Derivatives of Carboxylic Acid : O: R C

Derivatives of Carboxylic Acid : O: R C

Derivatives of Carboxylic Acid : O: R C R .. Cl .. : : O: C R R C .. O .. C .. _ O ..: carboxylate acid chloride :O: :O: R .. OH .. N: C nitrile : O: C acid anhydride R :O: R C :O: .. O .. ester R R C amide .. H

N H 1 Nomenclature of Acid Halides IUPAC: alkanoic acid alkanoyl halide Common: alkanic acid alkanyl halide NH2 O : O: R NO2 CH2 CH2 C Cl O C .. Cl .. : H3C CH CH2 CH2 C Cl 3-aminopropanoyl chloride 4-nitropentanoyl chloride Nomenclature of Acid Anhydrides Acid anhydrides are prepared by dehydrating carboxylic acids O O CH3 C OH + O H O C CH3 acetic acid - H2 O CH3 O C O C CH3 acetic anhydride ethanoic anhydride ethanoic acid O CH3 C O O C H ethanoic methanoic anhydride 2

Nomenclature of Esters : O: Esters occur when carboxylic acids react with alcohols alkyl I: alkanoate c: alkanate O CH3 O C CH3 methyl ethanoate R C .. OH .. carboxylic acid O O C H phenyl methanoate + H .. O .. alcohol R - :O: H2O H+ R C .. O .. R ester O C O C(CH3)3 t-butyl benzenecarboxylate Nomenclature of Amides 3 Nomenclature of Amides 1 amide O R C N O O

3 amide R R C N N,N-disubstituted amide R H 2 amide R C N R N-substituted amide H H 1 amides: alkanoic acid + amide alkanamide O CH3CH2CH2 C N H H butanamide Cl O C N O NO2 H C N H 3-chlorocyclopentanecarboxamide H H I: p-nitrobenzenecarboxamide 2 and 3 amides are N-substituted amides O CH3 O CH3CH C N CH3 C N CH3 CH2CH3 H N,2-methylpropanamide N-ethyl-N-methylcyclobutanecarboxamide O H3C C N H N-phenylethanamide 4 Nomenclature of Nitriles O R C N

H H POCl3 R C N - H2O Nitriles are produced when 1 amides are dehydrated with reagents like POCl3 IUPAC: alkane + nitrile alkanenitrile CH3 C N ethanenitrile acetonitrile N C CH2CH2CH2 4-iodobutanenitrile I HS CN p-thiobenzenecarbonitrile 3-methoxycyclohexanecarbonitrile 5 Nucleophilic Addition to Aldehydes and Ketones Recall that electron donors (Nu: -s) add to the electrophilic carbonyl C in aldehydes and ketones. The C=O bond breaks and the pair of electrons are stabilized on the electronegative O atom. R (alkyl groups) and hydrogens (H) bonded to the C=O carbon remain in place. R- and H- are too reactive (pKb of 40 and -21). R and H are not leaving groups, so the carbonyl group becomes an alkoxide as the sp2 C becomes a tetrahedral sp3 C. - O O R C H R C H CH3 MgBr tetrahedral alkoxide with sp3 carbon. CH3 A second addition of a nucleophile cannot occur since alkoxides are not nucleophilic. The reaction is usually completed by protonation of the alkoxide with H3O+ forming an alcohol. This later reaction is simply an acid/base reaction. The characteristic reaction of aldehydes and ketones is thus nucleophilic addition. O - R C H CH3 H + H

O H O+H R C H CH3 + H O H 6 Nucleophilic Acyl Substitution in Acid Derivatives Carboxylic acid derivatives commonly undergo nucleophilic substitution at the carbonyl carbon rather than addition. The first step of the mechanism is the same. The C=O bond breaks and the pair of electrons are stabilized on the electronegative O atom. A tetrahedral alkoxide is temporarily formed. O R C Cl R C Cl sp2 carbonyl C - O CH3 MgBr O R C CH3 + CH3 Cl Chlorine is a fair leaving group. sp2 carbonyl reforms alkoxide C js sp3 In carboxylic acid derivates, one of the groups that was bonded to the carbonyl C is a leaving group. When this group leaves, the sp3 tetrahedral alkoxide reverts back to an sp2 C=O group. Thus substitution occurs instead of addition. In many cases, the substitution product contains a carbonyl that can react again. O O - R C CH3 R C CH3 CH3 MgBr CH3 H H O+H O H R C CH3 + H O H CH3 Note that because the C=O group reforms, the nucleophile can react a second time. 7 Nucleophilic Acyl Substitution in Acid Derivatives

In carboxylic acid derivatives, the acyl group (RCO) is bonded to a leaving group (-Y). O R C R C Y acyl group - O Nu:- O O R C Nu + Y: R C Y - Draw the mechanism. Nu The leaving group (-Y) becomes a base (Y:-) . The acid derivative is reactive If the base formed is weak (unreactive). Weak bases are formed from good leaving groups. For the carboxylic acid derivatives shown, circle the leaving group. Then draw the structure of the base formed, give its pKb, and describe it as a strong or weak base. acid derivative leaving group pKb strength as base Cl +21 non basic +9 weak base O R -2 strong base NH2 -21 v. strong base O R C Cl O O R C O C R O R C O R O R C NH2 - O O C R -

8 Nucleophilic Acyl Substitution in Acid Derivatives We will study the reaction of only a few nucleophiles with various carboxylic acid derivatives and we will see that the same kinds of reactions occur repeatedly. Hydrolysis: Reaction with water to produce a carboxylic acid Alcoholysis: Reaction with an alcohol to produce an ester Aminolysis: Reaction with ammonia or an amine to produce an amide Grignard Reaction: Reaction with an organometallic to produce a ketone or alcohol Reduction: Reaction with a hydride reducing agent to produce an aldehyde or alcohol Draw the structures of the expected products of these nucleophilic substitution reactions, then circle the group that has replaced the leaving group (-Y) O R C Y + O R C Y + O R C Y + O R C Y + O R C Y + H OH H OR H NH2 O hydrolysis alcoholysis R C O H O R C O R O aminolysis R C NH2 R MgX Grignard reduction LiAlH3 H hydride reduction O H R C R R O H R C H H 9 Nucleophilic Acyl Substitution of Carboxylic Acids O O R C O H R C Y Nucleophilic acyl substitution converts carboxylic acids into carboxylic acid derivatives, i.e., acid chlorides, anhydrides, esters and amides. : O: R C ..

Cl .. : acid chloride :O: R C .. O .. : O: SOCl2 R : O: -H2O R C acid anhydride C .. OH .. NH3,, -H2O :O: R C amide ROH H+ :O: R C .. O .. .. H N H R ester 10 Synthesis Problems Involving Carboxylic Acids Write equations showing how the following transformations can be carried out. Form a carboxylic acid at some point in each question. H3C ? CH3 Cl O KMnO4

HO C O O C C Cl O SOCl2 C OH MgBr 2. Mg ether Br O C OH C OH O 2 CH3OH H+ O 1. CO2 C OH - H2O H3O+ O ? O C O C NaCN CN H2O O - H2O C OH H+ 11 Chemistry of Acid Halides In the same way that acid chlorides are produced by reacting a carboxylic acid with thionyl chloride (SOCl2), acid bromides are produced by reacting a carboxylic acid with phosphorus tribromide (PBr3). : O: R C R + OH : O: SOCl2

R C + Cl + SO2 HCl O .. C O (or PCl3) .. + OH R PBr 3 C + Br PBr2OH Most acid halide reactions occur by a nucleophilic acyl substitution mechanism. The halogen can be replaced by -OH to produce an acid, -OR to produce an ester, -NH2 to produce an amide. Hydride reduction produces a 1 alcohol, and Grignard reaction produces a 3 alcohol. : O: R C acid .. OH : O: R H2O C ester .. O .. R O R - R': MgBr C Cl : O:

R R [H] C R .. C NH2 amide C [H] R' ketone R':- MgBr+ : O: NH3 ROH O + H aldehyde RCH2OH 1 alcohol OH R C R' R' 3 alcohol 12 Reduction of Acid Chlorides to Alcohols 1. With hydride : Acid chlorides are reduced by LiAlH4 to produce 1 alcohols. The alcohols can of course be produced by reduction of the carboxylic acid directly. excess 1. LiAlH4 CH3 O H3C C C Cl CH3 CH3 H3C C 2. H3O+ 2,2-dimethyl-1-propanol CH2OH CH3 However, the reaction will stop at the aldehyde if exactly 1 equivalent of a weaker hydride is used, i.e., diisobutylaluminum hydride (DIBAH) at a low temperature (-78C). O NO2 C Cl

- 78C 1 equiv. 1. DIBAH 2. H3O+ O NO2 C H p-nitrobenzaldehyde 2. with Grignards Grignard reagents react with acid chlorides producing 3 alcohols in which 2 alkyl group substituents are the same. The mechanism the 1st equivalent of Grignard reagent adds to the acid chloride, loss of Cl- from the tetrahedral intermediate yields a ketone, and a 2nd equivalent of Grignard immediately adds to the ketone to produce an alcohol.C Cl O O O CH3 MgBr C CH3 CH3 MgBr C CH3 CH3 H3O+ O H C CH3 CH3 2-phenyl-2-propanol 13 Practice Questions for Acid Chloride Reductions Draw the reagents that can be used to prepare the following products from an acid chloride by reduction with hydrides, Grignards and Gilman reagent. Draw all possible combinations. I: ethanoyl chloride excess OH 1. O MgBr I: 1,1-dicyclopentylethanol CH3 C 2. O C CH2CH3 H3C C O 1. C H 2. C Cl H3O+ DIBAH 1 equiv. - 78C 2CuLi O 1 equiv. - 78C CH3CH2 C Cl + H3O

I: 1-phenyl-1-propanone c: ethyl phenyl ketone CH3 O H3C C H3O+ or 2. excess 1. LiAlH4 2. 1. O H3O+ CH2 CH3 H3O+ CH3CH2 2CuLi 1. 1 equiv. - 78C 2. CH3 OH H3C C Cl C Cl I: 2,2-dimethylpropanoyl chloride I: 2,2-dimethyl-1-propanol CH3 O C Cl I: cyclohexanecarbonyl chloride I: cyclohexanecarbaldehyde 14 :O: Preparations of Acid Anhydrides R C .. O .. : O: C R Preparation of Acid Anhydrides: Dehydration of carboxylic acids as previously discussed is difficult and therefore limited to a few cases. O O O O CH3 C OH + H O C CH3 CH3 C O C CH3 - H2O acetic anhydride acetic acid A more versatile method is by nucleophilic acyl substitution of an acid chloride with a carboxylate anion. Both symmetrical and unsymmetrical anhydrides can be prepared

this way. : O: .. : O .. H C _ : O: Na+ sodium formate + Cl C : O: ether 25C CH3 SN2 H C .. O .. : O: C CH3 + NaCl acetic formic anhydride acetyl chloride Draw all sets of reactants that will produce the anhydride shown with an acid chloride. O O O CH3 C O C O CH3 C O- Na+ + O O CH3 C Cl Cl C + Na+ -O C 15 :O: Reactions of Acid Anhydrides R ..

O .. C : O: C R The chemistry of acid anhydrides is similar to that of acid chlorides except that anhydrides react more slowly. Acid anhydrides react with HOH to form acids, with ROH to form esters, with amines to form amides, with LiAlH4 to form 1 alcohols and with Grignards to form 3 alcohols. Note that of the anhydride is wasted so that acid chlorides are more often used to acylate compounds. Acetic anhydride is one exception in that it is a very common acetylating agent. O O : O: 2 R C acid H2O R .. C O C R - R': MgBr OH [H] : O: ester + acid R C .. HO .. O .. R' R :O: C : O: R R C 2 R .. C NH2

amide C [H] R' ketone R':- MgBr+ : O: NH3 R'OH O + H aldehyde 2 RCH2OH 1 alcohol OH R C R' R' 3 alcohol 16 Practice Questions for Acid Anhydrides Show the product of methanol reacting with phthalic anhydride O O C C OCH3 2-(methoxycarbonyl)benzoic acid O + CH3OH C C OH O O Draw acetominophen; formed when p-hydroxyaniline reacts with acetic anhydride O HO O O NH2 + CH3 C O C CH3 HO O N C CH3 + CH3 C OH H N-(4-hydroxyphenyl)acetamide 17 Preparation of Esters 1. SN2 reaction of a carboxylate anion with a methyl or 1 alkyl halide : O: R

C .. _ : O .. : O: Na + R' + Br R S N2 C .. O .. R' 2. Fischer esterification of a carboxylic acid + alcohol + acid catalyst : O: R C : O: + .. OH + R' OH H R C .. O .. R' 3. Acid chlorides react with alcohols in basic media : O: O R C Cl + R' OH R C .. O .. R'

+ HCl 18 Reactions of Esters Esters react like acid halides and anhydrides but are less reactive toward nucleophiles because the carbonyl C is less electrophilic. Esters are hydrolyzed by HOH to carboxylic acids, react with amines to amides, are reduced by hydrides to aldehydes, then to 1alcohols, and react with Grignards to 3 alcohols. : O: R C H2O : O: R C acid NH3 + .. .. H OH : O: R R':- MgBr + O .. R' .. C NH2 amide O R [H] C - R': MgBr : O: R ketone R' C H aldehyde [H] RCH2OH + R'OH +

OH R C R' R' 3 alcohol 1 alcohols 19 Hydride Reduction of Esters Esters are easily reduced with LiAlH4 to yield 1 alcohols. The mechanism is similar to that of acid chloride reduction. A hydride ion first adds to the carbonyl carbon temporarily forming a tetrahedral alkoxide intermediate. Loss of the OR group reforms the carbonyl creating an aldehyde and an OR - ion. Further addition of H: - to aldehyde gives the 1 alcohol. Draw the mechanism and show all products. O LiAlH4 R C O R' LiAlH4 O R C H - - O O H R C H H H excess 1. LiAlH4 O 2. H3O+ R C H OR' Draw and name the products. O - + R'OH CH2OH OH H3O+ 20 Grignard Reduction of Esters Esters react with 2 equivalents of Grignard reagent to yield 3 alcohols in which the 2 substituents are identical. The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard to yield a 3 alcohol. MgBr O C OCH3 methyl benzoate O C

- - OCH3 benzophenone MgBr triphenylmethoxide O C H H3O+ O C + CH3OH triphenylmethanol 21 Practice with Esters What ester and Grignards will combine to produce the following 2-phenyl-2-propanol CH3 C O + OR C OH CH3 1. 2 CH3MgBr 2. H3O+ 1,1-diphenylethanol OH C CH3 O RO C CH3 + 1. 2 CH3MgBr 2. H3O+ 22 Chemistry of Amides Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted and disubstituted amines (but not trisubstituted amines) all react. O .. NH3 O R C R NH2 C NR3 Cl NH2R 1 amine 1 amide NHR2 2 amine

C NHR 2 amide 3 amine O O R no reaction R C NR2 3 amide 23 Alcoholysis of Amides (to Esters) Alcoholysis of amides occurs by the same acid catalyzed mechanism as acid hydrolysis except that the amido group of the amide is replaced with by an alcohol rather than water. Dry acid, e.g., HCl(g) or H2SO4 must be used otherwise water would compete with the alcohol as the nucleophile producing some carboxylic acid product in place of an ester. The reaction will require a long reflux period because amides are weak electrophiles and alcohols are weak nucleophiles. O C N(CH3)2 OH CH3CHCH2CH3 H2SO4 N,N-dimethylcyclopentanecarboxamide O C + + NH2(CH3)2 O CH3CHCH2CH3 sec-butyl cyclopentanecarboxylate 24 Hydride Reduction of Amides Amides are reduced by LiAlH4. The product is an amine rather than an alcohol. The amide carbonyl group is converted to a methylene group (-C=O -CH2). This is unusual. NH2CH3 O O C Cl C NHCH3 H H3O+ H 2. N benzoyl chloride

1. LiAlH4 C NHCH3 N-methylbenzamide Grignard Reduction of Amides Grignards deprotonate 1 and 2 amides and are not reactive enough to add to the imide ion product. N-H protons are acidic enough (pKa = 17) to be abstracted by Grignards. : O: R C .. N H R 2 amide .. _ : O: + :CH3 MgBr R _ CH 4 C .. N imide anion R :CH3 +MgBr 25 Chemistry of Nitriles + C R N: The carbon atom in the nitrile group is electrophilic because it is bonded to an electronegative N atom and a bond in the nitrile is easily broken, i.e., as if it were providing a leaving group. Preparation of Nitrile: 1. Nitriles are easily prepared by SN2 reaction of cyanide ion (CN-) with methyl halides or a 1 alkyl halide. 2 alkyl halides also work but some E2 product also forms. 3 alkyl halides will result in mostly an alkene (E2) product instead of a nitrile. (pKb of CN - = 4.7) bromoethane ethyl bromide SN2 CH3CH2 Br + - propanenitrile CH3CH2 C N Na CN

2. Another method of preparing nitriles is by dehydration of a 1 amide using any suitable dehydrating agent such as SOCl2, POCl3, P2O5, or acetic anhydride. Initially, SOCl2 reacts with the amide oxygen atom and elimination follows. This method is not limited by steric hindrance. O C NH2 SOCl2 , benzene C N + SO2 + 2 HCl 80C SOCl2 Recall: R R Cl OH POCl3 in pyridine OH PBr 3 R _ H2O Br 26 Reactions of Nitriles + C R N: Like carbonyl groups, the nitrile group is strongly polarized and the nitrile C is electrophilic. Nucleophiles thus attack yielding an sp2 hybridized imine anion. _ .. : O: : O: sp 2 C C Nu - Nu:

+ E R sp products sp 3 + C + E N: C R Nu:- .. _ N: products Nu sp 2 imine anion Nitriles are hydrolyzed by HOH to amides and subsequently to carboxylic acids, reduced by hydrides to amines or aldehydes, and by Grignards to ketones. H2O O R C 1 amide R NH2 POCl3 _HO 2 N: C O RMgX R R ketone [H] [H] C O R CH2 1 amine

NH2 R C H aldehyde 27 Hydrolysis of Nitriles into Carboxylic Acids + C R N: Nitriles are hydrolyzed in either acidic or basic aqueous solution to yield carboxylic acids plus ammonia or an amine. R C N O H2O + H or OH - + NH3 R C O H In acid media, protonation of N produces a cation that reacts with water to give an imidic acid (an enol of an amide). Keto-enol isomerization of the imidic acid gives an amide. The amide is then hydrolyzed to a carboxylic acid and ammonium ion. It is possible to stop the reaction at the amide stage by using only 1 mole of HOH per mole of nitrile. Excess HOH forces carboxylic acid formation. H3O+ R C N: R C + N .. .. R H C + N :O .. R .. C OH acid H3O+

: O: R C amide .. NH2 N +O H .. H H .. .. H H : O: C R H H2O .. R N C H : O: hydroxyimine H 28 Hydrolysis of Nitriles into Carboxylate Salts R + C N: In basic media, hydrolysis of a nitrile to a carboxylic acid is driven to completion by the reaction of the carboxylic acid with base. The mechanism involves nucleophilic attack by hydroxide ion on the electrophilic C producing a hydroxy imine, which rapidly isomerizes to an amide. Further hydrolysis yields the carboxylate salt. : O: - OH R C N: R

C :O .. H H H .. _ N: _ OH- R C : O: .. H N R C hydroxy imine : O: NH3 + H : O: .. _ + : O .. Na R C .. NH2 amide OHH2O Show how the following transformation can be carried out without using a Grignard. Br ? O C OH H3O+ Na+CNSN2 CN H3O+ O C NH2 29 Reduction of Nitriles R

+ C N: Alcoholysis of Nitriles doesnt work. Alcohols are weak nucleophiles and nitriles are weak electrophiles Aminolysis of Nitriles doesnt work. Amines are weak nucleophiles and nitriles are weak electrophiles. Reduction with Hydrides: Reduction of nitriles with 2 equivalents of LiAlH4 gives 1 amines. LiAlH4 is a very good nucleophile and can break 2 bonds forming a dianion. H R C N: 1. H:- R C H .. _ N: R - H: C .. _ 2 N: H 2. H2O .. H dianion H2O .. R C NH2 H + 2 OH- If less powerful DIBAH is used, only 1 equivalent of hydride can add. Subsequent addition of HOH yields the aldehyde. C N 1. LiAlH4 2. CH3 o-methylbenzonitrile H2O 1 equiv. 1. DIBAH , toluene , -78C 2.

H2O or H3O+ CH2NH2 CH3 O C H 2-methylbenzaldehyde CH3 30 Reduction of Nitriles with Grignards R + C N: Grignards add to nitriles giving intermediate imine anions which when hydrolyzed yield ketones. The mechanism is similar to hydride reduction except that the attacking nucleophile is a carbanion (R-). Grignards are not as strongly nucleophilic as LiAlH4 and so can only add once a dianion is not formed. 1. R C R R:- MgBr+ N: R C .. _ N: 2. R R H3O+ .. - .. R H N C imine anion :O .. NH4 + NH3 + R .. C R

R C H H R : O: H3O + N : O: C N .. +O H R .. H H H H H C N 1. CH3CH3 MgBr 2. benzonitrile + H3O O C CH2CH3 1-phenyl-1-propanone ethyl phenyl ketone 31

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