Carboxylic_Acid_Derivatives_CHEM265_Spring_2024.pdf
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Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Carboxylic Acid Derivatives Carboxylic acid derivatives are defined as compounds with functional groups that can be converted to carboxylic acids by a simple acidic or ba...
Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Carboxylic Acid Derivatives Carboxylic acid derivatives are defined as compounds with functional groups that can be converted to carboxylic acids by a simple acidic or basic hydrolysis.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Structures and Nomenclature of Carboxylic Acid Derivatives Esters are carboxylic acid derivatives in which the hydroxy group (—OH) is replaced by an alkoxy (—OR).. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Cyclic Esters — Lactones. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Amides An amide is a composite of a carboxylic acid and ammonia or an amine. Ammonium salts are converted to amides at high temperatures with loss of H2O.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Amides. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Cyclic Amides — Lactams. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Nitriles Nitriles contain the cyano group.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Electronic Structure of Nitriles The atoms at the ends of the triple bonds are sp hybridized, and the bond angle is 180°.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Halides Acid halides are also called acyl halides. Acid halides are “activated” derivatives (highly electrophilic) used in the synthesis of other acyl compounds such as an ester.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Anhydrides The word anhydride means “without water.” An acid anhydride contains two molecules of acid, with loss of a molecule of water. Acid anhydrides are “activated” derivatives of carboxylic acids (highly electrophilic).. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Spectroscopy of Carboxylic Acid Derivatives. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Spectroscopy of Carboxylic Acid Derivatives. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Spectroscopy of Carboxylic Acid Derivatives O O O O O O α-valerolactone γ-butyrolactone β-propriolactone 1735 cm-1 1770 cm-1 1800 cm-1 no strain moderate strain highly strain O O O NH NH NH α-valerolactam γ-butyrolactam β-propriolactam 1670 cm-1 1700 cm-1 1745 cm-1 no strain moderate strain highly strain Most acid derivatives have C=O stretches between 1700 cm–1 and 1800 cm–1.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) 1H NMR Spectroscopy of Carboxylic Acid Derivatives The proton chemical shifts found in acid derivatives are close to those of similar protons in ketones, aldehydes, alcohols, and amines.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) 1H NMR Spectroscopy of Carboxylic Acid Derivatives 1H NMR Spectrum of DMF. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) 13C NMR Spectroscopy of Carboxylic Acid Derivatives. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Nucleophilic Acyl Substitution Interconversion of acid derivatives occurs by nucleophilic acyl substitution. The substitution proceeds via an addition–elimination mechanism. Step 1: The nucleophile adds to the carbonyl, forming a tetrahedral intermediate.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Nucleophilic Acyl Substitution Step 2: Elimination of the leaving group regenerates the carbonyl. Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group to the attacking nucleophile.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Nucleophilic Acyl Substitution Reactivity of Carboxylic Acid Derivatives. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Nucleophilic Acyl Substitution Interconversion of Carboxylic Acid Derivatives More reactive derivatives can be converted to less reactive derivatives.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chlorides to Anhydrides The carboxylic acid attacks the acyl chloride, forming the tetrahedral intermediate. Chloride ion leaves, restoring the carbonyl. Deprotonation produces the anhydride.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chlorides to Esters The alcohol attacks the acyl chloride, forming the tetrahedral intermediate. Chloride ion leaves, restoring the carbonyl. Deprotonation produces the ester.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chlorides to Amides Ammonia yields a 1° amide. A 1° amine yields a 2° amide. A 2° amine yields a 3° amide.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Anhydrides to Esters Alcohol attacks one of the carbonyl groups of the anhydride, forming the tetrahedral intermediate. The other acid unit is eliminated as the leaving group.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Anhydrides to Amides Ammonia yields a 1° amide; a 1° amine yields a 2° amide; and a 2° amine yields a 3° amide.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Esters to Amides — Ammonolysis The nucleophile must be NH3 or 1° amine. Prolonged heating is required. Alternatively, ClMgNRR’ (formed by the reaction of iPrMgCl with HNRR’) reacts with esters under mild reaction conditions.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Leaving Groups in Nucleophilic Acyl Substitutions A strong base, such as an alkoxide (–OR), is not usually a leaving group, except in an exothermic step.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Leaving Groups in Nucleophilic Acyl Substitutions In the nucleophilic acyl substitution of esters, the elimination of the alkoxide is highly exothermic, converting the tetrahedral intermediate into a stable molecule.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Transesterification One alkoxy group can be replaced by another with acid or base catalyst. Use large excess of desired alcohol to displace the equilibrium.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid-Catalyzed Transesterification Mechanism. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Base-Catalyzed Transesterification Mechanism. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Acid Chlorides and Anhydrides Hydrolysis occurs quickly, even in moist air with no acid or base catalyst. Reagents must be protected from moisture.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Esters: Saponification The base-catalyzed hydrolysis of ester is known as saponification. Saponification means “soap-making.”. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Amides Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Amides - Basic Conditions Similar to the hydrolysis of an ester. The hydroxide ion attacks the carbonyl, forming a tetrahedral intermediate. The amino group is eliminated and a proton is transferred to the nitrogen to give the carboxylate salt.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Amides - Acidic Conditions. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Hydrolysis of Nitriles Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Base-Catalyzed Hydrolysis of Nitriles. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Esters to Alcohols Lithium aluminum hydride (LiAlH4) reduces esters, acids, and acyl chlorides to primary alcohols.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Esters to Alcohols with LiAlH4 - Mechanism Lithium aluminum hydride (LiAlH4) reduces esters, acids, and acyl chlorides to primary alcohols.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Acyl Halides to Aldehydes Lithium tri-tert-butoxyaluminum hydride is a milder reducing agent. Reacts faster with acyl chlorides than with aldehydes.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Esters to Aldehydes Using DIBAL-H Di-isobutylaluminum hydride, commonly called DIBAL or DIBAL-H, is another mild reducing agent that can reduce esters to aldehydes at -78 °C.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Amides to Amines Amides will be reduced to the corresponding amine by LiAlH4.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Amides to Amines - Mechanism. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reduction of Nitriles to Amines Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Organometallic Reagents Grignard and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Mechanism of Grignard Addition to Esters Esters react with two moles of Grignards or organolithium reagents to produce an alcohol. The ketone intermediate will react with a second mole of organometallic to produce the alcohol.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Addition of Dialkylcuprate Reagents to Acid Chlorides Acid chlorides react just once with dialkylcuprates (Gilman reagents) to give ketones.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reaction of Nitriles with Grignard Reagents A Grignard reagent or organolithium reagent attacks the cyano group to form an imine, which is hydrolyzed to a ketone.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Synthesis of Acid Chlorides Thionyl chloride (SOCl2), oxalyl chloride (COCl)2, and phosgene (COCl2) are the most convenient reagents because they produce only gaseous side products.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chloride Reactions - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chloride Reactions - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Acid Chlorides in Friedel-Crafts Acylation Reactions. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) General Synthesis of Anhydrides The most generalized method for making anhydrides is the reaction of an acid chloride with a carboxylic acid or a carboxylate salt. Pyridine is sometimes used to deprotonate the acid and form the carboxylate.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reaction of Anhydrides. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Friedel-Crafts Acylation Reactions Using Anhydrides Using a cyclic anhydride allows for only one of the acid groups to react, leaving the second acid group free to undergo further reactions.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Synthesis of Esters - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Ester Reactions - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Formation of Lactones Formation is favored for five- and six-membered rings. For larger rings, remove water to shift equilibrium toward products.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reactions of Amides. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Dehydration of Primary Amides to Nitriles Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile. Phosphorus oxychloride (POCl3) or phosphorus pentoxide (P2O5) can be used as dehydrating agents.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Synthesis of Amides - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Formation of Lactams Five-membered lactams (γ-lactams) and six-membered lactams (δ-lactams) often form on heating or adding a dehydrating agent to the appropriate γ-amino acid or δ-amino acid.. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Synthesis of Nitriles - Summary. Carboxylic Acid Derivatives Wade 9th Edition - Chapter 21 (pp. 1043-1111) Reactions of Nitriles.
