Derivatives of Carboxylic Acid PDF

Derivatives of Carboxylic Acid Dr. Ayad MR Raauf 1st Semester College of Pharmacy, Al-Farahidi University 1  Derivatives of...

Derivatives of Carboxylic Acid Dr. Ayad MR Raauf 1st Semester College of Pharmacy, Al-Farahidi University 1  Derivatives of Carboxylic acit M/1 Carboxylic Acid :O: &35 -10 8.. _ -lo R C..: O &Y1 Jjy : O: · ind!.. carboxylate X R C.. : Cl &j Jim acid chloride sa - : O: R C N: l.. R C OH.. nitrile :O: : O:.. R C.. O C R :O: :O:.. H.. R C N acid anhydride R O R - C.. H 55555 -1/18 amide - ester S - Glo 6 2 - , -  Nomenclature of Acid Halides GCho jas -1994 -2/18 Alkane IUPAC: alkanoic acid → alkanoyl halide - N : O: - -.. - Common: alkanic acid → alkanyl halide.. : pentanit isO R C Cl propana chlorite O NH2 O NO2. S1 = 5. 561 CH2 CH2 C Cl H3C CH CH2 CH2 C Cl 3 2. 19130 3 2 1 51 -digss 3-aminopropanoyl chloride - - - 4-nitropentanoyl chloride Giddin · is is a dis Nomenclature of Acid Anhydrides Anhytrites M is Acid anhydrides are prepared by dehydrating carboxylic acids · s.. acid O O O O carboxy c  is is 21 · CH3 C OH H O C CH3 CH3 C O C CH3 & " & = + - - H2O - = & 601-46* acetic anhydride Functionalof 90 acetic acid : -i group Acid Anhydrides alleanoic cit methanoic ethanoic anhydride a ethanoic acid O acing O function group j1418d Simi o R & ethanoic a cit iii) ethanoic 8 u - CH3 C - - O C= H - 3 ethanoic methanoic anhydride - - Nomenclature of Esters Esters occur when carboxylic : O:.... - H2O :O:.. OH H O R C.. +.. acids react with alcohols R carboxylic alcohol H+ R C ester O.. R acid I: alkanoate c: alkanate O & alkyl O : O O C H C o O C(CH3)3 & = > i CH3 O C CH3 > - - = - - phenyl methanoate t-butyl methyl ethanoate T - - benzenecarboxylate ate : ic acities function group GoR · & exigu 2 60. &R 5.. S1 o i givi Gr 8.. S19 4  "15& Nomenclature of Amides 1° amide O O H O 3° amide R O 2° amide R C N R C N - H N-substituted amide - R N,N-disubstituted amide R R C N function group of amia- H g = - n NHe  1° amides: ‘alkanoic acid’ + amide → ‘’alkanamide’ - 80 NHR wit - Toa -2 amike iSse I NRe &sigs - N -= 4) acit O butanoic O Cl O H H H NO2 C N CH3CH2CH2 C N C N H 4321 H H butanamide 3-chlorocyclopentanecarboxamide I: p-nitrobenzenecarboxamide & Ges (primary , seconding , firtary JTIs *  2° and 3° amides are N-substituted amides ·. ossR 2004 => 8 8 is misdain C butanamite 42 Methyl N-ethyl propanamide & - N - CH3CHzCHnConct Hy CHc-cti methyl O CH3 O CH3 CH3 - &C N - O CH3CH C N - CH2CH3 H3C C N H fig hyl H 2-methy-N- N-ethyl-N-methylcyclobutanecarboxamide N-phenylethanamide -- - methylpropanamide panamit 5  -xjj9 Nucleophilic Acyl Substitution in Acid Derivatives - - - In carboxylic acid derivatives, the acyl group (RCO) is bonded to a leaving group (-Y). substitution leaving group R C O O R C Y reaction - R C O Y O i O R C Nu + Y: - Draw the mechanism. Nu:- acyl group Nu wealhil fo se Nuclophil NuclophilB -, * The leaving group (-Y) becomes a base (Y:-). The acid derivative is reactive If the -5 & base formed is weak (unreactive). Weak bases are formed from good leaving groups. NigtaVe charge For the carboxylic acid derivatives shown, circle the leaving group. Then draw the strong Nuclo structure of the base formed, give its pKb, and describe it as a strong or weak base. Phil &-j6= 25 -j acid derivative leaving group · pKb strength as base Nutral E : -T spe - -Sisal 591jy O Br & 21055 - &jeig R C Cl Br Cl 70 , /1 +21 non basic regis and 1149 O O - O weak base weaeclophil g - -- R C O C R O C R +9 - unshere d , pere of O -in strong nuclophi electron - R C O R leaving O R -2 strong base essbsi) - group -1041936 NH3 NHRNR2 O U strong Nuclophil - NRz. WHR R C NH2 ~ Re NH2 -21 v. strong base dig = Reagentamaon product + Reproduct Nu)9 80 6 ↳staran e) substrate. + on % 9.515 jet Acylgroup Nuclophil - -05-0 Nu  -18 Nucleophilic Acyl Substitution in Acid Derivatives We will study the reaction of only a few nucleophiles with various carboxylic acid Nuclophil derivatives and we will see that the same kinds of reactions occur repeatedly. 2155 Jan 24524 Lets NoH) Hydrolysis: Reaction with water to produce a carboxylic acid & 800 - - ↑ Jas Alcoholysis: Reaction with an alcohol to produce an ester - RCNa RNH2 & Aminolysis: Reaction with ammonia or an amine to produce an amide 50 -135 - RMX Grignard Reaction: Reaction with an organometallic to produce a ketone or alcohol & - 8 -0 = Mil Reduction: Reaction with a hydride reducing agent to produce an aldehyde or alcohol 2y · - H Draw the structures of the expected products of these nucleophilic substitution reactions, then circle the group that has replaced the leaving group (-Y) Clien O hydrolysis O H OH R C Y + R C O H O alcoholysis O H OR R C Y + R C O R O aminolysis O H NH2 R C Y + R C NH2 O Grignard O H - R MgX R C Y + reduction R C R O H O hydride R R C H LiAlH3 H 98/ R C Y + reduction H 7  -- i & sin Chemistry of Acid Halides In the same wayYthat acid chlorides are produced by reacting a carboxylic acid with thionyl chloride (SOCl2), acid bromides are produced by reacting a carboxylic acid with phosphorus tribromide (PBr3). reduction, i di : O: (or PCl3) O rducing agent.. R C OH + SOCl2 R C Cl + SO2 + HCl LiALI God /1 O 1989 : O:.. PBr2OH It very very strong + PBr3 R C Br + R C OH uuclophil 1) it dischesde Nuclophil's is (H) 1 Most acid halide reactions occur by a nucleophilic acyl substitution mechanism. The halogen can be replaced by -OH to produce an acid, -OR to produce an ester, -NH2 to produce an amide. Hydride reduction produces a 1 alcohol, and Grignard reaction produces a 3 alcohol. O O : O: H2O R':- MgBr+.. R C Cl R C R' ketone R C OH [H] - + acid R': MgBr : O: ROH NH3 : O:.. R C H aldehyde OH R C O.. R : O: R C R' ester.. [H] RCH2OH R C NH2 R' amide 1º alcohol 3º alcohol 8  Reduction of Acid Chlorides to Alcohols 1. With hydride : Acid chlorides are reduced by LiAlH4 to produce 1 alcohols. The alcohols can of course be produced by reduction of the carboxylic acid directly. & 15-455 - excess CH acidhalide O - CH3 O 3 - 1. LiAlH4 H3C C C Cl H3C C & CH2OH 2,2-dimethyl-1-propanol primary alchol 2. H3O + CH3 CH3 -Hydrolifsis However, the reaction will stop at the aldehyde if exactly 1 equivalent of a weaker hydride is used, i.e.,- i diisobutylaluminum hydride (DIBAH) at a low temperature & (-78°C). - agent - - 78°C ↳ weak reducing 1 equiv. O 1. DIBAH O ealdentde NO2 C Cl NO2 C H 2. H3O+ p-nitrobenzaldehyde , do 2. with Grignards very strong Nuclophil like (H) (RY Grignard reagents react with acid chlorides producing 3 alcohols in which 2 alkyl group substituents are the same. The mechanism the 1st equivalent of Grignard reagent adds to the acid chloride, loss of Cl- from the tetrahedral intermediate yields a ketone, and a 2nd equivalent of Grignard immediately adds to the ketone to produce an alcohol.- & fitrgalcho Sayi O O H3O+ O H O M R - C CH3 C CH3 C CH3 C O Cl CH3 MgBr = CH3 MgBr - - CH3 CH3 *Z J 9 RM - 2-phenyl-2-propanol  " Practice Questions for Acid Chloride Reductions Draw the reagents that can be used to prepare the following products from an acid chloride by reduction with hydrides, Grignards and Gilman reagent. Draw all possible combinations. OH excess I: ethanoyl chloride CH C 1. MgBr O I: 1,1-dicyclopentylethanol 3 H3C C Cl 2. H3O+ 2CuLi CH3CH2 2CuLi O 1. O 1. O 1 equiv. - 78°C 1 equiv. - 78°C C CH2CH3 C Cl or CH3CH2 C Cl 2. + 2. H3O+ H3O excess I: 1-phenyl-1-propanone CH3 OH 1. LiAlH4 CH3 O c: ethyl phenyl ketone H3C C CH2 H3C C C Cl CH3 2. H3O+ CH3 I: 2,2-dimethylpropanoyl chloride I: 2,2-dimethyl-1-propanol O DIBAH O 1. 1 equiv. - 78°C C Cl I: cyclohexanecarbonyl chloride C H I: cyclohexanecarbaldehyde 2. H3O+ 10  :O: : O: Preparations of Acid Anhydrides.. R C.. O C R Preparation of Acid Anhydrides: Dehydration of carboxylic acids as previously discussed is difficult and therefore limited to heat a few cases. O O O O O  CH3 C OH + H O C CH3 CH3 C O C CH3 - H2O acetic acid acetic anhydride A more versatile method is by nucleophilic acyl substitution of an acid chloride with a carboxylate anion. Both symmetrical and unsymmetrical anhydrides can be prepared this way. same 550) : O: : O: : O: carboxylic a cit : O: ether 25ºC.. _.. H C O.. : O Na + + Cl C CH3 SN2 H C O.. C CH3 + NaCl Ge sodium formate acetyl chloride acetic formic anhydride Acidhaliea Draw all sets of reactants that will produce the anhydride shown with an acid chloride. O O CH3 C O- Na+ + Cl C O O CH3 C O C O O CH3 C Cl + Na+ -O C 11  - :O: : O: Reactions of Acid Anhydrides.. R C.. O C R The chemistry of acid anhydrides is similar to that of acid chlorides except that anhydrides react more slowly. Acid anhydrides react with HOH to form acids, with ROH to form esters, with amines to form amides, with LiAlH4 to form 1 alcohols and with Grignards to form 3 alcohols. Note that ½ of the anhydride is wasted so that acid chlorides are more often used to acylate compounds. Acetic anhydride is one exception in that it is a very & common acetylating agent. O O % : O:.. H2O - R C O C R R':- MgBr+ O ketone 2 R R C R' C OH [H] weak acid Nuclophil R':- MgBr+ : O: R'OH NH3 : O:.. OH = R C O 2 R C H aldehyde ester.. R' : O: R C R'.. [H] 2 RCH2OH + :O: R C NH2 R'.. amide 1º alcohol acid HO C R = 3º alcohol 12 Practice Questions for Acid Anhydrides Show the product of methanol reacting with phthalic anhydride O O C C OCH3 O + CH3OH 2-(methoxycarbonyl)benzoic acid C C OH O O Draw acetominophen; formed when p-hydroxyaniline reacts with acetic anhydride O O O O HO NH2 + CH3 C O C CH3 HO N C CH3 + CH3 C OH H N-(4-hydroxyphenyl)acetamide 13 Preparation of Esters 1. SN2 reaction of a carboxylate anion with a methyl or 1 alkyl halide & Estar is o : O: : O:.. _.. R' R C O R C O.. : Na+ + Br SN2.. R' 2. Fischer esterification of a carboxylic acid + alcohol + acid catalyst - : O: -Nas : O:.. + H.. R R' R C O C OH + OH.. R' weal whil 3. Acid chlorides react with alcohols in basic media = O 3as : O:.. R' R C O + HCl R C Cl + - OH.. R' e ~ weaephil 14  110=22 Reactions of Esters Esters react like acid halides and anhydrides but are less reactive toward nucleophiles because the carbonyl C is less electrophilic. Esters are hydrolyzed by HOH to carboxylic acids, react with amines to amides, are reduced by hydrides to aldehydes, then to 1alcohols, and react with Grignards to 3 alcohols. : O:.. O R C O.. R' R':- MgBr+ H2O R C R' ketone [H] : O: H + NH3 R':- MgBr+.. : O: R C OH OH : O: R C H aldehyde acid.. R C R' R C NH2 [H] RCH2OH amide + R' 3º alcohol - R'OH 1º alcohols 15  %- - Hydride Reduction of Esters Esters are easily reduced with LiAlH4 to yield 1 alcohols. The mechanism is similar to that of acid chloride reduction. A hydride ion first adds to the carbonyl carbon temporarily forming a tetrahedral alkoxide intermediate. Loss of the –OR group reforms the carbonyl creating an aldehyde and an OR - ion. Further addition of H: - to aldehyde gives the 1 alcohol. Draw the mechanism and show all products. strong rucef asent - O H 0-0-2 O LiAlH4 O LiAlH4 O H3O+ R C O R' R C H R C H + R'OH R C H - H H sodised - - OR' Primar So Draw and name the products. O excess 1. LiAlH4 CH2OH O OH 2. H3O+ 16 Grignard Reduction of Esters Esters react with 2 equivalents of Grignard reagent to yield 3 alcohols in which the 2 substituents are identical. The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard to yield a 3 alcohol. triphenylmethoxide of MgBr MgBr - O O O C OCH3 C C H3O+ - H - OCH3 methyl benzoate O benzophenone C + CH3OH a cide life like triphenylmethanol 17  = Practice with Esters What ester and Grignards will combine to produce the following 2-phenyl-2-propanol CH3 C OH C O + 1. 2 CH3MgBr OR 2. H3O+ CH3 1,1-diphenylethanol OH O C CH3 1. 2 CH3MgBr RO C CH3 + 2. H3O+ 18 Chemistry of Amides - Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted and disubstituted amines (but not trisubstituted amines) all react... O NR3 O NH3 R no reaction C Cl - 3º amine R C NH2 NH2R NHR2 is · 1º amide - 2º amine I 1º amine O O a cidkalid R C NR2 Estan R C NHR 3º amide Anhttret - 2º amide "Win-12y5x is & Reagent 19 Alcoholysis of Amides (to Esters) Alcoholysis of amides occurs by the same acid catalyzed mechanism as acid hydrolysis except that the amido group of the amide is replaced with by an alcohol rather than water. Dry acid, e.g., HCl(g) or H2SO4 must be used otherwise water would compete with the alcohol as the nucleophile producing some carboxylic acid product in place of an ester. The reaction will require a long reflux period because amides are weak electrophiles and alcohols are weak nucleophiles. OH O O · CH3CHCH2CH3 + - Ce N(CH3)2 - C + NH2(CH3)2 ob H2SO4 O * (g) CH3CHCH2CH3 - N,N-dimethylcyclopentanecarboxamide => sec-butyl cyclopentanecarboxylate Heson < Estar is s (fal) o 20 Hydride Reduction of Amides Amides are reduced by LiAlH4. The product is an amine rather than an alcohol. The amide carbonyl group is converted to a methylene group (-C=O → -CH2). This is - unusual. acel o 0 O NH2CH3 O H halid 1. LiAlH4 C Cl C NHCH3 C NHCH3 + N 2. H3O H benzoyl chloride N-methylbenzamide Grignard Reduction of Amides Grignards deprotonate 1º and 2º amides and are not reactive enough to add to the imide ion product. N-H protons are acidic enough (pKa = 17) to be abstracted by Grignards... _ zi : O: : O: + :CH3 MgBr R C.. N H R C.. N R NoRe. _ CH ↑ 2º amide R 4 imide anion :CH3 +MgBr 21