Lecture 22 The Claisen Condensation CH 3 CCH 2 CH 3 CH 2 CCH 2 CH 3 April 10, 2018
Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. RCNHR' + + H 2 + H RCH + + R'NH 3
Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. This makes the reaction irreversible! RCNHR' + H RC + R'NH 2
Chemistry of Nitriles Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and both contain a bond Both both are electrophiles Nitrile Carboxylic Acid
Naming Nitriles Name the parent alkane (include the carbon atom of the nitrile as part of the parent) followed with the word -nitrile. The carbon in the nitrile is given the #1 location position. It is not necessary to include the location number in the name because it is assumed that the functional group will be on the end of the parent chain. Cycloalkanes are followed by the word -carbonitrile. Cyclopentane carbonitrile
Preparation of Nitriles Sandmeyer rection of diazonium salts Sn2 reactions with Cyanide anion Cyanohydrin formation Dehydration of Amides There are many more.
Preparation of Nitriles by Dehydration Reaction of primary amides RCNH 2 with SCl 2 (or other dehydrating agents) Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN)
Mechanism of Dehydration of Amides Nucleophilic amide oxygen atom attacks SCl 2 followed by deprotonation and elimination
Addition of HCN to Carbonyls Mechanism of cyanohydrin formation CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 2 CH 2 N C - H 3 + CH 2 C N C C - N C C H + Mg +2 THF dil. CH 3 CH 3 CH 3
Cyanohydrins The value of cyanohydrins is for the new functional groups into which they can be converted acid-catalyzed dehydration of the 2 alcohol gives a valuable monomer H CH 3 CHC N acid catalyst CH 2 =CHC N + H 2 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) Propenenitrile (Acrylonitrile)
Carbon Fiber Heat Boeing 787 Dream liner wing spar
Cyanohydrins acid-catalyzed hydrolysis of the cyano group gives an a-hydroxycarboxylic acid H CHC N + H 2 acid catalyst H CHCH Benzaldehyde cyanohydrin (Mandelonitrile) 2-Hydroxy-2-phenylethanoic acid (Mandelic acid)
Cyanohydrins catalytic reduction of the carbon-nitrogen triple bond converts the cyano group to a 1 amine H CHC N + 2 H 2 Ni H CHCH 2 NH 2 Benzaldehyde cyanohydrin 2-Amino-1-phenylethanol LiAlH 4 also works well... But what about Pd/C and H 2
Hydrolysis: Conversion of Nitriles into Carboxylic Acids Hydrolyzed in with acid or base gives a carboxylic acid and ammonia
Reaction of Nitriles with rganometallic Reagents Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone
Reduction: Conversion of Nitriles into Amines Reduction of a nitrile with LiAlH 4 gives a primary amine
Some loose ends before we go on Spectrosopy of acid derivatives A selective reduction for your tool box
Reduction of Acid Derivatives Acids (page 736-738) Esters (page 796-798) Please work through the example in section 18.9 Amides (page 798-799) Nitriles (page 800) Selective reductions with NaBH 4 Esters to aldehydes by DiBAlH (page 797-798)
DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78 C selectively reduces esters to aldehydes at -78 C, the tetrahedral intermediate does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated Stable at low temperature
Infrared Spectroscopy C= stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide. C= stretching frequency n CH 3 CCl CH 3 CCCH 3 CH 3 CCH 3 CH 3 CNH 2 1822 cm -1 1748 and 1815 cm -1 1736 cm -1 1694 cm -1
Infrared Spectroscopy Anhydrides have two peaks due to C= stretching. ne from symmetrical stretching of the C= and the other from an antisymmetrical stretch. C= stretching frequency n CH 3 CCCH 3 1748 and 1815 cm -1
Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching that is all alone in the 2210-2260 cm -1 region.
t-butyl esters
t-butyl esters
t-butyl ester hydrolysis Note which bond is broken in this hydrolysis!!
The Claisen Condensation CH 3 CCH 2 CH 3 CH 2 CCH 2 CH 3
Recall our discussion of the acidity of protons a to carbonyls The anion is stabilized by resonance The better the stabilization, the more acidic the a proton Acidity of a protons on normal aldehydes and ketones is about that of alcohols and less than water pka ~ 18-20 Some are far more acidic, i.e. b-dicarbonyl compounds that have quite low pka s
CH 3 C 2 H HF HCl H 4.75 3.45-9.0!! 10 pka of some acids and some a protons H H C C C H H 5.0 CH 3 H CH 3 CCH 2 CCH 3 16 10 CH 3 CCH 3 CH 3 CH 3 20 50
Some Acid Base Chemistry 2 C H 3 C H 2 H + 2 N a H 2 + 2 C H 3 C H 2 - N a + CH 3 CCH 2 CH 3 + CH 3 CH 2 - CH 2 CCH 2 CH 3 + CH 3 CH 2 H pka 25 pka 16 CH 3 CCH 2 CCH 2 CH 3 + CH 3 CH 2 CH 3 CCHCCH 2 CH 3 + CH 3 CH 2 H 10 16 CH 3 CCH 3 20 16 + CH 3 CH 2 CH 3 CCH 2 - + CH 3 CH 2 H Which way do the equilibria lie?
Rainer Ludwig Claisen (1851-1930): Born in Köln and studied chemistry at Bonn, and briefly at Göttingen. He earned his doctorate at Bonn under August Kekulé (1829-1896).
Classical Claisen Condensation 2CH 3 CCH 2 CH 3 1. NaCH 2 CH 3 2. H 3 + CH 3 CCH 2 CCH 2 CH 3 Two moles of ethyl acetate condense to give ethyl acetoacetate or (acetoacetic ester)
Mechanism Step 1: CH 3 CH 2 H CH 2 CCH 2 CH 3
Mechanism Step 1: CH 3 CH 2 H CH 2 CCH 2 CH 3 CH 3 CH 2 H CH 2 CCH 2 CH 3
Mechanism Step 1: The enolate anion is stabilized by resonance CH 2 CCH 2 CH 3 CH 2 CCH 2 CH 3
Mechanism Step 2: Nucleophilic acyl substitution CH 3 CCH 2 CH 3 CH 2 CCH 2 CH 3
Mechanism Step 2: CH 3 C CH 2 CCH 2 CH 3 CH 2 CH 3 CH 3 CCH 2 CH 3 CH 2 CCH 2 CH 3
Mechanism Step 2: CH 3 C CH 2 CCH 2 CH 3 CH 2 CH 3
Mechanism Step 3: CH 3 C CH 2 CCH 2 CH 3 CH 2 CH 3 CH 3 C CH 2 CCH 2 CH 3 + CH2 CH 3
Mechanism Step 3: CH 3 C CH 2 CCH 2 CH 3 + CH2 CH 3 The product is ethyl acetoacetate. However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small. Something else does happen. Ethoxide abstracts a proton from the CH 2 group to give a stabilized anion. The equilibrium constant for this acid-base reaction is very favorable.
Classical Claisen Condensation An excellent path to b-keto esters 2CH 3 CCH 2 CH 3 1. NaCH 2 CH 3 2. H 3 + CH 3 CCH 2 CCH 2 CH 3 Two moles of ethyl acetate condense to give ethyl 3-oxobutanoate or ethyl acetoacetate aka acetoacetic ester
Crossed Claisen Condensation What is wrong with this? CH 3 CH 2 C CH 2 CH + 3 + CH 3 C CH 2 CH 3 1) NaCH 2 CH 3 2) Cold, dil, H 3 + No No No it gives a mixture of products, a big fat mess!! CH 3 CH 2 C CH 2 C CH 2 CH 3
Crossed Claisen Condensation Crossed reactions can work if one does it carefully and one of the reactants does not have an alpha hydrogen such as: HCEt EtCEt EtC-CEt CEt Ethyl formate Diethyl carbonate D iethyl ethaned ioate (D iethyl oxalate) Ethyl ben zoate
Crossed Claisen Condensation -- An Example C CH 2 CH 3 a acceptor Base C CH 2 C CH 2 CH 3 + a CH 3 C CH 2 CH 3 donor
Crossed Claisen Condensation Crossed Claisen condensations between two different esters, each with a-hydrogens, give bad mixtures. They are not useful and will not be accepted as legitimate answers in our class You can do this if you use one component with no a-hydrogen and if you run the reaction properly How would YU run the reaction?? What sequence of additions? What stoichiometry? What base?
Deprotonation of Simple Esters Ethyl acetoacetate (pka ~11) is completely deprotonated by alkoxide bases. Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original ester, and Claisen condensation occurs. Do there exist bases strong enough to completely deprotonate simple esters, giving ester enolates quantitatively?
Lithium diisopropylamide (LDA) CH 3 CH 3 Li + H C N C H CH 3 CH 3 LDA is a strong base (just as NaNH 2 is a very strong base). pka ~36 Because it is so sterically hindered, LDA does not add to carbonyl groups.
Lithium diisopropylamide (LDA) LDA converts simple esters quantitatively to the corresponding enolate. CH 3 CH 2 CH 2 CCH 3 pk a ~ 22 + LiN[CH(CH 3 ) 2 ] 2 CH 3 CH 2 CHCCH 3 + HN[CH(CH 3 ) 2 ] 2 + Li + pk a ~ 36
Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. CH 3 CH 2 CHCCH 3 CH 3 CH 2 I CH 3 CH 2 CHCCH 3 CH 2 CH 3 (92%)