TOPIC 4. CARBOXYLIC ACIDS AND THEIR DERIVATES: NUCLEOPHILIC ADDITION-ELIMINATION AT THE ACYL CARBON (Chapter 17)

Transcription

1 L TPI 4. ABXYLI AIDS AND TEI DEIVATES: NULEPILI ADDITIN-ELIMINATIN AT TE AYL ABN (hapter 17) 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

2 INTDUTIN S:17.1 eview of carbonyl chemistry Nu Nu -Nu Nu eview of nucleophilic substitution at sp 3 carbons L Nu Nu Preview of hapter 17 L L Nu Nu Nu FUNTINAL GUPS S:17.2 Prob:17.19,20 [] general name example with = 3 alkanoic acid acetic acid Ph l [l] alkan acetyl chloride [() 2 ] alkan acetic anhydride

3 alkane ' alkan alkyl acetate N' 2 alkan acetamide N N alkan acetonitrile Angelic acid defense substance for certain beetles, from the Swedish plant Garden Angelica (Archangelica officinalis) in1740s Traumatic Acid A plant hormone which causes injured cells to divide and help repair the trauma - Moronic acid

4 Properties of arboxylic Acids esonance stabilized conjugate base carboxylic acids are more acidic than alcohols ydrogen-bonding carboxylic acids have higher boiling points than other molecules with similar molecular weights PEPAATIN F ABXYLI AIDS eview: xidation ' 1. KMn 4, -, or 1. 3 ' S:17.3 Prob: or 1. KMn 4, -, KMn 4, -,

5 ydrolysis of Nitriles N Na, 2, or l, 2, arboxylation of Grignard reagents 1. 2 MgBr MgBr

6 Both of these methods increase the length of the chain by one carbon MgBr Br N Problem [Solomons 17.21b] ow would you carry out the following transformation? 2? l l

7 ADDITIN-ELIMINATIN AT TE AYL ABN verview S:17.4 Nu L Nu L Nu L Nu L Nu elative Electrophilicity of Acid Derivatives l l ' ' N' 2 N' 2 N' 2

8 Transformations of acids and acid derivatives l ' N N' 2? Problems ?

9 L AYL LIDES S:17.5 Prob:17.24 Formation of acyl chlorides from carboxylic acids (and reverse reaction: hydrolysis) Sl 2 or Pl 3 or Pl 5 Nucleophilic displacement of chloride from acyl chlorides: General Mechanism l Nu Nu l Nu eactions of acyl chlorides ' l Na l ' l ' 2 N Acid chlorides are reactive enough that these reactions do not need to be catalyzed by acid or base.

10 ANYDIDES S:17.6 Prob:17.25 Formation of acid anhydrides from carboxylic acids (and reverse reaction: hydrolysis) Formation of acid anhydrides from acyl chlorides: see above eactions of acid anhydrides ' ' 2 N ydrolysis: see above Acid anhydrides are reactive enough that these reactions do not need to be catalyzed by acid or base. l l

11 ESTES S:17.7 Prob:17.29,42 Acid catalyzed formation of esters from carboxylic acids Fischer Esterification (and reverse reaction: hydrolysis) ' 2 S 4 Formation of esters from acid chlorides: see above Formation of esters from acid anhydrides: see above eactions of esters Amidation ' '' 2 N ydrolysis (saponification) ' Esters are quite unreactive hydrolysis requires base (or acid) catalysis.

12 Saponification animal fat 2 2 ( 2 ) ( 2 ) 14 3 ( 2 ) 7 ( 2 ) 7 3 Na, 2 Na ( 2 ) Na ( 2 ) 14 3 soap 2 glycerol Na ( 2 ) 7 ( 2 ) 7 3 Problem - ow could you prepare ethyl 4-aminobenzoate (benzocaine)? 2 N benzocaine 2 N novocaine N

13 Problem [Solomons 17.42] Explain the following observations. 2 +? 2? 2 No reaction AMIDES Formation of amides from carboxylic acids (and reverse reaction: hydrolysis) ' 2 N N' S:17.8A-F Prob:17.30,39 lactam N' A more common synthetic method makes use of a two step synthesis, via acyl chloride Sl 2 ' 2 N N' 2 Formation of amides from acid anhydrides: see above Formation of amides from esters: see above

14 Problem - Propose a synthesis of N,N-diethyl-m-toluamide (DEET), the active ingredient in a number of commercial insect repellants. N( 2 3 ) 2? 3 N-(1,1-dimethylethyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide Type II 5α-reductase is an enzyme that metabolises testosterone (an androgen, or male sex hormone) into dihydrotestosterone, which is responsible for onset of male pattern baldness. Propecia (finasteride) is a inhibitor of the enzyme, and an effective treatment for baldness., N tbun N

15 eactions of amides ydrolysis 1. Na, 2 N' Amides are quite unreactive hydrolysis requires base (or acid) catalysis. Dehydration N 2 P 2 5 NDENSATIN PLYMES Polyester Sb 2 5 n Nylon 2 N N 2 3 N N 3 N N n Proteins 2 N enzyme N n

16 Poly(lactic Acid) n? Problems 17.24,25,29,30,39?

17 EATINS F AID DEIVATIVES WIT EDUING AGENTS AND GANMETALLIS Acid hlorides eduction l 1. LiAl LiAl l LiAl(t-Bu) 3-78 eaction with rganocopper eagents l 1. 'MgBr (or 'Li) l 1. ' 2 uli ( 3 ) 2 uli l

18 Problem - 3-exanone revisited. Provide a synthesis of 3-hexanone from alcohols with three of fewer carbon atoms. previously? Br Br Li Esters eduction 3 1. LiAl LiAl DIBAL- -78 o eaction with Grignard reagents 1. Et MgI Ph Ph 3 3 via:

19 Problem - Propose a synthesis of 2-methyl-2-hexanol from pentanoic acid? Amides eduction Synthesis of amines 1. LiAl 4 N() N() 2 ompare to the case with acids and esters (cleavage of -) bond) () 1. LiAl

20 L NITILES S:17.8G Formation and eactions N' 2 '= N eduction N 1. LiAl N 2 N 1. DIBAL- -78 o

21 eaction with Grignard eagents N 1. 3 MgBr 2. 2 Methadone binds to the opioid receptor in the brain, lowering the patient s desire for heroin. N N 1. EtBr, Mg Ph Ph Ph Ph N

22 SYNTETI STATEGIES Problem - Bis(2-ethylhexyl)phthalate is commonly used as a plasticizer for PV. ow could it be prepared on an industrial scale from inexpensive starting materials? Prob:17.28,33, 34,45? Problem - Propose a synthesis of 3-chlorobenzonitrile l? N

23 Problem - Propose a synthesis of novocaine (procaine) 2 N N? Spectroscopy Problem! (do problems 17.35,36) Elemental analysis:, 72.0%;, 6.7%? I: 1740 cm -1 1 NM: 2.2 (s, 3), 5.2 (s, 2), 7.4 (br. S, 5)

24 Problem The following compound was prepared at Georgia Tech as part of a National Institutes of ealth study of novel treatments of cocaine addiction. ow could this compound be prepared? [int: amides are reduced to amines with lithium Ph aluminum hydride, i.e., N 2 gives 2 N 2 ] N 2 TPI 4 (APTE 17) 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.