release from fat cells.

Beta-lactam Antibiotics

  • Penicillins: Initially believed to be a single compound, a variety of structurally similar penicillins produced by mold exhibit antibacterial properties, denoted with a general formula indicating variability in the R group.

  • Key Structural Feature: Each penicillin contains an amide group within a beta (β) lactam ring, which is particularly reactive due to ring strain and can undergo hydrolysis to release strain and activate antibacterial properties.

  • Mechanism of Action: Beta-lactams acylate the transpeptidase enzyme critical for bacterial cell wall synthesis, thereby inhibiting bacterial reproduction and allowing immune system action against bacteria.

  • Resistance to Penicillins: Some bacterial strains have developed resistance through acquisition of β-lactamases, which hydrolyze the β-lactam ring before it can inactivate transpeptidase, negating its antibiotic function.

Local Anesthetics

  • Amide Local Anesthetics: Lidocaine is a common amide anesthetic widely utilized in medical settings.

Medicinal Uses of Carboxylic Acids

  • Acetic Acid:

    • Utilized as an injection for tumors, treatment of otitis externa, and as an antiseptic at a 1% solution with broad-spectrum antimicrobial activity.

  • Lactic Acid:

    • Used in pharmaceuticals for producing water-soluble lactates, topical preparations for acidity adjustment, disinfectant, keratolytic properties, and as a buffer.

  • Benzoic Acid:

    • Employed for fungal skin disease treatment like tinea, ringworm, and athlete's foot.

  • Salicylic Acid:

    • Utilized in acne treatment, psoriasis management, eczema relief, viral wart treatment, and dandruff control and is also a precursor for aspirin synthesis.

  • Methyl Salicylate:

    • Acts as a rubefacient and analgesic, a nonselective COX inhibitor for treating joint/muscle pain, and serves as an anti-inflammatory and analgesic agent.

  • Benzyl Benzoate:

    • Key in treating scabies and lice infestation; also has therapeutic effects in asthma and cough medications as well as non-medical repellent use against ticks and mosquitoes.

References

  • Klein, D. R. (2016). Organic Chemistry (4th ed.). John Wiley & Sons, Inc.

  • McMurry, J. E. (2010). Fundamentals of Organic Chemistry. Cengage Learning.

  • Physical Properties of Amides. (2014, July 17). Chemistry Libre Texts. https://chem.libretexts.org/Bookshelves/IntroductoryChemistry/Basicsof_General Organic and Biological Chemist

  • Sathe, N., Sharma, R., Malav, M., & Thagele, R. (n.d.). A textbook of Pharmaceutical Organic Chemistry-1. CP Publication.

  • Solomons, G., Fryhle, C. B., & Snyder, S. A. (2016). Organic Chemistry. John Wiley & Sons.

  • Wade, L. G. (2013). Organic Chemistry. Pearson.