21.8: Carboxylic Acid Derivatives W Nucleophiles

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Mechanism

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unless another base added, starting amine acts as base in last step

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Using a tertiary amine such as pyridine or triethylamine does not interfere w amide formation by another amine bc

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a tertiary amine itself cannot form an amide

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Schotten-Baumann technique

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reaction is run with an acid chloride in a separate layer over aq. soln NaOH = the amine reacts to yield an amide & aq. NaOH extracts & neutralizes the protonated amine that is formed

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Hydrolysis of the acid chloride by NaOH is avoided bc acid chlorides

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are typically insoluble in h2o, so not in direct contact w h2o-soluble hydroxide ion

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Either 2 equiv of amine must be used or

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an equivalent of base must be added to effect the final neutralization

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Why doesn't the HCl liberated not need to be neutralized?

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alcohols & phenols are not basic enough to be extensively protonated by the acid but pyridine used to neutralize the HCl

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Even though carboxylate salts are weak nuc, acid chlorides

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reactive enough to react w carboxylate salts to give anhydrides

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Use of acid chlorides in organic synthesis

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anhydrides react w nuc to yield amide, ester etc

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Why is this only used w inexpensive & readily available anhydrides?

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one equivalent of parent acid is wasted as a LG

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exception: from cyclic anhydrides are formed

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half-esters and half amides

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Reaction of esters w ammonia

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yields amides

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Esters are much less reactive toward amines and alcohols, but sometimes useful

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Hydroxamate test

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hydroxamic acid products easily recognized bc form highly colored complexes w ferric ion

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when an ester reacts w alcohol + acid or alkoxide w base

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An ester is formed

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Transesterification

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the conversion of one ester into another by rxn w an alcohol

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equilibrium constant typically

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~1 because neither ester strongly favored @ equilibrium

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The reaction is driven to completion by the use of

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an excess of the displacing alcohol or by removal or a relatively volatile alcohol by product as it is formed

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Lithium aluminum hydride reduces all CA derivatives

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reduction of esters gives primary ROHs: by product methanol or ethanol typically discarded

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The active nucleophile is the hydride ion

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Mechanism 2

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Aldehyde reacts rapidly w LiAlH4 to give the alcohol after protonolysis

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NaBH4 is ___ reactive than LiAlH4

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less: reduces aldehydes & ketones but reacts sluggishly w most esters - can be used to reduce aldehydes & ketones selectively in presence of esters

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The excess of acid that is typically used converts the amine, which is a base, into its conjugate-acid ammonium ion & hydroxide is required to neutralize the ammonium salt & give neutral amine. h2o can be used but acid more convenient, so neutralization necessary

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preparation of secondary/tertiary amines from secondary & tertiary amides

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Ester reduction

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carbonyl oxygen lost as LG

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Amide reduction

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Why is the carbonyl oxygen lost in amide reduction?

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The weakly acidic amide proton reacts w equiv. hydride, strong base, to give AlH3 & lithium salt of amide

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Mechanism 2

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The lithium salt of the amide, a LB, reacts with the LA AlH3

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Mechanism 3 - the resulting species is an active hydride reagent, conceptually like LiAlH4 and can deliver hydride to the C=N double bond

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The O-AlH2 group then lost from tetrahedral intermediate bc less basic than other possible LG resulting in imine

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the C=N of the imine undergoes nuc add w H-

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addition of acid to the rxn mixture converts add intermediate into an amine by protonolysis, then into conj. acid ammonium ion, which is neutralized to free amine when -OH is added

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isolation of the neutral amine requires addition of -OH @ conclusion of rxn

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Nitrile reduction mechanism

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first nuc add

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Nitrile reduction mechanism 2

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In the resulting derivative both the N-Li and the N-Al bonds are very polar and the N has anionic character

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both bonds are susceptible to protonolysis, so an amine then ammonium is formed when aq. acid is added to the rxn mixture

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Mechanism

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Raney nickel is a type of nick-Al alloy

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What is the intermediate in the rxn?

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Imine, which is hydrogenated to the amine product

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Any synthesis of a CA can be used as part of an amine synthesis, but the amine prepared must have the form

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Rosenmund reduction

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What are catalyst poisons?

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Amines, sulfides, prevents further reduction of aldehyde product

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Hydride derived by replacement of 3 H of LiAH4 by tert-butoxy groups => less reactive reagents obtained

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poor reactivity of hydride

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rxn of LiAlH4 w tert-butyl alcohol stops after 3 moles of alcohol consumed, remaining hydride reduces only most reactive func groups

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reagent reacts preferentially w acid Cl over product aldehyde bc

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acid Cl are more reactive than aldehydes toward nucs

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LiAlH is so reactive that

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it fails to discriminate btwn aldehyde + acid Cl group, so reduces acid chlorides to primary alcohols

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reaction of LiAlH w CA or ester involves aldehyde intermed but product is

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primary alcohol bc aldehyde intermed is more reactive than the acid or ester

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Li tri tertbutoxy Al H reduction of acid Cl can be stopped @ aldehyde bc

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acid cl more reactive than aldehydes - product aldehyde in competition w remaining acid Cl for hydride reagent - more reactive acid Cl consumed before aldehyde has chance to react

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relative reactivities of carbonyl cmpds

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nitriles < amides < esters, acids << ketones < aldehydes < acid chlorides (MOST REACTIVE)

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relative reactivity is determined by the stability of

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each type of carbonyl cmpd relative to TS for add/sub

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esters are less reactive than aldehydes bc

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stabilized by resonance

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acid Cl destabilized by

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e-attracting polar effect of Cl

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TS energies for nuc sub rxn of acid Cl lowered by

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favorable LG properties of Cl

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tertiary alcohol formed after protonolysis

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nuc acyl sub followed by addition

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2 equiv of organometallic reagent react per mole ester, second alcohol produced in rxn

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ketone intermed not isolated bc

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ketones are more reactive than esters towards nuc reagents, so reacts w 2nd equiv of grignard reagent to form magnesium alkoxide, which after protonolysis gives the alcohol

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bc acid cl more reactive than ketones

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reaction of acid cl w grignard reagent can give ketone w/o further rxn of ketone itself

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transformation is diff to achieve in practice w/o careful control of rxn conditions bc

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grignard reagents are very reactive (hard to prevent further rxn of product ketone w grignard reagent to give alcohol)

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lithium dialkylcuprates are less reactive than grignard and organolithium reagents - typically react readily w acid Cl, aldehydes, epoxides, slowly w ketones, not at all w esters

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ketones do not react further bc

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they are much less reactive than acid Cl toward lithium dialkylcuprates

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nitriles can be particularly useful as an intermediate step in the preparation of a CA bc

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nitriles are prepared from cmpds other than CA derivatives

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most important occurrence of amides in nature

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proteins: polymers in which a-amino CA units connected by amide linkages

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nylon

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group of polymeric amides/ polyamides

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more vigorous conditions needed than rxn of amine w ester bc

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amine is basic, equil on L favors salt

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In salt amine is protonated and therefore

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not nuc, and carboxylate ion unreactive toward nuc

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small amt amine and CA in equil w salt

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react when salt is heated, pulling equil to R

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starting material for nylon-6

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e-caprolactam

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both adipic acid and e-caprolactam are prepared from

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cyclohexanone, prepared by oxidation of cyclohexane

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cyclohexane comes from

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petroleum (example of dependence of important segment of chem economy on petroleum feedstocks)

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Condensation polymer

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formed in a rxn that liberates a small mlc

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nylon as a condensation polymer

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formation of each amide bond accompanied by loss of small mlc H2O

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addition polymer

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polyethylene is an example: one mlc adds to other w/o loss of mlclr fragment

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polyesters

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condensation polymers derived from rxn diols & dicarboxylic acids

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polyester prod. depends on raw materials derived from

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petroleum

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waxes, fats and phospholipids are all important naturally occurring

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ester derivatives of fatty acids

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wax

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ester of a fatty acid & fatty alcohol, primary alcohol w long unbranched C chain

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fat

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ester derived from mlc of glycerol & 3 mlcs fatty acid

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acyl groups in a fat

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may be same or different

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unsaturation

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form of 1+ cis db

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saturated fats

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no db, typically solids i.e. lard

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unsaturated fats

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contain db, often oily liquid i.e. olive oil

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Saponification

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treatment of fats w NaOH or KOH for glycerol & Na or K salts of fatty acids

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phospholipids

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esters of glycerol

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structural diff. btwn fat & phospholipid

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in phospholipid, one glyceryl primary hydroxy group esterified to a polar phosphoric acid derivative rather than to a fatty acid