Synthesis of Carboxylic Acids

Transcription

1 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 1 Synthesis of Carboxylic Acids 1. From 1º Alcohols and Aldehydes: xidation (Section 112B and 1820) 2 Cr 4 2 Cr 4 1º Alcohol No mechanism required for the reaction 2. From Alkenes: xidative eavage: (Section 815A and 910) 2 KMn 4 1 acid 1 2 ketone No mechanism required for the reaction Where C=C begins, C= ends. But where an attached begins, an ends. C=C would give two acids; C=C 2 would give an acid and carbonic acid ( 2 C 3 ), etc.. 3. From Aromatics: xidation of Alkylbenzenes (Section 1714A) KMn 4 No mechanism required for the reduction While toluenes (methylbenzenes) oxidize especially well, other alkyl benzenes can also be oxidized in this way. 4. From 1,3Diesters: Via ydrolysis/decarboxylation: (Chapter 22) 1. Na 2. X 3, heat Mechanism: Deprotation/Alkylation covered previously. The hydrolysis of the esters to acids will be required (see reaction 8b)

2 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 2 5. From Grignard eagents: Via Carboxylation: (Section 208B) MgX 1. C 2 2. C 2 X Alkyl or Aryl alide Mg ether MgX Grignard eagent 1. C 2 2. Protonate Access: Alkyl or Aryl Acids Alkyl group can be 1º, 2º, or 3º Mechanism required. (From Grignard on.) 6. From Nitriles: ydrolysis (Section 208C) C N, 2 Mechanism not required. 7. From alides: Either via Formation and Carboxylation of Grignards (eaction 5) or via Formation and ydrolysis of Nitriles (eaction 6) X Alkyl or Aryl alide Mg ether MgX Grignard eagent 1. C 2 2. Protonate If X is 1º alkyl halide NaCN C N, 2 Formation/ydrolysis of Nitriles equires a 1º Alkyl alide to begin, since the formation of the nitrile proceeds via S N 2 eaction via the Grignard has no such limitation For 1º alkyl halides, the formation/hydrolysis of the nitrile is technically easier, since there is no need to handle airsensitive Grignard reagents

3 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 3 8. From Acid Chlorides, Anhydrides, Esters, or Amides: ydrolysis (Section 208C) a) Downhill hydrolysis: From acids or anhydrides with NEUTAL WATE alone mechanism required: additioneliminationdeprotonation 2 Chloride ("") 2 ' Anhydride ("A") ' b) Lateral hydrolysis: From esters with water and acid catalysis (ACID WATE) mechanism required: protonationadditiondeprotonation (to hemiacetal intermediate) followed by protonationeliminationdeprotonation (hemiacetal to acid) These reactions are under equilibrium control. With excess water, you go to the acid. With removal of water and/or excess alcohol, the equilibrium favors the ester 1 Ester ("E") 2, ', via 1 hemiacetal c) Basic hydrolysis using Na (BASIC WATE) (always downhill) followed by workup mechanism required: additioneliminationdeprotonation (to carboxylate intermediate) followed by protonation Since the reaction with Na is always downhill, all of these reactions work Chloride ("") ' Anhydride ("A") ' Ester ("E") 1. Na Na Na 2. ' ' via Carboxylate ("") via Carboxylate ("") via Carboxylate ("") N Amide ("N") 1. Na 2. N 2 via Carboxylate ("")

4 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 4 eactions of Carboxylic Acids 9. eaction as a proton Acid (Section 204, 205) Na (or other bases, including amines) X (proton acid) Na carboxylate salt (basic) Mechanism: equired (deprotonation) everse Mechanism: equired (protonation) Carboxylic acids are completely converted to carboxylate salts by base Carboxylate salts are completely neutralized back to carboxylic acids by strong acid The resonanance stabilization makes carboxylates much more stable than hydroxide or alkoxide anions, which is why the parents are carboxylic acids Carboxylic acids are more acidic than ammonium salts Patterns in acid strength: eflect stabilization/destabilization factors on the carboxylate o Electron donors destabilize the carboxylate anion, so make the parent acid less acidic o Electron withdrawers stabilize the carboxylate anion, so make the parent acid more acidic 10. Conversion to Acid Chlorides (Section 2011, 215) S 2 Na S 2 Mechanism: Not equired Easy (but smelly) reaction. Side products and S 2 are gases, so can just evaporate away leaving clean, useful product. So no workup is required, nice! Extremely useful because the acid chlorides are so reactive, and can be converted into esters, anhydrides, or amides. 11. Indirect Conversion to Anhydrides (Section 215) 1. S 2 2. 'C 2 ' mechanism required for acid chloride to anhydride conversion: additioneliminationdeprotonation Conversion of the acid chloride to the anhydride is a downhill reaction energetically. Conversion of the acid to the anhydride directly would be an uphill reaction

5 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Direct Conversion to Esters (Sections , 215) ', ' ' 2, mechanism required: protonationadditiondeprotonation (to hemiacetal intermediate) followed by protonationeliminationdeprotonation (hemiacetal to ester) These reactions are under equilibrium control. With excess water, you go to the acid. With removal of water and/or excess alcohol, the equilibrium favors the ester This is a lateral reaction, neither uphill nor downhill energetically This is the exact reverse of reaction 8b 13. Indirect Conversion to Esters via Acid Chlorides (Sections , 215) 1. S 2 2. ' ' mechanism required for acid chloride to ester conversion: additioneliminationdeprotonation Conversion of the acid chloride to the ester is a downhill reaction energetically. 14. Direct Conversion to Amides (Sections 2011, 2013, 215) N 2, heat N mechanism not required This is a downhill reaction energetically, but is complicated and retarded by acidbase reactions. Normally the indirect) conversion is more clean in the laboratory This reaction occurs routinely under biological conditions, in which enzymes catalyze the process rapidly even at mild biological temperatures. 15. Indirect Conversion to Amides (Sections 2011, 2013, 215) 1. S 2 2. N 2 N mechanism required for acid chloride to amide conversion: additioneliminationdeprotonation This reaction sequence works very well in the laboratory

6 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides eduction to Primary Alcohol (Sections 1011, 2014) 1. LiAl 4 2. mechanism not required 17. Alkylation to Form Ketones (Section 1819, 2015) acid 1. 2 Li 2. ketone acid 1. 2 Li 2. Li carboxylate anion Li Li tetrahedral dianion acid tetrahedral "hydrate" acid ketone mechanism not required

7 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Interconversions of Acids and Acid Derivatives (Section 215 and many others) Acid Chloride ("") Anhydride (A") ' S 2 S 2 Ester ("E") = Acid Ester Acid Amide ("N") N Carboxylate ("") AvEN ChloridesAnhydridesEsters (and Acids)AmidesCarboxylates Any downhill step can be done directly Any lateral step (acid to ester or viceversa) can be done with acid Any uphill sequence requires going up through the Acid Chloride, either directly (from an acid or a carboxylate) or indirectly (conversion to carboxylate; react with S 2 to get to the top; then go downhill from there.) Mechanism is required for any downhill conversion and is the same: protonationadditiondeprotonation (addition to produce the hemiacetal intermediate) followed by protonationeliminationdeprotonation (elimination)

8 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 8 Mechanisms A. Miscellaneous 5. From Grignard eagents: Via Carboxylation: C exactly like any Grignard reaction 9. eaction as a Proton Acid B. Any Downhill Interconversions (8a, 8c, 11, 13, 15, 18): All Proceed by Addition EliminationDeprotonation General Examples eaction 8a Y Z Z Z Add Y Elim Deprot Add Elim Deprot Y Y eaction 8c (Note: Slightly different because hydroxide nucleophile is anionic, not neutral; and product carboxylate is anionic, not neutral) Me Me Me Add Me Elim Deprot Z eaction 13 Me Add Me Elim Me Deprot Me eaction 15 MeN N N Add Elim Me Me Deprot NMe

9 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 9 C. Lateral Interconversions (8b/12): AcidCatalyzed conversion from Ester to Acid (8b) or From Acid to Ester (12): (ACID WATE) General Mechanism: protonationadditiondeprotonation (acidcatalyzed addition to a carbonyl to produce the tetrahedral hemiacetal intermediate) followed by protonationeliminationdeprotonation (acid catalyzed elimination) Examples eaction 8b: Ester to Acid 1 1 Add Ester Protonate 1 Deprotonate 1 hemiacetal Protonate Acid Deprotonate Eliminate 1 1 eaction 12: Acid to Ester Acid Protonate 1 Add 1 Deprotonate 1 hemiacetal Protonate 1 Ester Deprotonate 1 Eliminate 1 2 1

10 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 10 Nomenclature (20.2) Formal: alkanoic acid (space in between) highest priority of any functional group Formal Common Methanoic acid Formic acid Ethanoic acid Acetic acid 3 C Benzoic acid Benzoic acid N 2 Pentanoic acid (S)2aminobutanoic acid 1. Nomenclature. Provide names or structures for the following. a. 3phenylbutanoic acid b. 2,2dichloropropanoic acid c. 2hydroxy3propanoyl4ethoxy5amino6hydroxyheptanoic acid N 2 ysical Properties (Section 20.3) Boiling Points: (weight being equal): acid > alcohol > 1,2º amines > nonbonders Acids boil about 20º higher than sameweight alcohols First four acids are completely water soluble Water solubility (weight being equal): amines > acids? ketones, alcohols, ethers >> alkanes Basicity is more important than acidity 2. Circle the one with higher boiling point, and square the one with the greater solubility in water.

11 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 11 Acidity/Basicity Table 19.2: With both Neutral and Cationic Acids and both Neutral and Anionic Bases (Section 204) ass Structure Ka Acid Strength Base Base Strength Strong Acids, 2 S Most acidic, S Least basic Smell Awful! ydronium 3, cationic , neutral umans Carboxylic Acid 10 5 Cuz enol People Ammonium Ion (Charged) N N Against Charged, but only weakly acidic! Neutral, but basic Water Alcohol Working Are Ketones and Aldehydes! 10 20! Kingdoms Amine (N) (ipr) 2 N (ipr) 2 N Li Animal Alkane (C) C Least acidic C 2 Most basic Quick Checklist of Acid/Base Factors 1. Charge 2. Electronegativity 3. esonance/conjugation 4. ybridization 5. Impact of Electron Donors/Withdrawers 6. Amines/Ammoniums When comparing/ranking any two acids or bases, go through the above checklist to see which factors apply and might differentiate the two. When A neutral acid is involved, it s often best to draw the conjugate anionic bases, and to think from the anion stability side. All

12 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 12 Acidity (204) Anion is stabilized by conjugation/resonance Charge dispersal Carboxylate is an anion, so is stabilized by electron withdrawing groups (increasing acidity) and destabilized by electron donating groups (decreasing acidity) Carboxylic Acid 10 5 Ammonium Ion (Charged) N N Charged, but only weakly acidic! Neutral, but basic Alcohol Acids are a million times more acidic than average ammoniums (despite charge) Acids are trillions more acidic than alcohols Amino Acids: o Which way does the equilibrium lie? o Equilibrium always favors the weaker acid and weaker base? o What happens under acid conditions, and what happens under base conditions? N 3 Both are in acid form at acidic p acid stronger acid N Eq. favors 2 weaker acid stronger base and weaker base base N weaker base 3 weaker acid Both are in ionic form at neutral p base N 2 base Both are in base form under basic conditions 3. Carboxylic Acids as Acids. ank the acidity of the following groups, 1 being most acidic and 3 being least acidic. [emember: the best guideline for acidity is the stability of the anion!] a. acetic acid ethanol phenol Stability of conjugate anions b. propanoic acid C 3 N 3 (C 3 ) 3 N carb acids beat ammoniums. 2. Alkyl donors stabilize ammoniums and reduce their acidity

13 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 13 Substituent Effects (20.4B) Withdrawers stabilize anions, increase acidity Donors destabilize anions, reduce acidity pposite from the effect of donors and withdrawers on amines and ammoniums 4. Carboxylic Acids as Acids. ank the acidity of the following groups, 1 being most acidic and 3 being least acidic. [emember: the best guideline for acidity is the stability of the anion!] a. propanoc acid 3Chloropropanoic acid 2fluoropropanoic acid Electron withdrawing groups stabilize carboxylate anion. The stronger and closer, the better. b. benzoic acid pmethylbenzoic acid pnitrobenzoic acid Donor (methyl) destabilizes carboxylate. Withdrawer (nitro) stabilizes carboxylate. 5. For each of the following acid/base reactions, draw a circle around the weakest base, and draw an arrow to show whether the reaction would proceed from left to right, or from right to left. a. Na Alkyl donor Na destabilizes the anion on the right side b. Na Na esonance stabilizes right side Na Na esonance stabilizes anion on right side c. d. NaC 3 Na 2 C 3 K a =10 5 K a =10 7 The left acid is the stronger based on K a. Equilibria always go from stronger to weaker. And the conjugate base of the stronger acid is always the weaker, more stable base. The reason bicarbonate is a stronger, less stable base than the carboxylate shown is because the extra oxygen on bicarbonate is an electron donor, and thus destabilizes the anion.

14 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Carboxylate Salts C 2 Na C 2 Na 2 Produces weaker acid and base Easy to make Ionic water soluble Acids are soluble in Na/water or NaC 3 / 2 Weak bases, react with C 2 Named: sodium alkanoate Purification Schemes for Acids from other rganics Based on Acidity a. Dissolve acid and neutral organic in ether b. Treat with Na/water Neutral stays neutral, goes in ether layer Acid is deprotonated to C 2 Na, goes into water layer c. Concentrate ether layer pure neutral organic d. Add to aqueous layer, results in: C 2 Na C 2 e. Neutral C 2 now has low solubility in water, so can be harvested by filtration (if solid) or by organic extraction 6. Design a solubility flow chart to separate benzoic acid ("A") from acetophenone C()C 3 ("B"). Make sure that your plan enables you to isolate both A and B. A B neutral B ether layer concentrate (boil off ether) Dissolve A B in ether Add Na water layer A anion Add excess Soaps (20.6, 25.4) (not for test) C 2 Na with variable long alkyl chains Ex: C C 2 Na B A neutral, insoluble in water Ether filter to get A, if it's a solid. therwise add ether to extract it, then boil off the ether layer to isolate pure A. Carboxylate head: hydrophilic water soluble ydrocarbon tail: hydrophobic can dissolve grease and organic materials Form micelles in water The hydrophobic hydrocarbon tails (strings) selfaggregate, while the ionic heads (circles) keep the microdroplet soluble in water. rganic materials can be dissolved inside the organic center, and carried through the water. Thus grease gets dissolved, and dirt protected by grease is freed. water water organic water water

15 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 15 B. Synthesis of Carboxylic Acids Synthesis of Carboxylic Acids eview (20.8) 1. From 1º Alcohols and Aldehydes: xidation (Section 112B and 1820) 1º Alcohol 2 Cr 4 2 Cr 4 No mechanism required for the reaction 2. From Alkenes: xidative eavage: (Section 815A and 910) 2 KMn 4 1 acid 1 2 ketone No mechanism required for the reaction Where C=C begins, C= ends. But where an attached begins, an ends. C=C would give two acids; C=C 2 would give an acid and carbonic acid ( 2 C 3 ), etc.. 3. From Aromatics: xidation of Alkylbenzenes (Section 1714A) KMn 4 No mechanism required for the reduction While toluenes (methylbenzenes) oxidize especially well, other alkyl benzenes can also be oxidized in this way. 4. From 1,3Diesters: Via ydrolysis/decarboxylation: (Chapter 22) 1. Na 2. X 3, heat Mechanism: Deprotation/Alkylation covered previously. The hydrolysis of the esters to acids will be required (see reaction 8b)

16 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 16 New outes 5. From Grignard eagents: Via Carboxylation: (Section 208B) MgX 1. C 2 2. C 2 X Alkyl or Aryl alide Mg ether MgX Grignard eagent 1. C 2 2. Protonate Access: Alkyl or Aryl Acids Alkyl group can be 1º, 2º, or 3º Mechanism required. (From Grignard on.) 6. From Nitriles: ydrolysis (Section 208C), 2 C N Mechanism not required. 7. From alides: Either via Formation and Carboxylation of Grignards (eaction 5) or via Formation and ydrolysis of Nitriles (eaction 6) X Alkyl or Aryl alide Mg ether MgX Grignard eagent 1. C 2 2. Protonate If X is 1º alkyl halide NaCN C N, 2 Formation/ydrolysis of Nitriles equires a 1º Alkyl alide to begin, since the formation of the nitrile proceeds via S N 2 eaction via the Grignard has no such limitation For 1º alkyl halides, the formation/hydrolysis of the nitrile is technically easier, since there is no need to handle airsensitive Grignard reagents

17 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 17 Problems 1. Preparation of Carboxylic Acids. Fill in the blanks for the following reactions. 2 Cr 4 a. (C 3 8 ) Bromobenzene 1. Mg 2. epoxide; Cr 4 b. 1. KMn 4 /Na/heat 2. c. ( carbonic acid) Benzene Br 2 FeBr 3 1. C 2 Br Mg MgBr 2. C 2 d PBr 3 NaCN CN 3 e. Br 1. NaCN 2. 3 f.

18 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides From Acid Chlorides, Anhydrides, Esters, or Amides: ydrolysis (Section 208C) a) Downhill hydrolysis: From acids or anhydrides with NEUTAL WATE alone mechanism required: additioneliminationdeprotonation 2 Chloride ("") 2 ' Anhydride ("A") ' b) Lateral hydrolysis: From esters with water and acid catalysis (ACID WATE) mechanism required: protonationadditiondeprotonation (to hemiacetal intermediate) followed by protonationeliminationdeprotonation (hemiacetal to acid) These reactions are under equilibrium control. With excess water, you go to the acid. With removal of water and/or excess alcohol, the equilibrium favors the ester 1 Ester ("E") 2, ', via 1 hemiacetal c) Basic hydrolysis using Na (BASIC WATE) (always downhill) followed by workup mechanism required: additioneliminationdeprotonation (to carboxylate intermediate) followed by protonation Since the reaction with Na is always downhill, all of these reactions work Chloride ("") ' Anhydride ("A") ' Ester ("E") 1. Na Na Na 2. ' ' via Carboxylate ("") via Carboxylate ("") via Carboxylate ("") N Amide ("N") 1. Na 2. N 2 via Carboxylate ("")

19 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 19 Interconversions and eactivity of Acids and Acid Derivatives (Section 215 and others) Acid Chloride ("") Anhydride (A") ' 2 S 2 2 S 2 Ester ("E") = Acid 2, Ester Acid Amide ("N") N Carboxylate ("") AvEN ChloridesAnhydridesEsters (and Acids)AmidesCarboxylates Any downhill step can be done directly Any lateral step (acid to ester or viceversa) can be done with acid Any uphill sequence requires protonation or going up through the Acid Chloride, either directly (from an acid or a carboxylate) or indirectly (conversion to carboxylate; react with S 2 to get to the top; then go downhill from there.) Mechanism is required for any downhill conversion and is the same: protonationadditiondeprotonation (addition to produce the hemiacetal intermediate) followed by protonationeliminationdeprotonation (elimination) AvEN applied to ydrolysis 1. Chlorides and Anhydrides are above acids, so can be converted to acids by direct hydrolysis with neutral water 2. Esters are lateral to acids, so can be hydrolyzed to acids by acidcatalyzed hydrolysis 3. Chloride, anhydrides, esters, and amides can all be basehydrolyzed (Na/water) to carboxylates. Subsequent acid workup protonates the carboxylate and produces the acid Base hydrolysis always works 4. For amides, basic hydrolysis is the only way to do it

20 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides For the following problems, draw the starting materials that would give the indicated hydrolysis products. All of these are drawn as basic hydrolyses, but some could also be done using neutral water or acidic water. Mark which could proceed using neutral hydrolysis or acidcatalyzed hydrolysis in addition to via basic hydrolysis. Me NMe 1. Na, Na, Me MeN 2 N 2 1. Na, N 3 1. Na, Na, Mechanism: General Mechanism for Any Downhill AvEN Interconversions (8a, 8c, 11, 13, 15, 18): All Proceed by AdditionEliminationDeprotonation General Y Z Z Z Add Y Elim Deprot Y Y Base Case, Using Anionic ydroxide: Slightly different because hydroxide nucleophile is anionic, not neutral; and product carboxylate is anionic, not neutral) Me Me Me Add Me Elim Deprot Z

21 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 21 AcidCatalyzed conversion from Ester to Acid (8b): (ACID WATE) General Mechanism: protonationadditiondeprotonation (acidcatalyzed addition to a carbonyl to produce the tetrahedral hemiacetal intermediate) followed by protonationeliminationdeprotonation (acid catalyzed elimination) 1 1 Add Ester Protonate 1 Deprotonate 1 hemiacetal Protonate Acid Deprotonate Eliminate 1 1 Draw the Mechanisms for the following ydrolyses Me 18 Me 18 workup Me 18 Me 18 The 18 label ends up in the product alcohol. 2 Add Elim Deprot

22 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 22 C. eactions of Carboxylic Acids 20.9, 21.5 Interconversions with Derivatives: AvEN Acid Chloride ("") Anhydride (A") ' S 2 S 2 Ester ("E") = Acid Ester Acid Amide ("N") N Carboxylate ("") AvEN ChloridesAnhydridesEsters (and Acids)AmidesCarboxylates All can be interconverted by substitution procedures: 1, 2, or 3 steps Any downhill step can be done directly Any lateral step (acid to ester or viceversa) can be done with acid Any uphill sequence requires going up through the Acid Chloride, either directly (from an acid or a carboxylate) or indirectly (conversion to carboxylate; react with S 2 to get to the top; then go downhill from there.) Mechanism is required for any downhill conversion and is the same: protonationadditiondeprotonation (addition to produce the hemiacetal intermediate) followed by protonationeliminationdeprotonation (elimination)

23 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 23 Acid Chlorides: Preparation and Uses (Sections and 21.5) 10. Conversion of acids or Carboxylates to Acid Chlorides (Section 2011, 215) S 2 Na S 2 Mechanism: Not equired Easy (but smelly) reaction. o Side products and S 2 are gases, so can just evaporate away leaving clean, useful product. So no workup is required, nice! Extremely useful because the acid chlorides are so reactive, and can be converted into esters, anhydrides, or amides. 11. Indirect Conversion to Anhydrides (Section 215) 1. S 2 2. 'C 2 ' mechanism required for acid chloride to anhydride conversion: additioneliminationdeprotonation Conversion of the acid chloride to the anhydride is a downhill reaction energetically. Conversion of the acid to the anhydride directly would be an uphill reaction Base often present to absorb the 13. Indirect Conversion to Esters via Acid Chlorides (Sections , 215) 1. S 2 2. ' ' mechanism required for acid chloride to ester conversion: additioneliminationdeprotonation Conversion of the acid chloride to the ester is a downhill reaction energetically. Base often present to absorb the 15. Indirect Conversion to Amides (Sections 2011, 2013, 215) 1. S 2 2. N 2 N mechanism required for acid chloride to amide conversion: additioneliminationdeprotonation This reaction sequence works very well in the laboratory Base often present to absorb the

24 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 24 Condensation/ydrolysis: Interconversions between Acids and Esters (20.10, 13, 21.7) 12. Direct Conversion to Esters (Sections , 215) ', ' ' 2, mechanism required: protonationadditiondeprotonation (to hemiacetal intermediate) followed by protonationeliminationdeprotonation (hemiacetal to ester) These reactions are under equilibrium control. 1. With excess water, you go to the acid. 2. With removal of water and/or excess alcohol, the equilibrium favors the ester This is a lateral reaction, neither uphill nor downhill energetically This is the exact reverse of reaction 8b Under base conditions, the equilibrium always goes completely away from the ester and goes to the acid side 1. The base deprotonates the carboxylic acid, so LeChatellier s principle says that the equilibrium keeps driving from ester towards acid to compensate 3. Draw the mechanism for the following reaction. Me, ase 1: addition Acid Me Tetrahedral intermediate Protonate 1 Add ase 2: elimination Me ( 2 ) Me Deprotonate Me hemiacetal Me Ester Deprotonate 14. Direct Conversion to Amides (Sections 2011, 2013, 215) N 2, heat N Me Eliminate 1 Protonate Me 2 mechanism not required This is a downhill reaction energetically, but is complicated and retarded by acidbase reactions. Normally the indirect) conversion is more clean in the laboratory This reaction occurs routinely under biological conditions, in which enzymes catalyze the process rapidly even at mild biological temperatures.

25 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides 25 Problems 4. Synthesis of Acid derivatives. Draw the products for the following reactions. a. S 2 b. 1. S butanol c. ethanol, d. 1. S 2 2. cyclopentanol e. 1. S butanol f. g. 1. S 2 2. diethylamine N h. 1. S 2 2. N 3 N 2 i. 1. S butanamine N j. diethylamine, heat NEt 2

26 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Draw the mechanism. b. N 3 b. N 2 N 3 N 2 N 2 6. Draw the products for the following reactions. a. 1. LiAl N 2 b. 1. MeLi (excess) 2. 3 C 3 Ch. 21 Carboxylic Acid Derivatives: X o chloride o A anhydride o E ester o N amide o : carboxylate 21.1,2 Structure, Names, Notes all are subject to hydrolysis All hydrolyze to acids (actually, to carboxylate anion) upon treatment with Na/ 2 Some ( and A) hydrolyze to acids under straight water treatment Esters hydrolyze to acids under acid catalysis ' ' N " General Alkanoyl chloride Alkanoic Anhydride Alkyl Alkanoate Alkanamide Example Butanoyl chloride Propanoic anhydride N Ethyl Benzoate Nisopropyl pentanamide igh reactivity Named as if ionic Named as if ionic

27 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Draw the structures for the following esters. a. propyl benzoate b. methyl ethanoate c. ethyl butanoate 21.5 Interconversion of Acid Derivatives: AvEN Acid Chloride ("") Anhydride (A") ' S 2 S 2 Ester ("E") = Acid Ester Acid Amide ("N") N Carboxylate ("") AvEN ChloridesAnhydridesEsters (and Acids)AmidesCarboxylates All can be interconverted by substitution procedures: 1, 2, or 3 steps Any downhill step can be done directly Any lateral step (acid to ester or viceversa) can be done with acid Any uphill sequence requires going up through the Acid Chloride, either directly (from an acid or a carboxylate) or indirectly (conversion to carboxylate; react with S 2 to get to the top; then go downhill from there.) Mechanism is required for any downhill conversion and is the same: protonationadditiondeprotonation (addition to produce the hemiacetal intermediate) followed by protonationeliminationdeprotonation (elimination)

28 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides ank the acidity of the following molecules, 1 being most acidic and 4 being least acidic. C 3 N 2 C ank the reactivity of the following toward hydrolysis. Do you see a similarity between your rankings for this question relative to your answers for question 8? C 3 NC The patterns are the same, because both reflect the stability of the anion. Acidity depends on the product anion; the reactivity in problem 14 also reflects the anion stability of the leaving group. > > C 3 > NC 3 Notes: Any downhill reaction can be done in one laboratory step Any downhill reaction involves a 3step mechanism: additioneliminationdeprotonation Y Add Z r 1 Elim r 1 Y Z Y Z Y Elim Deprot r 2 The overall reactivity correlates the leaving ability of the Y for two reasons 1. This affects the kinetic r 2 /r 1 partion. If r 2 is slow, the addition is simply reversible 2. The same factors that make Y a good leaving group also make the initial carbonyl more reactive toward addition (step 1, r 1 ). 3. Thus good leaving groups have benefits at both r 1 and r 2 Memory o Think anion stability o iff AvEN B. Uphill eaction Sequences: 3steps Z 1. Na, 2 Ex: Y 1. Na, 2 2. S 2 3. Z Z 1. Na, 2 N 2 2. S 2 C 3 3. C 3 S 2 C 3 Na C 3 2. S 2 3. S 2 NEt 3 N 3 C 3

29 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Which will proceed easily/directly? ( downhill?) Add Appropriate eactant(s) and Side Product. If it doesn t go directly, give indirect route. a. b. c. d. e. f. g. h. N 3 Downhill, yes. N 2 N Downhill, yes. A E 2 Downhill, yes. E C No, Uphill 3 C 3 E 1. Na Indirect route, via hydrolysis then S 2 C 3 2. E 3. S 2 E NMe 2 Yes, downhill C 3 NMe C 3 2 E N Na C 3 Na E C 3 Yes, downhill Na NMe 2 N Na NMe 2 Yes, downhill Me NMe N 2 Me E NMe 2 No, uphill i. E N NMe 2 1. Na S 2 4. Me Me A 1. Na E C 3 2. E 3. S 2 4. E E Me Indirect route, via hydrolysis then S 2 Note: direct catalyzed conversion from acid to ester also fine. Me No, uphill A Indirect route, via hydrolysis then S 2

30 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Draw the products for the following reactions. a. S 2 b. 1. S2 2. Acetic acid, pyridine c. Me N 2 N d. NMe 1. Na, 2; 2. S2 3. Me, pyridine Me e. ethanol, pyridine C 2 C 3 f. CN Me, Me 12. Draw the mechanism for the following reaction. C 2 C 3 (3 steps)

31 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Provide reagents for the following transformations. C 3, a. 1. S 2 2. C 3 b. Me Me (Method 1) (Method 2) c. 1. S 2 2. N 3 N 2 (Method 1) d. N 3, heat (E to N, downhill) N 2 (Method 2) N 3 (E to N, downhill...) e. Me N 2 1. Na 2. f. N 2 3. S 2 4. C 3 Me Me 1. Na S 2 4. g. h. C Cr 4 2. S 2 3. C 3 or 1. 2 Cr 4 2., C 3 Me

32 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Provide products for the following condensation or hydrolysis transformations. Me a. Me N 2 heat N b. c. 2 d. N 1. Na 2. 2 N e. 1. Na 2. f. g. Me 1. Na 2. Me

33 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Cyclic Esters and Amides: Provide products or starting reactants for the following condensation or hydrolysis reactions involving cyclic esters or amides. a. b. 1. Na 2. 3 c. N 1. Na 2. 3 N d. N 2 Me eat N Me 16. ank the following as acids or bases. a. F C 3 N 3 N (C 3 ) 2 N 2 N 3 b c. Et 3 N EtN 2 N MgBr

34 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Provide reagents for the following transformations. There may be more than one solution. 1. PCC 2., NaB 3 CN, N a. 2 N b N 2. LiAl 4 N 1. or, NaB 3 CN, c. N 2 2. LiAl 4 N 2 N, NaB 3 CN, N d. 1. PBr 3 e. N 2. N 2 3 (excess) 1. PBr 3 f. 2. KCN 3. LiAl 4 N 2

35 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Provide reagents for the following transformations. There may be more than one solution. 1. Na or 2, a. C 3 2. b. C 3 N(C 3 ) 2 (downhill, E to N) N(C 3 ) 2 1. Na 2. C 3 3. S 2 4. c Cr 4 d. 2. S 2 e. 1. PBr 3 2. KCN 3., 2 f. KMn 4

36 Chem 360 Jasperse Ch. 20, 21 Notes Answers. Carboxylic Acids, Esters, Amides Provide mechanism for the following reactions. C 3 C 3 Add Ester Protonate C 3 Deprotonate C 3 hemiacetal Protonate a. Acid Deprotonate Eliminate C 3 C 3 1. Na, 2 2. b. c. Add Elim Deprot 3 C N2 3 C Br S N 2 3 C N 3 C Deprotonate 3 C NC3 S N 2 3 C Br d. 3 C N C 3 3 C C 3 Br S N 2 C 3 3 C N(C3 ) 2 Deprotonate 3 C N 3 C C 3