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Carboxylic Acid Derivatives Topics Organic Chemistry Notes by Jim Maxka [email protected] CH 21: Carboxylic Acid Derivatives Topics: Naming Interconversion of Acid Derivatives Reactions of each functional group Connections: O O H3C Cl H3C OH H3C OH O O O anhydride acid ester H C Cl H3C R 3 R H3C Cl amide H3C OH R O O O O acid H3C OH ester H C O CH H C O CH 3 3 3 3 amide H3C OH O O O acid H C H amide H C OR 3 3 R H3C OR H3C OH R O O acid H3C NH2 nitriles H3C NH2 H3C NH2 CH21-1 Organic Chemistry Notes by Jim Maxka [email protected] CH21: Derivatives of Carboxylic Acids: Naming Acid Halides The yl form of acids is based on the IUPAC or common names. Drop the ic acid and add yl. Examples: methanoyl benzoyl acetyl formyl Acid Anhydrides O O O O Cl H Cl H3C Br CH3CH2 Br methanoyl chloride ethanoyl bromide propanoyl bromide formyl chloride acetyl bromide benzoyl chloride O O O O O O O O H C 3 O CH 3 succinic anhydride acetic anhydride benzoic anhydride Amides: root + amide; when there is an attachment to the N, it is designated by an N in front (to distinguish from chain substitution). O O O O CH H H CH 3 3 H N H N H3C N H N CH H H H 3 ethanamide N-methylmethanamide methanamide acetamide N,N-Dimethylmethanamide formamide N-methylformamide N,N-Dimethylformamide Esters: Take the acid into the conjugate base of the acid. Prefix with the substituent name of the alcohol part O O O O CH3 CH3 t-Bu CH3 CH O O H O H3C O CH3 tert-Butyl benzoate methyl methanoate isopropyl ethanoate methyl benzoate methyl formate isopropyl acetate CH21-2 Organic Chemistry Notes by Jim Maxka [email protected] Reaction Scheme for Carboxyl acid derivatives on the C=O. (1) Nucleophilic Attack on the C=O + (2) elimination = substitution O O O H Y + Y: Nu: H Y H Nu Nu elimination = Substitution Nucleophilic Addition + Reactivity Acyl halides and anhydrides are very reactive because the halide and the acid anion are such good leaving groups. Acids are much less reactive because is a BAD leaving Group, as are esters because of . Amides are the most unreactive because is a horrible LG. Because they are the most stable, bonds are the basis for proteins. The next most stable bonds are for fats. You can see the reactivity in the pKa chart. The reactivity is based on ease of the leaving group. - Cl is the best leaving group, pKa (CA) carboxylate is the next best, pKa (CA) , rd - alkoxide and hydroxide are about the same (ranked 3 ) pKa (CA) , and last is amide (NH2 ) pKa (CA) . Cl- is the worst base (no affinity for protons=conjugate base of a strong acid) - and NH2 is the best base. Most Reactive O CA of LG pKa HCl -3 O O H3C Cl synthetic H3C O CH3 RCO2H 5 O R O H3C O ROH 16 H2O 16 O H3C OH nature R H3C N R2NH 35 Least Reactive R Formation of acyl chloride: In order to go uphill there must be very strong reagents. For carboxylic acids, there must be a dehydrating agent that will remove water and replace the OH. One such reagent is SOCl2, thionyl chloride. You need to complete some arrows. - O - Cl O O - O O O O- Cl - O Cl Cl Cl S S S S O Cl O Cl O Cl Cl OH H H O O O HCl SO2 (g) Cl S O Cl Cl This reaction is so great because the formation of gas at the end forces the reaction to completion. CH21-3 Organic Chemistry Notes by Jim Maxka [email protected] Formation of anhydride Two acids – water = anhydride: O O O O O O- -H2O R R OH H R O R O R R O OH2+ Formation of esters from acids and alcohols Fischer Esterification is an equilibrium reaction because the stability of acids and esters are based on the conjugate acids of the LG which are . and . pKa= The reaction is performed with acid catalysis. + O O H O H - H O H H+ CH3OH OH OH OH OH OMe H OMe + H H O H O O H + H + H2O OH OMe OMe OMe Why is the reaction an equilibrium? The reactivity of the acid and the ester are about . The pKa of water = and the pKa of alcohol is . To force the reaction to the right, we need to add excess . Forcing to the left, we add excess . We must remove any water or acid or what will happen to the product? SN2 Formation of esters from carboxylate and alkyl halides Nucleophilic alkylation of carboxylate anion to make esters. HO HO H HO H H C C C CH3 NaOH H C Br C OH + - 3 C O C O O O O Interconversion of Carboxylic Derivatives happen according to the reactivity. The downhill reaction is always spontaneous: example acyl halide any derivative. For the examples below assume acet. Start with acetyl chloride. Acetyl chloride is extremely reactive. What is the inorganic byproduct of each reaction? Acyl Halides react with Acids Anhydrides O O + H C Cl 3 H3C OH Water Acids O + H2O H3C Cl Alcohols esters O + ROH H3C Cl Amines amides O + R2NH H3C Cl CH21-4 Organic Chemistry Notes by Jim Maxka [email protected] Anhydrides are also extremely reactive. What is the byproduct of each of these reactions? Acetic anhydride will react with Water Acids O O + H2O H3C O CH3 Alcohols acid + ester O O + ROH H3C O CH3 Amines acid + amide O O + R2NH H3C O CH3 Ester/Acids are very similar in reactivity. Acetic Acid reacts with alcohol to form ester (Fischer O acid catalyst Esterfication) in equilibrium + ROH H 3 C O H Esters react with + water to form acid and alcohol O H (Hydrolysis) in equilibrium with + H2O acid catalysis R H3C O better in base (sapnification) O OH-(aq) + H2O R H3C O Esters react with Amines amides O + R2NH R H C O 3 + Given that pKa of RCO2H = 5 and R2NH2 = 9. What is the problem with trying to make an amide from a carboxylic acid directly. O H + H2N R H3C O How would we avoid this difficulty? The reaction can proceed uphill, but only with special reagents: SOCl2 or dehydrating conditions or in some cases a huge excess of reactant to invoke the law of mass action. If you can get to the acyl chloride, you can get anywhere. Reactions of Carboxylic Acid Derivatives Reactions of Acyl Halides Acyl halides react with acids, water, alcohols and amines as above. They have more reactions worth looking at: O O O + Me2CuLi Cl H3C Cl H3C H3C CH3 CH21-5 H3C Organic Chemistry Notes by Jim Maxka [email protected] But MeMgBr reacts differently. See, Cuprates cannot react with ketones remember what the product of this reaction is: O + Me2CuLi CH3 Grignards do react with ketones. So, two moles of Grignard reagent reacts with acid halides or esters to make a 3o alcohol. O O O OH + MeMgBr Cl + MeMgBr Acid WU H3C Cl H C or ester 3 H3C CH3 H3C There is also the Friedel Craft acylation:of benzene derivatives: Practice: Using Friedel-Crafts acylation from benzene, how would you make acetophenone? Using Gilman reagents from Benzoyl chloride Acetyl chloride Finally, there is the reduction with hydride reagents. LAH reacts with acetyl chloride with H:- as the nucleophile: O O - Cl- O OH - - Acid WU + H: Cl + H: H3C Cl H C H3C H or ester 3 H3C H H H If you use a very hindered Al reagent, (DIBAH) it is sometimes possilble to stop at the aldehyde, but this is not always successful. Reactions of Anhydrides: Anhydrides have been previously discussed. They are extremely useful for reacting with aromatic compounds because the acyl halide may be prone react with benzene in the - reaction. Below is the synthesis of Acetaminophen and Aspirin. Both use acetic anhydride. Tylenol from p-aminophenol: Aspirin from salicylic acid: Anhydrides otherwise react just like halides with Grignards and hydrides. They’re kind of exotic, though. CH21-6 Organic Chemistry Notes by Jim Maxka [email protected] Reactions of Esters: Esters react in equilibrium reactions with weak nucleophiles, but esters react a lot like halides with strong nucleophiles like Grignards and hydrides. Saponification (Soap Making). Soap making is one of the major reactions involving esters. It goes like this. Fats are esters composed of grycerol and long chain acids. That means three ester linkages. For the mechanism it is easier to see one ester linkage break: Even though alkoxide is a bad LG, the reaction is pulled through because of the last step. Calculate the Keq of this step. O O - O - OR O + HO:- + HO:- H C OR OR 3 + H O or ester H3C H3C OH 2 HO H3C O- pKa= pKa= magnitude of K = eq This reaction is called saponification (soap making) because the carboxylate anion makes a good soap. All soaps used to be made this way, but now we have detergents. Detergents don’t form soap scum. Trans-esterification: If acid is present, then alcohols can exchange on any ester. The esters are constantly interconverting. Here we see how ethyl acetate becomes methyl acetate in the presence of methanol. The reverse reaction occurs just as quickly.
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