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