Chemistry of Carbonyls and Carboxyls i. ii. iii. iv. v. vi.

Nucleophilic Addition to Carbonyl Group pKa Carboxylic Acid Derivatives and Nucleophilic Substitution Nucleophilic Substitution at the Carbonyl with loss of Carbonyl Oxygen Oxidation/Reduction Enol and Enolate Chemistry

i.

Nucleophilic Addition to Carbonyl Group

1. Nucleophilic attack involves the filled nucleophile orbital attacking the * antibonding orbital Nucleophile attacks at 107: compromise between maximising orbital overlap and minimising electron-electron repulsion

2. CN attacks to form cyanohydrins NaOH and H2O reverses cyanohydrins formation

3. The larger the equilibrium constant, the more the equilibrium lies to the right 4. Sodium Borohydride reduces aldehydes and ketones to 1 and 2 alcohols respectively. An alcohol is present in large amounts, making this termolecular reaction act more as a bimolecular reaction 5. LiAlH4 followed by H2O results in an alcohol and Al(OH)4 6. Grignard reagents (RMgX) and organolithium reagents convert carbonyls to alcohols. They add a carbon to the carbonyl 7. Water can be added to an aldehyde/ketone at pH 7 to form a hydrate: R(CO)R + H2O (HO)2(C)R2

8. Addition of alcohols to aldehydes and ketones yields hemiacetals Hemiacetals are formed via two different mechanisms depending on whether the alcohol and carbonyl are under acidic (protonation of the carbonyl) or basic (back side attack of OR group to carbonyl) conditions Acidic conditions carbonyl group is more electrophilic Basic conditions nucleophile more nucleophilic

ii.

pKa

1. pH=-log10[H+] whilst pKa=-log10Ka 2. The stronger the acid, the weaker its conjugate base pKa for strong acids is low An acid is strong if its conjugate base is stable (it can cope with losing a proton) Carboxylic acids are stronger acids than phenols which are stronger acids than alcohols

iii.

Carboxylic Acid Derivatives and Nucleophilic Substitution

1. Substitution involves nucleophilic addition followed by elimination of a leaving group 2. Factors that affect substitution are leaving group ability and electrophilicity of carbonyl carbon The best leaving groups are those whose conjugate acids have low pKa values (Means they are stable with

negative charge: Halides are the best leaving groups, Carbanions are the worst) Acyl chlorides are the most reactive as the chlorine is electron withdrawing, causing the carbonyl carbon to be more electrophilic Anhydrides follow, then esters and finally amides and the least reactive. The nitrogen lone pair is readily available to stabilise the carbonyl carbon

3. Alkanoyl chlorides/acyl chlorides and alcohols form esters +

4. Anhydrides and alcohols form esters Pyridine is a better nucleophile than the alcohol and thus reacts with the carbonyl instead. A highly electrophilic intermediate is formed which the alcohol ultimately reacts with Pyridine acts as a nucleophilic catalyst and as a base

5. Alkanoyl/Acyl chlorides and amines form amides The Schotten-Baumann synthesis of amides from amines and acid chlorides occurs under a two phase solvent system consisting of an organic solvent and water The base within the water phase neutralises the acid, ensuring the amine is not protonated so it can act as an effective nucleophile

6. Carboxylic acids and SOCl2 react to form Alkanoyl/Acid chlorides

7. Acids can NOT be converted to esters and amides under basic conditions Carbanions are formed instead Desired conversion of a carboxylic acid to ester results in a carboxyl carbanion and alcohol being formed instead

Desired conversion of a carboxylic acid to an amide results in a carboxyl carbanion and +NH2R2 cation being formed instead

8. Acid catalysed ester synthesis (and hydrolysis: reaction in equilibrium) sees protonation of carboxyl oxygen Dry HCl gas and excess alcohol drives the reaction towards esterification from carboxylic acid Catalytic H2SO4 and the drying agent silica gel removes water and pulls equilibrium towards ester

9. Rate of hydrolysis of an ester to a carboxylic acid can be increased by varying conditions Catalytic H2SO4 and excess water and acetone drives equilibrium towards carboxylic acid

10.Although esterification cannot occur under basic conditions, hydrolysis of esters to carboxylic acids can occur under basic conditions The carboxylic acid produced reacts with the base to form a carbanion, an irreversible reaction Although the reaction of hydrolysis of ester to carboxylic acid is base catalysed, one unit of base is consumed to turn the carboxylic acid to its carbanion conjugate

11.Amide hydrolysis can be catalysed under acid or basic conditions The acid catalysed hydrolysis sees the carboxyl oxygen protonated The base attacks the back side of the carbonyl and the oxygen of the carbonyl becomes negatively charged

12.Carboxylic acids and amines can form amides. The reaction is catalysed by DDC which is very electrophilic It takes the proton from the hydroxyl, forming an anion which then causes it to bind to the DDC cation The amine then reacts via back side attack

13.Grignard reagents and organolithium reagents react with esters to form a ketone that is more reactive than the ester itself, resulting in further reaction to an ultimate tertiary alcohol

Weinreb provided a solution where an amide known as the Weinreb amide is produced that only collapses at the end of the reaction after work-up with acid

iv.

Nucleophilic Substitution at the Carbonyl With Loss of Carbonyl Oxygen

1. Aldehyde/ketone + Alcohol (acid/base conditions) Hemiacetal 2. Hemiacetal +Alcohol (acid conditions ONLY) Acetal OH is converted to OH2+ which is a better leaving group

3. Upon formation of the hemiacetal, the equilibrium is favoured to revert back to the aldehyde/ketone form. There are two solutions to this problem to ensure an acetal is formed: Excess of one of the reagents Remove water using a molecular sieve

4. Acetals are hydrolysed with HCl (3%) and H 2O 5. Acetals protect carbonyls and diols An acetal and TsOH is used to protect the carbonyl bromide Mg inserts between the R group and Br to form a Grignard reagent It subsequently reacts with a secondary carbonyl to form a OMgBr group H3O+ is added to restore the carbonyl

A diether and sulfonic acid is used to protect diols

6. Aldehydes/Ketones + 1 amines Imine (-C=N-) Reaction is pH dependent, optimum ~4-6

7. 2 amines + Aldehydes/Ketones Enamine Under catalytic acid conditions where oxygen on carbonyl is protonated

8. Wittig reaction converts aldehydes and ketones to alkenes Phosphonium ylid + Aldehyde/Ketone Alkene + Phosphine Oxide Phosphonium ylid generated by triphenylphosphine and an alkyl halide Phosphonium ylid + hemiacetal alkene

v.

Oxidation/Reduction

1. 1 alcohol oxidised to aldehyde oxidised to carboxylic acid Jones oxidation: Na2Cr2O7 in dilute H2SO4

2. 2 alcohol oxidised to ketone Jones oxidation: Na2Cr2O7 in dilute H2SO4

3. Carboxylic acid reduced using DIBAL to aldehyde Aldehyde reduced using NaBH 4 to form 1 alcohol

4. Ketone reduced using NaBH 4 to form 2 alcohol 5. Baeyer-Villiger reaction converts ketones to esters Ketone + peracid Ester

vi.

Enol and Enolate Chemistry

1. Keto and enol forms differ only in position of double bond and a proton: known as tautomers Acid conditions catalyse the conversion of a keto form to enol form by protonating the oxygen of the carbonyl Basic conditions catalyse the conversion of keto form to enol form via pushing electrons onto the oxygen of the carbonyl

2. The way keto forms and enol forms are related by the same type of tautomerism is mirrored by imines and enamines

3. The enolate anion resonates between itself and its carbanion counterpart

4. Enolisation destroys a stereogenic centre next to a carbonyl

5. Acid/Basic conditions catalyse bromination of a carbonyl

Bromine added at -carbon to carbonyl Enol intermediate formed under acidic conditions Enolate intermediate formed under basic conditions

6. Aldol reaction where a C-C bond is formed between -carbon of one carbonyl and carbonyl carbon of another Acid catalysed mechanism shown below:

Base catalysed mechanism:

7. Crossed aldol reactions are where two different carbonyls are used. There are two conditions: Only one can enolise The other must be more electrophilic

8. The Claisen ester condensation involves an alkoxide and ether Ether is deprontonated by alkoxide and an enolate is formed Enolate double bond reacts with another ether molecule Negatively charged oxygen forms a double bond and RO is lost

Intramolecular Claisen reactions can occur where there are two ether groups per molecule

9. Conjugated addition involves addition of an enolate and unsaturated carbonyl compound Preferred over direct addition, product is more stable Direct addition results in alkene more hindered and less stable

10.Robinson annelation/annulations results in ring formation Formation of an ,-unsaturated cyclohexene ring by Michael addition Michael addition is part of the larger class of conjugate additions. It is The addition of a carbanion to an ,-unsaturated carbonyl compound via nucleophilic addition