318-15 - Textbook Assignment: Chapter 18 Homework (for...

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Unformatted text preview: Textbook Assignment: Chapter 18 Homework (for credit): POW 7 posted (Due 3/22) Today’s Topics: Carboxylic Acids- Derivatives Kyle Williams OH: 4-5 PM March 10th and April 7th Carboxylic Acids Diazomethane • Diazomethane, CH2N2 – a potentially explosive, toxic, yellow gas, is best represented as a hybrid of two contributing structures H C N N: H + H C N N: H + – treating a carboxylic acid with diazomethane gives a methyl ester : : O RCOH + CH2 N 2 Diazomethane ether O RCOCH3 + N 2 A methyl ester Diazomethane • Esterification occurs in two steps Step 1: proton transfer to diazomethane O RCOH+ O CH2 N N + R C O: – + CH3 N N + A carboxylate an ion Methyldiazonium cati o n Step 2: nucleophilic displacement of N2 O R C O:– + CH3 N N + SN 2 O R C O CH3 + N N Acid Chlorides • The functional group of an acid halide is a carbonyl group bonded to a halogen atom – among the acid halides, acid chlorides are by far the most common and the most widely used O - C- X Functional group of an acid halide O CH3 CCl A cetyl chloride O C-Cl Benzoyl chloride Acid Chlorides – acid chlorides are most often prepared by treating a carboxylic acid with thionyl chloride O OH Bu tanoic acid O + SOCl2 + SO2 + HCl Cl Th ionyl ch loride Butanoyl chlorid e Acid Chlorides • The mechanism for this reaction is divided into two steps. Step 1: reaction with SOCl2 transforms OH, a poor leaving group, into a chlorosulfite group, a good leaving group O O O O R-C-O-H + Cl-S-Cl R C O S Cl + H-Cl A chloros ulfite grou p Acid Chlorides Step 2: attack of chloride ion gives a tetrahedral carbonyl addition intermediate, which collapses to give the acid chloride O R C O S Cl O + Cl - O O: R C O S Cl O R-C-Cl + SO2 + Cl - Cl A tetrah edral carbonyl ad di ti o n i nte rme d i ate Note: the reaction is irreversible Decarboxylation • Decarboxylation: loss of CO2 from a carboxyl group – carboxylic acids, if heated to a very high temperature, undergo thermal decarboxylation O R- C-OH decarb oxylation h e at R-H + CO2 – most carboxylic acids, however, are quite resistant to moderate heat and melt or even boil without decarboxylation Decarboxylation The most important exceptions are carboxylic acids that have a carbonyl group beta to the carboxyl group i.e.- β keto-acids –this type of carboxylic acid undergoes decarboxylation on mild heating O O O + CO 2 warm βα OH 3-Oxobu tan oic acid (Acetoacetic acid) Acetone Decarboxylation – thermal decarboxylation of a β-ketoacid involves rearrangement of six electrons in a cyclic six-membered transition state O H O O (A cyclic s ix-membered tran sition state) O H O +C O O + CO2 A ketone (1) (2) En ol of a k e to n e Decarboxylation – decarboxylation occurs if there is any carbonyl group beta to the carboxyl – malonic acid and substituted malonic acids, for example, also undergo thermal decarboxylation O O 140-150°C HOCCH2 COH Prop anedioic acid (Malon ic acid ) O CH3 COH + CO2 – thermal decarboxylation of malonic acids also involves rearrangement of six electrons in a cyclic six-membered transition state O HO H O O (1) HO O H O +C O (2) O HO A carb oxylic acid + CO2 A cyclic six-membered Enol of a transition s tate carb oxylic acid acetaminophen Organic acid derivatives • There are five classes of organic acid derivatives • Each arises from a dehydration reaction, usually a condensation • Therefore, each derivative can also be hydrolyzed O RCCl A n acid chloride - H2 O OO RCOCR' An acid anhydride - H2 O O O RC- OH H-OCR' O RCOR' An ester O RCNH2 An amide RC N A nitrile - H2 O HO H RC=N Th e enol of an am i de - H2 O O RC- OH H-OR' - H2 O O RC- OH H-NH2 O RC- OH H-Cl Acid halides • The functional group of an acid halide is an acyl group bonded to a halogen – the most common are the acid chlorides – to name, change the suffix -ic acid to -yl yl halide halide O O RCAn acyl g roup O CH3 CCl Cl Cl O Cl O Hexan edioyl ch loride (Adip oyl chloride) Ethan oyl ch loride Benzoyl chloride (Acetyl ch loride) Sulfonyl Chlorides – replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride sulfonyl O CH3 SOH O Methanes ulfon ic acid O H3 C SOH H3 C O p -Toluen esulfon ic acid O CH3 SCl O Methanes ulfonyl ch loride (Mesyl ch loride, MsCl) O SCl O p -Toluen esulfon yl chloride (Tosyl chlorid e, TsCl) Acid Anhydrides • The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom – the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups) – to name, replace acid of the parent acid by acid anhydride anhydride OO CH3 COCCH3 A cetic an h ydrid e OO COC Ben zoic anh ydrid e Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived O O O O O Phthalic anhydride O O Succinic anhydride O O Maleic anhydride Esters • The functional group of an ester is an acyl group bonded to -OR or -OAr – name the alkyl or aryl group bonded to oxygen followed by the name of the acid – change the suffix -ic acid to -ate O O O O Ethyl ethan oate (Ethyl acetate) Is op ropyl ben zoate EtO O OEt O D iethyl butaned ioate (D ieth yl s uccin ate) Esters • Cyclic esters are called lactones lactones – name the parent carboxylic acid, drop the suffix -ic acid and add -olactone O α 1 2 O 34 α 2 β3 1 O O α β γ 3 4 2 56 1 O O H3 C 3-Bu tanolactone (β -Butyrolactone) βγ 4-Bu tanolactone (γ-Bu tyrolacton e) δ ε 6-Hexan olacton e (ε -Cap rolactone) Amides • The functional group of an amide is an acyl group bonded to a nitrogen atom – IUPAC: drop -oic acid from the name of the parent acid and add -amide – if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by NO CH3 CNH2 A cetamide (a 1° amide) OH CH3 C-N CH3 O CH3 H-C-N CH3 N- Methylacetamide N ,N-D imethyl(a 2° amid e) formamid e (DMF) (a 3° amide) Amides • Cyclic amides are called lactams lactams – name the parent carboxylic acid, drop the suffix -ic acid and add -lactam α α 2 β3 1 O NH β γ 3 4 5 2 6 O 1 NH H3 C 3-Butanolactam (β-Butyrolactam) penam –old term for β-lactam δ ε 6-Hexan olactam (ε-Caprolactam) Penicillins the penicillins are a family of β-lactam antibiotics The compound is an exceptional “acylating” agent because of the ring strain of the lactam. Inhibit cell wall synthesis by acylating and de-activating the required enzymes. Penicillins HO The penicillin s differ in the grou p bond ed to the acyl carb on O the penicillins are a family of β-lactam antibiotics H NH H2 N β-lactam O N COOH H S Amoxicillin (a β-lactam an tib iotic) Pharmacophoresubstructure responsible for the biological activity Cephalosporins the cephalosporins are also β-lactam antibiotics The cephalosporins d iffer in the group bonded to the acyl carbon an d the s ide chain of the thiazin e rin g O NH2 N H O HH N S Me COOH β-lactam Cep halexin (Keflex) Bacteria develop resistance by producing β-lactamases-enzymes, which can hydrolyze the lactam before it can inhibit cell wall synthesis. Imides • The functional group of an imide is imide two acyl groups bonded to nitrogen – both succinimide and phthalimide are cyclic imides O NH O Succinimide O NH O Phthal i m i de Acidity of N-H bonds • Amides are comparable in acidity to alcohols – water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water-soluble salts • Sulfonamides and imides are more acidic than amides O CH3 CNH2 Acetamide pKa 15-17 O SNH2 O O NH O NH O O Ben zenesu lfonamide Succinimide Phth alimide p K a 10 p Ka 9.7 p Ka 8.3 Prontosil First sulfonamide (sulfa) antibiotic Acidity of N-H bonds Imides are more acidic than amides because: 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and 2. the imide anion is stabilized by resonance delocalization of the negative charge O N O O N O A re so nanc e -stabi l i z e d an i on O N O Acidity of N-H bonds – imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts O NH + NaOH O pKa 8.3 (stronger acid) O N Na + O (stronger base) (weaker base) pKa 15.7 (weaker acid) + H2 O This property is used to render pharmaceutical agents water soluble: Thalidomide-sedative, hypnotic Barbituric Acid Acidity of this H is used to Make the derivatives soluble 1. Sedative was used in pregnant women from 1956~1962 in Europe/Africa 1. Never approved in US 2. Caused birth defects (teratogen) 3. Later found use in leprosy treatment Barbituric Acid Sodium Pentothal® -Sodium thiopental S Na HN Phenobarbital N O CH2 O HN NH O CH2 H 3C O H 3C H 3C CH3 O Anticonvulsant, hypnotic, anxiolytic Characteristic Reactions • Nucleophilic acyl substitution: an addition-elimination sequence resulting in substitution of one nucleophile for another -: + :Nu- O R C Y R O C Nu R O C Nu + :Y- Y Tetrah edral carbonyl addition in termediate S ubs titu tion p rodu ct Characteristic Reactions – in the general reaction, the leaving group, as an anion, illustrates an important point: – the weaker the base, the better the leaving group O R2 N - RO - RCO - X - Increasin g leaving ability Increasin g b asicity Reaction with H2O - Acid Chlorides – low-molecular-weight acid chlorides react rapidly with water – higher molecular-weight acid chlorides are less soluble in water and react less readily O CH3 CCl + H2 O Acetyl chlorid e O CH3 COH + HCl Hydrolysis-bond breaking using water Reaction with H2O - Anhydrides – low-molecular-weight acid anhydrides react readily with water to give two molecules of carboxylic acid – higher-molecular-weight acid anhydrides also react with water, but less readily OO CH3 COCCH3 + H2 O Acetic an hydrid e O O CH3 COH + HOCCH3 Step 1: addition of H2O to give a TCAI H+ O H O CH3 -C-O-C-CH3 + O O CH3 -C-O-C-CH3 O-H H H O H O-H H OO + + H-O-H CH3 -C-O-C-CH3 O H H Tetrah edral carbonyl addition intermediate H Step 2: protonation followed collapse of the TCAI H H +O H H O H O O H +H O H H H +O H CH3 O O C+O C O H CH3 H OO CH3 -C-O-C-CH3 O H CH3 C O C CH3 H ...
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