Chapter 20 & 21 Reaction Chart – Carboxylic acids and derivatives

-Chapter 20 and 21 deals with reaction/synthesis of carboxylic acids and its derivatives. There are essentially 5 different derivatives of carboxylic acid: Acid Chlorides, Anhydrides, Esters, Amides, and Nitriles. Essentially, the majority of the reactions covered in this chapter are interconverting into the different derivative forms, with the rest of the reactions mostly review from previous chapters. Again, there are 2 general mechanisms for a Carboxylic acid/derivate reaction: The Acid catalyzed mechanism, and the Basic Catalyzed mechanism, which are both shown below.

-The Basic catalyzed mechanism is primarily utilized for Acid Chlorides and Anhydrides. Since the substituent attached to the acyl group (Cl or carboxylate ion) are good leaving groups, it makes the Acid Chloride and Anhydride good electrophiles so that the nucleophile can directly attack the carbonyl carbon without having to protonate the oxygen to make it more electrophilic. In this reaction, an acid chloride is reacting with an alcohol. Once it attacks, a tetrahedral intermediate will form, with an alkoxide, chloride, an alcohol as substituents on the carbonyl carbon. Now, at this point, the most stable leaving group will be kicked off. In this case, Chloride is the most stable leaving group, so it will leave, with the oxygen reforming the carbonyl group. Chloride will then extract a hydrogen, and an ester will form.

-In the acid catalyzed mechanism, the main difference is that the carbonyl oxygen is first protonated to make it a better electrophile. Therefore this mechanism typically occurs for Esters, Amides, and Carboxylic acids, which are less reactive than Acid Chlorides and Anhydrides. Once the oxygen is protonated, the nucleophile will attack, and a tetrahedral compound will form.

In this case, the OH will be protonated to form water, and will be kicked off. The oxygen will reform the carbonyl again, and a hydrogen will be extracted to form the ester.

-Below is a diagram from the book that shows the reactivity of the carboxylic acid derivatives. The reactivity of the carboxylic acid/derivate is dictated by the substituent attached on the acyl group. The more stable the leaving group is on the carboxylic acid derivative, the faster the reaction will occur in a nucleophilic substitution reaction. The leaving group of an acid chloride is a chloride ion, which is a very weak base, and is very stable by itself. Therefore, it will readily be kicked off, and will be the most reactive carboxylic acid derivative. Essentially, carboxylic acid derivates can ONLY react to form less reactive derivatives. Therefore, though an Acid Chloride can directly convert to an amide, an Amide can’t be directly converted into an acid chloride since the amine ion is much more reactive than a chloride ion. Know this reactivity chart really well! You may be asked to rank carboxylic acid derivatives by their reactivity, which is dictated by the stability of their leaving group! It is also very important to consider when approaching reaction questions!

Below I have drawn a general flowchart of the conversion of the various forms. This is probably the most important aspect of Chapter 20 & 21, so know which derivatives can be converted to which another form and the reagents needed to perform the reaction! Basically, if you want to form an acid chloride, use SOCl2. If you want to form an anhydride, add a carboxylic acid. If you want to form an ester, add an alcohol. If you want to form an amide, add an amine, and if you want to reform a carboxylic acid, add water and H+.

-There are many review reactions from previous Chapters that are on this chart. You should already have a good understanding of those reactions, so I will try to emphasize the new reactions you should know.

Synthesis of Carboxylic acids

Reaction Example (Mechanism) Reactants, Reagent, Products

Important things to note

Oxidation of Primary

alcohols/alde-hydes (Ch 11)

-From Chapter 11, a primary alcohol can be oxidized with a chromium reagent, which will first oxidize the alcohol to an aldehyde. However, since chromium is a strong oxidizing agent, it will continue to oxidize the aldehyde into a carboxylic acid.

Reactant– Primary Alcohol or aldehydesReagent: A Chromium (VI) reagent – Cr(VI) (Na2Cr2O7, or CrO3 in H2SO4), or KMnO4

Product – A carboxylic acid

- Won’t be directly asked this, but know this reaction because it is useful for synthesis questions!

Oxidative Cleavage of Alkenes (Ch

8)

-From O.Chem 1, an Alkene can react with warm, acidic, and concentrated KMnO4 to form ketones/aldehydes. Any aldehydes present will oxidize further to carboxylic acids.

Reactant- An AlkeneReagent – Warm, acidic, or concentrated KMnO4

Product – Mixtures of ketones, or carboxylic acids

- Shouldn’t be asked this, know in case, specifically for synthesis questions!-Remember, the permangate has to be in warm, concentrated, or acidic conditions to form ketones/carboxylic acids

Oxidation of alkynes (Ch 9)

-From O.Chem 1, an alkyne can react with warm, basic, concentrated KMnO4 to cleave the triple bond to form carboxylate salts, which can be protonated to form carboxylic acids

-An alkyne can also react with ozone and H2O that will cleave the triple bond to form 2 carboxylic acids as well

Reactant An Alkyne (terminal or internal)Reagent: Warm, basic, concentrated KMnO4 or O3 and H2OProduct: Multiple Carboxylic acids

- Shouldn’t be asked this, know in case, specifically for synthesis questions!- Warm, concentrated, and basic, NOT acidic KMnO4 is needed to form carboxylic acid

Oxidation of alkylbenzene

(Ch 17)

-Remember from Ch 17 that KMnO4 or hot chromic acid can be used to oxidize carbon groups on benzene rings to carboxylic acids. Only alkane carbon groups will react, any other group will not be reacted!

Reactant- Benzene ring with carbon (alkane) substituents

- Won’t be directly asked this, but know this reaction because it is useful for

Reagent – KMnO4, NaOH (basic conditions), or Chromic acid and heatProduct – carboxylic acids on benzene rings

synthesis questions!-Will oxidize any adjacent carbon group (alkyl groups, carbonyl groups, etc…)

Carboxylation of Grignard

reagent

Remember from O.Chem 1 that Grignard reagents are very strong nucleophilies. Therefore, a Grignard reagent can react with CO2, and can form a carboxylic acid.

Reactant: A Grignard reagent (R-MgBr)Reagent: Carbon dioxide (CO2)Product: A carboxylic acid

-Know this reaction! Not really a new reaction, but a good reaction to synthesis carboxylic acids with.

Hydrolysis of Nitriles (Ch 18)

-Nitriles (-CN) can be hydrolyzed under acidic conditions. The nitrile will first be hydrated to form an amide, which will be hydrated again to form a carboxylic acid.

Reactant: A Nitrile (R-CN)Reagent: H+ and H2OProduct: A Carboxylic acid

- Know this reaction! It is a useful reaction for converting cyanides to carboxylic acids

Reactions of Carboxylic Acids

Reaction Example (Mechanism) Reactants, Reagent, Products

Important things to note

The Fischer Esterification

(Ch 11)

-A carboxylic acid can be reacted with an alcohol. Since the carboxylic acid is not a good electrophilie, it will be protonated first to make it more electrophilic. After protonation, the alcohol will attack, and a tetrahedral intermediate will form

-One of the alcohols will be protonated, leaving as water, forming an ester with the alcohol attached to the carbonyl carbon.

Reactant– Carboxylic acid Reagent: An Alcohol in acidic conditions Product – Ester, with the alcohol R group attached to the O

-Know this reaction and the mechanism! It essentially follows the acid catalyzed mechanism.-Remember, the carboxylic acid has to be reacted in acidic conditions to protonate the oxygen to make it more electrophilic!

The overall reaction is shown below

Esterfication using

Diazomethane

-A carboxylic acid can react with Diazomethane (Diazonium with a methyl attached) to form an ester. The negatively charged carbon will first extract the carboxylic acid hydrogen, now forming a negative charge on the oxygen, which will then attack the methyl group, with N2 leaving, forming the ester.

Reactant- Carboxylic acidReagent – Diazomethane (CH2N2)Product – An ester, with the methyl group attached to the oxygen

-Don’t need to know the mechanism, but know the reaction! -Usually only uses diazomethane (CH3N2).

Direct synthesis of Amides (Ch

19)

-Similar to the reaction of the diazomethane, the carboxylic acid hydrogen will first be extracted by the amine, forming the carboxylate ion. Under heated conditions, this will react with the amine to form an amide.

-Though a carboxylic acid can be converted straight to an amide, it is usually preferred to convert the carboxylic acid to an acid chloride, then to the amide since weaker conditions can be used

Reactant: Carboxylic acidReagent: An amine (can be ammonia, primary or secondary), and heatProduct: An Amide, with the amine replacing the OH

-Don’t need to know the mechanism, but know the reaction! -Usually better to convert carboxylic acid to an acid chloride, then form the amide

Reduction of Carboxylic

Acids to alcohols (Ch

10)

-Remember that carboxylic acids can react with LAH to form primary alcohols. The first addition will actually form an aldehyde, and the second addition will form the primary alcohol.

- BH3*THF can also be used to reduce carboxylic acids to primary alcohols, but will preferentially react with carboxylic acids over any other carbonyl group. Therefore, with only 1 addition, will only reduce the carboxylic acid

Reactant- Carboxylic acidsReagent – LiAlH4 (LAH) or BH3*THFProduct – Primary alcohols

- Don’t need to know the mechanism, but know the reaction! -Remember, LiAlH4 is reactive, not selective, while BH3*THF is selective for carboxylic acids

Synthesis of Acid

Chlorides

-Acarbonyl oxygen of the carboxylic acid can react with SOCl2 to form a resonance stabilized compound shown below

-The chloride will then leave, and the carbonyl on the sulfur will reform, with the chloride extracting a hydrogen from the carbonyl oxygen, forming a chlorosulfite anhydride

-Chloride will then attack the anhydride, preferentially the carbon instead of the sulfur. The ester substituent will then be removed, now forming the acid chloride. You don’t need to know the mechanism!

-The overall reaction is shown below

Reactant: Carboxylic acidsReagent: SOCl2 or (COCl)2

Product: Acid chlorides

-Don’t need to know the mechanism, but know the reaction!-One of the only reactions to form acid chlorides! They are the most reactive carboxylic acid derivatives, and essentially form every single carboxylic acid derivative.-SOCl2 can only be reacted on carboxylic acids to form acid chlorides. It will not work with anhydrides, esters, and amides!

Reduction of carboxylic

acids to

There is no direct way to convert a carboxylic acid into an aldehyde. It must be converted to an acid chloride first by reacting a carboxylic acid can be reacted with SOCl2 to attach a chlorine on the carbonyl carbon.

Reactant: An acid chloride (can be generated by adding a carboxylic acid

-Don’t need to know the mechanism, but know the reaction!

aldehydes (Ch 18)

The acid chloride can then be reduced by Lithium tri- tert -butoxyaluminum hydride (LiAlH(O-t-bu)3). This is a weaker reducing agent than LAH, so will only reduce the acid chloride to the aldehyde and not the alcohol. Notice that this only forms aldehydes, not ketones!

with a thionyl chloride (SOCl2)Reagent: Lithium tri- tert - butoxyaluminum hydride (LiAlH(O t-Bu)3)Product: An aldehyde,

-LiAlH(O t-Bu)3 is a weaker reducing agent and can reduce the acid chloride to the aldehyde form, while LiAlH4 would reduce it all the way to an alcohol

Alkylation of Carboxylic

Acids to form ketones (Ch

18)

From Ch 18, to convert a carboxylic acid into a ketone, 2 additions of a organolithium are needed (any R group can be used for the organolithium compound). The first organolithium reagent is used to deprotonate the acidic carboxylic hydrogen to form a carboxylate ion. The second addition will be used to form a dianion.

Protonation of the dianion will cause a dehydration, and reformation of the carbonyl, now forming a ketone

The overall reaction is shown below

Reactant- A carboxylic acidReagent – 2 organolithium compounds (any R group can be used). Notice that in the first deprotonation, a weaker base such as –OH can be usedProduct – A ketone with another R group attached replacing the OH.

-Don’t need to know the mechanism, but know the reaction! Keep in mind you need 2 organolithium reagents to form the ketone!-One of the only reactions that directly converts an carboxylic acid to a ketone

Reactions involving Acid Chlorides

Reaction Example (Mechanism) Reactants, Reagent, Important things to note

ProductsInterconvers-ions of Acid Chloride to Carboxylic

acid derivative

(anhydride, ester, amide,

carboxylic acid)

-Remember that acid chlorides react under basic catalyzed mechanisms since they are more reactive than other derivatives. Therefore, nucleophilies can directly attack the carbonyl carbon without protonation of the oxygen. Below are different reactions of acid chlorides to convert to different carboxylic acid derivatives.-Acid chloride can react with with a carboxylic acid (or carboxylate ion), forming a tetrahedral intermediate, and the loss of chloride, forming an anhydride

-If an Acid chloride reacts with an alcohol, it will follow the same mechanism, with the –Cl leaving, forming an ester

-If an Acid chloride reacts with an amine, it will form an amide

-Acid chlorides can also react with water (no acidic conditions needed), to reform carboxylic acid.

Reactant– An Acid ChlorideReagent: Depends on what derivative is formed -Formation of anhydride – carboxylic acid or the salt form-Formation of an ester – an alcohol -Formation of an amide – ammonia, primary or secondary amine-Formation of a carboxylic acid –waterProduct – Anhydride, ester, amide, or carboxylic acid

- Know this reaction and the mechanism! -Essentially follows the basic catalyzed mechanism, where the nucleophile attacks first, forms the tetrahedral intermediate, and kicks off chloride-Remember the reactivity chart! Since acid chlorides are the most reactive, with –Cl being a good leaving group, it can interconvert to all the different derivatives: anhydrides, ester, amide, or carboxylic acid again.

Reduction of Acid

Chlorides(Ch 10, 18)

Acid chlorides can be reduced by different reagents to form different products, all listed below.-The acid chloride can then be reduced by Lithium tri- tert -butoxyaluminum hydride (LiAlH(O-t-bu)3). This is a weaker reducing agent than LAH, so will only reduce the acid chloride to the aldehyde and not the alcohol. Notice that this only forms aldehydes, not ketones!

Reactant An acid chloride Reagent: Formation of an aldehyde - (LiAlH(O t-Bu)3

- Don’t need to know the mechanism, but know the reaction!-The strength of the

-If LiAlH4 is used, it will reduce the acid chloride all the way to a primary alcohol. Remember LAH adds twice, with the first time forming the aldehyde, and the second forming the alcohol.

-To convert an acid chloride into a ketone, A lithium dialkylcuprate (Gilman reagent) is needed to add an R group to the acid chloride. Notice that 2 R groups are attached to the reagent in order for just one to attach onto the carbonyl to form the ketone

Formation of an alcohol - LAH-Formation of a ketone – R2CuLiProduct: An aldehyde, alcohol, or ketone

reducing agent dictates the product form. A weaker reducing agent such as the hindered LAH will only form the aldehyde, while unhindered LAH will react to reduce the acid chloride all the way to an alcohol

Grignard reactions of

acid chlorides (Ch 10)

-An acid chloride will react with a Grignard reagent 1 time to form a ketone, which will react again with the Grignard reagent for form a tertiary alcohol, with 2 additions of the Grignard on the carbonyl group. A tertiary alcohol is always formed, with 2 additions of Grignards!

Reactant: An Acid ChlorideReagent: Grignard reagent (R-MgBr)Product: A tertiary alcohol, with 2 additions of the Grignard reagent

-Don’t need to know the mechanism, but know the reaction!-A ketone will form with 1 equivalent addition, but an additional equivalent will form the 3 o alcohol with 2 additions of grignards

Reactions involving Anhydrides

Reaction Example (Mechanism) Reactants, Reagent, Products

Important things to note

Formation of a cyclic

anhydride

-Under acidic conditions, a compound with 2 carboxylic acids in a chain can cyclize. One of the carbonyl oxygens will get protonated, allowing for the opposite carboxylic acid to attack the more electrophilic carbon, forming a cyclic tetrahedral shown below.

-Under acidic conditions, one of the alcohols will get protonated, and leave as water, reforming the carbonyl and forming the cyclic anhydride

-The cyclic anhydride can react with a nucleophile, breaking the ring and reacting with 1 side of the carboxylic acid, forming unsymmetrical carboxylic acid derivative compounds. Notice that the side that kicks off the most stable leaving group is reacted. The carboxylic acid with the fluorines attached is more stable because it helps to stabilize the excess electron density

Reactant– A dicarboxylic acidReagent: Acidic (H+) conditionsProduct – A cyclic anhydride (2 carbonyl groups adjacent to a cyclic O), which can be reacted further to form multiple carboxylic acid derivatives

- Know this reaction and the mechanism! You will be given several questions that involves the formation of cyclic carboxylic acid derivatives!

Interconversi-on of

Anhydrides to other

carboxylic acid

derivatives (esters,

amides, and carboxylic

acids)

-Like acid chlorides, an anhydride reacts in a basic catalyzed mechanism involved a direct nucleophilic attack onto the electrophilic carbon, forming the tetrahedral intermediate, and kicking off the carboxylate ion, forming the new carboxylic acid derivative.

-Besides being able to react with an alcohol to form an ester, anhydrides can react with an amine, to form an amide.

Reactant: Anhydride Reagent: -Formation of an ester – an alcohol -Formation of an amide – ammonia, primary or secondary amine-Formation of a carboxylic acid – add waterProduct: ester, amide, or carboxylic acid

- Know this reaction and the mechanism! -Essentially follows the basic catalyzed mechanism, where the nucleophile attacks first, forms the tetrahedral intermediate, and kicks off a carboxylate ion-Remember the reactivity chart! Since anhydrides are less reactive than acid chlorides, anhydrides are unable to be directly converted to an acid

-Anhydrides can also react with water, to form 2 carboxylic acids. The other carboxylic acids is not drawn below

chloride. It can only react with a nucleophile that forms a less stable carboxylic acid derivate. Therefore, it can only react with alcohols, amines, and water to form esters, amides, and carboxylic acids!

Reactions with Esters

Reaction Example (Mechanism) Reactants, Reagent, Products

Important things to note

Interconversi-on of esters

(amides, carboxylic

acids

-An ester can react with an amine in an acid catalyzed mechanism. The ester will be protonated first to form a more electrophilic compound. Then the amine can attack the carbonyl carbon, forming the tetrahedral intermediate below. The alcohol will then be kicked off (it will be protonated first, then leave, not shown below), forming the amide.

-An ester can react with acidic water, forming the similar tetrahedral intermediate. The alcohol will then leave (protonated first), and then form the carboxylic acid

Reactant– An esterReagent: -Formation of an amide – ammonia, primary or secondary amine-Formation of a carboxylic acid – H+ and H2OProduct – either an amide or a carboxylic acid

-Know this reaction and the mechanism! -Essentially follows the acidic catalyzed mechanism, where the nucleophile attacks first, forms the tetrahedral intermediate, and kicks off an alcohol-Esters are relatively unreactive. They can react to form only amides, carboxylic acids, and other esters, which is shown below.

Transesterfic-ation (switch R groups on

an ester)

-An ester can react with an alcohol under acidic conditions, to form a new ester, with a different substituent attached to the alcohol. It will undergo the same acid-catalyzed mechanism, form the tetrahedral intermediate, and kick off the initial alcohol attached

Reactant An esterReagent: An alcohol and H+ Product: An ester, with a different R group attached to the oxygen atom

- Know this reaction and the mechanism!-The easiest way of switch a R group on an ester-Essentially follows the acidic catalyzed mechanism, where the nucleophile attacks first, forms the tetrahedral intermediate, and kicks off an alcohol

Reaction of thiolesters

-A thiolester (S instead of O), has very similar reactivity to an ester. It is actually more reactive than an ester and amide, but less reactive than an acid chloride and an anhydride. Therefore, a thiolester can be converted into an ester, amide, or carboxylic acid. It will follow a similar mechanism of an ester. Below is a thiolester reacting with an amine, forming an amide

Reactant An thiolesterReagent: -Formation of an ester – an alcohol -Formation of an amide – ammonia, primary or secondary amine-Formation of a carboxylic acid – add water

-Know this reaction and the mechanism! It is essentially the same as an ester, but with a sulfur instead of a oxygen-Thiolsulfurs are more reactive than esters, but less reactive than anhydrides

Product: An ester, amide, or carboxylic acid

and acid chlorides.

Reaction of Grignard’s to esters, and

reduction of esters

-Similar to acid chlorides, esters can react with Grignard reagents twice, similar to acid chlorides, to form a tertiary alcohol with 2 addition of Grignards

-Similar to Carboxylic acids, esters can react with LAH to form primary alcohols. Two additions of LAH are needed to form the primary alcohol

Reactant An esterReagent: -Formation of 3 o alcohol – Grignards-Formation of 1 o alcohol - LAHProduct: An ester, with a different R group attached to the oxygen atom

-Don’t need to know the mechanism, but know the reaction!-Know these reaction for synthesis questions, just in case

Reactions involving Amides

Reaction Example (Mechanism) Reactants, Reagent, Important things to note

ProductsHydrolysis of

Amides (forms

Carboxylic acid)

-Amides are the least reactive out of all of the carboxylic acid derivatives. Therefore, an amide can’t directly convert to an acid chloride, anhydride, thiolester, or ester. It can be converted back to a carboxylic acid through an acid catalyzed mechanism that requires the protonation of the carbonyl oxygen. After formation of the tetrahedral intermediate, the amine will get kicked off, forming the carboxylic acid.

Reactant– An AmideReagent: H+ and waterProduct – Carboxylic Acids

- Know this reaction and the mechanism!- Can’t directly convert to an acid chloride, anhydride, thiolester, or ester! Can only be converted into a carboxylic acid

Dehydration of Amides to

Nitriles

-Primary amides can be dehydrated using a strong dehydrating agent such as POCl3 or P2O5 to form a nitrile. Amides are the only carboxylic acid derivative that can convert into an nitrile

Reactant AmideReagent: - POCl3 or P2O5

Product: A nitrile

- Don’t need to know the mechanism, but know the reaction!- The only carboxylic acid derivative that can convert into an nitrile

Review reactions of amides (Ch

19)

From Ch 19, Primary, Secondary or tertiary amides can be reduced by LiAlH4 to form an amine

-Primary amides can also react with halogens, -OH and water, which undergoes a rearrangement of the carbonyl substituent so that it then attaches to the amine, forming a substituted amine. See the Ch 19 chart for more details on the mechanism

Reactant AmideReagent: - LAH, or NaOH, and a halogenProduct: Amines

- Don’t need to know the mechanism, but know the reaction!-See the chapter 19 chart for more information. Again the mechanism is not important, just know the reagents, what they do and what is formed

Reactions with Nitriles

Reaction Example (Mechanism) Reactants, Reagent, Important things to note

ProductsHydrolysis of

Nitriles (forming

Carboxylic acids)

-Nitriles can react under acidic hydrolysis to form carboxylic acids. Under weak conditions, it will only go to the amide form, but under strong conditions or acidic), will continue to go to the carboxylic acid form

Reactant– A nitrileReagent: H+ and waterProduct – Carboxylic Acid

-Don’t need to know the mechanism, but know the reaction!-When doing this reaction, will usually always go to form the carboxylic acid!

Review reactions of Nitriles (Ch

19)

-From Ch 19, Nitriles can react with LiAlH4 to form amines

-Nitriles can also react with Grignards forming an imine first, but with further reaction under acidic conditions, will form a ketone

Reactant– A nitrileReagent: -Formation of an Amine – LAH-Formation of a ketone – Grignards, then H+Product – Amine or Ketone

-Don’t need to know the mechanism, but know the reaction!-See Ch 19 notes for more details