CH 3 C H 3 O. anhydride acid. ester amide. O acid O. amide. acid. amide. acid. nitriles

Transcription

1 C 21: Carboxylic Acid Derivatives Topics: aming Interconversion of Acid Derivatives eactions of each functional group Connections: anhydride acid ester amide acid ester amide acid amide 2 acid nitriles 2 2 C21-1

2 C21: Derivatives of Carboxylic Acids: aming Acid alides 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 Br C 2 Br methanoyl chloride ethanoyl bromide propanoyl bromide formyl chloride acetyl bromide benzoyl chloride acetic anhydride benzoic anhydride succinic anhydride Amides: root amide; when there is an attachment to the, it is designated by an in front (to distinguish from chain substitution). methanamide formamide ethanamide acetamide -methylmethanamide -methylformamide,-dimethylmethanamide,-dimethylformamide Esters: Take the acid into the conjugate base of the acid. Prefix with the substituent name of the alcohol part C t-bu methyl methanoate methyl formate isopropyl ethanoate isopropyl acetate methyl benzoate tert-butyl benzoate C21-2

3 eaction cheme for Carboxyl acid derivatives on the C=. (1) ucleophilic Attack on the C= (2) elimination = substitution u: Y ucleophilic Addition u Y Y: u elimination = ubstitution eactivity 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. - is the best leaving group, pka (CA) carboxylate is the next best, pka (CA), alkoxide and hydroxide are about the same (ranked 3 rd ) pka (CA), and last is amide ( - 2 ) pka (CA). - is the worst base (no affinity for protons=conjugate base of a strong acid) and - 2 is the best base. Most eactive CA of LG pka -3 C 2 5 synthetic nature 2 35 Least eactive ormation of acyl chloride: In order to go uphill there must be very strong reagents. or carboxylic acids, there must be a dehydrating agent that will remove water and replace the. ne such reagent is 2, thionyl chloride. You need to complete some arrows (g) This reaction is so great because the formation of gas at the end forces the reaction to completion. C21-3

4 ormation of anhydride Two acids water = anhydride: ormation of esters from acids and alcohols ischer 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. 2 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. orcing to the left, we add excess. We must remove any water or acid or what will happen to the product? - 2 ormation of esters from carboxylate and alkyl halides ucleophilic alkylation of carboxylate anion to make esters. C C C a C - Br C C Interconversion of Carboxylic Derivatives happen according to the reactivity. The downhill reaction is always spontaneous: example acyl halide any derivative. or the examples below assume acet. tart with acetyl chloride. Acetyl chloride is extremely reactive. What is the inorganic byproduct of each reaction? Acyl alides react with Acids Anhydrides Water Acids 2 Alcohols esters Amines amides 2 C21-4

5 Anhydrides are also extremely reactive. What is the byproduct of each of these reactions? Acetic anhydride will react with Water Acids Alcohols acid ester Amines acid amide 2 2 Ester/Acids are very similar in reactivity. Acetic Acid reacts with alcohol to form ester (ischer Esterfication) in equilibrium acid catalyst Esters react with water to form acid and alcohol (ydrolysis) in equilibrium with acid catalysis better in base (sapnification) 2 2 -(aq) Esters react with Amines amides 2 Given that pka of C 2 = 5 and 2 2 = 9. What is the problem with trying to make an amide from a carboxylic acid directly. 2 ow would we avoid this difficulty? The reaction can proceed uphill, but only with special reagents: 2 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. eactions of Carboxylic Acid Derivatives eactions of Acyl alides Acyl halides react with acids, water, alcohols and amines as above. They have more reactions worth looking at: 2 CuLi C21-5

6 But MgBr reacts differently. ee, Cuprates cannot react with ketones remember what the product of this reaction is: C 3 2 CuLi Grignards do react with ketones. o, two moles of Grignard reagent reacts with acid halides or esters to make a 3 o alcohol. or ester MgBr MgBr Acid WU There is also the riedel Craft acylation:of benzene derivatives: Practice: Using riedel-crafts acylation from benzene, how would you make acetophenone? Using Gilman reagents from Benzoyl chloride Acetyl chloride inally, there is the reduction with hydride reagents. LA reacts with acetyl chloride with : - as the nucleophile: : : - Acid WU or ester 3 C If you use a very hindered Al reagent, (DIBA) it is sometimes possilble to stop at the aldehyde, but this is not always successful. eactions 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. C21-6

7 eactions of Esters: Esters react in equilibrium reactions with weak nucleophiles, but esters react a lot like halides with strong nucleophiles like Grignards and hydrides. aponification (oap Making). oap making is one of the major reactions involving esters. It goes like this. ats are esters composed of grycerol and long chain acids. That means three ester linkages. or 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 K eq of this step. : - or ester - - : - pka= magnitude of K eq = - 2 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. ere we see how ethyl acetate becomes methyl acetate in the presence of methanol. The reverse reaction occurs just as quickly. - What is the difference of trans-esterification and hydrolysis? Esters and strong nucleophiles Esters react like acyl chlorides with strong nucleophiles. Let s look at the reaction of ethyl acetate with excess MgBr: pka= Proton transfer C 2 - MgBr - MgBr C 2 Acid Workup Draw the ketone here 3 o alcohol w/ 2x ow does this reaction relate to the reaction of excess MgBr and acetyl chloride? C21-7

8 ydrides react just the same (2 times with the elimination of - ) C 2 : C 2 Draw the aldehyde here Acid Workup 1 o alcohol inally, esters react with ammonia to go to amides: (elimination of - ). The reaction goes downhill and is spontaneous. eactions of Amides: Amides don t react as easily as the above because the - 2 is such a bad LG. The main reactions are hydrolysis and reduction: Amides are unusually non-basic compared to other sp 3 amines. 3 4 pka = 9 C 2 C 3 pka = -5 Draw resonance structures to show why ydrolysis is usually done with acid or base, a huge excess of water and heat followed by loss of amine or ammonia. Just think about what happens after we eat beans: Protein aqueous acid acids and amines Although sometimes, something else happens. Phewy! 2 Another reaction is the LA reduction to make an amine. - Al 3 : Al 3 : C21-8

9 ydrolysis of Aspartame 2 2 acid catalyst p = first hydrolysis product p < 4 second hydrolysis product p > 10 ynthesis of Zyvox Zyvox (Linezolid), was the first member of a new class of antibiotics, the oxazolidinones, to receive DA approval. The nine step synthesis is shown below. Zyvox is used against hospital acquired infections like antibiotic-resistant taph aureus, Enterococcus faecium, and trep pneumoniae. 1. IPr 2, Ac,heat - 2. n, - C BuLi, T, -78C C 2 C 2 2. ()-glycidyl butyrate Pr - 1. Tos, 3 2. K phthalimide, acetonitrile, heat Ac 2, pyridine 68% 2 C21-9