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Carboxylic Acids and Their Derivatives Carboxylic Acid Derivatives can be prepared from, and converted into carboxylic acids. Preparation from a Carboxylic Acid O R C O OH SOCl2 C R O C 2 R OH - H2O C C R O R Cl O O O C Anhydrides R R H + R'OH Cl O O C C O C R O + H2O R C OR' R + H2O R O O Cl + HNR'2 R C R NR'2 + HCl O C H OR' + H2O R O R C C OR' + HO - H2O R C R C N + H2O OH + R'OH C O- + R'OH H+ NR'2 + H2O C O NR'2 + HO - H2O R Nitriles NH2 C O O R H3PO4, ∆ OH O Amides C C 2 R R O R + HCl OH + + OH H2O O Esters O O Hydrolysis to O carboxylic C acids R Acid Halides R C N + H2O C O- + HNR'2 O ∆, H+ R C OH + NH4+ Nucleophilic Addition to Aldehydes and Ketones vs. Nucleophilic Substitution of Carboxylic Acid Derivatives For example, with a strong nucleophile, "H -", a hydride: Addition Substitution O O C C OH - H R H H R + R H C H C R H Aldehydes and ketones have no substituents that are leaving groups. Remember, H - and H3C - are absolutely terrible leaving groups. Just as in SN2 reactions, you cannot displace a leaving group by a species that is itself a better leaving group. For example: - C Cl R The reverse reactions Cl - CH2 OH R Cl - HO - + R Cl CH2 OH R + - OH + Cl - O C Cl C R Cl - + R C OH + Cl - O O CH2 H Nucleophiles add to carboxylic acid derivatives to form a tetrahedral intermediate. This intermediate can reform the carbonyl by displacing the attached leaving group. The net result is the substitution of the leaving group by the nucleophile. O CH2 Cl C R "Tetrahedral Intermediate" HO - R R Cl O H H H - O- O OH The order of reactivity of carboxylic acid derivatives is simply from best leaving group to worst: Acid chloride > anhydride > carboxylic acid = ester > amide Cl > R-CO2 > HO = RO - > R2N Any derivative on the right can be prepared from one to its left, but not the other way around (except for carboxylic acids that can be prepared from all these derivatives). R C Cl + - OH Nucleophilic Addition-elimination Reactions of Carboxylic Acid derivatives and their relative reactivity Nucleophilic Acyl Substitution SN2 Nu: H2 C R X R H2 C R R C Cl O R C Cl O X R C Nu + X "Tetrahedral Intermediate" Nu: O O R C O C R O X C R O Nu R C O C R O C Nu + X O O O O R C OR' O R C OR' O R C OH O R C OH O R C NH2 O R C NH2 O R C O C R Leaving Group (X) Just as in SN2, you cannot displace a leaving group by a better leaving group. O R C O O R C O Preparation of Carboxylic Acids Carboxylic Acids can be prepared from the hydrolysis of their derivatives. Other methods O CH2CH3 C Aq. KMnO4, heat CO2H Aq. KMnO4, heat Jone's Reagent C CH2OH C Pentanal (or other strong oxidizing agents) H Benzoic Acid Hexanedioic Acid (Adipic Acid) CO2H 1-Pentanol or OH Pentanoic O Acid (Valeric Acid) O O Br Mg, Et2O Bromocyclohexane OH MgBr C 1.) CO2 2.) H + Cyclohexylmagnesium Bromide OH Cyclohexanoic Acid Hydrolysis of Nitriles O CH2 C N H2O, H2SO4 100°C, 3 h Phenylacetonitrile C 1-Cyanocyclohexene N 1.) KOH (aq.), reflux, 17 h 2.) H + CH2 C OH 78% 2-Phenylethanoic acid (Phenylacetic acid) CO2H 79% 1- Cyclohexenoic Acid Acid Halides (u su a lly ch lor id es or b r om id es) O O C C CH3 Br Eth a n oyl Ch lor id e (Acetyl Ch lor id e) Cl Ben zoyl Br om id e Prepared by heating a carboxylic acid in Thionyl Chloride CH3 O O C C OH CH3 + SOCl 2 O O O S + Cl - +H O C CH3 Cl - O S Cl Cl + Th ion yl Br om id e gives a cyl b r om id es O SO2 + Cl - O - C CH3 Cl Prepared by heating a carboxylic acid with PBr3 . Ph O O C C OH Ph + PBr 3 OCOPh O P Ph OCOPh + Br - + +H OCOPh C O P OCOPh Br PCl 3 gives a cid ch lor id es. O H3 PO3 Oxalyl Chloride is a kin d er , gen tler m eth od of for m in g a cid ch lor id es. O H C O OH Cl C H C H CH3 CO2 OCH3 Br Cl H CH3 CO2 C O O C Ph OCH3 Cl Reactions of Acid Halides Anhydrides upon reaction with carboxylate salts. This is one of the best ways to prepare "mixed anhydrides" (anhydrides derived from two different carboxylic acid parents). O O CH3 C + ONa+ Cl Sodium Acetate O C CH3 O C O C Acetic Benzoic Anhydride Benzoyl Chloride Carboxylic Acids upon reaction with HO - or water O O C Cl C OH aq. NaOH + NaCl Benzoic Acid Esters upon reaction with alcohols. O HO O C HO O CH3 PhCOCl, Ph Pyridine, CH2Cl2 O C O O O C O HO CH3 Phenyl esters can be prepared this way. (Difficult otherwise) O OH Cl C CH 3 Pyridine Useful way to tie up the acidic proton. As in aspirin. O C O CH3 CH3 CH3 Amides upon reaction with amines O O C Br CH3CH2 Propanoyl Bromide O CH3 C C NH2 CH3CH2 Propanamide (A 1° amide) + NH3 Ammonia Cl + CH3 C + N H N-Phenylethanamide (A 2° amide) O CH CH Aniline O C ClH4N O H2N Ethanoyl Chloride + NH4Br 2 CH2CH3 Cl C 3 N H N CH2CH3 CH2CH3 ClH2N CH2CH3 CH2CH3 Benzoyl Chloride N,N-Diethylbenzamide (A 3° amide) Diethylamine Aldehydes upon reaction with Lithium tri-t-butoxyaluminumhydride, LiHAl(t-BuO)3 O H C H Cl C O H Al O C O C O H C H CH3CO2 CH3CO2 OCH3 OCH3 Aryl Ketones upon Friedel-Crafts reaction with aromatic compounds O O Cl C CH 3 C AlCl3 CH3 CH3O OCH3 Methoxybenzene (Anisole) p-Methoxyacetophenone H Reactions of Anhydrides Carboxylic Acids with water or hydroxide as the nucleophile O O H2O + 2 CH3CO2H C C H3C O CH3 Esters from alcohols Another good method of making phenyl esters (esters of phenol). COOH COOH O OH + Salicylic Acid H3C C O O C CH3 CH3 Acetic anhydride Acetyl salicylic Acid Cyclic Anhydrides give "half esters": + CH3COOH O O CH2CH3 C O HO CH CH2CH2CH3 C 2-Ethylhexanol O Phthalic Anhydride O O O CH2CH3 C O CH CH2CH2CH3 C OH O H+ CH2CH3 C O CH CH2CH2CH3 CH2CH3 HO CH CH2CH2CH3 C O CH CH2CH2CH3 CH2CH3 O "Dioctyl Phthalate", a plasticizer (used principally in PVC) [Di-(2-ethylhexyl)phthalate] Amides with amines. O H3C C O O C O H2N CH3 H3C C N H N-Phenylacetamide (Acetanilide) O Esters R = H, Alkyl or Aryl R' = Alkyl or Aryl C R' R O Nomenclature - Esters are chemically derived from two portions - an alcohol and a carboxylic acid - and are named as such. O CH3CH2 O H HO C CH3 H O + C CH3 + H2O Ethanol Water Ethanoic acid Ethyl Ethanoate (or Acetic Acid) (or Ethyl Acetate) The reaction described above is often referred to as a "condensation reaction". CH3CH2 O If the alcohol and acid are located on the same molecule, then a cyclic ester is the product. Such molecules are called "lactones" and are in all respects, esters. O O C H+ HO C O + H2O OH 3-Hydroxybutanoic Acid Butyrolactone Esters are prepared from the reaction of : Acid halides + alcohols Anhydrides + alcohols These are the best methods for the preparation of phenyl esters (esters of phenol) and esters of sterically hindered alcohols. O O CH3 CH3 NEt3 (Triethylamine) C C CH3 O C CH3 Cl + HO C CH3 Ph t-Butyl Benzoate CH3 CH3 Benzoyl Chloride t-Butanol O O Pyridine, OH CH2CH3 O CH2Cl2 C C Pr Pr C O O Propanoic Anhydride Phenyl Propanoate Phenol Occasionally, esters are prepared by Sn2 reactions where the nucleophile is a carboxylate. O O C O - Na+ + CH3I Sodium Methyl Acrylate Iodide C OCH3 Methyl Acrylate Acid Catalyzed Esterification O: : C H OH CH3 Acet ic acid C CH3 + H O 2 O Meth yl Aceta te CH3 HO CH3 Meth an ol : CH3 + + H O: O OH C C OH CH3 OH + CH3 C OH + H O CH3 OH HO CH3 OH C CH3 O OH OH2 + CH3 CH3 CH3 OH C+ O CH3 C H OH + CH3 OH O H CH3 OH2 CH3 OH C O+ CH3 C OH O + CH3 + H O CH3 O C O CH3 CH3 Th is r ea ction is called a con d en sat ion r ea ction b ecau se wat er is p r od u ced . C H + O CH3 Transesterification One thing to keep in mind with handling esters is the possiblity of transesterification. For example, let's say you wanted to convert the following aldehyde into its dimethyl acetal. The alkyl group on the ester is also liable to be exchanged. We call this transesterifcation. It can be a nuisance. Of course, it works the other way too. Attempts to prepare esters from carboxylic acids that also incorporate an acetal can also be complicated by transacetalation. O C O OCH3 CH3O H C CH3OH, H + C C O OCH2CH3 C H O OCH3 H OCH3 CH3O OCH2CH3 CH3CH2O C CH3OH, H + C O H C OCH3 OH Transacetalation in the preparation of an ester. Transesterification during the preparation of an acetal. There is a very important example of a useful transesterification reaction between a diester and a diol. O CH3O O C C OCH3 HO Dimethyl Terephthalate H+ OH CH3O O O C C Ethylene glycol HO CH3O CH3O O O C C O O C C O O O O + CH3OH OH HO O OH O O O C C O OH + CH3OH OCH3 O O C C O O C C O n Poly(ethylene terephthalate), a polyester. OH + CH3OH Terylene, Dacron (mylar film, magnetic recording tape, frozen food packaging, yarn) Reactions of Esters Base Induced Hydrolysis - "Saponification" O O C OCH3 + NaOH C H2O O - Na + + CH3OH Na+ O O C C OCH3 + OH O C OCH3 OH O H - OCH3 Na+ Na Methyl Benzoate O O C Subsequent Addn of HCl OH C O- + Na + CH3OH + NaCl Note that an SN2 mechanism is also plausible, but does not in fact compete. How do we know? O O C OCH3 - C OH O - + CH3OH A very important example of a saponification reaction. O H2C HC H2C O C O (CH2)16CH3 (CH2)18CH3 NaOH O C O O C (CH2)20CH3 O A triacylglycerol or triglyceride. H2C HC H2C OH Na+ - O C (CH2)16CH3 OH Na+ - O C (CH2)18CH3 OH Glycerol Na+ - O O C (CH2)20CH3 O Sodium salts of Palmitic, Stearic, and Arachidic acids resp. Lipids - Fats and Oils The only difference between fats and oils? Both are triglycerides. Fats (butter, lard) Oils (corn, olive, peanut, coconut, canola, sesame etc.) As we have seen, fats and oils are triglycerides - triesters of glycerol and three fatty acids (long straight-chain carboxylic acids). The acid components of these esters are usually different. Saturated Fatty Acids Lauric CH3(CH2)10COOH Myristic CH3(CH2)12COOH Palmitic CH3(CH2)14COOH Stearic CH3(CH2)16COOH Arachidic CH3(CH2)18COOH Unsaturated Fatty Acids Palmitoleic Acid Oleic Acid CH3(CH2)4CH2 CH2(CH2)6COOH CH3(CH2)6CH2 CH2(CH2)6COOH Linoleic Acid CH3(CH2)3 Linolenic Acid CH3 CH2 Arachidonic Acid CH3(CH2)3 CH2 O2C Fat O2C O2C O2C Oil O2C O2C CH2 CH2(CH2)6COOH CH2(CH2)6COOH CH2(CH2)2COOH Still More Reactions of Esters Ammonolysis Reaction with Amines (or ammonia) gives Amides via Nucleophilic Substitution O O C OR + H-N(CH3)2 CH3 CH3 C N(CH ) 3 2 Reduction - Esters can be reduced to alcohols by LAH but not by NaBH4. Note that both portions of the ester (alcohol and acid) are liberated as alcohols. Since this is the case mixtures may result. If one of the alcoholic products is easily removed, this is an excellent way to prepare alcohols. O CH2OH C 1.) LAH, Et2O OCH2CH3 2.) H + _ O C H O OCH2CH3 C - H _ + CH3CH2O O C OCH2CH3 H H_ O OH C CH3CH2OH H H H C + H H Grignard Reactions OH O C OCH3 Et2O + 2 CH3CH2MgBr 2.) H + C CH2CH3 CH2CH3 This is a great way to make 3° alcohols in which two of the alkyl substituents are the same (both derived from the Grignard reagent). The mechanism for this process is completely analogous to that of hydride reaction above. Just replace "H - " with "Et-" and you have it. O Amides R C NR' 2 A word about the electronic nature of amides in comparison to other functional groups. In amides and esters, the lone pair electrons of the heteroatom next to the carbonyl can be delocalized into the C=O bond. Nitrogen can do this much more effectively than oxygen (because N is less electronegative). As a result, the delocalized resonance structure contributes more to the nature of amides than the corresponding structure for esters. This helps explain why amides are less basic than amines and less reactive than esters (which are, in turn less reactive than aldehydes/ketones). There are other manifestations of this property. Aldehydes/ Ketones O IR C=O R C H 1715 cm-1 Amides O R O Esters O - + R' C N R R' 1695-1650 cm-1 C NR' 2 Because of the delocalization of electrons, there is substantial single-bond character in the carbonyl. This lowers the force constant and consequently the position of the C=O band. R C OR' O- O- + R C OR' R C + OR' 1750-1735 cm-1 In esters, an inductive effect is said to be operating (left-most structure). This increases the polarization of the C=O bond increasing the attraction of the two atoms and therefore increasing the force constant. This also implies that there is a substantial amount of double-bond character in the C-N O bond. This in turn implies that there may not CH3 C be free rotation about the C-N bond. There is H N clear evidence of this in the NMR spectra of CH3 3° amides (as shown for N,N-Dimethylformamide). The two methyl groups resonate at different positions. O- + CH 31.1 ppm 3 C N H CH3 36.2 ppm Nomenclature and Classification Like esters, amides can be thought to consist of two parts: a carboxylic acid portion and an amine portion. O OH NH3 - H2O C : : C O A primary amide. NH2 Benzamide Ammonia Benzoic Acid O H2N - H2O C H OH Methanoic Acid (Formic Acid) H C A secondary amide. : : O N H N-Phenylmethanamide (N-Phenylformamide) Aniline O CH3 OH Ethanoic Acid (Acetic Acid) N CH3 - H2O CH3 CH3 C : H C : O N CH3 A tertiary amide. CH3 N,N-Dimethylethanamide (Dimethyl acetamide, DMA a teratogen) Dimethylamine O N : C + H2N-OH - H2O C OH O H+ Beckman Rearrangement C : : Cyclic Amides are called "Lactams" N H Caprolactam As we have already noted, amides can be prepared from the reaction of amines with Acid halides Anhydrides Esters Carboxylic acids i.e. from all of the other carboxylic acid derivatives. Reactions of Amides Hydrolysis with Aqueous Acid or Base CH3CH2 C CH : O NH2 O H2O, H2SO4 CH3CH2 Heat CH C _ + + NH4 HSO4 OH 88% H3C NH2 KOH, heat ethanol/water : C : 2-Phenylbutanamide O _ + CH3CO2 K N 95% H Reduction (with strong hydride reducing agents) O H H : N CH2CH3 1.) LAH, Ether 2.) H + CH2CH3 N,N-Diethylbenzamide C N CH2CH3 : C CH2CH3 Benzyldiethylamine Polymerization C Cat. Nu- N C C H : Nu O O Nu N _ H N : N H O: C : O C Nu O C N _ H N H O C O H A polyamide. C N n _ : N HO : : C : O : Nu N H H Another polyamide HO O C C H2N OH 1,6-Hexanediamine (Hexamethylene Diamine) O Hexanedioic Acid (Adipic Acid) _ O NH2 O + H3N C _ O C + NH3 n Heat to drive off H2O O C O O H C N N n H Polyhexamethyleneadipamide Nylon 6,6 Developed during the war to replace silk. Nylon first debuted in toothbrushes. It is one of the strongest of all synthetic fibres. Now used mainly in tires where its strength is important. Nylon was developed by W. H. Carothers of DuPont. Believing himself to be a failure as a scientist, he committed suicide three weeks before the patent was filed. Nylon stockings were first sold in New York on May 15, 1940. In two hours, 4 million pair were sold. Yet another polyamide HO2C CO2H H2N NH2 - H2O C Kevlar C N N O O H H n Still yet another polyamide R1 H2N CH R CO2H H2N C O H O N C R2 R3 N C H O H O N C R4 R5 N C H O OH R = H, CH3, CH2OH, CH2SH, CH2CO2H, (CH2)4NH2, iPr, iBu, PhCH2 and many more !