21: Ca Derivatives

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CA derivative

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A cmpd that can be hydrolyzed under acidic or basic conditions to give related CA: can all be conceptually derived by replacing a small part of the CA structure w other groups

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All CA derivatives contain

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a carbonyl group except nitriles

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The cyano group of nitriles reactivity resembles

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a carbonyl group

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Esters are named as derivatives of their parent CA by

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the group attached to carb O named first as simple alkyl or aryl group followed by name of parent carboxylate

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Substitution is indicated by numbering

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the acid portion of the ester in CA nomenclature starting w carbonyl as C-1 (substitutive) or w adjacent as a-position (common)

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primary vs secondary vs tertiary amide

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Front 7

Substitution on nitrogen in secondary & tertiary amides is designated w

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the letter N italicized or underlined

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lactams

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cyclic amides

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gamma-lactam

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five membered ring

Front 10

beta lactam

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four membered ring

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Imides

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nitrogen analogs of anhydrides

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priorities for citing principal groups in a CA derivative

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Front 13

The nitrile bond length is ___ than the C=_C bond length

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shorter (smaller atoms)

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In an amide, both the carbonyl C and the amide N have

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trigonal planar bonding due to db character

Front 15

Which predominates in secondary/tertiary amides, E or Z conformation?

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Z bc VDW avoided

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The interconversion of E & Z forms of amides is

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rapid @ room temp but slow compared to ordinary C-C sb rotation

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Esters are polar mlcs but lack

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the capability to donate H bonds like CA

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Lower esters are

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volatile, fragrant liquids that have lower densities than H2O - most insoluble in H2O

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Most lower anhydrides & acid chlorides are

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dense, water-insoluble liquids w acrid piercing odors & bp not very diff. from those of other polar mlcs of about the same mlclr mass/shape

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Simplest anhydride, formic anhydride & simplest acid chloride, formyl chloride are

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unstable, cannot be isolated under ordinary conditions

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Nitriles are

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polar, high bp

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Is acetonitrile miscible w h2o?

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yes

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higher nitriles soluble in h2o?

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no

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useful polar aprotic solvent

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acetonitrile

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The lower amides are

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water-soluble, polar mlcs w high bp

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primary & secondary amides like CA tend to associate into

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H-bonded dimers or higher aggregates in the solid state, pure liquid, or solvents that do not form H bonds

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along a series in which H in primary amides replaced by methyl groups, bp

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decrease w inc substitution

Front 28

Esters are readily differentiated from CA, aldehydes or ketones by

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unique ester carbonyl absorption at 1735-1745 cm-1

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Lactones, lactams & cyclic anhydrides like cyclic ketones have

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carbonyl absorption frequencies that inc significantly as ring size dec

Front 30

Anhydrides + some acid chlorides have

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two carbonyl absorptions due to symm + unsymm stretching of carbonyl

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carbonyl absorptions of amides occur at much ___ freq than other carbonyl cmpds

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lower

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The C-=N stretching absorption of nitriles occurs in the triple bond region and are ___ than the C-=C absorptions of alkynes

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stronger: large bond dipole of C-N triple bond @ higher frequencies

Front 33

The a-proton resonances of all CA derivatives are obesrved in the

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1.9-3 region of proton NMR spectrum

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In esters, the chem shift of protons on the alkyl C adjacent to the carboxylate O are 0.6 ppm ___ than analogous proton in alcohols and ethers

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greater due to electroneg character of carbonyl group

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N-alkyl protons of amides have chem shifts in the ___ chem shift region

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2.6-3

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NH proton resonances of primary/secondary amides are observed in the

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7.5-8.5 region

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the resonances for protons like CA OH protons are sometimes

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broad: slow chem exchange w protons of other protic substances (like moisture) & unresolved splitting w 14N, which has a nuclear spin

Front 38

Amide NH resonances can be washed out by

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exchange w d2o

Front 39

The two N-methyl groups in N,N-dimethylacetamide have

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diff. chem shifts & appear as 2 closely spaced singlets: chem. nonequiv because of db character = smaller rate internal rotation about this bond. time scale of NMR measurement so small that IR about CN bond appears frozen, so N-methyls behave like substituents on a db (one is cis and one is trans)

Front 40

13 CNMR: carbonyl chem shifts of CA derivatives in

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165-180 range like CA

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chem shifts in 13C NMR are in

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115-120 range but greater than those of acetylenic carbons

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CA derivatives are weakly

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basic: can be protonated on carbonyl O by strong acids

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Nitriles are weakly

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basic at nitrogen

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The basicity of an ester is ___ as the basicity of the corresponding CA

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the same

Front 45

amides are considerably more ___ than other CA derivatives

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basic: reflects reduced electroneg of N relative to O -

Front 46

Both esters & amides protonate on the

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carbonyl oxygen

Front 47

protonation of esters on the carboxylate oxygen or of amides on the nitrogen would

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give a cation that is not resonance stabilized & destabilized by e-attracting polar effect of carbonyl group

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Nitriles are very weak ___

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bases

Front 49

rxn of CA & derivatives as Bronsted base is reaction type

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1a: often first step in acid-catalyzed rxns of CA derivatives

Front 50

As with CA, the major carbonyl group rxn of CA derivatives is a reaction of type

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1b

Front 51

Acyl substitution

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substitution at the carbonyl C: acyl group transferred between x and y group

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addition rxn of nitriles

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sometimes stable prod, usually react further

Front 53

All CA derivatives undergo hydrolysis

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cleavage rxn w h2o to yield CA

Front 54

Saponification of esters

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Cleavage w hydroxide ion to yield carboxylate salt and alcohol - CA formed when strong acid added

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Mech ester saponification

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rxn nuc hydroxide ion @ carbonyl C to give tetrahedral addition intermediate from which alkoxide ion expelled and reacts w acid to give carboxylate salt & alcohol

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Mech 2

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equilibrium lies to the right bc CA is a much stronger acid than methanol - Le Chateliers principle: rxn removes CA from equilibrium as salt driving hydrolysis to completion

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Is saponification reversible?

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No

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Saponification solvent

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can be alcohol despite alcohol as a prod

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Acid catalyzed ester hydrolysis

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esters hydrolyzed to CA in aq. soln of storng acid - mostly slow, excess h2o (esters insoluble)

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Saponification followed by acidification is more convenient because

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it is faster, irreversible, carried out in water & variety of solvents even alchols

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Saponification mechanism

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reverse of mechanism of acid-catalyzed esterification - ester first protonated by acid catalyst

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Saponification mech 2

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h2o as nuc reacts at carbonyl carbon, loses proton to give tetrahedral addition intermediate

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Mechanism acid-catalyzed hydrolysis 3

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protonation of leaving O - lose group - protonated CA from which proton removed to give CA itself

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Diff btwn acid-catalyzed hydrolysis & ester saponification

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in ACH, carbonyl C reacts w weak nuc h2o bc carbonyl O protonated. In base, carbonyl O unprotonated, so stronger base than h2o required to react at carbonyl C. acid catalyzes ester hydrolysis, but base is consumed in rxn. saponification is irreversible

Front 65

Nucleophilic acyl substitution mechanisms

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substituting group reacts as nuc at carbonyl C - nuc approach the carbonyl C from above/below plane of carbonyl group, first interacting with n* MO of carbonyl group - tetrahedral intermediate - LG expelled departing from above or below plane of new carbonyl group

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Lactones

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cyclic esters - undergo saponification - converted into carboxylate salt of corresponding hydroxy acid

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Upon acidification, the hydroxy acid forms, but if a hydroxy acid is allowed to stand in acidic solution,

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it comes to equilibrium w the corresponding lactone

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The formation of a lactone from a hydroxy acid is nothing more than an

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intramolecular esterification & is acid catalyzed

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Lactones containing five and sex membered rings are ___ at equilibrium

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favored over corresponding hydroxy acids

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amides can be hydrolyzed to CA & ammonia or amines by

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heating them in acidic or basic solution

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In acid, ___ drives the hydrolysis equil. to completion

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protonation of the ammonia or amine prod

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The amine can be isolated by

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addition of base to the reaction mixture following hydrolysis

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The conditions for acid & base-promoted amide hydrolysis are more ___ than corresponding rxns of esters

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severe - amides are less reactive than esters

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Mechanism of amide hydrolysis

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nuc acyl substitution

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Nitriles are hydrolyzed to CA & ammonia by

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heating in strongly acidic or strongly basic solution

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nitriles hydrolyze more ___ than esters & amides

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slowly (requires more severe conditions)

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Mechanism nitrile hydrolysis in acidic solution

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protonation of the nitrogen, making nitrile C much more electrophilic

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Mechanism nitrile hydrolysis in acidic solution 2

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nuc rxn of h2o at nitrile C + loss of proton gives imidic acid intermediate

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acid chlorides and anhydrides react rapidly w h2o even in absence of acids/bases

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hydrolysis of acid chlorides/anhydrides almost never used to prepare CA bc usually prepared from acids

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reactivities of carboxylic acid derivatives in nuc acyl sub rxns

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generalized nuc sub rxn free energy diagram

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assume reactants/prod of comparable stability

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How does the stability of the carbonyl cmpd affect the rate of carbonyl sub. rxn?

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An amide is stabilized by the resonance interaction of unshared e pair of N w carbonyl group, inc energy diff btwn amide & tetrahedral addition intermed in which no resonance

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How does the LG ability of X affect rate carbonyl sub rxn?

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the difficulty in expelling a basic LG reflected in a higher free-energy barrier for the 2nd step => rate limiting

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delta G for amide hydrolysis

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diff btwn standard free energy of RLS & starting amide

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Amide hydrolysis is a particularly __ rxn

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slow

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Why are prod less stable than reactants?

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LG is more basic than nuc (last ionization & protonation drives base-promoted amide hydrolysis to completion)

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What governs the reactant-stabilization effect?

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The amide nitrogen's ability to donate e by resonance

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Amides in which resonance is absent are

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quite reactive

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Esters are also stabilized by resonance

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places pos charge on carboxylate o

Front 91

Why is resonance interaction less important in an ester than an amide?

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O is more electroneg than N

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Why are esters more reactive than amides?

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An alkoxide ion is much less basic than an amide ion

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Why are acid chlorides stabilized much less by resonance than esters or amides?

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Poor overlap of chlorine 3p orbital with carbon 2p orbital and polar effect of Cl destabilizes the carbonyl cmpd through unfavorable interaction of C-Cl bond dipole w partial pos charge on carbonyl C

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LG effect in hydrolysis of an acid chloride

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Cl is a weak base: decreased TS energy so first step (rxn w nuc) becomes RLS = much smaller overall delta G

Front 95

Resonance stabilization of anhydride more important than in acid chloride but less important than an ester

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repulsion btwn pos charge on carboxylate O & partial pos charge on carbonyl C

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LG in an anhydride

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carboxylate anion more basic than Cl, less than alkoxide

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Stabilization of the carbonyl cmpd ___ reactivity

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decreases

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Increasing reactivity

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Why are reactions of nitriles in base slower than those of other acid derivatives?

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N is less electroneg than O, accepts additional e less readily - nitriles have low basicity

Front 100

What form of nitrile reacts w nuc in acid soln?

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protonated - so little that rxn rate is small