Carboxylic acids and DerivativesCarboxylicAcidEsterCarboxylic AcidAnhydrideAcid ChlorideAmidePreparation: Oxidation (Which of the follow reactions will produce carboxylic acids?KMnO4/NaOHKMnO4/NaOHKMnO4/NaOHKMnO4/NaOH

Carbonyl compounds

Nucleophilic Addition-Elimination at the Acyl CarbonRecall that aldehydes and ketones undergo nucleophilic addition to the carbon-oxygen double bondThe nucleophile reacts at the carbonyl group to form a tetrahedral intermediateThe tetrahedral intermediate eliminates a leaving group (L)The carbonyl group is regenerated; the net effect is an acyl substitution

Carbonyl compounds

To undergo nucleophilic addition-elimination the acyl compound must have a good leaving group or a group that can be converted into a good leaving groupAcid chlorides react with loss of chloride ion

Anhydrides react with loss of a carboxylate ion

Esters, carboxylic acids and amides generally react with loss of the leaving groups alcohol, water and amine, respectively (These leaving groups are generated by protonation of the acyl compound)

Aldehydes and ketones cannot react by this mechanism because they lack a good leaving group

Carbonyl compounds

Relative Reactivity of Acyl CompoundsThe relative reactivity of carboxylic acids and their derivatives is as follows:In general, reactivity can be related to the ability of the leaving group to departLeaving group ability is inversely related to basicityChloride is the weakest base and the best leaving groupAmines are the strongest bases and the worst leaving groupsAs a general rule, less reactive acyl compounds can be synthesized from more reactive onesSynthesis of more reactive acyl derivatives from less reactive ones is difficult and requires special reagents (if at all possible)

Carbonyl compounds

Acid ChloridesSynthesis of Acid ChloridesAcid chlorides are made from carboxylic acids by reaction with thionyl chloride, phosphorus trichloride or phosphorus pentachlorideThese reagents work because they turn the hydroxyl group of the carboxylic acid into an excellent leaving group

Carbonyl compounds

Mechanism with Thionyl Chloride(Nucleophilic addition-elimination reaction)Mechanism 1

Carbonyl compounds

Mechanism with Phosphorous Trichloride(Nucleophilic addition-elimination reaction)+d+d-d-d-+ Cl+reacts two more timesReactions of Acyl ChloridesAcyl chlorides are the most reactive acyl compounds and can be used to make any of the other derivativesSince acyl chlorides are easily made from carboxylic acids they provide a way to synthesize any acyl compound from a carboxylic acidAcyl chlorides react readily with water, but this is not a synthetically useful reaction

Carbonyl compounds

d+d-

Carbonyl compounds

Mechanism 2Mechanism 3

Carbonyl compounds

All the Mechanisms are similar. The main difference is the nucleophiled+d-H-Nud-+ ClH-Nuor solvent+ NuH2sp3 tetrahedralintermediate

Carbonyl compounds

Carboxylic Acid AnhydridesAcid chlorides react with carboxylic acids to form mixed or symmetrical anhydridesIt is necessary to use a base such as pyridine to remove the proton on the OH group Sodium carboxylates react readily with acid chlorides to form anhydridesforms tetrahedral intermediatechloride leavesThis is not a mechanismIt is a thought processd+d-d+d-

Carbonyl compounds

Cyclic anhydrides with 5- and 6-membered rings can be synthesized by heating the appropriate diacidReactions of Carboxylic Acid AnhydridesCarboxylic acid anhydrides are very reactive and can be used to synthesize esters and amidesHydrolysis of an anhydride yields the corresponding carboxylic acidsd+d-

Carbonyl compounds

d+d-

Carbonyl compounds

Mechanism 4

Carbonyl compounds

EsterificationMechanism (acid catalyzed)H2SO4 or HClH+ProtonTransfer+ H2O + H+(regenerates catalyst)Esterification is an equilibrium reaction. To make the reaction favor the ester side use excess of either reagent (the alcohol or acid) and remove water. To push the reaction to the hydrolysis side of the equilibrium use a large excess of water by refluxing with a dilute acid.

Carbonyl compounds

+H+This is not a mechanismIt is a thought processMechanism 5

Carbonyl compounds

ExamplesCH3OHH2SO4This is not a mechanismIt is a thought process12341234+H2SO4H+acetoneTrans-EsterificationExcesssp2

Carbonyl compounds

Lactonesg- or d-Hydroxyacids undergo acid catalyzed reaction to give cyclic esters known as g- or d-lactones, respectively

Carbonyl compounds

AmidesAmides can be prepared from acyl chlorides, acid anhydrides, esters, carboxylic acids and carboxylic salts

Carbonyl compounds

Examples++ ClExcess++H3O+d+d-electrophile(acid)nucleophile(base)

Carbonyl compounds

Examples+ NH3+ NH3+ NH4solid saltheat+ H2Odehydration of the salt produces the amide but generally in poor yieldA good way to synthesize an amide is to convert a carboxylic acid to an acid chloride and to then to react the acid chloride with ammonia or an amineDicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic acids and amines

d+d-d-

Carbonyl compounds

DCC activates the carbonyl group of a carboxylic acid toward nucleophilic addition-elimination

Carbonyl compounds

Hydrolysis (acid or base) of Carboxylic Acid DerivativesDilute acid or baseHeatWhen using acid conditions it is called a hydrolysis reaction. When using basic conditions it is called saponification H2SO4/H2O++NaOH/H2O+d+d-

Carbonyl compounds

Mechanism for the acid catalyzed Hydrolysis of an Ester:Mechanism 6

Carbonyl compounds

Mechanism for the Saponification of an Ester:Mechanism 7

Carbonyl compounds

H+Mechanism for the hydrolysis of the Nitrile H2OProtonTransfer- H+amideH+H2OProtonTransfer+ NH3H+NH4- H+

Carbonyl compounds

What are the products of the following reactions: (not balanced)NaOH/H2ONaOH/H2OH2SO4/H2ONaOH/H2OH2SO4/H2OH2SO4/H2ORCO2 + NH3 + HO RCO2H + NH4RCO2 + NH3 RCO2H + NH4 RCO2 + Cl d+d-NaOH/H2ORCO2H + Cl H2SO4/H2O

Carbonyl compounds

Mechanism 8Urethane

Carbonyl compounds

Mechanism 9Urea

Carbonyl compounds

SummaryAll downward arrows indicates that this conversion is possible in one step

Carbonyl compounds

Aldehydes and KetonesThe carbonyl group is susceptible to nucleophilic attack.Nucleophile(base)Electrophile(acid)Addition of a Strong Nucleophile

Carbonyl compounds

Reactivity of Aldehydes and KetonesTwo factors: 1) the amount of positive charge on the carbonyl carbon and 2) steric interaction.The tetrahedral carbon resulting from addition to an aldehyde is less sterically hindered than the tetrahedral carbon resulting from addition to a ketone Aldehyde carbonyl groups are more electron deficient because they have only one electron-donating group attached to the carbonyl carbonalkyl groups are electron donating d+d-d+d-d+d-increasing reactivitydecreasing steric interaction increasing reactivityAldehydes are generally more reactive than ketones

Carbonyl compounds

Acid catalyzed Nucleophilic Addition of a Nucleophile

Carbonyl compounds

Reaction with Water+ H2Obase nucleophileacid electrophiled+d-hydrate (generally not stable)+ H2OH+H+H+electron withdrawing makes carbonyl carbon more reactive (more positive)no alkyl groupschloral hydrate chief ingredient in knock out drops chloralformaldehydeFormalin is a 10% solution of formaldehyde in water; used as a disinfectant or to preserve biological specimens. methylene hydrate HOCH2OH reacts with various parts of proteins to form methylene cross-links to fix and stabilize the proteins and stop decomposition.d+d-+ H2O

Carbonyl compounds

Oxygen Nucleophiles Reaction with alcohols: Acetal and Ketal formationR1 = alkyl or HH3O+hemi-ketal R1 = alkylmemi-acetal R1 = HH3O+ketal R1 = alkylacetal R1 = HCH3CH2OH, H+H3O+-H2O+ H2O + H++ H2O + H+memi-acetalacetal R1 = HExample acid catalyst

Carbonyl compounds

Mechanism d+d-H+CH3CH2OH- H+H+- H2OCH3CH2OHresonance structures both are occurring at the same time- H+hemi-acetalacetalacidbasenucleophileelectrophilebaseacidH2O great leaving groupresonance stabilized carbocationnucleophileelectrophileacid/basenot shownacid/basenot shown

Carbonyl compounds

R1 = alkyl or HH3O+hemi-ketal R1 = alkylmemi-acetal R1 = HH3O+ketal R1 = alkylacetal R1 = H+ H2O + H+acid catalystThis is a reversible reaction and usually the reverse reaction is favored (aldehyde). The reaction can be made to go forward by dissolving the aldehyde in an excess of anhydrous alcohol and add an anhydrous acid or by removing the water that is formed in the reaction. This can be done by azeotropic distillation with benzene, or adding molecular sieves that absorb water or by using a quenching agent like AlCl2

Carbonyl compounds

Acetal formation from ketones and simple alcohols is less favorable than formation from aldehydesFormation of cyclic 5- and 6- membered ring acetals from ketones is, however, favorableSuch cyclic acetals are often used as protecting groups for aldehydes and ketonesThese protecting groups can be removed using dilute aqueous acid

Carbonyl compounds

Mechanism 10

Carbonyl compounds

Nitrogen Nucleophiles The Addition of Primary and Secondary AminesAldehydes and ketones react with primary amines (and ammonia) to yield iminesThey react with secondary amines to yield enamines

Carbonyl compounds

The reaction is pH dependant. If it is too acidic RNH2 will protonate (RNH2 + H+ RNH3+) and will no longer be a nucleophile. Elimination of water increases with increasing pH but will slow down the first step of the reaction. The optimal pH is 3-4. Some of the amine will be protonated but there will be enough free base for a reaction to occur. Mechanism 11

Carbonyl compounds

Reactions

reagent(R) NH2Producthydroxylamine(HO) - NH2

an oximehydrazine(H2N)-NH2

a hydrazonearylhydrazine(Ar-NH)-NH2

an arylhydrazonesemi-carbazide

a semi-carbazone

Carbonyl compounds

RCommon aromatic compounds used:phenylhydrazinetosylhydrazine2,4-dinitrophenylhydrazine (2,4-DNPH)NHNH2CH3SOONHNH2O2NNO2NHNH2Note: When R = H (i.e. a reaction with NH3) the unsubstituted imine results is unstable and will polymerize. +electrophile(acid)nucleophile(base)d+d-leaves as H2OC6H5-NH-NH2 + CH3CH2COHelectrophile(acid)nucleophile(base)RRRC6H5-NH-N=CHCH2CH3Example

Carbonyl compounds

EnaminesSecondary amines cannot form a neutral imine by loss of a second proton on nitrogenAn enamine is formed insteadMechanism 12

Carbonyl compounds

Carbon Nucleophiles Grignard Reactions (previously looked at)Cyanohydrin FormationNaCN-HCNbufferSlightlyalkalined+d-H-CNHClH2Oheata-hydroxy acid95% H2SO4heatLiAlH4/Et2OH2O+ NaCNa, b unsaturated carboxylic acid

Carbonyl compounds

Aldol CondensationsThe Acidity of the a Hydrogens of Carbonyl Compounds: Enolate AnionsHydrogens on carbons a to carbonyls are unusually acidicThe resulting anion is stabilized by resonance to the carbonyl

Carbonyl compounds

The enolate anion can be protonated at the carbon or the oxygenThe resultant enol and keto forms of the carbonyl are formed reversibly and are interconvertible

Carbonyl compounds

Keto and Enol TautomersEnol-keto tautomers are constitutional isomers that are easily interconverted by a trace of acid or baseMost aldehydes and ketones exist primarily in the keto form because of the greater strength of the carbon-oxygen double bond relative to the carbon-carbon double bond

Carbonyl compounds

Aldol Condensationsaldol aldehyde and alcoholA condensation reaction is one in which two or more smaller molecules combine to form a larger molecule often with the loss of a small moleculeHOacetaldehyde3-hydroxybutanol (50%)(acetaldol or aldol)H2OHOd+d-stronger base than OHaldehyde morereactive than ketones- more positive carbonylcarbon less stericinteraction

Carbonyl compounds

The reaction between 2 moles of an Aldehyde is called a self condensation reactionMechanism 13

Carbonyl compounds

Dehydration of the Aldol ProductIf the aldol reaction mixture is heated, dehydration to an a,b-unsaturated carbonyl compound takes placeDehydration is favorable because the product is stabilized by conjugation of the alkene with the carbonyl group

In some aldol reactions, the aldol product cannot be isolated because it is rapidly dehydrated to the a,b-unsaturated compound

Carbonyl compounds

Acid-Catalyzed Aldol CondensationThis reaction generally leads directly to the dehydration product

Carbonyl compounds

What is the product of the following reaction?Crossed Aldol condensationReadily dehydrates to an a,b-unsaturated aldehyde. Forms a stable conjugated product. Helps drive the reaction to productshydroxide is considered a poor leaving group but becausethis step is intermolecular and the product is stabilized by conjugation even a poor leavinggroup such as a hydroxide canleaveMechanism 14

Carbonyl compounds

Practical Crossed Aldol ReactionsCrossed aldol reactions give one predictable product when one of the reaction partners has no a hydrogensThe carbonyl compound without any a hydrogens is put in basic solution, and the carbonyl with one or two a hydrogens is added slowlyDehydration usually occurs immediately, especially if an extended conjugated system results

Carbonyl compounds

Claisen-Schmidt Reactions

Crossed-aldol reactions in which one partner is a ketone are called Claisen-Schmidt reactionsThe product of ketone self-condensation is not obtained because the equilibrium is not favorable

Carbonyl compounds

What is the product of the following reaction?NaOHHeat++ H2O + HO+85%no a hydrogensa hydrogensd+d-NaOHHeata hydrogens94%1212no a hydrogensa hydrogensabcabcabcabcabc

Carbonyl compounds

Cyclization via Aldol Condensations

Intramolecular reaction of dicarbonyl compounds proceeds to form five- and six-membered rings preferentiallyIn the following reaction the aldehyde carbonyl carbon is attacked preferentially because an aldehyde is less sterically hindered and more electrophilic than a ketone

Carbonyl compounds

Lithium Enolates

In the presence of a very strong base such as lithium diisopropyl amide (LDA), enolate formation is greatly favoredWeak bases such as sodium hydroxide produce only a small amount of the enolate

Carbonyl compounds

Regioselective Formation of Enolate AnionsUnsymmetrical ketones can form two different enolatesThe thermodynamic enolate is the most stable enolate i.e. the one with the more highly substituted double bond A weak base favors the thermodynamic enolate because an equilibrium between the enolates is estabilished

The kinetic enolate is the enolate formed fastest and it usually is the enolate with the least substituted double bondA strong, sterically hindered base such as lithium diisopropyl amide favors formation of the kinetic enolate

Carbonyl compounds

Lithium Enolates in Directed Aldol Reactions

Crossed aldol reactions proceed effectively when a ketone is first deprotonated with a strong base such as LDA and the aldehyde is added slowly to the enolate

Carbonyl compounds

Direct Alkylation of Ketones via Lithium Enolates

Enolates can also be alkylated with primary alkyl halides via an SN2 reactionUnsymmetrical ketones can be alkylated at the least substituted position if LDA is used to form the kinetic enolate

Carbonyl compounds

Enolates and Carbanions: Building blocks for organic synthesisAcidity of the Alpha Hydrogenresonance stabilizedenolate ionketoneesterMinor resonance structure but oxygen caries a partial negative charge on the carbonyl carbon. Thus the carbonyl group is less able to help stabilize the negative charge of the enolate ion.B:B:enolalcohol andalkene

Carbonyl compounds

Acidity of the a hydrogen next to the carbonyl carbonHHHHHHacetoacetoneethyl acetoacetatean alkylacetoacetic aciddiethyl malonate (malonic ester)acetoneethyl acetatepKa = 9pKa = 11pKa = 13pKa = 13pKa = 20pKa = 25CH3CH2OHCH3OHHNH2pKa = 16pKa = 15.5pKa = 35Compounds that are separated by two carbonyl compounds are called b-dicarbonyl compoundsa b-keto estera malonic esterabababpKb =14 9 = 5NH2pKb =14 35 = -21

Carbonyl compounds

SynthesisCH3CH2ONaCH3CH2OHor NaNH2or NaH in a aprotic solventCH3CH2- BrSN2NaHCH3-BrSN2enolateenolateH+, H2Oheata b-diacidheat-CO22-methylbutanoic acidEt -CH2CH3ordiethyl malonateor basehydrolysis

Carbonyl compounds

Mechanism for decarboxylation+ CO2+ CO2enoltautomers

Carbonyl compounds

Li N[CH(CH3)2]2, coldLDA lithum diisopropylamideenolateCH3BrwarmMechanism 15

Carbonyl compounds