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 Ï 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 Ï Anhydrides O O + H C Cl 3 H3C OH Water Ï Acids O + H2O H3C Cl Alcohols Ï esters O + ROH H3C Cl Amines Ï 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 Ï Acids O O + H2O H3C O CH3 Alcohols Ï acid + ester O O + ROH H3C O CH3 Amines Ï 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 Ï amides O + R2NH R H3C O + 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 H C CH 3 3 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. H + H O O + O H Et Et Et Me OH H3C O H3C O + H3C O O Me H Proton H transfer O O + + H - H O Et OH Et Me + Me H C O H3C O 3 O H3C O H Me 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 EtMgBr:
O O - + CH2CH3 Et MgBr H3C O CH2CH3 H3C O Et Draw the ketone here O Et- MgBr+ Acid Workup Me Et
o 3 alcohol w/ Et 2x
How does this reaction relate to the reaction of excess EtMgBr and acetyl chloride?
CH21-7 Organic Chemistry Notes by Jim Maxka [email protected] Hydrides react just the same (2 times with the elimination of RO-) O O
CH2CH3 H: H3C O CH2CH3 H3C O H Draw the aldehyde here O H Acid Workup Me H
o 1 alcohol
Finally, esters react with ammonia to go to amides: (elimination of RO-). The reaction goes downhill and is spontaneous.
- Reactions of Amides: Amides don’t react as easily as the above because the NR2 is such a bad LG. The main reactions are hydrolysis and reduction: Amides are unusually non-basic compared to other sp3 amines. + + NH3 + H NH4 pKa = 9 + + RCONH2 + H RCONH3 pKa = -5 Draw resonance structures to show why O O
R R H C N 3 H3C N
R R
Hydrolysis 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. + O O H OH R HO R + + H2O H2O H OH2 R H R H3C N H3C N H3C N H3C N + O H HO H H H H H
+ OH O H R O + H2O R H NH + + 2 H OH2 H3C NH H3C OH H3C OH OH H Although sometimes, something else happens. Phewy!
Another reaction is the LAH reduction to make an amine. - O O AlR O 3 H3C H H3C H AlR3 H H: H H: H + + H C N H C N N N 3 3 H3C N H H H H H H H H H
CH21-8 Organic Chemistry Notes by Jim Maxka [email protected] Hydrolysis of Aspartame CH3
O O O H2O
H2N NH
acid catalyst O
OH first hydrolysis product pH =
pH < 4 second hydrolysis product pH > 10
Synthesis of Zyvox Zyvox (Linezolid), was the first member of a new class of antibiotics, the oxazolidinones, to receive FDA approval. The nine step synthesis is shown below. Zyvox is used against hospital acquired infections like antibiotic-resistant Staph aureus, Enterococcus faecium, and Strep pneumoniae. F F
O 1. IPr2EtN, EtOAc,heat + O NH + F N O N NH2 - 2. Sn, HCl O F O O O - HCO - O N N 3 Cl O
1. BuLi, THF, -78C F O
CH3CH2CH2 O 2. (R)-glycidyl butyrate O
O N NH O O
O O F O
O Pr N - O N N R O OH O O 1. TosCl, Et3N + 2. K phthalimide, acetonitrile, heat
O F F O Ac2O, pyridine 68%
O O O N N O N N NH NH2 CH3
O
CH21-9