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1 Derivatives of Carboxylic Acid acid chloride acid anhydride ester amide nitrile carboxylate.

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2 1 Derivatives of Carboxylic Acid acid chloride acid anhydride ester amide nitrile carboxylate

3 2 Nomenclature of Acid Halides IUPAC: alkanoic acid  alkanoyl halide Common: alkanic acid  alkanyl halide I: 3-aminopropanoyl chloride c:  -aminopropionyl chloride I: benzenecarbonyl bromide c: benzoyl bromide Rings: (IUPAC only): ringcarbonyl halide I: 3-cylcopentenecarbonyl chloride I: hexanedioyl chloride c: adipoyl chloride I: 4-nitropentanoyl chloride c:  -nitrovaleryl chloride

4 3 Nomenclature of Acid Anhydrides Acid anhydrides are prepared by dehydrating carboxylic acids acetic anhydride ethanoic anhydride ethanoic acid I: benzenecarboxylic anhydride c: benzoic andhydride I: butanedioic acid c: succinic acid I: benzoic methanoic anhydride c: benzoic formic anhydride I: butanedioic anhydride c: succinic anhydride I: cis-butenedioic anhydride c: maleic anhydride Some unsymmetrical anhydrides I: ethanoic methanoic anhydride c: acetic formic anhydride

5 4 Nomenclature of Esters Esters occur when carboxylic acids react with alcohols I: methyl ethanoate c: methyl acetate I: phenyl methanoate c: phenyl formate I: t-butyl benzenecarboxylate c: t-butyl benzoate I: isobutyl cyclobutanecarboxylate c: none I: cyclobutyl 2-methylpropanoate c: cyclobutyl  -methylpropionate I: dimethyl ethanedioate c: dimethyl oxalate

6 5 I: 4-hydroxybutanoic acid c:  -hydroxybutyric acid I: 4-hydroxybutanoic acid lactone c:  -butyrolactone Nomenclature of Cyclic Esters, “Lactones” Cyclic esters, “lactones”, form when an open chain hydroxyacid reacts intramolecularly. 5 to 7- membered rings are most stable.  ‘lactone’ is added to the end of the IUPAC acid name.  ‘olactone’ replaces the ‘ic acid’ of the common name and ‘hydroxy’ is dropped but its locant must be included. I: 4-hydroxypentanoic acid lactone c:  -valerolactone I: 6-hydroxy-3-methylhexanoic acid lactone c:  -methyl-  -caprolactone I: 5-hydroxypentanoic acid lactone c:  -valerolactone I: 3-hydroxypentanoic acid lactone c:  -valerolactone

7 6 Nomenclature of Amides 1° amide 2° amide N-substituted amide 3° amide N,N-disubstituted amide  1° amides: ‘alkanoic acid’ + amide  ‘’alkanamide’  a ring is named ‘ringcarboxamide’ I: butanamide c: butyramide I: 3-chlorocyclopentanecarboxamide c: none I: p-nitrobenzenecarboxamide c: p-nitrobenzamide  2° and 3° amides are N-substituted amides I: N,2-dimethylpropanamide c: N,  -dimethylpropionamide I: N-phenylethanamide c: N-phenylacetamide I: N-ethyl-N-methylcyclobutanecarboxamide c: none c: acetanilide

8 7 Nomenclature of Cyclic Amides, “Lactams” Cyclic amides, “lactams”, form when an open chain aminoacid reacts intramolecularly. 5 to 7- membered rings are most stable. I: 4-aminobutanoic acid c:  -aminobutyric acid I: 4-aminobutanoic acid lactam c:  -butyrolactam  ‘lactam’ is added to the end of the IUPAC acid name.  ‘olactam’ replaces the ‘ic acid’ of the common name and ‘amino’ is dropped but its locant must be included. I: 5-aminohexanoic acid lactam c:  -caprolactam I: 3-amino-2-bromopropanoic acid lactam c:  -bromo-  -propionolactam I: 4-amino-3-methylbutanoic acid lactam c:  -methyl-  -butyrolactam

9 8 Nomenclature of Nitriles Nitriles are produced when 1° amides are dehydrated with reagents like POCl 3 IUPAC: alkane + nitrile  ‘alkanenitrile’ IUPAC rings: ‘ringcarbonitrile’ Common: alkanic acid + ‘onitrile’  ‘alkanonitrile’ I: ethanenitrile c: acetonitrile I: 4-iodobutanenitrile c:  -iodobutyronitrile I: 3-methoxycyclohexanecarbonitrile c: none I: p-thiobenzenecarbonitrile c: p-mercaptobenzonitrile I: 2-cyanocyclopentanecarboxylic acid c: none

10 9 Nomenclature Practice Exercise I: cyclobutanecarbonitrile c: none I: bromomethyl ethanoate c: bromomethyl acetate I: sodium ethanoate c: sodium acetate I: pentanedioic anhydride c: glutaric anhydride I: 3-oxobutanoyl chloride c:  -oxobutyryl chloride I: 3-bromo-N-methylpentanamide c:  -bromo-N-methylvaleramide I: 2-ethyl-5-hydroxypentanoic acid lactone c:  -ethyl-  -valerolactone I: 6-amino-6-chlorohexanoic acid lactam c:  -chloro-  -caprolactam

11 10 most reactive acid chloride acid anhydride aldehyde ketone ester carboxylic acid amide nitrile carboxylate least reactive Relative Reactivity of Carbonyl Carbons  Nucleophiles (electron donors), like OH -, bond with the sp 2 hybridized carbonyl carbon.  The order of reactivity is shown.

12 11 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 sp 2 C becomes a tetrahedral sp 3 C. A second addition of a nucleophile cannot occur since alkoxides are not nucleophilic. The reaction is usually completed by protonation of the alkoxide with H 3 O + forming an alcohol. This later reaction is simply an acid/base reaction. The characteristic reaction of aldehydes and ketones is thus ‘nucleophilic addition’. tetrahedral alkoxide with sp 3 carbon. Nucleophilic Addition to Aldehydes and Ketones

13 12 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. In carboxylic acid derivates, one of the groups that was bonded to the carbonyl C is a leaving group. When this group leaves, the sp 3 tetrahedral alkoxide reverts back to an sp 2 C=O group. Thus substitution occurs instead of addition. In many cases, the substitution product contains a carbonyl that can react again. Chlorine is a fair leaving group. sp 2 carbonyl reforms sp 2 carbonyl C alkoxide C js sp 3 Note that because the C=O group reforms, the nucleophile can react a second time.

14 13 In carboxylic acid derivatives, the acyl group (RCO) is bonded to a leaving group (-Y). Nucleophilic Acyl Substitution in Acid Derivatives acyl group 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 derivativeleaving grouppKbstrength as base non basic weak base strong base v. strong base Draw the mechanism.

15 14 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. Nucleophilic Acyl Substitution in Acid Derivatives 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) hydrolysis alcoholysis aminolysis Grignard reduction hydride reduction

16 15 Nucleophilic acyl substitution converts carboxylic acids into carboxylic acid derivatives, i.e., acid chlorides, anhydrides, esters and amides. Nucleophilic Acyl Substitution of Carboxylic Acids acid chloride acid anhydride ester amide SOCl 2  -H 2 O ROH H + NH 3, , -H 2 O

17 16 Conversion of Carboxylic Acids to Acid Halides The S atom in SOCl 2 is a very strong electrophile. S is electron deficient because it is bonded to 3 electronegative atoms (Cl and O). Cl is a leaving group. The hydroxyl O atom in a carboxylic acid has non bonded pairs of electrons, making it a nucleophile. This O atom bonds with S (replacing a Cl) and forming a chlorosulfite intermediate. The chlorosulfite group is a very good leaving group. It is easily displaced by a Cl - ion via an S N 2 mechanism yielding an acid chloride. Use curved arrows to draw the initial steps of the mechanism shown below. PBr3 will substitute Br for OH converting a carboxylic acid to an acid bromide Draw and name the products of the following reactions. I: p-methylbenzenecarbonyl chloride c: p-methylbenzoyl chloride I: ethanoyl chloride c: acetyl chloride

18 17 Conversion of Carboxylic Acids to Acid Anhydrides High temperature dehydration of carboxylic acids results in two molecules of the acid combining and eliminating one molecule of water. acetic anhydride ethanoic anhydride ethanoic acid Cyclic anhydrides with 5 or 6-membered rings are prepared by dehydration of diacids. I: butanedioic acid c: succinic acid I: butanedioic anhydride c: succinic anhydride Draw a reaction showing the preparation of cyclohexanecarboxylic anhydride.

19 18 Conversion of Carboxylic Acids to Esters Two methods are used: SN2 reaction of a carboxylate and Fischer Esterification 1.S N 2 reaction of a carboxylate with a methyl halide or 1  alkyl halide is straightforward. 2  and 3  alkyl halides are not used because carboxylate is only a fair nucleophile and is basic enough (pKb = 9) that elimination of HX from the alkyl halide will compete with substitution. The carboxylate will be protonated and the alkyl halide eliminates HX becoming an alkene. E2 isobutylene I: 5-hydroxypentanoic acid lactone c:  -valerolactone I: 5-bromopentanoic acid c:  -bromovaleric acid sodium propionoate I: sodium 5-bromopentanoate c: sodium  -bromovalerate

20 19 S N 1, E1 SN2SN2 E2E2 SN2SN2 SN2SN2 SN1SN1 SN2SN2 SN2SN2 E2E2 E2E2 SN2SN2 E2 (S N 2) E2E2 no reaction S N 1, E1 4.7 v. gd. moderate SN2SN2 SN2SN2 SN2SN2 E2E2 6.0 / 7.0 moderate v. gd. SN2SN2 SN2SN2 E2E2 SN2SN2 9 weak fair SN2SN2 SN2SN2 E2E2 E2E2 SN2SN2 SN2SN2 SN1SN1 SN1SN1 Conversion of Carboxylic Acids to Esters

21 20 2.Fischer Esterification: (RCOOH  RCOOR) Esters are produced from carboxylic acids by nucleophilic acyl substitution by a methyl or 1º alcohol. Heating the acid and alcohol in the presence of a small quantity of acid catalyst (H 2 SO 4 or HCl (g)) causes ester formation (esterification) along with dehydration. The equilibrium constant is not large (Keq ~ 1) but high yields can be obtained by adding a large excess of one of the reactants and removing the H 2 O formed. The reaction is reversible. A large excess of H 2 O favors the reverse reaction. Bulky (sterically hindered) reagents reduce yields. Since alcohols are weak nucleophiles, acid catalyst is used to protonate the carbonyl oxygen which makes the carbonyl C a better electrophile for nucleophilic attack by ROH. Proton transfer from the alcohol to the hydroxyl creates a better leaving group (HOH). Learn the mechanism since it is common to other reactions. Conversion of Carboxylic Acids to Esters The net effect of Fischer esterification is substitution of the –OH group of a carboxylic acid with the –OR group of a methyl or 1° alcohol.

22 21 I: propanedioic acid c: malonic acid I: diethyl propanedioate c: diethyl malonate Conversion of Carboxylic Acids to Esters Draw and name the products of the following reactions. cyclopentylmethyl benzoate Draw the reagents that will react to produce the following ester. Why will an S N 2 reaction of a carboxylate and an alkyl halide not work here? I: isopropyl 2-methylpropanoate c: isopropyl isobutyrate Isopropyl bromide is a 2° alkyl halide and would undergo an E2 rather than S N 2 reaction. Draw the complete mechanism for Fischer esterification of benzoic acid with methanol.

23 22 Conversion of Carboxylic Acids to Amides Amides are difficult to prepare by direct reaction of carboxylic acids with amines (RNH 2 ) because amines are bases that convert carboxylic acids to non electrophilic carboxylate anions and themselves are protonated to non nucleophilic amine cations, (RNH 3 + ) High temperatures are required to dehydrate these quaternary amine salts and form amides. This is a useful industrial method but poor laboratory method. In the lab amides are often prepared from acid chloride after converting the carboxylic acid to the acid chloride. Explain why methylamine is a Bronsted base. Explain why methylamine is a Lewis base. Explain why methylamine is not an Arrhenius base Proton (H + ) acceptor Electron pair donor Has no OH - group

24 23 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.

25 24 Chemistry of Acid Halides In the same way that acid chlorides are produced by reacting a carboxylic acid with thionyl chloride (SOCl 2 ), acid bromides are produced by reacting a carboxylic acid with phosphorus tribromide (PBr 3 ). Reactions of Acid Halides: Acid halides are among the most reactive of the carboxylic acid derivatives and are readily converted to other compounds. Recall that acid chlorides add to aromatic rings via electrophilic aromatic substitution (EAS) reactions called Friedel-Crafts Acylation with the aid of Friedel-Crafts catalysts.

26 25 Chemistry of Acid Halides Draw a reaction showing how propylbenzene can be produced by a Friedel Crafts acylation reaction. I: 1-phenyl-1-propanone c: ethyl phenyl ketone 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, -NH 2 to produce an amide. Hydride reduction produces a 1  alcohol, and Grignard reaction produces a 3  alcohol.

27 26 Hydrolysis: Conversion of Acid Halides into Acids Acid chlorides react via nucleophilic attack by H 2 O producing carboxylic acids and HCl. Tertiary amines, such as pyridine, are sometimes used to scavenge the HCl byproduct and drive the reaction forward. 3º amines will not compete with water as a nucleophile because their reaction with acid halide stops at the intermediate stage (there is no leaving group). Eventually, water will displace the amine from the tetrahedral intermediate, regenerating the 3º amine and forming the carboxylic acid. Draw the mechanism of the reaction of cyclopentanecarbonyl chloride with water.

28 27 Alcoholysis: Conversion of Acid Halides into Esters Acid chlorides react with alcohols producing esters and byproduct HCl by the same mechanism as hydrolysis above. Draw and name the products of the following reaction. Once again, 3º amines such as pyridine may be used to scavenge the HCl byproduct or for water insoluble acid halides, aqueous NaOH can be used to scavenge HCl since it will not enter the organic layer and attack the electrophile (thus it cannot compete with the alcohol as the nucleophile). I: ethanoyl chloride c: acetyl chloride I: isopropyl ethanoate c: isopropyl acetate Draw the mechanism of the reaction of benzoyl chloride and ethanol.

29 28 Practice on Synthesis of Esters Write equations showing all the ways that benzyl benzoate can be produced. Consider Fischer esterification, S N 2 reaction of a carboxylate with an alkyl halide, and alcoholysis of an acid chloride. Answer the same question as above but for t-butyl butanoate This is the only method that will work. Explain why the other methods will fail.

30 29 Aminolysis: Conversion of Acid Halides into Amides Acid chlorides react rapidly with ammonia or 1  or 2  but not 3  amines producing amides. Since HCl is formed during the reaction, 2 equivalents of the amine are used. 1 equivalent is used for formation of the amide and a second equivalent to react with the liberated HCl, forming an ammonium chloride salt. Alternately, the second equivalent of amine can be replaced by a 3º amine or an inexpensive base such as NaOH (provided it is not soluble in the organic layer). Using NaOH in an aminolysis reaction is referred to as the Schotten-Baumann reaction. I: N,N-dimethylbenzenecarboxamide c: N,N-dimethylbenzamide Write equations showing how the following products can be made from an acid chloride. N-methylacetamide propanamide

31 30 Reduction of Acid Chlorides to Alcohols with Hydride Acid chlorides are reduced by LiAlH 4 to produce 1  alcohols. The alcohols can of course be produced by reduction of the carboxylic acid directly. The mechanism is typical nucleophilic acyl substitution in which a hydride (H: - ) attacks the carbonyl C, yielding a tetrahedral intermediate, which expels Cl -. The result is substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by LiAlH 4 in a second step to yield a 1  alcohol. Draw the reaction and name the product when 2,2-dimethylpropanoyl chloride is reduced with LiAlH 4 I: 2,2-dimethyl-1-propanol c: neopentyl alcohol

32 31 The aldehyde cannot be isolated if LiAlH 4 (and NaBH 4 ) are used. Both are too strongly nucleophilic. 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 (-78°C). Under these conditions, even nitro groups are not reduced. Reduction of Acid Chlorides to Aldehydes with Hydride  DIBAH is weaker than LiAlH 4. DIBAH is neutral; LiAlH 4 is ionic.  DIBAH is similar to AlH 3 but is hindered by its bulky isobutyl groups.  Only one mole of H: - is released per mole of DIBAH. p-nitrobenzaldehyde

33 32 Grignard reagents react with acid chlorides producing 3  alcohols in which 2 alkyl group substituents are the same. The mechanism is the same as with LiAlH 4 reduction. 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. Reduction of Acid Chlorides to Alcohols with Grignards The ketone intermediate can’t be isolated with Grignard reaction but can be with Gilman reagent (diorganocopper), R 2 CuLi. Only 1 equivalent of Gilman is used at -78°C to prevent reaction with the ketone product. Recall the preparation of ketones (Ch. 19). This reagent does not react other carbonyl compounds (although it does replace halogens in alkyl halides near 0  C) I: 3-methyl-2-butanone c: isopropyl methyl ketone I: 2-phenyl-2-propanol

34 33 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. Practice Questions for Acid Chloride Reductions I: 1,1-dicyclopentylethanol I: ethanoyl chloride I: 2,2-dimethyl-1-propanol I: 2,2-dimethylpropanoyl chloride I: cyclohexanecarbaldehyde I: cyclohexanecarbonyl chloride c: ethyl phenyl ketone I: 1-phenyl-1-propanone

35 34 Preparation of Acid Anhydrides: Dehydration of carboxylic acids as previously discussed is difficult and therefore limited to a few cases. acetic anhydride 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. Preparations of Acid Anhydrides Draw all sets of reactants that will produce the anhydride shown with an acid chloride.

36 35 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 LiAlH 4 to form 1  alcohols and with Grignards to form 3  alcohols. Note that ½ 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. Reactions of Acid Anhydrides Write the mechanism for the following reactions and name all products: aniline with acetic anhydride (2 moles aniline are needed or use 1 mole + aq. NaOH) cyclopentanol with acetic formic anhydride (the formic carbonyl is more reactive). methyl magnesium bromide with acetic propanoic anhydride (Grignards are not nucleophilic enough to react with carboxylate by products) lithium aluminum hydride with acetic formic anhydride (LiAlH 4 is so powerful a nucleophile that it will reduce even carboxylates).

37 36 Show the product of methanol reacting with phthalic anhydride Practice Questions for Acid Anhydrides 2-(methoxycarbonyl)benzoic acid Draw acetominophen; formed when p-hydroxyaniline reacts with acetic anhydride N-(4-hydroxyphenyl)acetamide

38 37 Esters are among the most widespread of all naturally occurring compounds. Most have pleasant odors and are responsible for the fragrance of fruits and flowers. Write chemical formulas for the following esters Chemistry of Esters FlavorName Structure pineapplemethyl butanoate bananasisopentyl acetate appleisopentyl pentanoate rumisobutyl propanoate oil of wintergreen methyl salicylate [methyl 2-hydroxybenzoate) nail polish removerethyl acetate new car smell (plasticizer for PVC) dibutyl phthalate

39 38 1.S N 2 reaction of a carboxylate anion with a methyl or 1  alkyl halide 2.Fischer esterification of a carboxylic acid + alcohol + acid catalyst 3.Acid chlorides react with alcohols in basic media Preparation of Esters

40 39 Esters react like acid halides and anhydrides but are less reactive toward nucleophiles because the carbonyl C is less electrophilic. Both acyclic esters and cyclic esters (lactones) react similarly. Esters are hydrolyzed by HOH to carboxylic acids, react with amines to amides, are reduced by hydrides to aldehydes, then to 1  alcohols, and react with Grignards to 3  alcohols. Reactions of Esters

41 40 Esters are hydrolyzed (broken down by water) to carboxylic acids or carboxylates by heating in acidic or basic media, respectively. Base-promoted ester hydrolysis is called saponification (Latin ‘soap-making’). Boiling animal fat (which contains ester groups) in an aqueous solution of a strong base (NaOH, KOH, etc.) makes soap. A soap is long hydrocarbon chain with an ionic end group. Base Hydrolysis of Esters The mechanism of base hydrolysis is nucleophilic acyl substitution in which OH - adds to the ester carbonyl group producing a tetrahedral intermediate. The carbonyl group reforms as the alkoxide ion leaves, yielding a carboxylate. c: potassium laurate liquid soap The leaving group, methoxide (OCH 3 - ), like all alkoxides, is a strong base (pKb = -2). It will deprotonate the carboxylic acid intermediate converting it to a carboxylate. The alkoxide, when neutralized, becomes an alcohol. c: sodium laurate I: sodium dodecanoate bar soap

42 41 Acidic hydrolysis of an ester yields a carboxylic acid (and an alcohol). The mechanism of acidic ester hydrolysis is the reverse of Fischer esterification. The ester is protonated by acid then attacked by the nucleophile HOH. Transfer of a proton and elimination of ROH yields the carboxylic acid. The reaction is not favorable. It requires at least 30 minutes of refluxing. Draw the complete mechanism of acid hydrolysis of methyl cyclopentanecarboxylate. Acid Hydrolysis of Esters Acid hydrolysis of an ester can be reversed by adding excess alcohol. The reverse reaction is called Fischer Esterification. Explain why base hydrolysis of an ester is not reversible.

43 42 Nucleophilic acyl substitution of an ester with an alcohol produces a different ester. The mechanism is the same as acid hydrolysis of esters except that that the nucleophile is an alcohol rather than water. A dry acid catalyst must be used, e.g., HCl(g) or H 2 SO 4. If water is present, it will compete with the alcohol as the nucleophile producing some carboxylic acid in place of the ester product. The process is also called Ester Exchange or Transesterification Alcoholysis of Esters dicyclobutyl terephthalate dicyclobutyl 1,4-benzenedicarboxylate diethyl terephthalate diethyl 1,4-benzenedicarboxylate cyclobutanol

44 43 Amines can react with esters via nucleophilic acyl substitution yielding amides but the reaction is difficult, requiring a long reflux period. Aminolysis of acid chlorides is preferred. Draw the mechanism aminolysis of methyl isobutyroxide with ammonia. Aminolysis of Esters c:  -methylpropionamide I: 2-methylpropanamide Write an equation showing how the following amide can be prepared from an ester. Note that the amide intermediate must deprotonate to form a stable, neutral amide. Thus the amine must have at least one H. NH 3, 1° and 2° amines will work but not 3°.

45 44 Esters are easily reduced with LiAlH 4 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. Hydride Reduction of Esters The hydride intermediate can be isolated if DIBAH is used as a reducing agent instead of LiAlH 4. 1 equivalent of DIBAH is used at very low temp. (-78  C). Draw and name the products. c:  -butyrolactone I : 4-hydroxybutanoic acid lactone c: none I : 1,4-butanediol c:  -valerolactone I : 4-hydroxypentanoic acid lactone I: 4-hydroxypentanal c:  -hydroxyvaleraldehyde

46 45 Esters and lactones 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. Grignard Reduction of Esters I: 4-hydroxybutanoic acid lactone methyl benzoate benzophenone triphenylmethanol triphenylmethoxide c:  -butyrolactone 4-methyl-1,4-pentanediol

47 46 What ester and Grignards will combine to produce the following Practice with Esters 2-phenyl-2-propanol 1,1-diphenylethanol

48 47 Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted and disubstituted amines (but not trisubstituted amines) all react. Chemistry of Amides Amides are much less reactive than acid chlorides, acid anhydrides, or esters. Amides undergo hydrolysis to yield a carboxylic acids plus an amine on heating in either aqueous acid or aqueous base. Basic hydrolysis occurs by nucleophilic addition of OH - to the amide carbonyl, followed by elimination of the amide ion, NH2 ‑,(a very reactive base – a difficult step requiring reflux) I: sodium cyclohexanecarboxamide

49 48 Acidic hydrolysis occurs by nucleophilic addition of HOH to the protonated amide, followed by loss of a neutral amine (after a proton transfer to nitrogen). Hydrolysis of Amides N-methylcyclohexanecarboxamide cyclohexanecarboxylic acid 5-aminopentanoic acid lactam  -valerolactam

50 49 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 H 2 SO 4 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. Alcoholysis of Amides (to Esters) N,N-dimethylcyclopentanecarboxamide sec-butyl cyclopentanecarboxylate Write a mechanism for this reaction. Refer to acid hydrolysis mechanism if necessary.

51 50 Amides are reduced by LiAlH 4. 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. It occurs only with amides and nitriles. Initial hydride attack on the amide carbonyl eliminates the oxygen. A second hydride ion is added to yield the amine. The reaction works with lactams as well as acyclic amides. Hydride Reduction of Amides Write equations showing how the above transformation can be carried out. N,N-dimethylcyclopentanecarboxamide benzoyl chloride N-methylbenzamide

52 51 Grignards deprotonate 1º and 2º 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. Grignard Reduction of Amides Write equations showing how the following transformation can be carried out.

53 52 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. Chemistry of Nitriles Preparation of Nitrile: 1.Nitriles are easily prepared by S N 2 reaction of cyanide ion (CN - ) with methyl halides or a 1  alkyl halide. 2º alkyl halides also work but some E2 product also forms. 3º alkyl halides will result in mostly an alkene (E2) product instead of a nitrile. (pKb of CN - = 4.7) propanenitrile bromoethane ethyl bromide 2.Another method of preparing nitriles is by dehydration of a 1  amide using any suitable dehydrating agent such as SOCl 2, POCl 3, P 2 O 5, or acetic anhydride. Initially, SOCl 2 reacts with the amide oxygen atom and elimination follows. This method is not limited by steric hindrance.

54 53 Like carbonyl groups, the nitrile group is strongly polarized and the nitrile C is electrophilic. Nucleophiles thus attack yielding an sp2 hybridized imine anion. Reactions of Nitriles Nitriles are hydrolyzed by HOH to amides and subsequently to carboxylic acids, reduced by hydrides to amines or aldehydes, and by Grignards to ketones.

55 54 Hydrolysis of Nitriles into Carboxylic Acids Nitriles are hydrolyzed in either acidic or basic aqueous solution to yield carboxylic acids plus ammonia or an amine. 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.

56 55 Hydrolysis of Nitriles into Carboxylate Salts 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. Show how the following transformation can be carried out without using a Grignard.

57 56 Reduction of Nitriles Alcoholysis of Nitriles doesn’t work. Alcohols are weak nucleophiles and nitriles are weak electrophiles Aminolysis of Nitriles doesn’t work. Amines are weak nucleophiles and nitriles are weak electrophiles. Reduction with Hydrides: Reduction of nitriles with 2 equivalents of LiAlH 4 gives 1  amines. LiAlH 4 is a very good nucleophile and can break 2  bonds forming a dianion. If less powerful DIBAH is used, only 1 equivalent of hydride can add. Subsequent addition of HOH yields the aldehyde. 2-methylbenzaldehyde

58 57 Reduction of Nitriles with Grignards 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 LiAlH 4 and so can only add once – a dianion is not formed. 1-phenyl-1-propanone ethyl phenyl ketone

59 58 Multistep Synthesis Problems Write equations to show how the following transformations can be carried out.

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