L TPI 4. ABXYLI AIDS AND THEI DEIVATES: NULEPHILI ADDITIN-ELIMINATIN AT THE AYL ABN (hapter 18) BJETIVES 1. Name carboxylic acids and acid derivatives: acyl chlorides, anhydrides, esters, amides and nitriles 2. Describe the preparation of acids and acid derivatives 3. Provide mechanisms for nucleophilic substitutions at acyl carbons bearing a leaving group and discuss implications of leaving group ability 4. Develop multistep syntheses
INTDUTIN S:18.1 eview of carbonyl chemistry H H- eview of nucleophilic substitution at sp 3 carbons L Preview of hapter 18 L L FUNTINAL GUPS S:18.2 Prob:18.19,20 H [H] general name example with =H 3 alkanoic acid acetic acid H H Ph l [l] alkan acetyl chloride [() 2 ] alkan acetic anhydride
alkane ' alkan alkyl acetate N' 2 alkan acetamide N N alkan acetonitrile Properties of arboxylic Acids esonance stabilized conjugate base carboxylic acids are more acidic than alcohols Hydrogen-bonding carboxylic acids have higher boiling points than other molecules with similar molecular weights
PEPAATIN F ABXYLI AIDS eview: xidation 1. KMn 4, - H, Δ H H 2. H ' 3 + or H 1. 3 ' H S:18.3 Prob:18.21-24 2. H 2 2 H 2 H or H 1. KMn 4, - H, Δ 2. H 3 + H H 1. KMn 4, - H, Δ 2. H 3 + H Hydrolysis of Nitriles N NaH, H 2, Δ or Hl, H 2, Δ H
arboxylation of Grignard reagents 1. 2 MgBr 2. H 3 + H MgBr Both of these methods increase the length of the chain by one carbon MgBr Br H N
Problem [Solomons 18.21b] How would you carry out the following transformation? 2 H? l l verview ADDITIN-ELIMINATIN AT THE AYL ABN S:18.4 L L L L
elative Electrophilicity of Acid Derivatives l l ' ' N' 2 N' 2 N' 2 Transformations of acids and acid derivatives l H ' N N' 2
? Problems 18.19-24? L AYL HLIDES S:18.5 Prob:18.24 Formation of acyl chlorides from carboxylic acids (and reverse reaction: hydrolysis) H Sl 2 or Pl 3 or Pl 5 cleophilic displacement of chloride from acyl chlorides: General Mechanism l l
eactions of acyl chlorides ' l Na l 'H l ' 2 NH Acid chlorides are reactive enough that these reactions do not need to be catalyzed by acid or base. ANHYDIDES S:18.6 Prob:18.25 Formation of acid anhydrides from carboxylic acids (and reverse reaction: hydrolysis) H Δ Formation of acid anhydrides from acyl chlorides: see above
eactions of acid anhydrides 'H ' 2 NH Hydrolysis: see above Acid anhydrides are reactive enough that these reactions do not need to be catalyzed by acid or base. l l ESTES S:18.7 Prob:18.29,42 Acid catalyzed formation of esters from carboxylic acids Fischer Esterification (and reverse reaction: hydrolysis) 'H H 2 S 4 Δ H Formation of esters from acid chlorides: see above Formation of esters from acid anhydrides: see above
eactions of esters Amidation ' '' 2 NH Hydrolysis (saponification) H ' Esters are quite unreactive hydrolysis requires base (or acid) catalysis. Saponification animal fat H 2 H H 2 (H 2 ) 7 H 2 H 3 (H 2 ) 14 H 3 (H 2 ) 7 (H 2 ) 7 H 3 NaH, H 2 Na (H 2 ) 7 H 2 H 3 H 2 H H H Na (H 2 ) 14 H 3 soap H 2 H glycerol Na (H 2 ) 7 (H 2 ) 7 H 3
Problem - How could you prepare ethyl 4-aminobenzoate (benzocaine)? NH 2 Problem [Solomons 18.42] Explain the following observations. H Δ H 2 +? H 2? H 2 H Δ No reaction
AMIDES Formation of amides from carboxylic acids (and reverse reaction: hydrolysis) H ' 2 NH Δ NH' H S:18.8A-F Prob:18.30,39 lactam N' A more common synthetic method makes use of a two step synthesis, via acyl chloride Sl 2 ' 2 NH H N' 2 Formation of amides from acid anhydrides: see above Formation of amides from esters: see above Problem - Propose a synthesis of N,N-diethyl-m-toluamide (DEET), the active ingredient in a number of commercial insect repellants. N(H 2 H 3 ) 2? H 3
eactions of amides Hydrolysis 1. NaH, H 2 Δ N' 2 2. H 3 + Amides are quite unreactive hydrolysis requires base (or acid) catalysis. Dehydration NH 2 P 2 5 Δ NDENSATIN PLYMES Polyester H H H H Sb 2 5 Δ n Nylon H H H 2 N NH 2 H 3 N NH 3 Δ H N N H n Proteins H 2 N H enzyme H N n
? Problems 18.24,25,29,30,39? EATINS F AID DEIVATIVES WITH EDUING AGENTS AND GANMETALLIS Acid hlorides eduction 1. LiAlH 4 l 2. H 3 + H 2 H 1. LiAlH 4 2. H 3 + H l LiAlH(t-Bu) 3-78
eaction with rganocopper eagents l 1. 'MgBr (or 'Li) 2. H 3 + l 1. ' 2 uli 2. H 3 + (H 3 ) 2 uli l Problem - 3-Hexanone revisited. Provide a synthesis of 3-hexanone from alcohols with three of fewer carbon atoms. previously H? Br H H Br H Li
Esters eduction H 3 1. LiAlH 4 2. H 3 + H 2 H 1. LiAlH 4 2. H 3 + H 1. DIBAL-H -78 o H 3 2. H 3 + eaction with Grignard reagents 1. Et 2 H H 3 + H 3 MgI Ph 2. H 3 + Ph H 3 H 3 via: Problem - Propose a synthesis of 2-methyl-2-hexanol from pentanoic acid H?
Amides eduction Synthesis of amines 1. LiAlH 4 NH() 2 2. H 3 + H 2 NH() 2 ompare to the case with acids and esters (cleavage of -) bond) H() 1. LiAlH 4 2. H 3 + H 2 H L NITILES S:18.8G Formation and eactions H N' 2 '=H N
eduction N 1. LiAlH 4 2. H 3 + H 2 NH 2 N 1. DIBAL-H -78 o 2. H 3 + eaction with Grignard eagents 1. H 3 MgBr N 2. H 2
SYNTHETI STATEGIES Problem - Bis(2-ethylhexyl)phthalate is commonly used as a plasticizer for PV. How could it be prepared on an industrial scale from inexpensive starting materials? Prob:18.28,33, 34,45? Problem - Propose a synthesis of 3-chlorobenzonitrile l N?
Problem - Propose a synthesis of novocaine (procaine) H 2 N N? http://www.corbis.com/ Spectroscopy Problem! (do problems 18.35,36) Elemental analysis:, 72.0%; H, 6.7%? I: 1740 cm -1 1 H NM: δ 2.2 (s, 3H), 5.2 (s, 2H), 7.4 (br. S, 5H)
Problem The following compound was prepared at Georgia Tech as part of a National Institutes of Health study of novel treatments of cocaine addiction. How could this compound be prepared? [Hint: amides are reduced to amines with lithium Ph aluminum hydride, i.e., NH 2 gives H 2 NH 2 ] H H H NH 2 TPI 4 (HAPTE 18) N EXAM 4 Types of Questions - Predict the product of reactions, provide a mechanistic rationale to account for the formation of a particular product, naming acids and derivatives - Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 4 - Get up-to-date NW! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the Learning Group Problem at the end of the chapter.