Synthesis of Carboxylic Acids
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 1
Synthesis of Carboxylic Acids
1. From 1º Alcohols and Aldehydes: Oxidation (Section 11-2B and 18-20) O O H CrO H CrO R OH 2 4 2 4 R OH R H 1º Alcohol
• No mechanism required for the reaction
2. From Alkenes: Oxidative Cleavage: (Section 8-15A and 9-10) H O O R KMnO4 + R 2 R OH R1 R2 R 1 acid ketone
• No mechanism required for the reaction • Where C=C begins, C=O ends. But where an attached H begins, an OH ends. • RCH=CHR would give two acids; RCH=CH2 would give an acid and carbonic acid (H2CO3), etc..
3. From Aromatics: Oxidation of Alkylbenzenes (Section 17-14A)
O
KMnO4 OH
• No mechanism required for the reduction • While toluenes (methylbenzenes) oxidize especially well, other alkyl benzenes can also be oxidized in this way.
4. From 1,3-Diesters: Via Hydrolysis/Decarboxylation: (Chapter 22)
O O O O O O O 1. NaOR H O+, heat 3 R RO OR HO OH HO RO OR 2. R-X R R
• Mechanism: Deprotation/Alkylation covered previously. The hydrolysis of the esters to acids will be required (see reaction 8b) Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 2
5. From Grignard Reagents: Via Carboxylation: (Section 20-8B)
1. CO2 R-MgX R-CO2H + 2. H
Mg 1. CO O X MgX 2 O Protonate R R ether + R O-- R OH Alkyl or Grignard 2. H Aryl Halide Reagent
• Access: Alkyl or Aryl Acids • Alkyl group can be 1º, 2º, or 3º • Mechanism required. (From Grignard on.)
6. From Nitriles: Hydrolysis (Section 20-8C) + O H , H2O R C N R OH
• Mechanism not required.
7. From Halides: Either via Formation and Carboxylation of Grignards (Reaction 5) or via Formation and Hydrolysis of Nitriles (Reaction 6)
Mg 1. CO X MgX 2 O Protonate O R R ether + R O-- Alkyl or Grignard 2. H R OH Aryl Halide Reagent
NaCN If R-X is 1º alkyl + O H , H2O halide R C N R OH
• Formation/Hydrolysis of Nitriles Requires a 1º Alkyl Halide to begin, since the formation of the nitrile proceeds via SN2 • Reaction 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 air-sensitive Grignard reagents Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 3
8. From Acid Chlorides, Anhydrides, Esters, or Amides: Hydrolysis (Section 20-8C) a) “Downhill” hydrolysis: From acids or anhydrides with NEUTRAL WATER alone • mechanism required: addition-elimination-deprotonation
O O H2O R Cl R OH + H-Cl Chloride ("Cl")
O O H2O O O + R O R' R OH HO R' Anhydride ("A")
b) “Lateral” hydrolysis: From esters with water and acid catalysis (ACID WATER) • mechanism required: protonation-addition-deprotonation (to hemiacetal intermediate) followed by protonation-elimination-deprotonation (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
O + H2O, H O OH + R'OH R OR1 via hemiacetal ROH, H+ R OH R OH Ester ("E") OR1
c) “Basic” hydrolysis using NaOH (BASIC WATER) (always downhill) followed by H+ workup • mechanism required: addition-elimination-deprotonation (to carboxylate intermediate) followed by protonation • Since the reaction with NaOH is always downhill, all of these reactions work
O 1. NaOH O O R Cl + H-Cl via + R OH R O-- Chloride ("Cl") 2. H Carboxylate ("O") O O 1. NaOH O O O + via -- R O R' R OH HO R' R O 2. H+ Anhydride ("A") Carboxylate ("O") O 1. NaOH O O + R'OH via - R OR' R O- + R OH Ester ("E") 2. H Carboxylate ("O") O 1. NaOH O O R NHR + RNH2 via -- + R OH R O Amide ("N") 2. H Carboxylate ("O") Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 4
Reactions of Carboxylic Acids
9. Reaction as a proton Acid (Section 20-4, 20-5)
O NaOH (or other bases, including amines) O - + R OH R O- Na H-X (proton acid) carboxylate salt (basic)
• Mechanism: Required (deprotonation) • Reverse Mechanism: Required (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: Reflect 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 20-11, 21-5)
O O SOCl O O 2 SOCl2 R OH R Cl R ONa R Cl
• Mechanism: Not Required • Easy (but smelly) reaction. Side products HCl and SO2 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 21-5)
O O 1. SOCl2 O O R OH R Cl R O R' 2. R'CO2H
• mechanism required for acid chloride to anhydride conversion: addition- elimination-deprotonation • 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
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 5
12. Direct Conversion to Esters (Sections 20-10-12, 21-5)
O OH O R'OH, H+ R OH + R OH R OR' H2O, H OR'
• mechanism required: protonation-addition-deprotonation (to hemiacetal intermediate) followed by protonation-elimination-deprotonation (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 20-10-12, 21-5)
O O O 1. SOCl2 R OH R Cl R OR' 2. R'OH
• mechanism required for acid chloride to ester conversion: addition-elimination- deprotonation • Conversion of the acid chloride to the ester is a “downhill” reaction energetically.
14. Direct Conversion to Amides (Sections 20-11, 20-13, 21-5)
O O RNH2, heat R OH R NHR
• mechanism not required • This is a “downhill” reaction energetically, but is complicated and retarded by acid-base 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 20-11, 20-13, 21-5)
O O O 1. SOCl2 R OH R Cl R NHR 2. RNH2
• mechanism required for acid chloride to amide conversion: addition- elimination-deprotonation • This reaction sequence works very well in the laboratory Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 6
16. Reduction to Primary Alcohol (Sections 10-11, 20-14)
O 1. LiAlH4 OH R OH R 2. H+
• mechanism not required
17. Alkylation to Form Ketones (Section 18-19, 20-15)
O 1. 2 RLi O
Ph OH Ph R 2. H+ acid ketone
O O 1. 2 RLi O LiO OLi acid HO OH acid Ph OH Ph R Ph R Ph R + Ph OLi acid 2. H ketone tetrahedral tetrahedral carboxylate "hydrate" anion dianion
• mechanism not required
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 7
18. Interconversions of Acids and Acid Derivatives (Section 21-5 and many others)
O Acid Chloride ("Cl") R Cl
O O SOCl2 Anhydride (A") R O R'
SOCl2
O O Ester ("E") = Acid R OR R OH Ester Acid
O
Amide ("N") R NHR
O Carboxylate ("O") R O--
• “Cl-A-vE-N-O” Chlorides-Anhydrides-Esters (and Acids)-Amides-Carboxylates • Any downhill step can be done directly • Any “lateral” step (acid to ester or vice-versa) 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 SOCl2 to get to the top; then go downhill from there.) • Mechanism is required for any downhill conversion and is the same: protonation- addition-deprotonation (addition to produce the hemiacetal intermediate) followed by protonation-elimination-deprotonation (elimination)
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 8
Mechanisms A. Miscellaneous 5. From Grignard Reagents: Via Carboxylation:
+ - O C O O H O R- - R O- R OH
• exactly like any Grignard reaction
9. Reaction as a Proton Acid
O OH-- O R OH -- R O
B. Any “Downhill” Interconversions (8a, 8c, 11, 13, 15, 18): All Proceed by Addition- Elimination-Deprotonation General
O O-- O Z-H - -- O + -Y- + Y Z H Z H R Y Add R R Z Y Elim Deprot R Examples Reaction 8a O O-- O HO-H -- Cl-- O + H -Cl + H R Cl R O R O Add Elim Deprot R OH Cl H H
Reaction 8c (Note: Slightly different because hydroxide nucleophile is anionic, not neutral; and product carboxylate is anionic, not neutral) O O-- O -- -- O OH -MeO-- OMe O H O H -- R OMe Add R R O OMe Elim Deprot R
Reaction 13 O O-- O MeO-H -- Cl-- O + H -Cl + H R Cl R O R O Add Elim Deprot R OMe Cl Me Me
Reaction 15 -- O O H O MeNH-H -- H Cl-- O + H -Cl + H R Cl R N R N Add Elim Deprot R NHMe Cl Me Me
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 9
C. “Lateral” Interconversions (8b/12): Acid-Catalyzed conversion from Ester to Acid (8b) or From Acid to Ester (12): (ACID WATER) • General Mechanism: protonation-addition-deprotonation (acid-catalyzed addition to a carbonyl to produce the tetrahedral hemiacetal intermediate) followed by protonation- elimination-deprotonation (acid catalyzed elimination)
Examples Reaction 8b: Ester to Acid
+ + O H OH OH OH HO-H + + H -H R OR R OR1 R O R OH 1 Protonate Add H Deprotonate OR Ester OR1 1 hemiacetal + H Protonate
+ O H O -H Eliminate OH R OH Deprotonate R + OH R OH -R1OH OR Acid 1 H +
Reaction 12: Acid to Ester + + H OH OH OH O R1OH + -H R OH R OH R OH R OH Protonate Add Deprotonate OR OR1 1 Acid H + hemiacetal + H
Protonate
O + O H -H Eliminate OH R OR R + OR + 1 Deprotonate 1 R OH2 Ester -R1OH OR1 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 O Methanoic acid Formic acid H OH O Ethanoic acid Acetic acid
H3C OH O Benzoic acid Benzoic acid Ph OH O Pentanoic acid OH O (S)-2-aminobutanoic acid OH H NH2
1. Nomenclature. Provide names or structures for the following.
O a. 3-phenylbutanoic acid OH Cl O
b. 2,2-dichloropropanoic acid Cl OH
c. 2-hydroxy-3-propanoyl-4-ethoxy-5-amino-6-hydroxyheptanoic acid
O O NH2
HO OH O OH
Physical Properties (Section 20.3) Boiling Points: (weight being equal): acid > alcohol > 1,2º amines > non-H-bonders • Acids boil about 20º higher than same-weight 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.
O O
OH OH
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 20-4) Acid Base Class Structure Ka Strength Base Strength
2 O Strong Acids H-Cl, H2SO4 10 Most Least Smell acidic Cl , HO S O basic Awful! O
+ + 0 Hydronium H3O , ROH 10 H2O, HOR Humans cationic neutral
Carboxylic O 10-5 O Cuz Acid R OH R O OH -10 Phenol 10 O People
Ammonium 10-12 Against R H R Ion (Charged) N N R R R R Charged, but only Neutral, but basic! weakly acidic!
-16 Water HOH 10 Working HO
-17 Alcohol ROH 10 Are RO Ketones and O 10-20 O Kingdoms Aldehydes ! H !
Amine (N-H) (iPr) N-H 10-33 Animal 2 (iPr) N Li 2 RCH -50 Alkane (C-H) 3 10 Least RCH2 Most All acidic basic Quick Checklist of Acid/Base Factors 1. Charge 2. Electronegativity 3. Resonance/Conjugation 4. Hybridization 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. Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 12 Acidity (20-4)
O O O -H R OH R O R O
• 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 O 10-5 O Acid R OH R O Ammonium 10-12 R H R Ion (Charged) N N R R R R Charged, but only Neutral, but basic! weakly acidic!
-17 Alcohol ROH 10 RO
• 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?
O O O O R stronger acid OH base OH H acid R R R OH O O H NH Eq. favors weaker base base 3 H NH H NH H NH 2 weaker acid 3 2 stronger base base Both are in acid and weaker weaker acid Both are in base form form at acidic pH base Both are in ionic under basic conditions form at neutral pH
3. Carboxylic Acids as Acids. Rank the acidity of the following groups, 1 being most acidic and 3 being least acidic. [Remember: the best guideline for acidity is the stability of the anion!]
a. acetic acid ethanol phenol 1 3 2 Stability of conjugate anions
b. propanoic acid CH3NH3Cl (CH3)3NHCl 1 2 3 1. carb acids beat ammoniums. 2. Alkyl donors stabilize ammoniums and reduce their acidity 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 • Opposite from the effect of donors and withdrawers on amines and ammoniums
4. Carboxylic Acids as Acids. Rank the acidity of the following groups, 1 being most acidic and 3 being least acidic. [Remember: the best guideline for acidity is the stability of the anion!]
a. propanoc acid 3-Chloropropanoic acid 2-fluoropropanoic acid 3 2 1
Electron withdrawing groups stabilize carboxylate anion. The stronger and closer, the better. b. benzoic acid p-methylbenzoic acid p-nitrobenzoic acid 2 3 1
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.
Alkyl donor OH + NaOH ONa + HOH destabilizes the anion a. on the right side
Resonance Ph OH + NaOH Ph ONa + HOH stabilizes right side b.
O O Resonance stabilizes + NaOH + HOH anion on right side OH ONa c.
O O The left acid is the stronger based on Ka. + NaHCO Equilibria always go from stronger to weaker. 3 + H CO OH ONa 2 3 And the conjugate base of the stronger acid -5 K =10-7 Ka=10 a 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 d. donor, and thus destabilizes the anion.
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 14 20.5 Carboxylate Salts
RCO2H + NaOH RCO2Na + H2O Produces weaker acid and base
• Easy to make • Ionic water soluble Acids are soluble in NaOH/water or NaHCO3/H2O • Weak bases, react with HCl RCO2H • Named: sodium alkanoate
Purification Schemes for Acids from other Organics Based on Acidity a. Dissolve acid and neutral organic in ether b. Treat with NaOH/water • Neutral stays neutral, goes in ether layer • Acid is deprotonated to RCO2Na, goes into water layer c. Concentrate ether layer pure neutral organic d. Add HCl to aqueous layer, results in: RCO2Na + HCl RCO2H e. Neutral RCO2H 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 PhC(O)CH3 ("B"). Make sure that your plan enables you to isolate both “A” and “B”. O Dissolve A + B O in ether OH Add NaOH A B ether water layer layer neutral B A anion
concentrate Add excess (boil off ether) HCl
B A neutral, insoluble in water Ether filter to get A, if it's a solid. Otherwise add ether to extract it, then boil off the ether layer to isolate pure A. Soaps (20.6, 25.4) (not for test) RCO2Na with variable long alkyl chains
Ex: C17H35CO2 Na
Carboxylate head: hydrophilic water soluble Hydrocarbon tail: hydrophobic can dissolve grease and organic materials Form “micelles” in water
The hydrophobic hydrocarbon tails (strings) water water self-aggregate, while the ionic heads (circles) keep the microdroplet soluble in water. Organic materials can be dissolved inside the organic organic center, and carried through the water. water Thus grease gets dissolved, and dirt protected water by grease is freed. Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 15
B. Synthesis of Carboxylic Acids Synthesis of Carboxylic Acids Review (20.8) 1. From 1º Alcohols and Aldehydes: Oxidation (Section 11-2B and 18-20) O O H CrO H CrO R OH 2 4 2 4 R OH R H 1º Alcohol
• No mechanism required for the reaction
2. From Alkenes: Oxidative Cleavage: (Section 8-15A and 9-10) H O O R KMnO4 + R 2 R OH R1 R2 R 1 acid ketone
• No mechanism required for the reaction • Where C=C begins, C=O ends. But where an attached H begins, an OH ends. • RCH=CHR would give two acids; RCH=CH2 would give an acid and carbonic acid (H2CO3), etc..
3. From Aromatics: Oxidation of Alkylbenzenes (Section 17-14A)
O
KMnO4 OH
• No mechanism required for the reduction • While toluenes (methylbenzenes) oxidize especially well, other alkyl benzenes can also be oxidized in this way.
4. From 1,3-Diesters: Via Hydrolysis/Decarboxylation: (Chapter 22)
O O O O O O O 1. NaOR H O+, heat 3 R RO OR HO OH HO RO OR 2. R-X R R
• Mechanism: Deprotation/Alkylation covered previously. The hydrolysis of the esters to acids will be required (see reaction 8b) Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 16 New Routes
5. From Grignard Reagents: Via Carboxylation: (Section 20-8B)
1. CO2 R-MgX R-CO2H + 2. H
Mg 1. CO O X MgX 2 O Protonate R R ether + R O-- R OH Alkyl or Grignard 2. H Aryl Halide Reagent
• Access: Alkyl or Aryl Acids • Alkyl group can be 1º, 2º, or 3º • Mechanism required. (From Grignard on.)
6. From Nitriles: Hydrolysis (Section 20-8C) + O H , H2O R C N R OH
• Mechanism not required.
7. From Halides: Either via Formation and Carboxylation of Grignards (Reaction 5) or via Formation and Hydrolysis of Nitriles (Reaction 6)
Mg 1. CO X MgX 2 O Protonate O R R ether + R O-- Alkyl or Grignard 2. H R OH Aryl Halide Reagent
NaCN If R-X is 1º alkyl + O H , H2O halide R C N R OH
• Formation/Hydrolysis of Nitriles Requires a 1º Alkyl Halide to begin, since the formation of the nitrile proceeds via SN2 • Reaction 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 air-sensitive Grignard reagents 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.
O H2CrO4 OH OH (C H O) a. 3 8
1. Mg OH 2. epoxide; H2O Bromobenzene 3. H2CrO4
O b.
OH 1. KMnO4/NaOH/heat Ph 2. H+ Ph O (+ carbonic acid) c.
Br 2 1. CO2 FeBr + Benzene 3 Ph-Br Mg 2. H Ph-MgBr PhCO2H d.
O PBr3 + 1. H3O OH 2. CN OH NaCN e.
1. NaCN OH + 2. H3O Ph Ph Br
O f. Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 18
8. From Acid Chlorides, Anhydrides, Esters, or Amides: Hydrolysis (Section 20-8C) a) “Downhill” hydrolysis: From acids or anhydrides with NEUTRAL WATER alone • mechanism required: addition-elimination-deprotonation
O O H2O R Cl R OH + H-Cl Chloride ("Cl")
O O H2O O O + R O R' R OH HO R' Anhydride ("A")
b) “Lateral” hydrolysis: From esters with water and acid catalysis (ACID WATER) • mechanism required: protonation-addition-deprotonation (to hemiacetal intermediate) followed by protonation-elimination-deprotonation (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
O + H2O, H O OH + R'OH R OR1 via hemiacetal ROH, H+ R OH R OH Ester ("E") OR1
c) “Basic” hydrolysis using NaOH (BASIC WATER) (always downhill) followed by H+ workup • mechanism required: addition-elimination-deprotonation (to carboxylate intermediate) followed by protonation • Since the reaction with NaOH is always downhill, all of these reactions work
O 1. NaOH O O R Cl R OH + H-Cl via -- Chloride ("Cl") 2. H+ R O Carboxylate ("O") O O 1. NaOH O O O + via -- R O R' R OH HO R' R O 2. H+ Anhydride ("A") Carboxylate ("O") O 1. NaOH O O + R'OH via - R OR' R O- + R OH Ester ("E") 2. H Carboxylate ("O") O 1. NaOH O O R NHR + RNH2 via -- + R OH R O Amide ("N") 2. H Carboxylate ("O") Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 19 Interconversions and Reactivity of Acids and Acid Derivatives (Section 21-5 and others)
O Acid Chloride ("Cl") R Cl
O O SOCl2 Anhydride (A") H2O R O R' SOCl H2O 2
O H2O, H O Ester ("E") = Acid R OR R OH OH Ester Acid
OH H O Amide ("N") R NHR
OH OH
O Carboxylate ("O") R O--
• “Cl-A-vE-N-O” Chlorides-Anhydrides-Esters (and Acids)-Amides-Carboxylates • Any downhill step can be done directly • Any “lateral” step (acid to ester or vice-versa) 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 SOCl2 to get to the top; then go downhill from there.) • Mechanism is required for any downhill conversion and is the same: protonation- addition-deprotonation (addition to produce the hemiacetal intermediate) followed by protonation-elimination-deprotonation (elimination)
“Cl-A-vE-N-O” applied to Hydrolysis 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 acid-catalyzed hydrolysis 3. Chloride, anhydrides, esters, and amides can all be base-hydrolyzed (NaOH/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
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 20
2. 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 acid-catalyzed hydrolysis in addition to via basic hydrolysis.
O O 1. NaOH, H2O OH + MeOH OMe + 2. H3O
O O 1. NaOH, H2O OH + MeNH2 NHMe + 2. H3O
O O 1. NaOH, H2O + NH NH OH 3 2 + 2. H3O
O O O O 1. NaOH, H O 2 Ph Ph OH + HO O + 2. H3O
O O 1. NaOH, H2O Ph OH + HO Ph + O 2. H3O
Mechanism: General Mechanism for Any “Downhill” Cl-A-vE-N-O Interconversions (8a, 8c, 11, 13, 15, 18): All Proceed by Addition-Elimination-Deprotonation General
O O-- O Z-H - -- O + -Y- + Y Z H Z H R Y Add R R Z Y Elim Deprot R
Base Case, Using Anionic Hydroxide: Slightly different because hydroxide nucleophile is anionic, not neutral; and product carboxylate is anionic, not neutral) O O-- O -- -- O OH -MeO-- OMe O H O H -- R OMe Add R R O OMe Elim Deprot R
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 21
Acid-Catalyzed conversion from Ester to Acid (8b): (ACID WATER) • General Mechanism: protonation-addition-deprotonation (acid-catalyzed addition to a carbonyl to produce the tetrahedral hemiacetal intermediate) followed by protonation- elimination-deprotonation (acid catalyzed elimination)
+ + O H OH OH OH HO-H + + H -H R OR R OR1 R O R OH 1 Protonate Add H Deprotonate OR Ester OR1 1 hemiacetal + H Protonate
+ O H O -H Eliminate OH R OH Deprotonate R + OH R OH -R1OH OR Acid 1 H +
Draw the Mechanisms for the following Hydrolyses O O H+ workup O + OH Ph OMe Ph O Ph OH 18 + HOMe 18
O O
Ph OH Ph O OMe OMe 18 18 H The O18 label ends up in the product alcohol. O H2O Cl O O-- O HO-H -- Cl-- O + H -Cl + H Cl O O Add Elim OH Cl H H Deprot
O OH H O HO O 2 H2O O O H H OH OH H -H -H H OH OH OH OH OH HO 2 HO O 2 O OH OH OH
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 22 C. Reactions of Carboxylic Acids 20.9, 21.5 Interconversions with Derivatives: Cl-A-vE-N-O
O Acid Chloride ("Cl") R Cl
O O SOCl2 Anhydride (A") R O R'
SOCl2
O O Ester ("E") = Acid R OR R OH Ester Acid
O
Amide ("N") R NHR
O Carboxylate ("O") R O--
• “Cl-A-vE-N-O” Chlorides-Anhydrides-Esters (and Acids)-Amides-Carboxylates • 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 vice-versa) 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 SOCl2 to get to the top; then go downhill from there.) • Mechanism is required for any downhill conversion and is the same: protonation- addition-deprotonation (addition to produce the hemiacetal intermediate) followed by protonation-elimination-deprotonation (elimination)
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 23 Acid Chlorides: Preparation and Uses (Sections 20.11 and 21.5)
10. Conversion of acids or Carboxylates to Acid Chlorides (Section 20-11, 21-5)
O O SOCl O O 2 SOCl2 R OH R Cl R ONa R Cl
• Mechanism: Not Required • Easy (but smelly) reaction. o Side products HCl and SO2 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 21-5)
O O 1. SOCl2 O O R OH R Cl R O R' 2. R'CO2H
• mechanism required for acid chloride to anhydride conversion: addition- elimination-deprotonation • 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 HCl
13. Indirect Conversion to Esters via Acid Chlorides (Sections 20-10-12, 21-5)
O O O 1. SOCl2 R OH R Cl R OR' 2. R'OH
• mechanism required for acid chloride to ester conversion: addition-elimination- deprotonation • Conversion of the acid chloride to the ester is a “downhill” reaction energetically. • Base often present to absorb the HCl
15. Indirect Conversion to Amides (Sections 20-11, 20-13, 21-5)
O O O 1. SOCl2 R OH R Cl R NHR 2. RNH2
• mechanism required for acid chloride to amide conversion: addition- elimination-deprotonation • This reaction sequence works very well in the laboratory • Base often present to absorb the HCl
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 24
Condensation/Hydrolysis: Interconversions between Acids and Esters (20.10, 13, 21.7) 12. Direct Conversion to Esters (Sections 20-10-12, 21-5)
O OH O R'OH, H+ R OH + R OH R OR' H2O, H OR'
• mechanism required: protonation-addition-deprotonation (to hemiacetal intermediate) followed by protonation-elimination-deprotonation (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. OH O HOMe, H+ O (+ H2O) OH Phase 1: OMe OMe addition OH Phase 2: Tetrahedral elimination intermediate + + H OH OH OH O R1OH + -H OH OH OH Add OH Protonate OMe Deprotonate OMe Acid H + hemiacetal + H
Protonate
O + O H -H Eliminate OH OMe + OMe + Deprotonate OH2 Ester -R1OH OMe 14. Direct Conversion to Amides (Sections 20-11, 20-13, 21-5) O O RNH2, heat R OH R NHR
• mechanism not required • This is a “downhill” reaction energetically, but is complicated and retarded by acid-base 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. 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.
O O SOCl2 a. Ph OH Ph Cl
O 1. SOCl2 O b. Ph OH Ph O 2. 1-butanol
O O ethanol, H+ c. Ph OH Ph O
O O 1. SOCl d. 2 Ph OH Ph O 2. cyclopentanol
O O 1. SOCl2 Ph O e. Ph OH 2. 2-butanol
O O H+ O f. HO OH H H Ph Ph
O O 1. SOCl g. 2 Ph OH Ph N 2. diethylamine
O 1. SOCl O h. 2 Ph OH Ph NH2 2. NH3
O 1. SOCl O i. 2 Ph OH 2. 2-butanamine Ph N H
O diethylamine, heat O j. Ph OH Ph NEt2 Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 26
5. Draw the mechanism. O O b. +NH3 Cl NH2 O O b. +NH3 Cl NH2
O O
NH2 NH2 Cl H H 6. Draw the products for the following reactions. O 1. LiAlH a. 4 Ph OH + Ph OH 2. H3O
O 1. MeLi (excess) O b. Ph OH + Ph CH3 2. H3O
O
Ch. 21 Carboxylic Acid Derivatives: R X o Cl chloride o A anhydride o E ester o N amide o O: carboxylate
21.1,2 Structure, Names, Notes • all are subject to hydrolysis • All hydrolyze to acids (actually, to carboxylate anion) upon treatment with NaOH/H2O • Some (Cl and A) hydrolyze to acids under straight water treatment • Esters hydrolyze to acids under acid catalysis
General Example O Alkanoyl O Butanoyl • High reactivity chloride chloride • Named as if ionic R Cl Cl O O Alkanoic O O Propanoic Anhydride anhydride R O R O O Alkyl O Named as if ionic R' Alkanoate Ethyl R O O Benzoate O O N-isopropyl R' Alkanamide pentanamide R N N H R" Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 27 7. Draw the structures for the following esters. a. propyl benzoate O
O b. methyl ethanoate O
O c. ethyl butanoate O
O
21.5 Interconversion of Acid Derivatives: Cl-A-vE-N-O
O Acid Chloride ("Cl") R Cl
O O SOCl2 Anhydride (A") R O R'
SOCl2
O O Ester ("E") = Acid R OR R OH Ester Acid
O
Amide ("N") R NHR
O Carboxylate ("O") R O-
• “Cl-A-vE-N-O” Chlorides-Anhydrides-Esters (and Acids)-Amides-Carboxylates • 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 vice-versa) 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 SOCl2 to get to the top; then go downhill from there.) • Mechanism is required for any downhill conversion and is the same: protonation- addition-deprotonation (addition to produce the hemiacetal intermediate) followed by protonation-elimination-deprotonation (elimination)
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 28 8. Rank the acidity of the following molecules, 1 being most acidic and 4 being least acidic. O
H Cl HOCH3 NH CH HO 2 3 1 2 3 4 9. Rank 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? O O O O O
Cl O OCH3 NHCH3 1 2 3 4 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. O > > Cl > OCH3 NHCH O 3 Notes: • Any “downhill” reaction can be done in one laboratory step • Any “downhill” reaction involves a 3-step mechanism: addition-elimination-deprotonation
O Z-H O-- O -- O Add r1 + -Y-- + Y Z H Z H R Y R R Z Y Elim Deprot R Elim r-1 r2 • The overall reactivity correlates the leaving ability of the Y for two reasons 1. This affects the kinetic r2/r-1 partion. If r2 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, r1). 3. Thus good leaving groups have benefits at both r1 and r2
• Memory o Think anion stability o Cliff Cl-A-vE-N-O
B. “Uphill” Reaction Sequences: 3-steps
O 1. NaOH, H2O O
R Y 2. SOCl2 R Z 3. HZ Ex: O 1. NaOH, H2O O O 1. NaOH, H2O O O Ph OCH Ph O Ph NH2 2. SOCl2 3 Ph OCH3 2. SOCl2 3. HOCH3 3. O OH HOCH3 OH NaOH HO NEt3 O O O O SOCl2 SOCl2 Ph O Ph Cl Ph O Ph Cl + NH3 + HOCH3 Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 29
10. Which will proceed easily/directly? (“downhill”?) Add Appropriate Reactant(s) and Side Product. If it doesn’t go directly, give indirect route. O O + NH3 + H-Cl Downhill, yes. Ph Cl Ph NH2 a. Cl N O O O O + HO + Downhill, yes. O O HO b. A E O O + H2O + H-Cl Downhill, yes. Cl OH c. Cl E O O No, Uphill + H-Cl + HOCH3 OCH Cl 3 Cl d. E O 1. NaOH O O O Indirect route, + OH via hydrolysis O then SOCl OCH3 2. H+ OH Cl 2 E O E Cl 3. SOCl2 O O + H-NMe2 Yes, downhill + HOCH3 OCH3 NMe2 N e. E O O + NaOH + HOCH3 Yes, downhill OCH3 ONa f. E O O O + NaOH + HNMe2 Yes, downhill NMe2 ONa g. N O O O + HOMe + HNMe No, uphill NMe 2 N 2 OMe h. E
O 1. NaOH O O O O Indirect route, via hydrolysis NMe + O OH Cl OMe then SOCl N 2 2. H O E Cl E 2 3. SOCl2 4. HOMe Note: direct H+ catalyzed conversion from acid to ester also fine. O O O O + + + HOMe No, uphill OMe HO O i. E A O 1. NaOH O O O O O Indirect route, via hydrolysis OCH O Cl O 3 2. H+ OH A then SOCl2 E O E Cl 3. SOCl2 O 4. HO Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 30
11. Draw the products for the following reactions.
O SOCl2 O a. Ph OH Ph Cl
O 1. SOCl2 O O b. Ph OH 2. Acetic acid, pyridine Ph O
O O c. PhNH2 Ph OMe Ph NHPh
O 1. NaOH, H2O; H+ O d. Ph NHMe 2. SOCl2 Ph OMe 3. MeOH, pyridine
O O O ethanol, pyridine e. Ph O Ph OCH2CH3
+ 1. H3O O f. Ph-CN + 2. MeOH, H Ph OMe
12. Draw the mechanism for the following reaction.
O O O O + (3 steps) + HO O OCH2CH3 HO
O O O O HO + O O HO
O O O + O O O O H H O
Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 31
13. Provide reagents for the following transformations.
O + O CH3OH, H (Method 1) a. Ph OH Ph OMe
O O 1. SOCl2 2. CH3OH (Method 2) b. Ph OH Ph OMe
O 1. SOCl2 2. NH3 O Ph OH (Method 1) c. Ph NH2
O NH3, heat (E to N, downhill) O Ph OH (Method 2) d. Ph NH2
O NH3 (E to N, downhill...) O Ph OMe e. Ph NH2
1. NaOH + O 2. H O Ph OMe Ph NH2 3. SOCl2 f. 4. CH3OH
1. NaOH O 2. H+ O O Ph OMe Ph O 3. SOCl2 4. O g. HO
1. H2CrO4 1. H2CrO4 + O 2. SOCl2 or 2. H , CH3OH Ph-CH2OH Ph OMe h. 3. CH3OH Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 32
14. Provide products for the following condensation or hydrolysis transformations.
O H+ O + MeOH a. Ph OH Ph OMe
OH heat NHPh + PhNH2 b. O O
O O H+ + H2O + O OH HO c.
O 1. NaOH O Ph Ph + N Ph 2. HCl H2N Ph d. H OH
O O 1. NaOH HO O H OH + H 2. HCl e.
O O H+ H OH O OH H f.
O O 1. NaOH O OH 2. HCl OH OMe OMe g. Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 33 15. Cyclic Esters and Amides: Provide products or starting reactants for the following condensation or hydrolysis reactions involving cyclic esters or amides.
O O OH H+ HO a. O
O O 1. NaOH O OH + H 2. H3O H b. Ph Ph OH
O O N 1. NaOH OH H + H 2. H3O Cl Cl N c. H
O O HO Heat HN NH2 H H Me Me d.
16. Rank the following as acids or bases.
O O NH F CH3NH3 3 a. OH OH
1 2 3 4
O
(CH3)2NH2 PhNH3 H2O b. OH
3 2 1 1
Et3N EtNH2 NH PhMgBr c.
2 3 4 1 Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 34
17. Provide reagents for the following transformations. There may be more than one solution.
1. PCC OH N + H 2. H , NaBH3CN, a. H2N
O 1. H2N Ph Ph Cl N b. 2. LiAlH4 H
O 1. + Cl or O , NaBH3CN, H
NH2 N H c. 2. LiAlH4
H N , NaBH CN, H+ H O 2 3 N d.
1. PBr3 OH NH2 e. 2. NH3 (excess)
1. PBr3 NH OH 2 2. KCN f. 3. LiAlH4 Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 35
18. Provide reagents for the following transformations. There may be more than one solution.
O 1. NaOH + O or H2O, H OCH3 + OH a. 2. H
O (downhill, E to N) O NH(CH3)2 OCH3 b. N(CH3)2
O 1. NaOH 2. H+ O O OCH 3 O Ph 3. SOCl2
4. O c. HO Ph
1. H2CrO4 O OH Cl d. 2. SOCl2
1. PBr3 OH OH 2. KCN + O e. 3. H , H2O
f. KMnO4 OH
O O Chem 360 Jasperse Ch. 20, 21 Notes + Answers. Carboxylic Acids, Esters, Amides… 36
19. Provide mechanism for the following reactions.
+ + O H OH OH + OH HO-H + -H O H OCH OCH3 OH 3 Protonate Add H Deprotonate OCH Ester OCH3 3 hemiacetal + H Protonate H O + O -H Eliminate OH OH Deprotonate + OH OH -CH3OH OCH Acid 3 a. H +
O O 1. NaOH, H2O OH O 2. H+ OH
OH H+ O O HO O H O O O b. O OH
O O-- O HO-H -- Cl-- O + H -Cl + H Cl O O Add Elim Deprot OH c. Cl H H
H C 3 Br H C H H3C 3 N OH H C NH2 3 H NHCH3 H3C Deprotonate SN2 S 2 N H C 3 Br
CH Br 3 CH OH H3C H H3C 3 H3C N N N(CH3)2 CH S 2 Deprotonate H C CH3 d. H3C 3 N 3