Carboxylic Acids and Their Derivatives—Nucleophilic Acyl Substitution PDF

Carboxylic Acids and Their Derivatives—Nucleophilic Acyl Substitution Carboxylic Acid Derivatives: Chapter-2 O O O O -H2O OH + HO O ANHYDRIDE 1 2 Types of anhydrides: Types of a...

Carboxylic Acids and Their Derivatives—Nucleophilic Acyl Substitution Carboxylic Acid Derivatives: Chapter-2 O O O O -H2O OH + HO O ANHYDRIDE 1 2 Types of anhydrides: Types of amides: 3 Cyclic esters and amides: Nitriles: 4 Structure and Bonding The two most important features of the carbonyl group are: 5  Three resonance structures stabilize carboxylic acid derivatives (RCOZ) by delocalizing electron density. The more resonance structures 2 and 3 contribute to the resonance hybrid, the more stable RCOZ is. 6 7  Because the basicity of Z determines the relative stability of the carboxylic acid derivatives, the following stability order results: In summary, as the basicity of Z increases, the stability of RCOZ increases because of added resonance stabilization. 8  The structure and bonding of nitriles is very different from that of other carboxylic acid derivatives, and resembles the C—C triple bond of alkynes. The carbon atom on the CN group is sp hybridized, making it linear with a bond angle of 180°. The triple bond consists of one  and two  bonds. 9 10 11 12 Introduction to Nucleophilic Acyl Substitution Nucleophilic acyl substitutions is the characteristic reaction of carboxylic acid derivatives. This reaction occurs with both negatively charged nucleophiles and neutral nucleophiles. 13  Other nucleophiles that participate in this reaction include: 14 To draw any nucleophilic acyl product: Find the sp2 hybridized carbon with the leaving group. Identify the nucleophile. Substitute the nucleophile for the leaving group. With a neutral nucleophile, the proton must be lost to obtain a neutral substitution product. 15 Based on this order of reactivity, more reactive compounds can be converted into less reactive ones. The reverse is not usually true. 16 Reactions of Acid Chlorides Acid chlorides react readily with nucleophiles to form nucleophilic substitution products. HCl is usually formed as a by-product. A weak base like pyridine is added to the reaction mixture to remove the strong acid (HCl), forming an ammonium salt. 17 Acid chlorides react with oxygen nucleophiles to form anhydrides, carboxylic acids and esters. 18  Acid chlorides also react with ammonia and 1° and 2° amines to form 1°, 2° and 3° amides respectively. Two equivalents of NH3 or amine are used. One equivalent acts as the nucleophile to replace Cl, while the other reacts as a base with the HCl by-product to form an ammonium salt. 19  As an example, reaction of an acid chloride with diethylamine forms the 30 amide N,N-diethyl-m- toluamide, popularly known as DEET. DEET is the active ingredient in the most widely used insect repellents, and is effective against mosquitoes, fleas and ticks. 20 21 Reactions of Anhydrides Nucleophilic attack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group. 22  Besides the usual steps for nucleophilic addition and elimination of the leaving group, the mechanism involves an additional proton transfer. 23 Reactions of Carboxylic Acids Nucleophiles that are also strong bases react with carboxylic acids by removing a proton first, before any nucleophilic substitution reaction can take place. 24  O Cl S Cl thionyl chloride Figure 22.2 Nucleophilic acyl substitution reactions of carboxylic acids N C N dicyclohexylcarbodiimide DCC 25  Treatment of a carboxylic acid with thionyl chloride (SOCl2) affords an acid chloride. This is possible because thionyl chloride converts the OH group of the acid into a better leaving group, and because it provides the nucleophile (Cl¯) to displace the leaving group. 26 27  Although carboxylic acids cannot readily be converted into anhydrides, dicarboxylic acids can be converted to cyclic anhydrides by heating to high temperatures. This is a dehydration reaction because a water molecule is lost from the diacid. 28  Treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst forms an ester. This reaction is called a Fischer esterification. The reaction is an equilibrium, so it is driven to the right by using excess alcohol or by removing water as it is formed. 29 30  Esterification of a carboxylic acid occurs in the presence of acid but not in the presence of base. Base removes a proton from the carboxylic acid, forming the carboxylate anion, which does not react with an electron-rich nucleophile. 31  Intramolecular esterification of - and -hydroxyl carboxylic acids forms five- and six-membered lactones. 32  Carboxylic acids cannot be converted into amides by reaction with NH3 or an amine because amines are bases, and undergo an acid-base reaction to form an ammonium salt before nucleophilic substitution occurs. However, heating the ammonium salt at high temperature (>100°C) dehydrates the resulting ammonium salt of the carboxylate anion to form an amide, although the yield can be low. 33  The overall conversion of RCOOH to RCONH2 requires two steps: Acid-base reaction of RCOOH with NH3 to form an ammonium salt. Dehydration at high temperature (>100°C). 34  A carboxylic acid and an amine readily react to form an amide in the presence of an additional reagent, dicyclohexylcarbodimide (DCC), which is converted to the by-product dicyclohexylurea in the course of the reaction. 35  DCC is a dehydrating agent. The dicyclohexylurea by-product is formed by adding the elements of H2O to DCC. DCC promotes amide formation by converting the carboxy group OH group into a better leaving group. 36 37 Reactions of Esters Esters are hydrolyzed with water in the presence of either acid or base to form carboxylic acids or carboxylate anions respectively. Esters react with NH3 and amines to form 1°, 2°, or 3° amides. 38 39  Basic hydrolysis of an ester is also called saponification. Hydrolysis is base promoted, not base catalyzed, because the base (OH–) is the nucleophile that adds to the ester and forms part of the product. It participates in 40 the reaction and is not regenerated later.  The carboxylate anion is resonance stabilized, and this drives the equilibrium in its favor. Once the reaction is complete and the anion is formed, it can be protonated with strong acid to form the neutral carboxylic acid. 41 Reactions of Amides Amides are the least reactive of the carboxylic acid derivatives. Amides are hydrolyzed in acid or base to form carboxylic acids or carboxylate anions. In acid, the amine by-product is protonated as an ammonium ion, whereas in base, a neutral amine forms. 42  The mechanism of amide hydrolysis in acid is exactly the same as the mechanism of ester hydrolysis in acid. The mechanism of amide hydrolysis in base has the usual two steps in the general mechanism for nucleophilic acyl substitution, plus an additional proton transfer. 43 Nitriles Nitriles have the general structural formula RCN. Two useful biologically active nitriles are letrozole and anastrozole. Nitriles are prepared by SN2 reactions of unhindered methyl and 1° alkyl halides with ¯CN. 44 Reactions of Nitriles—Hydrolysis Nitriles are hydrolyzed with water in the presence of acid or base to yield carboxylic acids or carboxylate anions. In this reaction, the three C—N bonds are replaced by three C—O bonds. 45  The mechanism of this reaction involves formation of an amide tautomer. Two tautomers can be drawn for any carbonyl compound, and those for a 1° amide are as follows: 46  The imidic acid and amide tautomers are interconverted by treatment with acid or base, analogous to keto-enol tautomers of other carbonyl compounds. 47 48 Reactions of Nitriles—Reduction Treatment of a nitrile with LiAlH4 followed by H2O adds two equivalents of H2 across the triple bond, forming a 10 amine. Treatment of a nitrile with a milder reducing agent such as DIBAL-H followed by water forms an aldehyde. H- Al+ Diisobutylaluminium hydride DIBAL-H 49  With LiAlH4, two equivalents of hydride are sequentially added to yield a dianion which is then protonated with H2O to form an amine. 50  With DIBAL-H, nucleophilic addition of one equivalent of hydride forms an anion which is protonated with water to generate an imine. The imine is then hydrolyzed in water to form an aldehyde. 51 Hydrolysis of an imine H A NH H2O NH2 NH2 H2N H2N OH H O NH2 OH H A 52 Reactions of Nitriles—Addition of Organometallic reagents Both Grignard and organolithium reagents react with nitriles to form ketones with a new C—C bond. 53  The reaction occurs by nucleophilic addition of the organometallic reagent to the polarized C—N triple bond to form an anion, which is protonated with water to form an imine. Water then hydrolyzes the imine, replacing the C=N with C=O. The final product is a ketone with a new C—C bond. 54 22.49) O O a) NaHCO3 + H2CO3 Ph Ph Na+ OH ONa OH - O O sodium bicarbonate O b) NaOH + H2O Ph ONa c) O SOCl2 Ph Cl 55  d) O NaCl Ph NO REACTION OH O e) NH3 Ph 1 equiv. ONH4 O f) NH3 Ph heat NH2 56  O g) CH3OH O Ph Ph H2SO4 OH OCH3 O h) CH3OH Ph NaOH ONa O i) NaOH O CH3COCl Ph O 57 j) O O Ph CH3NH2 Ph NHCH3 DCC OH O k) Ph SOCl2 CH3CH2CH2NH2 NHCH2CH2CH3 O l) SOCl2 Ph (CH3)2CHOH OCH(CH3)2 58 22.50) O a) SOCl2 NO REACTION H3CH2CH2C OCH2CH3 O b) H3O+ H3CH2CH2C OH O c) H2O NaOH + CH3CH2OH H3CH2CH2C ONa 59 d) O O NH3 + CH3CH2OH H3CH2CH2C OCH2CH3 H3CH2CH2C NH2 O e) CH3CH2NH2 + CH3CH2OH H3CH2CH2C NHCH2CH3 60 22.51) a) O O + Ph H3O Ph NH2 OH b) H2O O Ph NaOH ONa 61 22.52) O a) C6H5H2C CN H3O+ C6H5H2C OH O H2O b) NaOH C6H5H2C ONa O CH3MgBr c) H2O C6H5H2C 62  O d) C6H5H2C CN CH3CH2LI H2O C6H5H2C O e) DIBAL-H H2O C6H5H2C H f) LiAlH4 H2O C6H5H2C NH2 63 Carboxylic acids, syntheses: 1. oxidation of primary alcohols RCH2OH + K2Cr2O7  RCOOH 2. oxidation of arenes ArR + KMnO4, heat  ArCOOH 3. carbonation of Grignard reagents RMgX + CO2  RCO2MgX + H+  RCOOH 4. hydrolysis of nitriles RCN + H2O, H+, heat  RCOOH 1. oxidation of 1o alcohols: CH3CH2CH2CH2-OH + CrO3  CH3CH2CH2CO2H n-butyl alcohol butyric acid 1-butanol butanoic acid CH3 CH3 CH3CHCH2-OH + KMnO4  CH3CHCOOH isobutyl alcohol isobutyric acid 2-methyl-1-propanol` 2-methylpropanoic acid 2. oxidation of arenes: KMnO4, heat CH3 COOH toluene benzoic acid CH3 COOH note: aromatic KMnO4, heat acids only! H3C HOOC p-xylene terephthalic acid KMnO4, heat CH2CH3 COOH + CO2 ethylbenzene benzoic acid 3. carbonation of Grignard reagent: Mg CO2 H+ R-X RMgX RCO2MgX RCOOH Increases the carbon chain by one carbon. Mg CO 2 H+ CH3CH2CH2-Br CH CH2CH2MgBr CH3CH2CH2COOH 3 n-propyl bromide butyric acid H+ O O O + RMgX + C R C + MgX R C O- OH O CH3 CH3 CH3 Mg CO2 H+ Br MgBr COOH p-toluic acid Br2, hv Mg CH3 CH2Br CH2MgBr CO2 H+ CH2 COOH phenylacetic acid 4. Hydrolysis of a nitrile: H2O, H+ R-CN R-CO2H heat H2O, OH- R-CN R-CO2- + H+  R-CO2H heat R-X + NaCN  R-CN + H+, H2O, heat  RCOOH 1o alkyl halide Adds one more carbon to the chain. R-X must be 1o or CH3!  Br2, hv NaCN CH3 CH2Br CH2 CN toluene H2O, H+, heat CH2 COOH phenylacetic acid KCN CH3CH2CH2CH2CH2CH2-Br CH3CH2CH2CH2CH2CH2-CN 1-bromohexane H2O, H+, heat CH3CH2CH2CH2CH2CH2-COOH heptanoic acid CH2OH KMnO4 CH3 KMnO4, heat CO2H Br MgBr Mg CO2; then H+ C N H2O, H+, heat carboxylic acids, reactions: 1. as acids 2. conversion into functional derivatives a)  acid chlorides b)  esters c)  amides 3. reduction 4. alpha-halogenation 5. EAS as acids: a) with active metals RCO2H + Na  RCO2-Na+ + H2(g) b) with bases RCO2H + NaOH  RCO2-Na+ + H2O c) relative acid strength? CH4 < NH3 < HCCH < ROH < HOH < H2CO3 < RCO2H < HF d) quantitative HA + H2O  H3O+ + A- ionization in water Ka = [H3O+] [A-] / [HA] Ka for carboxylic acids  10-5 Why are carboxylic acids more acidic than alcohols? ROH + H2O  H3O+ + RO- RCOOH + H2O  H3O+ + RCOO- ΔGo = -2.303 R T log Keq The position of the equilibrium is determined by the free energy change, ΔGo. ΔGo = ΔH - TΔS ΔGo  ΔH Ka is inversely related to ΔH, the potential energy difference between the acid and its conjugate base. The smaller the ΔH, the larger the Ka and the stronger the acid. Effect of substituent groups on acid strength of benzoic acids? Electron withdrawing groups will stabilize the anion, decrease the ΔH, shift the ionization to the right, increasing the Ka, increasing acid strength. COO- G Electron donating groups will destabilize the anion, increase the ΔH, shift the ionization in water to the left, decreasing the Ka, decreasing acid strength. COO- G -NH2, -NHR, -NR2 -OH -OR electron donating -NHCOCH3 -C6H5 -R -H -X -CHO, -COR -SO3H -COOH, -COOR electron withdrawing -CN -NR3+ -NO2 Relative acid strength? Ka p-aminobenzoic acid 1.4 x 10-5 p-hydroxybenzoic acid 2.6 x 10-5 p-methoxybenzoic acid 3.3 x 10-5 p-toluic acid 4.2 x 10-5 benzoic acid 6.3 x 10-5 p-chlorobenzoic acid 10.3 x 10-5 p-nitrobenzoic acid 36 x 10-5 2. Conversion into functional derivatives: a)  acid chlorides O SOCl2 O R C R C OH or PCl3 Cl orPCl5 CO2H + SOCl2 COCl O PCl3 O CH3CH2CH2 C CH3CH2CH2 C OH Cl b)  esters “direct” esterification: H+ RCOOH + R´OH  RCO2R´ + H2O -reversible and often does not favor the ester -use an excess of the alcohol or acid to shift equilibrium -or remove the products to shift equilibrium to completion “indirect” esterification: RCOOH + PCl3  RCOCl + R´OH  RCO2R´ -convert the acid into the acid chloride first; not reversible  O H+ O C + CH3OH C + H2O OH O CH3 SOCl2 O CH3OH C Cl c)  amides “indirect” only! RCOOH + SOCl2  RCOCl + NH3  RCONH2 amide O O PCl3 NH3 O OH Cl NH2 3-Methylbutanoic acid Directly reacting ammonia with a carboxylic acid results in an ammonium salt: RCOOH + NH3  RCOO-NH4+ acid base  O PCl3 O NH3 O C C C OH Cl NH2 amide NH3 O C ammonium salt O NH4  3. Reduction: RCO2H + LiAlH4; then H+  RCH2OH 1o alcohol LiAlH4 H+ CH3CH2CH2CH2CH2CH2CH2COOH Octanoic acid (Caprylic acid) CH3CH2CH2CH2CH2CH2CH2CH2OH 1-Octanol Carboxylic acids resist catalytic reduction under normal conditions. RCOOH + H2, Ni  NR  O H2, Pt CH2 C NR OH LiAlH4 H+ CH2CH2OH 4. Alpha-halogenation: (Hell-Volhard-Zelinsky reaction) RCH2COOH + X2, P  RCHCOOH + HX X α-haloacid X2 = Cl2, Br2 CH3CH2CH2CH2COOH + Br2,P CH3CH2CH2CHCOOH pentanoic acid Br 2-bromopentanoic acid COOH Br2,P NR (no alpha H) RCH2COOH + Br2,P RCHCOOH + HBr + Br n H H; the O NH3 Na RCHCOOH RCHCOOH aminoacid NH2 OH KOH(alc) RCH2CHCOOH RCH=CHCOOH Br then H+ 5. EAS: (-COOH is deactivating and meta- directing) CO2H HNO3,H2SO4 NO2 CO2H H2SO4,SO3 CO2H SO3H CO2H benzoic acid Br2,Fe Br CH3Cl,AlCl3 NR spectroscopy: IR: -COOH O—H stretch 2500 – 3000 cm-1 (b) C=O stretch 1680 – 1725 (s) nmr: -COOH 10.5 – 12 ppm Carboxylic acids, syntheses: 1. oxidation of primary alcohols RCH2OH + K2Cr2O7  RCOOH 2. oxidation of arenes ArR + KMnO4, heat  ArCOOH 3. carbonation of Grignard reagents RMgX + CO2  RCO2MgX + H+  RCOOH 4. hydrolysis of nitriles RCN + H2O, H+, heat  RCOOH carboxylic acids, reactions: 1. as acids 2. conversion into functional derivatives a)  acid chlorides b)  esters c)  amides 3. reduction 4. alpha-halogenation 5. EAS