Chapter 4 Carboxylic acids 1 Structure  The functional group of a carboxylic acid is a carboxyl group : O: : C :O COOH H CO 2 H  the general formula of an aliphatic carboxylic acid is RCOOH  that of an aromatic carboxylic acid is ArCOOH 2 Org Chem II Chapter 4 Dr. Estifanos E. 2 Nomenclature (review) • IUPAC names: drop the -e from the parent alkane and add the suffix -oic acid  if the compound contains a carbon-carbon double bond, change the infix -an- to -enCOOH C6 H5 COOH 3-Methylbutanoic acid t rans -3-Phenylprop enoic acid (Isovaleric acid ) (Cinn amic acid) OH COOH (R)-5-Hydroxyhexanoic acid O COOH 3 5-Oxohexanoic acid H2N COOH 4-Aminobutanoic acid 3 Nomenclature  dicarboxylic acids: add -dioic acid to the name of the parent alkane containing both carboxyl groups  there is no need to use numbers to locate the carboxyl groups; they can only be on the ends of the chain O HO O OH O Ethanedioic acid (Oxalic acid) O HO O OH O Butanedioic acid (Succinic acid) HO O HO OH Propanedioic acid (Malonic acid) O O OH Pentanedioic acid (Glutaric acid) HO OH O Hexanedioic acid (Adipic acid) 4 4 Nomenclature  if the carboxyl group is bonded to a ring, name the ring compound and add the suffix -carboxylic acid 2 3 1 COOH 2-Cyclohexenecarboxylic acid H OOC COOH trans- 1,3-Cyclopentanedicarboxylic acid 5 5 Nomenclature  when common names are used, the letters etc. are often used to locate substituents O     5 1 4 3 2 O H2 N  OH O  OH 4-A min ob utanoic acid (-Aminobutyric acid; GABA ) OH NH2 2-Aminopropanoic acid (-Aminop ropionic acid; alanin e)  in common nomenclature, keto indicates the presence of a ketone, and CH3CO- is named an aceto group O O OH 3-oxob utanoic acid -Ketobutyric acid ; acetoacetic acid) O CH3 CAcetyl group (aceto group) 6 6 Physical Properties  Carboxylic acids have significantly higher boiling points than other types of organic compounds of comparable molecular weight  they are polar compounds and form very strong intermolecular hydrogen bonds  Carboxylic acids are more soluble in water than alcohols, ethers, aldehydes, and ketones of comparable molecular weight  they form hydrogen bonds with water molecules through their C=O and OH groups 7 7 Physical Properties  water solubility decreases as the relative size of the hydrophobic portion of the molecule increases 8 8 Acidity  Carboxylic acids are weak acids  values of pKa for most aliphatic and aromatic carboxylic acids fall within the range 4 to 5  the greater acidity of carboxylic acids relative to alcohols, both of which contain an OH group, is due to resonance stabilization of the carboxylate anion CH3 COOH Acetic acid pKa : 4.76 ClCH2 COOH Cl2 CHCOOH Chloroacetic D ich loroacetic acid acid 2.86 1.48 Increasin g acid strength Cl3 CCOOH Trich loroacetic acid 0.70 9 9 Acidity  the acid-strengthening effect of a halogen substituent falls off rapidly with increasing distance from the carboxyl group COOH Cl COOH Cl 2-Chlorob utanoic 3-Chlorobutan oic acid acid (pK a 2.83) (p Ka 3.98) Cl COOH 4-Ch lorobutanoic acid (pK a 4.52) COOH Butan oic acid (pK a 4.82) Decreas ing acid strength 10 10 Aromatic Carboxylic Acids  Electron-withdrawing groups (EWG) enhance the acid strength and electron-donating groups (EDG) decrease the acid strength.  Effects are strongest for substituents in the ortho and para positions. 11 11 12 12 Preparation of Carboxylic Acids  Oxidation of primary alcohols and aldehydes with chromic acid.  Cleavage of an alkene with hot KMnO4 produces a carboxylic acid if there is a hydrogen on the double-bonded carbon.  Alkyl benzene oxidized to benzoic acid by hot KMnO4 or hot chromic acid. 13 Org Chem II Chapter 4 Dr. Estifanos E. 13 Oxidation of Primary Alcohol to Carboxylic Acids  Primary alcohols and aldehydes are commonly oxidized to acids by chromic acid (H2CrO4 formed from Na2Cr2O7 and H2SO4).  Potassium permanganate is occasionally used, but the yields are often lower. 14 Org Chem II Chapter 4 Dr. Estifanos E. 14 Cleavage of Alkenes Using KMnO4  Warm, concentrated permanganate solutions oxidize the glycols, cleaving the central C═C bond.  Depending on the substitution of the original double bond, ketones or acids may result. 15 Org Chem II Chapter 4 Dr. Estifanos E. 15 Alkyne Cleavage Using Ozone or KMnO4 With alkynes, either ozonolysis or a vigorous permanganate oxidation cleaves the triple bond to give carboxylic acids. 16 Org Chem II Chapter 4 Dr. Estifanos E. 16 Side Chain Oxidation of Alkylbenzenes 17 Org Chem II Chapter 4 Dr. Estifanos E. 17 Conversion of Grignards to Carboxylic Acids  Grignard reagent react with CO2 to produce, after protonation, a carboxylic acid.  This reaction is sometimes called “CO2 insertion” and it increases the number of carbons in the molecule by one. 18 Org Chem II Chapter 4 Dr. Estifanos E. 18 Hydrolysis of Nitriles CH2Br NaCN acetone CH2CN H+, H2O CH2CO2H  Basic or acidic hydrolysis of a nitrile (—CN) produces a carboxylic acid.  The overall reaction, starting from the alkyl halide, adds an extra carbon to the molecule. 19 Org Chem II Chapter 4 Dr. Estifanos E. 19 Reaction with Bases  Carboxylic acids, whether soluble or insoluble in water, react with NaOH, KOH, and other strong bases to give water-soluble salts COOH + N aOH - H2 O Benzoic acid (slightly soluble in water) COO Na + H2 O + Sodium benzoate (60 g/100 mL water)  They also form water-soluble salts with ammonia and amines COOH + N H3 Benzoic acid (slightly soluble in water) 20 - H2 O COO NH4 + A mmonium benzoate (20 g/100 mL water) Org Chem II Chapter 4 Dr. Estifanos E. 20 Reaction with Bases  Carboxylic acids react with sodium bicarbonate and sodium carbonate to form water-soluble salts and carbonic acid  carbonic acid, in turn, breaks down to carbon dioxide and water CH3 COOH + + Na HCO3 - H2 O H2 CO3 + CH3 COOH + Na HCO3 21 + CH3 COO Na + H2 CO3 CO2 + H2 O + CH3 COO Na + CO2 + H2 O Org Chem II Chapter 4 Dr. Estifanos E. 21 Reduction  The carboxyl group is very resistant to reduction  it is not affected by catalytic hydrogenation under conditions that easily reduce aldehydes and ketones to alcohols, and reduce alkenes and alkynes to alkanes  it is not reduced by NaBH4 22 Org Chem II Chapter 4 Dr. Estifanos E. 22 Reduction  Lithium aluminum hydride reduces a carboxyl group to a 1° alcohol  reduction is carried out in diethyl ether, THF, or other nonreactive, aprotic solvents O H 1 . LiAlH4 , eth er 2 . H2 O 23 OH + LiOH + Al(OH) 3 Org Chem II Chapter 4 Dr. Estifanos E. 23 LiAlH4 or BH3 Reduction of Carboxylic Acids  LiAlH4 reduces carboxylic acids to primary alcohols.  The intermediate aldehyde reacts faster with the reducing agent than the carboxylic acid.  BH3•THF (or B2H6,) can also reduce the carboxylic acid to the alcohol 24 Org Chem II Chapter 4 Dr. Estifanos E. 24 Reduction of Acid Chlorides to Aldehydes  Lithium aluminum tri(tert-butoxy)hydride is a weaker reducing agent than lithium aluminum hydride.  It reduces acid chlorides because they are strongly activated toward nucleophilic addition of a hydride ion.  Under these conditions, the aldehyde reduces more slowly, and it is easily isolated. 25 Org Chem II Chapter 4 Dr. Estifanos E. 25 Selective Reduction  Catalytic hydrogenation does not reduce a COOH group  we can use H2/M to reduce an alkene in the presence of a COOH group O O OH + H2 5-Hexen oic acid Pt 25°C, 2 atm OH Hexanoic acid  we can use NaBH4 to reduce an aldehyde or ketone in the presence of a COOH group O C6 H5 OH O OH 5-Oxo-5-p henylpentan oic acid 26 1 . NaBH 4 2 . H2 O C6 H5 O OH 5-Hyd roxy-5-phen ylpen tanoic acid Org Chem II Chapter 4 Dr. Estifanos E. 26 Conversion of Carboxylic Acids to Ketones A general method of making ketones involves the reaction of a carboxylic acid with two equivalents of an organolithium reagent. 27 Org Chem II Chapter 4 Dr. Estifanos E. 27 Mechanism of Ketone Formation OH OLi O R C OH 2 R' Li R C OLi H3O+ R C OH R' R' dianion hydrate of ketone O R C R' + H 2O ketone  The first equivalent of organolithium acts as a base, deprotonating the carboxylic acid.  The second equivalent adds to the carbonyl.  Hydrolysis forms the hydrate of the ketone, which converts to the ketone. 28 Org Chem II Chapter 4 Dr. Estifanos E. 28 Fischer Esterification  Esters can be prepared by treating a carboxylic acid with an alcohol in the presence of an acid catalyst, commonly H2SO4 or gaseous HCl 29 29 Fischer Esterification  Fischer esterification is an equilibrium reaction  by careful control of experimental conditions, it is possible to prepare esters in high yield  if the alcohol is inexpensive relative to the carboxylic acid, it can be used in excess to drive the equilibrium to the right  a key intermediate in Fischer esterification is the tetrahedral carbonyl addition intermediate formed by addition of ROH to the C=O group O R C OH + HOCH3 H + H O R C OCH3 O H + H O R C OCH3 + HOH 30 30 Mechanism of Fisher Esterification 31 31 Esterification Using Diazomethane  Carboxylic acids are converted to their methyl esters very simply by adding an ether solution of diazomethane.  The reaction usually produces quantitative yields of ester.  Diazomethane is very toxic, explosive gas that is safe to use as a solution in ether. 32 32 Mechanism of Diazomethane Esterification 33 33 Decarboxylation • Decarboxylation: loss of CO2 from a carboxyl group  most carboxylic acids, if heated to a very high temperature, undergo thermal decarboxylation O RCOH decarb oxylation heat RH + CO2  most carboxylic acids, however, are quite resistant to moderate heat and melt or even boil without decarboxylation 34 34 Decarboxylation  exceptions are carboxylic acids that have a carbonyl group beta to the carboxyl group  this type of carboxylic acid undergoes decarboxylation on mild heating O O warm   OH 3-Oxobu tan oic acid (Acetoacetic acid) O + CO2 Acetone 35 35 Decarboxylation  thermal decarboxylation of a -ketoacid and malonic acids involve rearrangement of six electrons in a cyclic sixmembered transition state O H enol of a ketone O O (1) H O C O O (2) + O CO 2 (A cyclic six-membered transition state) O HO H O O (1) O A cyclic six-membered transition state HO H O C O (2) O HO + CO 2 Enol of a carboxylic acid 36 36 Decarboxylation  Problem: draw the product of decarboxylation O COOH heat  Problem: draw the -ketoacid that undergoes decarboxylation to give this ketone O -ketoacid heat + CO2 37 37