Organic Lecture Series Functional Derivatives of Carboxylic Acids 111 Organic Lecture Series 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 O O O O RCCl RCOCR' RCOR' RCNH2 RC N An acid An acid An ester An amide A nitrile chloride anhydride -H O -H O -H O -H O 2 -H2 O 2 2 2 O O O O O HO H RC-OH H-Cl RC-OH H-OCR' RC-OH H-OR' RC-OH H-NH2 RC=N The enol of an amide 222 Organic Lecture Series 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 halide O O O O Cl Cl Cl RC- CH CCl 3 O An acyl Ethanoyl chloride Benzoyl chloride Hexanedioyl chloride group (Acetyl chloride) (Adipoyl chloride) 333 Organic Lecture Series Sulfonyl Chlorides – replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride O O CH3 SOH CH3 SCl O O Methanesulfonic Methanesulfonyl chloride acid (Mesyl chloride, MsCl) O O H3 C SOH H3 C SCl O O p-Toluenesulfonic p-Toluenesulfonyl chloride acid TsOH (Tosyl chloride, TsCl) 444 Organic Lecture Series 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 anhydride OO O O CH3 COCCH3 COC Acetic anhydride Benzoic anhydride 555 Organic Lecture Series Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived O O O O O O O O O Succinic Maleic Phthalic anhydride anhydride anhydride 666 Organic Lecture Series 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 OEt O EtO O O Ethyl ethanoate Isopropyl Diethyl butanedioate (Ethyl acetate) benzoate (Diethyl succinate) 777 Organic Lecture Series Esters • Cyclic esters are called lactones – name the parent carboxylic acid, drop the suffix -ic acid and add -olactone O ααα O ααα O βββ 2 2 1 1 3 1 ααα 2 O βββ 3 O γγγ 4 O H C 3 4 5 6 3 βββ γγγ δδδ εεε 3-Butanolactone 4-Butanolactone 6-Hexanolactone (((β(βββ-Butyrolactone) (((γ(γγγ-Butyrolactone) (((ε(εεε-Caprolactone) 888 Organic Lecture Series 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 N- O O O H CH3 CH3 CNH2 CH3 C-N H-C-N CH3 CH3 Acetamide N-Methylacetamide N,N-Dimethyl- (a 1° amide) (a 2° amide) formamide (DMF) (a 3° amide) 999 Organic Lecture Series Amides • Cyclic amides are called lactams – name the parent carboxylic acid, drop the suffix -ic acid and add -lactam ααα O βββ 2 ααα O 3 1 2 1 3 γγγ 4 NH βββ NH 5 6 H3 C δδδ εεε 3-Butanolactam 6-Hexanolactam (((β(βββ-Butyrolactam) (((ε(εεε-Caprolactam) penam –old term for βββ-lactam 101010 Organic Lecture Series Penicillins the penicillins are a family of βββ-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. 111111 Organic Lecture Series Penicillins the penicillins are a family of βββ-lactam antibiotics HO O The penicillins H H differ in the NH S group bonded H N to the acyl carbon 2 N O βββ-lactam COOH Amoxicillin (a βββ-lactam antibiotic) 121212 Organic Lecture Series Cephalosporins the cephalosporins are also βββ-lactam antibiotics The cephalosporins differ in the group bonded to the acyl carbon and the side chain of the thiazine ring O H H S N H NH2 N O Me βββ-lactam COOH Cephalexin (Keflex) Bacteria develop resistance by producing βββ-lactamases-enzymes, which can hydrolyze the lactam before it can inhibit cell wall synthesis. 131313 Organic Lecture Series Meropenem Highly resistant to degradation by beta-lactamases or cephalosporinases. 141414 Organic Lecture Series Imides • The functional group of an imide is two acyl groups bonded to nitrogen – both succinimide and phthalimide are cyclic imides O O NH NH O O Succinimide Phthalimide 151515 Acidity of N-H bonds Organic Lecture Series • 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 O O O SNH2 NH NH CH3 CNH2 O O O Acetamide Benzenesulfonamide Succinimide Phthalimide pK 15-17 a pKa 10 pKa 9.7 pKa 8.3 Sulfonamides are the class of “sulfa antibiotics” 161616 Organic Lecture Series Sulfanilamide As an antibiotic, it functions by competitively inhibiting (i.e. by acting as a substrate analogue) enzymatic reactions involving para-aminobenzoic acid (PABA). PABA is needed in enzymatic reactions that produce folic acid which acts as a coenzyme in the synthesis of purine, pyrimidine and other amino acids. 171717 Organic Lecture Series Sulfanilamide tragedy of 1937: Elixir sulfanilamide was an improperly prepared sulfanilamide medicine that caused mass poisoning in the United States in 1937. The preparation used diethylene glycol as the solvent and caused the deaths of more than 100 people. The public outcry caused by this incident and other similar disasters led to the passing of the 1938 Federal Food, Drug, and Cosmetic Act. 181818 Acidity of N-H bonds Organic Lecture Series 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 O O NN N O O O A resonance-stabilized anion 191919 Organic Lecture Series Acidity of N-H bonds – imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts O O - + NH+ NaOH N Na + H2 O O O pK a 8.3 pK a 15.7 (stronger (stronger (weaker (weaker acid) base) base) acid) This property is used to render pharmaceutical agents water soluble: 202020 Organic Lecture Series 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 212121 Organic Lecture Series Barbituric Acid Sodium Pentothal® -Sodium thiopental S N a HNN Phenobarbital O O O CH 2 H C HNNH 3 CH H 3 C 3 O O CH 2 H 3 C Anticonvulsant, hypnotic, anxiolytic 222222 Organic Lecture Series Characteristic Reactions • Nucleophilic acyl substitution: an addition-elimination sequence resulting in substitution of one nucleophile for another - O :O O C + :Nu- C C + :Y- R Y R Nu R Nu Y Tetrahedral carbonyl Substitution addition intermediate product 232323 Organic Lecture Series Fischer Esterifications O O R'OH C C + HOH R OH + H (cat) R OR' Carboxylic Acid Ester 242424 Organic Lecture Series 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 Increasing leaving ability Increasing basicity 252525 Organic Lecture Series Reaction with H 2O - 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 O CH3 CCl + H2 O CH3 COH + HCl Acetyl chloride These are hydrolysis reactions- “breaking of bonds with water” 262626 Organic Lecture Series Reaction with H 2O - Acid Chlorides • Step 1: Make a new bond between a nucleophile and an electrophile. Water attacks the carbonyl carbon directly to give a tetrahedral carbonyl addition intermediate. 272727 Organic Lecture Series Reaction with H 2O - Acid Chlorides • Step 2: Take a proton away. Proton transfer is rapid and reversible. 282828 Organic Lecture Series Reaction with H 2O - Acid Chlorides • Step 3: Break a bond to give stable molecules or ions. Collapse of the tetrahedral intermediate and expulsion of chloride ion gives the carboxylic acid . 292929 Organic Lecture Series Reaction with H 2O - 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 O O O O CH3 COCCH3 + H2 O CH3 COH + HOCCH3 Acetic anhydride 303030 Organic Lecture Series –Step 1: addition of H2O to give a TCAI H + H O O O H O O O + CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 + H-O-H + O H O H O-H H H O-H Tetrahedral carbonyl H H addition intermediate 313131 Organic Lecture Series –Step 2: protonation followed collapse of the TCAI H H H H H H + O O + O H H H H + H H O O O O O O CH C + CH3 -C-O-C-CH3 CH3 CO C CH3 3 O C CH3 O O O H H H 323232 Organic Lecture Series Reaction with H 2O - Esters • Esters are hydrolyzed only slowly, even in boiling water – hydrolysis becomes more rapid if they are heated with either aqueous acid or base • Hydrolysis in aqueous acid is the reverse of Fischer esterification – the role of the acid catalyst is to protonate the carbonyl oxygen and increase its electrophilic character toward attack by water (a weak nucleophile) to form a tetrahedral carbonyl addition intermediate – collapse of this intermediate gives the carboxylic acid and alcohol 333333 Organic