carbonyls - esters + amides Flashcards
(40 cards)
outline the anatomy of an ester
same as standard carbonyl
the carbonyl O has a lewis basic lone pair
the carbonyl C is δ+ = electrophilic
has α acidic protons, pKa ~ 30, more than ketones ~25 - the more electron withdrawing the R group, the more acidic the proton, as electron density destabilises the conjugate base increasing pKa of proton
rationalise the place of esters in the carbonyl reactivity series
esters lie in the middle of the carbonyl reactivity series
this is because the lone pair of the O of OR group can adopt an orientation allowing the lone pair to conjugate into the π-system, specifically the π* orbitals, which makes the C less δ+ and therefore less reactive
the lone pair is stabilised by conjugation and π* is pushed up becoming higher in energy and less reactive
for aliphatic esters to take part in reactions either HOMO π* needs to be lowered in energy or nucleophiles reacting need to be more powerful
how do lactones differ from aliphatic esters in reactivity?
in lactones the atoms are more rigidly fixed in place so there is no orbital overlap + conjugation of lone pair p-orbital and π-systems, making this functional group more reactive, closer to that of ketones
what are 3 classic methods of ester synthesis?
- condensation reaction of carboxylic acid + alcohol in acidic conditions, aka fischer esterification
- substitution reaction of acid anhydride/acyl chloride + alcohol, with non nucleophilic base NEt3
- steglich reaction of carboxylic acid + alcohol, with DCC + nucleophilic catalyst + non nucleophilic base
give 2 disadvantages of fischer esterification
- the reaction is reversible under the same conditions and has an unfavourable chemical equilibrium, the reaction needs to be modified to get high yields, this is done by removing water
- alcohol is a poor nucleophile and carboxylic acid is a poor electrophile, so modification needs to occur to lower π* of carboxylic acid or increase nucleophilicity of alcohol
why do carboxylic acids have such poor reactivity?
similarly to esters the lone pair of O on OH undergoes p-orbital overlap/conjugation with the π-system, destabilising π* and making the carbonyl less electrophilic
how is the HOMO π* of the carboxylic acid lowered in fischer esterification?
acid protonates the O lone pair on the carbonyl (step 1)
- the giving of lone pair on O to form a new bond causes O to pull electron density back towards itself from the carbonyl bond, making C more δ+ again and causing π* to drop in energy
give 2 advantages of using substitution as a method of esterification instead of fischer reaction
- reaction is not reversible
- no need to modify reaction/remove water to get a high yield, conversion is good
give 1 disadvantage of esterification via substitution
acyl chlorides/acid anhydrides are very reactive and can be air + moisture sensitive, so they need to be used quickly
why are non-nucleophilic bases required for all esterifications?
this is because otherwise reactivity of base > alcohol so carboxylic acid/anhydride/etc would react with the base instead
why do acid anhydrides/acyl chlorides not need to be activated?
for acid anhydrides, one carbonyl C still gets the effects of lone pair donation from the central O atom, decreasing reactivity, but the O can only donate a lone pair to one carbonyl, so this simultaneously makes the other carbonyl more reactive as electron density is moved away, making its carbonyl C very electrophilic
for acyl chlorides, the electronegative Cl draws electron density away from the carbonyl C and also cannot donate a lone pair into the π-system, so reactivity of the carbonyl C is not an issue
give 1 other requirement for the base used in esterification
the base must be an amine base because it will only deprotonate after the key acyl bond has been formed
the pKaH of NEt3 ~9, bases can only deprotonate things with a lower pKa, alcohol pKa ~15 whereas acyl pKa ~1/2 so deprotonated can take place
why are esters good protecting groups?
they can be easily hydrolysed into carboxylic acids, so are able to act as a protecting group for carboxylic acids
what types of conditions can ester hydrolysis occur under?
acidic + basic
how does acid hydrolysis of esters work?
- ester carbonyl is protonated via lewis basic lone pair on O, O attracts more electron density towards itself + away from C, allowing the weak nucleophile water to attack the more δ+ C (this is the rate determining slow step, sped up by acid)
- as a result of nucleophilic attack carbonyl bond is broken
- PT from protonated water to connecting O of ester, carbonyl bond reformed and OR of ester group leaves = alcohol side product
- deprotonation of carbonyl forms carboxylic acid
how does base hydrolysis of esters work?
- OH- from base attacks ester δ+ C and breaks carbonyl bond (this is the slow step)
- carbonyl bond reforms and alcohol group leaves
- OH- from base attacks OH proton, forming carboxylate ion
- work up reprotonates back to carboxylic acid
what impacts the rate of base hydrolysis of esters?
functional groups - different esters have different reactivities to base hydrolysis, generally the larger the alcohol R group, the slower the rate of hydrolysis
in order of decreasing reactivity:
methyl ester
ethyl ester
phenyl ester
secondary branched ester
tertiary branches ester = completely unreactive
how are tertiary esters hydrolysed?
only under dry acid conditions
e.g. F3C-C(=O)-OH + CH2Cl2
or HCl + Et2O (an org solvent)
what 2 types of functional group interconversions are possible via reduction of esters?
reduction via hydrides produces primary alcohols
reductions via carbon nucleophiels produces tertiary alcohols
how are esters reduced to produce primary alcohols?
using LiAlH4 + THF + H+aq
- LiAlH4 forms Li+ AlH4- in solution
- δ- H on AlH4- attacks the carbonyl C causing the carbonyl bond to break and reform a bond with Li+ = unstable intermediate
- intermediate breaks down, Li-O bond is broken and carbonyl bond is reformed, alcohol group leaves via elimination, product = aldehyde which is more reactive than starting product
- another H on AlH4- attacks carbonyl carbon, and again bond breaks and reforms with Li+
- base metal salt swapping causes Li-O bond to break and Al-O bond to form instead with AlH3, forms salt with Li+
- work up removes this and forms primary alcohol
how can reduction of esters via hydrides be improved?
LiAlH4 is very reactive, can reduce anything
often replaced with DIBAL-H which is a lewis acid, and reduced electron rich carbonyls most effectively, this is more selective and allows precision + control, to receive a particular product
how does DIBAL-H reduce esters?
- DIBAL-H is lewis acidic so reacts with carbonyl O lone pairs forming a salt
- δ- H from AL-H bond attacks carbonyl C, causes carbonyl bond to break
- this forms a tetrahedral intermediate which cannot decompose until acid is added, stable
- acid work up allows intermediate to break down, proton replaces DIBAL salt situation to form OH, also protonates connecting O making it a better LG
- OH bond breaks to reform carbonyl bond, alcohol group leaves
- aldehyde formed as product
outline the anatomy of an amide
amides are the least electrophilic functional group
the carbonyl O has a lewis basic lone pair
the carbonyl C is weakly electrophilic
has α acidic protons, pKa ~35 and acidic N-H, pKa ~25
weak bases via O lone pairs, helped by resonance of N lone pairs, this resonance also destabilises the C=O bond as C-N bond is given slight double bond character, creating new π bonds which pushes LUMO π* orbital up higher in energy making it even less accessible for orbital overlap - evidence is sp2 hybridisation of N, and restricted rotation around C-N bond
low reactivity of amides is due to the stability of carbonyl C
how is spectroscopy of amides affected by its structural effects?
the C=O stretch is weakened and appears at ~1600 rather than ~1700s
